| Underlined text has been added, text with strike through deleted:
Table 1: Interactions and dose recommendations with other medicinal products
|
Medicinal product by therapeutic area (dose of Invirase used in study)
|
Interaction
|
Recommendations concerning co-administration
|
|
Antiretroviral agents
Nucleoside reverse transcriptase inhibitors (NRTIs)
|
|
|
|
- Zalcitabine and/or
Zidovudine
(saquinavir/ritonavir)
|
- No pharmacokinetic interaction studies have been completed. Interaction with zalcitabine is unlikely due to differential routes of metabolism and excretion.
For zidovudine (200 mg every 8 hours) a 25 % decrease in AUC was reported when combined with ritonavir (300 mg every 6 hours). The pharmacokinetics of ritonavir remained unchanged.
|
- No dose adjustment required when zidovudine is co-administered with ritonavir.
|
|
- Zalcitabine and/or
Zidovudine
(unboosted saquinavir)
|
- Saquinavir «
Zalcitabine «
Zidovudine «
|
|
|
Didanosine
400 mg single dose
(saquinavir/ritonavir 1600/100 mg qd)
|
Saquinavir AUC ¯ 30%
Saquinavir Cmax ¯ 25%
Saquinavir Cmin «
|
No dose adjustment required.The changes are of doubtful clinical significance.
|
|
Tenofovir disoproxil fumarate 300 mg qd
(saquinavir/ritonavir 1000/100 mg bid)
|
Saquinavir AUC ¯ 1%
Saquinavir Cmax ¯ 7%
Saquinavir Cmin «
|
No dose adjustment required.
|
|
Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
|
|
|
|
- Delavirdine
(saquinavir/ritonavir)
|
- Interaction with Invirase/ritonavir not studied.
|
|
|
- Delavirdine
(unboosted saquinavir)
|
- Saquinavir AUC ↑ 348%.
There are limited safety and no efficacy data available from the use of this combination. In a small, preliminary study, hepatocellular enzyme elevations occurred in 13 % of subjects during the first several weeks of the delavirdine and saquinavir combination (6 % Grade 3 or 4).
|
- Hepatocellular changes should be monitored frequently if this combination is prescribed.
|
|
Efavirenz 600 mg qd
(saquinavir/ritonavir 1600/200 mg qd, or
saquinavir/ritonavir 1000/100 mg bid, or
saquinavir/ritonavir 1200/100 mg qd)
|
Saquinavir «
Efavirenz «
|
No dose adjustment required.
|
|
- Nevirapine
(saquinavir/ritonavir)
|
- Interaction with Invirase/ritonavir not studied.
|
|
|
- Nevirapine
(unboosted saquinavir)
|
- Saquinavir AUC ¯ 24%
Nevirapine AUC «
|
- No dose adjustment required.No dose adjustment for Invirase or nevirapine recommended.
|
|
|
|
|
|
Key: ¯ reduced, ↑ increased, « unchanged, ↑↑ markedly increased
Table 1 (continued): Interactions and dose recommendations with other medicinal products
|
Medicinal product by therapeutic area (dose of Invirase used in study)
|
Interaction
|
Recommendations concerning co-administration
|
|
HIV protease inhibitors (NNRTIPIs)
|
|
|
|
Atazanavir 300 mg qd
(saquinavir/ritonavir 1600/100 mg qd)
|
Saquinavir AUC ↑ 60%
Saquinavir Cmax ↑ 42%
Ritonavir AUC ↑ 41%
Ritonavir Cmax ↑ 34%
Atazanavir «
No clinical data available for the combination of saquinavir/ritonavir 1000/100 mg bid and atazanavir.
|
|
|
Fosamprenavir
700 mg bid
(saquinavir/ritonavir 1000/100 mg bid)
|
Saquinavir AUC ¯ 15%
Saquinavir Cmax ¯ 9%
Saquinavir Cmin ¯ 24% (remained above the target threshold for effective therapy.)
|
No dose adjustment required for Invirase/ritonavir.
|
|
- Indinavir
(saquinavir/ritonavir)
|
- Low dose ritonavir increases the concentration of indinavir.
|
Increased concentrations of indinavir may result in nephrolithiasis.
|
|
- Indinavir 800 mg tid
(saquinavir 600-1200 mg single dose)
|
- Saquinavir AUC ↑ 4.6-7.2 fold
Indinavir «
No safety and efficacy data available for this combination. Appropriate doses of combination not established.
|
|
|
Lopinavir/ritonavir 400/100 mg bid
(saquinavir/ritonavir 1000/100 mg bid in combination with 2 or 3 NRTIs)
|
Saquinavir «
Ritonavir ¯ (effectiveness as boosting agent not modified).
Lopinavir « (based on historical comparison with unboosted lopinavir)
|
No dose adjustment required.
|
|
- Nelfinavir
(saquinavir/ritonavir)
|
- Interaction with Invirase/ritonavir not studied.
|
|
|
- Nelfinavir 750 mg tid
(unboosted saquinavir 1200 mg tid)
|
- Saquinavir AUC ↑ 392%
Saquinavir Cmax ↑ 179%
Nelfinavir AUC ↑ 18%
Nelfinavir Cmax «
|
- Quadruple therapy, including saquinavir soft capsules and nelfinavir in addition to two nucleoside reverse transcriptase inhibitors gave a more durable response (prolongation of time to virological relapse) than triple therapy with either single protease inhibitor. Concomitant administration of nelfinavir and saquinavir soft capsules resulted in a moderate increase in the incidence of diarrhoea.
|
|
|
|
|
|
Table 1 (continued): Interactions and dose recommendations with other medicinal products
|
Medicinal product by therapeutic area (dose of Invirase used in study)
|
Interaction
|
Recommendations concerning co-administration
|
|
Ritonavir 100 mg bid
(saquinavir 1000 mg bid)
|
Saquinavir ↑
Ritonavir «
In HIV-infected patients, Invirase or saquinavir soft capsules in combination with ritonavir at doses of 1000/100 mg twice daily provide saquinavir a systemic exposure of saquinavir over a 24 hour period similar to or greater than thosethat achieved with saquinavir soft capsules 1200 mg three times daily (see section 5.2).
|
This is the approved combination regimen. No dose adjustment is recommended.
|
|
Tipranavir/ritonavir
(saquinavir/ritonavir)
|
Saquinavir Cmin ¯ 78%
Dual-boosted protease inhibitor combination therapy in multiple-treatment experienced HIV-positive adults.
|
Concomitant administration of tipranavir, co-administered with low dose ritonavir, with saquinavir/ritonavir, is not recommended. If the combination is nevertheless considered necessary, monitoring of the saquinavir plasma levels is strongly encouraged.
|
|
HIV fusion inhibitor
|
|
|
|
Enfuvirtide
(saquinavir/ritonavir 1000/100 mg bid)
|
Saquinavir «
Enfuvirtide «
No clinically significant interaction was noted.
|
No dose adjustment required.
|
|
Other medicinal products
Antiarrhythmics
|
|
|
|
Bepridil
Lidocaine (systemic) Quinidine
(saquinavir/ritonavir)
|
Concentrations of bepridil, systemic
lidocaine or quinidine may be increased when co-administered with Invirase/ritonavir.
|
Caution is warranted.
Therapeutic concentration monitoring is recommended, if available.
|
|
Amiodarone
flecainide
propafenone
(saquinavir/ritonavir)
|
Concentrations of amiodarone, flecainide or propafenone may be increased when co-administered with Invirase/ritonavir.
|
Contraindicated in combination with saquinavir/ritonavir due to potentially life threatening cardiac arrhythmia (see section 4.3).
|
|
Anticoagulant
|
|
|
|
Warfarin
(saquinavir/ritonavir)
|
Concentrations of warfarin may be affected.
|
INR (international normalised ratio) monitoring recommended.
|
|
Anticonvulsants
|
|
|
|
- Carbamazepine Phenobarbital
Phenytoin
(saquinavir/ritonavir)
|
- Interaction with Invirase/ritonavir not evaluatedstudied.
|
|
|
- Carbamazepine Phenobarbital
Phenytoin
(unboosted saquinavir)
|
- These medicinal products will induce CYP3A4 and may therefore decrease saquinavir concentrations.
|
|
|
|
|
|
|
Table 1 (continued): Interactions and dose recommendations with other medicinal products
|
Medicinal product by therapeutic area (dose of Invirase used in study)
|
Interaction
|
Recommendations concerning co-administration
|
|
Antidepressants
|
|
|
|
Tricyclic antidepressants
(e.g. amitriptyline, imipramine) (saquinavir/ritonavir)
|
Invirase/ritonavir may increase concentrations of tricyclic antidepressants.
|
Therapeutic concentration monitoring recommended.
|
|
- Nefazodone
(saquinavir/ritonavir)
|
- Interaction with saquinavir/ritonavir not evaluated.
|
|
|
- Nefazodone
(unboosted saquinavir)
|
- Nefazodone inhibits CYP3A4. Saquinavir concentrations may be increased.
|
- Monitoring for saquinavir toxicity recommended.
|
|
Antihistamines
|
|
|
|
Terfenadine
Astemizole
(saquinavir/ritonavir)
|
Terfenadine AUC ↑, associated with a prolongation of QTc intervals.
A similar interaction with astemizole is likely.
|
Terfenadine and astemizole are contraindicated with boosted or unboosted saquinavir (see section 4.3).
|
|
Anti-infectives
|
|
|
|
- Clarithromycin
(saquinavir/ritonavir)
|
- Interaction with Invirase/ritonavir not studied.
|
|
|
- Clarithromycin
500 mg bid
(unboosted saquinavir 1200 mg tid)
|
- Saquinavir AUC ↑ 177 %
Saquinavir Cmax ↑ 187 %
Clarithromycin AUC ↑ 40 %
Clarithromycin Cmax ↑ 40 %
|
- No dose adjustment is required when co-administered for a limited time at the doses studied.
|
|
- Erythromycin
(saquinavir/ritonavir)
|
- Interaction with Invirase/ritonavir not studied.
|
|
|
- Erythromycin
250 mg qid
(unboosted saquinavir 1200 mg tid)
|
- Saquinavir AUC ↑ 99 %
Saquinavir Cmax ↑ 106 %
|
- No dose adjustment required.
|
|
- Streptogramin antibiotics
(saquinavir/ritonavir)
|
- Interaction with Invirase/ritonavir not studied.
|
|
|
- Streptogramin antibiotics
(unboosted saquinavir)
|
- Streptogramin antibiotics such as quinupristin/dalfopristin inhibit CYP3A4. Saquinavir concentrations may be increased.
|
- Monitoring for saquinavir toxicity recommended.
|
|
Antifungals
|
|
|
|
Ketoconazole 200 mg qd
(saquinavir/ritonavir 1000/100 mg bid)
|
Saquinavir AUC «
Saquinavir Cmax «
Ritonavir AUC «
Ritonavir Cmax «
Ketoconazole AUC ↑ 168%
(90% CI 146%-193%)
Ketoconazole Cmax ↑ 45%
(90% CI 32%-59%)
|
No dose adjustment required when saquinavir/ritonavir combined with £ 200 mg/day ketoconazole. High doses of ketoconazole
(> 200 mg/day) are not recommended.
|
|
- Itraconazole
(saquinavir/ritonavir)
|
- Interaction with Invirase/ritonavir not studied.
|
|
|
- Itraconazole
(unboosted saquinavir)
|
- Itraconazole is a moderately potent inhibitor of CYP3A4 like ketoconazole. An interaction of similar magnitude is possible.
|
Monitoring for saquinavir toxicity recommended.
|
|
|
|
|
|
Table 1 (continued): Interactions and dose recommendations with other medicinal products
|
Medicinal product by therapeutic area (dose of Invirase used in study)
|
Interaction
|
Recommendations concerning co-administration
|
|
Fluconazole/miconazole
(saquinavir/ritonavir)
|
Interaction with Invirase/ritonavir not studied.
|
|
|
Antimycobacterials
|
|
|
|
Rifampicin 600 mg qd
(saquinavir/ritonavir 1000/100 mg bid)
|
In a clinical study 11 of 17 (65 %) healthy volunteers developed severe hepatocellular toxicity with transaminase elevations up to > 20-fold the upper limit of normal after 1 to 5 days of co-administration.
|
Rifampicin is contraindicated in combination with Invirase/ritonavir
(see section 4.3).
|
|
Rifabutin
(saquinavir/ritonavir 1000/100 mg bid)
|
Interaction with saquinavir/ritonavir 1000/100 mg not studied.
|
A dosage reduction to rifabutin
150 mg every three days is recommended based on experience with low dose ritonavir boosted protease inhibitors. Patients receiving rifabutin with Invirase/ritonavir should be closely monitored for liver function test elevations and emergence of adverse events associated with rifabutin therapy. Further dosage reduction of rifabutin may be necessary. Therapeutic concentration monitoring for saquinavir is recommended.
|
|
Benzodiazepines
|
|
|
|
Midazolam 7.5 mg
single dose (oral)
(saquinavir/ritonavir 1000/100 mg bid)
|
Midazolam AUC ↑ 12.4 fold
Midazolam Cmax ↑ 4.3 fold
Midazolam t1/2 ↑ from 4.7 h to 14.9 h
No data are available on concomitant use of ritonavir boosted saquinavir with intravenous midazolam. Studies of other CYP3A modulators and i.v. midazolam suggest a possible 3-4 fold increase in midazolam plasma levels.
|
Co-administration of Invirase/ritonavir with orally administered midazolam is contraindicated (see section 4.3). Caution should be used with co-administration of Invirase and parenteral midazolam.
If Invirase is co-administered with parenteral midazolam it should be done in an intensive care unit (ICU) or similar setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage adjustment should be considered, especially if more than a single dose of midazolam is administered.
|
|
Alprazolam
Clorazepate
Diazepam
Flurazepam
(saquinavir/ritonavir)
|
Concentrations of these medicinal products may be increased when co-administered with Invirase/ritonavir.
|
Careful monitoring of patients with regard to sedative effects is warranted. A decrease in the dose of the benzodiazepine may be required.
|
|
|
|
|
|
Table 1 (continued): Interactions and dose recommendations with other medicinal products
|
Medicinal product by therapeutic area (dose of Invirase used in study)
|
Interaction
|
Recommendations concerning co-administration
|
|
Triazolam
(saquinavir/ritonavir)
|
Concentrations of triazolam may be increased when co-administered with Invirase/ritonavir.
|
Contraindicated in combination with saquinavir/ritonavir, due to the risk of potentially prolonged or increased sedation and respiratory depression (see section 4.3).
|
|
Calcium channel blockers
|
|
|
|
Felodipine, nifedipine, nicardipine, diltiazem, nimodipine, verapamil, amlodipine, nisoldipine, isradipine
(saquinavir/ritonavir)
|
Concentrations of these medicinal products may be increased when co-administered with Invirase/ritonavir.
|
Caution is warranted and clinical monitoring of patients is recommended.
|
|
Corticosteroids
|
|
|
|
- Dexamethasone
(saquinavir/ritonavir)
|
- Interaction with Invirase/ritonavir not studied.
|
|
|
- Dexamethasone
(unboosted saquinavir)
|
- Dexamethasone induces CYP3A4 and may decrease saquinavir concentrations.
|
- Use with caution. Saquinavir may be less effective in patients taking dexamethasone.
|
|
Fluticasone propionate
50 mcg qid, intranasal
(ritonavir 100 mg bid)
|
Fluticasone propionate ↑
Intrinsic cortisol ¯ 86%
(90% CI 82%-89%)
Greater effects may be expected when fluticasone propionate is inhaled. Systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression have been reported in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate; this could also occur with other corticosteroids metabolised via the P450 3A pathway e.g. budesonide.
Effects of high fluticasone systemic exposure on ritonavir plasma levels yet unknown.
|
Concomitant administration of boosted saquinavir and fluticasone propionate and other corticosteroids metabolised via the P450 3A pathway (e.g. budesonide) is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects (see section 4.4).
Dose reduction of the glucocorticoid should be considered with close monitoring of local and systemic effects or a switch to a glucocorticoid, which is not a substrate for CYP3A4 (e.g. beclomethasone).
In case of withdrawal of glucocorticoids progressive dose reduction may have to be performed over a longer period.
|
|
Medicinal products that are substrates of P-glycoprotein
Digitalis glycosides
|
|
|
|
Digoxin 0.5 mg
single dose
(saquinavir/ritonavir 1000/100 mg bid)
|
Digoxin AUC0-72 ↑ 49%
Digoxin Cmax ↑ 27%
Digoxin levels may differ over time. Large increments of digoxin may be expected when saquinavir/ritonavir is introduced in patients already treated with digoxin.
|
Caution should be exercised when Invirase/ritonavir and digoxin are co-administered. The serum concentration of digoxin should be monitored and a dose reduction of digoxin should be considered if necessary.
|
|
|
|
|
|
Table 1 (continued): Interactions and dose recommendations with other medicinal products
|
Medicinal product by therapeutic area (dose of Invirase used in study)
|
Interaction
|
Recommendations concerning co-administration
|
|
Histamine H2-receptor antagonist
|
|
|
|
- Ranitidine
(saquinavir/ritonavir)
|
- Interaction with Invirase/ritonavir not studied.
|
|
|
- Ranitidine
(unboosted saquinavir)
|
- Saquinavir AUC ↑ 67 %
|
- Increase not thought to be clinically relevant. No dose adjustment of saquinavir recommended.
|
|
HMG-CoA reductase inhibitors
|
|
|
|
Pravastatin
Fluvastatin
(saquinavir/ritonavir)
|
Interaction not studied. Metabolism of pravastatin and fluvastatin is not dependent on CYP3A4. Interaction via effects on transport proteins cannot be excluded.Pravastatin and fluvastatin are not metabolised by CYP3A4. No interactions expected with protease inhibitors including ritonavir.
|
Interaction unknown. If no alternative treatment is available, use with careful monitoring.If treatment with a HMG-CoA reductase inhibitor is indicated, either pravastatin or fluvastatin is the product recommended.
|
|
Simvastatin
Lovastatin
(saquinavir/ritonavir)
|
Simvastatin ↑↑
Lovastatin ↑↑
Plasma concentrations highly dependent on CYP3A4 metabolism.
|
Increased concentrations of simvastatin and lovastatin have been associated with rhabdomyolysis. These medicinal products are contraindicated for use with Invirase/ritonavir (see section 4.3).
|
|
Atorvastatin
(saquinavir/ritonavir)
|
Atorvastatin is less dependent on CYP3A4 for metabolism.
|
When used with Invirase/ritonavir, the lowest possible dose of atorvastatin should be administered and the patient should be carefully monitored for signs/symptoms of myopathy (muscle weakness, muscle pain, rising plasma creatinine kinase levels).
|
|
Immunosuppressants
|
|
|
|
Ciclosporin
Tacrolimus
Rapamycin
(saquinavir/ritonavir)
|
Concentrations of these medicinal products increase several fold when co-administered with Invirase/ritonavir.
|
Careful therapeutic drug monitoring is necessary for immunosuppressants when co-administered with Invirase/ritonavir.
|
|
Narcotic analgesics
|
|
|
|
Methadone 60-120 mg qd
(saquinavir/ritonavir 1000/100 mg bid)
|
Methadone AUC ¯ 19 %
(90 % CI 9 % to 29 %)
None of the 12 patients experienced withdrawal symptoms.
|
No dosage adjustment is required when ritonavir boosted saquinavir is combined with methadone.
|
|
Neuroleptics
|
|
|
|
Pimozide
(saquinavir/ritonavir)
|
Concentrations of pimozide may be increased when co-administered with Invirase/ritonavir.
|
Due to a potential for life threatening cardiac arrhythmias, Invirase/ritonavir is contra-indicated in combination with pimozide (see section 4.3).
|
|
Oral contraceptives
|
|
|
|
Ethinyl estradiol
(saquinavir/ritonavir)
|
Concentration of ethinyl estradiol may be decreased when co-administered with Invirase/ritonavir.
|
Alternative or additional contraceptive measures should be used when oestrogen-based oral contraceptives are co-administered.
|
|
|
|
|
|
Table 1 (continued): Interactions and dose recommendations with other medicinal products
|
Medicinal product by therapeutic area (dose of Invirase used in study)
|
Interaction
|
Recommendations concerning co-administration
|
|
Phosphodiesterase type 5 (PDE5) inhibitors
|
|
|
|
- Sildenafil
(saquinavir/ritonavir)
|
- Interaction with Invirase/ritonavir not studied.
|
|
|
- Sildenafil 100 mg
(single dose)
(unboosted saquinavir 1200 mg tid)
|
- Saquinavir «
Sildenafil Cmax ↑ 140 %
Sildenafil AUC ↑ 210 %
- Sildenafil is a substrate of CYP3A4.
|
- Use sildenafil with caution at reduced doses of no more than 25 mg every 48 hours with increased monitoring of adverse events when administered concomitantly with Invirase/ritonavir.
|
|
Vardenafil
(saquinavir/ritonavir)
|
Concentrations of vardenafil may be increased when co-administered with Invirase/ritonavir.
|
Use vardenafil with caution at reduced doses of no more than 2.5 mg every 72 hours with increased monitoring of adverse events when administered concomitantly with Invirase/ritonavir.
|
|
Tadalafil
(saquinavir/ritonavir)
|
Concentrations of tadalafil may be increased when co-administered with Invirase/ritonavir.
|
Use tadalafil with caution at reduced doses of no more than 10 mg every 72 hours with increased monitoring of adverse events when administered concomitantly with Invirase/ritonavir.
|
|
Proton pump inhibitors
|
|
|
|
Omeprazole 40 mg qd
(saquinavir/ritonavir 1000/100 mg bid)
|
Saquinavir AUC ↑ 82%
(90 % CI 44-131 %)
Saquinavir Cmax ↑ 75%
(90 % CI 38-123 %)
Ritonavir «
|
Monitoring for potential saquinavir toxicities is recommended.
|
|
Other proton pump inhibitors (saquinavir/ritonavir 1000/100 mg bid)
|
No data are available on the concomitant administration of Invirase/ritonavir and other proton pump inhibitors.
|
No data are available on the concomitant administration of Invirase/ritonavir and other proton pump inhibitors. If omeprazole or other proton pump inhibitors are taken concomitantly with Invirase/ritonavir, monitoring for potential saquinavir toxicities is recommended.
|
|
Others
|
|
|
|
Ergot alkaloids (e.g. ergotamine, dihydroergotamine, ergonovine, and methylergonovine)
(saquinavir/ritonavir)
|
Invirase/ritonavir may increase ergot alkaloids exposure, and consequently, increase the potential for acute ergot toxicity.
|
The concomitant use of Invirase/ritonavir and ergot alkaloids is contra-indicated (see section 4.3).
|
|
- Grapefruit juice
(saquinavir/ritonavir)
|
- Interaction with Invirase/ritonavir not studied.
|
|
|
- Grapefruit juice
(single dose)
(unboosted saquinavir)
|
- Saquinavir ↑ 50% (normal strength grapefruit juice)
- Saquinavir ↑ 100% (double strength grapefruit juice)
|
- Increase not thought to be clinically relevant. No dose adjustment required of Invirase is recommended.
|
|
|
|
|
|
Table 1 (continued): Interactions and dose recommendations with other medicinal products
|
Medicinal product by therapeutic area (dose of Invirase used in study)
|
Interaction
|
Recommendations concerning co-administration
|
|
- Garlic capsules
(saquinavir/ritonavir)
|
- Interaction with Invirase/ritonavir not studied.
|
|
|
- Garlic capsules
(dose approx. equivalent to two 4 g cloves of garlic daily)
(unboosted saquinavir 1200 mg tid)
|
- Saquinavir AUC ¯ 51 %
Saquinavir Ctrough ¯ 49 % (8 hours post dose)
Saquinavir Cmax ¯ 54 %.
|
- Patients on saquinavir treatment must not take garlic capsules due to the risk of decreased plasma concentrations and loss of virological response and possible resistance to one or more components of the antiretroviral regimen.
|
|
- St. John’s wort
(saquinavir/ritonavir)
|
- Interaction with Invirase/ritonavir not studied.
|
|
|
- St. John’s wort
(unboosted saquinavir)
|
- Plasma levels of saquinavir can be reduced by concomitant use of the herbal preparation St. John’s wort (Hypericum perforatum). This is due to induction of drug metabolising enzymes and/or transport proteins by St. John’s wort.
|
- Herbal preparations containing St. John’s wort must not be used concomitantly with Invirase. If a patient is already taking St. John’s wort, stop St. John’s wort, check viral levels and if possible saquinavir levels. Saquinavir levels may increase on stopping St. John’s wort, and the dose of saquinavir may need adjusting. The inducing effect of St. John’s wort may persist for at least 2 weeks after cessation of treatment.
|
|
Other potential interactions
Medicinal products that are substrates of CYP3A4
|
|
|
|
e.g. dapsone, disopyramide, quinine, fentanyl, and alfentanyl
(unboosted saquinavir)
|
Although specific studies have not been performed, co-administration of Invirase/ritonavir with medicinal products that are mainly metabolised by CYP3A4 pathway may result in elevated plasma concentrations of these medicinal products.
|
These combinations should be given with caution.
|
|
Medicinal products reducing gastrointestinal transit time
|
|
|
|
Metoclopramide
|
It is unknown whether medicinal products which reduce the gastrointestinal transit time could lead to lower saquinavir plasma concentrations.
|
|
|
|
|
|
|
Antiretroviral agents
Nucleoside reverse transcriptase inhibitors (NRTIs):
Zalcitabine and/or zidovudine: Saquinavir/ritonavir: No pharmacokinetic interaction studies have been completed with these agents given in combination with saquinavir/ritonavir. However, for zalcitabine an interaction is unlikely as this medicinal product has differential routes of metabolism and excretion and is unlikely to affect absorption of saquinavir/ritonavir. For zidovudine given 200 mg every 8 hours a 25 % decrease in AUC of zidovudine was reported when combined with ritonavir (300 mg every 6 hours), whereas the pharmacokinetics of ritonavir was not affected by zidovudine. No dose modification of zidovudine is warranted when zidovudine is co-administered with ritonavir. Saquinavir: Concomitant use of Invirase with zalcitabine and/or zidovudine has been studied in adults. Absorption, distribution and elimination of each of the medicinal products are unchanged when they are used together.
Didanosine: Saquinavir/ritonavir: The effects of a single dose of didanosine 400 mg on the pharmacokinetics of saquinavir in eight healthy subjects who received saquinavir soft capsules /ritonavir 1600/100 mg once daily for 2 weeks was investigated. Didanosine decreased saquinavir AUC and Cmax approximately 30 % and 25 %, respectively, and had essentially no effect on Cmin of saquinavir. These changes are of doubtful clinical significance.
Tenofovir: Saquinavir/ritonavir: Concomitant administration of tenofovir disoproxil fumarate with Invirase/ritonavir 1000/100 mg had no clinically significant effect on saquinavir exposure. In 18 HIV-infected patients treated with Invirase/ritonavir 1000/100 mg twice daily and tenofovir disoproxil fumarate 300 mg once daily, saquinavir AUC and Cmax values were 1 % and 7 % lower than those seen with saquinavir/ritonavir alone. No dose adjustment is required when ritonavir boosted Invirase is combined with tenofovir disoproxil fumarate.
Non-nucleoside reverse transcriptase inhibitors (NNRTIs):
Delavirdine: Saquinavir/ritonavir: The interaction between Invirase/ritonavir and delavirdine has not been evaluated. Saquinavir: Co-administration of delavirdine with Invirase resulted in a 348 % increase in saquinavir plasma AUC. Currently there are limited safety and no efficacy data available from the use of this combination. In a small, preliminary study, hepatocellular enzyme elevations occurred in 13 % of subjects during the first several weeks of the delavirdine and saquinavir combination (6 % Grade 3 or 4). Hepatocellular changes should be monitored frequently if this combination is prescribed.
Efavirenz: Saquinavir/ritonavir: No clinically relevant alterations of either saquinavir or efavirenz concentrations were noted in a study in twenty-four healthy subjects who received saquinavir soft capsules /ritonavir/efavirenz 1600/200/600 mg once daily. Two additional studies in HIV patients investigated the effect of concomitant administration of efavirenz with either a twice-daily boosted regimen (Invirase/ritonavir 1000/100 mg twice daily) (n=32) or a once-daily boosted regimen (saquinavir soft capsules /ritonavir 1200/100 mg once daily) (n=35). No clinically significant alterations of either saquinavir or efavirenz concentrations were noted in either study.
Nevirapine: Saquinavir/ritonavir: The interaction between Invirase/ritonavir and nevirapine has not been evaluated. Saquinavir: Co-administration of nevirapine and Invirase resulted in a 24 % decrease in plasma saquinavir AUC and no change to nevirapine AUC. The decrease is not thought to be clinically relevant and no dose adjustments of Invirase or nevirapine are recommended.
HIV protease inhibitors (PIs):
Atazanavir: Saquinavir/ritonavir: Concomitant administration of Invirase/ritonavir 1600/100 mg once daily with atazanavir 300 mg once daily to 18 HIV-infected patients resulted in saquinavir AUC and Cmax values which were 60 % and 42 % respectively, higher than those seen with Invirase/ritonavir (at 1600/100 mg once daily) alone. Ritonavir AUC and Cmax values were increased by 41 % and 34 % respectively, whereas pharmacokinetic parameters of atazanavir remained unchanged. No clinical data exist with the approved dosing regimen of saquinavir/ritonavir and atazanavir.
Fosamprenavir: Saquinavir/ritonavir: Concomitant administration of fosamprenavir with Invirase/ritonavir 1000/100 mg had no clinically significant effect on saquinavir exposure. In 18 HIV-infected patients treated with Invirase/ritonavir 1000/100 mg and fosamprenavir 700 mg twice daily, saquinavir AUC and Cmax values were 15 % and 9 % lower than those seen with saquinavir/ritonavir alone. Saquinavir Cmin remained above the target threshold for effective therapy (decreasing by 24 % from 508 to 386 ng/ml). No dose adjustment is required when ritonavir boosted Invirase is combined with fosamprenavir.
Indinavir: Saquinavir/ritonavir: The administration of low dose ritonavir increases the concentrations of indinavir, which may result in nephrolithiasis. Saquinavir: Co-administration of indinavir (800 mg three times daily) and single doses of Invirase (600 mg) or saquinavir soft capsules (800 or 1200 mg) in six healthy volunteers each resulted in 4.6 – 7.2 fold increases in plasma saquinavir AUC0-24. Indinavir plasma levels remained unchanged. Currently, no safety and efficacy data are available from the use of this combination. Appropriate doses of the combination have not been established.
Lopinavir: Saquinavir/ritonavir: The pharmacokinetic parameters of saquinavir, ritonavir and lopinavir have been investigated in HIV-infected patients treated with either saquinavir soft capsules/ritonavir 1000/100 mg twice daily in combination with 2 or 3 NRTIs (n=32) or saquinavir soft capsules 1000 mg twice daily and the fixed combination of lopinavir/ritonavir 400/100 mg twice daily (n=45). Lopinavir did not alter the pharmacokinetics of boosted saquinavir. The ritonavir exposure was significantly lower in the patients taking lopinavir but its effectiveness as a boosting agent was not modified. Concentrations of lopinavir did not appear to be affected when lopinavir/ritonavir and saquinavir were combined, based on historical comparison with lopinavir/ritonavir alone. No dose adjustment is required when ritonavir boosted Invirase is combined with lopinavir.
Nelfinavir: Saquinavir/ritonavir: The interaction between Invirase/ritonavir and nelfinavir has not been evaluated. Saquinavir: Concomitant administration of a single 1200 mg dose of saquinavir soft capsules on the fourth day of multiple nelfinavir dosing (750 mg three times daily) to 14 HIV infected patients resulted in saquinavir AUC and Cmax values which were 392 % and 179 % higher than those seen with saquinavir alone. Concomitant administration of a single 750 mg dose of nelfinavir on the fourth day of multiple saquinavir soft capsules dosing (1200 mg three times daily) to the same patients resulted in nelfinavir AUC values which were 18 % higher than those seen with nelfinavir alone, while Cmax values remained unchanged. Quadruple therapy, including saquinavir soft capsules and nelfinavir in addition to two nucleoside reverse transcriptase inhibitors gave a more durable response (prolongation of time to virological relapse) than triple therapy with either single protease inhibitor. The regimens were generally well tolerated. However, concomitant administration of nelfinavir and saquinavir soft capsules resulted in a moderate increase in the incidence of diarrhoea.
Ritonavir: Saquinavir has been shown not to alter the pharmacokinetics of ritonavir following single or multiple oral doses in healthy volunteers. Ritonavir extensively inhibits the metabolism of saquinavir resulting in greatly increased saquinavir plasma concentrations. In HIV-infected patients, Invirase or saquinavir soft capsules in combination with ritonavir at doses of 1000/100 mg twice daily provide saquinavir systemic exposure over a 24 hour period similar to or greater than those achieved with saquinavir soft capsules 1200 mg three times daily (see section 5.2).
Tipranavir: Saquinavir/ritonavir: In a clinical study of dual-boosted protease inhibitor combination therapy in multiple-treatment experienced HIV-positive adults, tipranavir, co-administered with low dose ritonavir, caused a 78% reduction in the Cmin of saquinavir. Therefore the concomitant administration of tipranavir, co-administered with low dose ritonavir, with saquinavir/ritonavir, is not recommended. If the combination is nevertheless considered necessary, a monitoring of the saquinavir plasma levels is strongly encouraged.
HIV fusion inhibitor:
Enfuvirtide: Saquinavir/ritonavir: No clinically significant interaction was noted from a study in 12 HIV patients who received enfuvirtide concomitantly with saquinavir soft capsules /ritonavir 1000/100 mg twice daily.
Other medicinal products
Antiarrhythmics:
Bepridil, systemic lidocaine, quinidine: Concentrations of these medicinal products may be increased when co-administered with Invirase/ritonavir. Caution is warranted and therapeutic concentration monitoring, if available, is recommended if these antiarrhythmics are given with Invirase/ritonavir.
Amiodarone, flecainide and propafenone: Concentrations of these medicinal products may be increased when co-administered with Invirase/ritonavir. Due to a potential for life threatening cardiac arrhythmia, amiodarone, flecainide and propafenone are contra-indicated with Invirase/ritonavir (see section 4.3).
Anticoagulant:
Warfarin: Concentrations of warfarin may be affected. It is recommended that INR (international normalised ratio) be monitored.
Anticonvulsants:
Carbamazepine, phenobarbital, phenytoin: These medicinal products will induce CYP3A4 and may decrease saquinavir concentrations if Invirase is taken without ritonavir. The interaction between Invirase/ritonavir and these medicinal products has not been evaluated.
Antidepressants:
Tricyclic antidepressants (e.g. amitriptyline, imipramine): Invirase/ritonavir may increase the concentrations of tricyclic antidepressants. Therapeutic concentration monitoring is recommended for tricyclic antidepressants when co-administered with Invirase/ritonavir.
Nefazodone: Will inhibit CYP3A4 and may increase saquinavir concentrations. If nefazodone is taken concomitantly with saquinavir, monitoring for saquinavir toxicity is recommended. The interaction between Invirase/ritonavir and nefazodone has not been evaluated.
Antihistamines:
Terfenadine, astemizole: Co-administration of terfenadine and saquinavir soft capsules leads to an increase in plasma terfenadine exposure (AUC) associated with a prolongation of QTc intervals. Hence, terfenadine is contraindicated in patients receiving saquinavir or saquinavir/ritonavir. As similar interactions are likely, saquinavir or saquinavir/ritonavir should not be administered with astemizole (see section 4.3).
Anti-infectives:
Clarithromycin: Saquinavir/ritonavir: The interaction between Invirase/ritonavir and clarithromycin has not been evaluated. Saquinavir: Concomitant administration of clarithromycin (500 mg twice daily) and saquinavir soft capsules (1200 mg three times daily) to 12 healthy volunteers resulted in steady-state saquinavir AUC and Cmax values which were 177 % and 187 % higher than those seen with saquinavir alone. Clarithromycin AUC and Cmax values were approximately 40 % higher than those seen with clarithromycin alone. No dose adjustment is required when the two medicinal products are co-administered for a limited time at the doses studied.
Erythromycin: Saquinavir/ritonavir: The interaction between Invirase/ritonavir and erythromycin has not been evaluated. Saquinavir: Concomitant administration of erythromycin (250 mg four times daily) and saquinavir soft capsules (1200 mg three times daily) to 22 HIV-infected patients resulted in steady-state saquinavir AUC and Cmax values which were 99 % and 106 % higher than those seen with saquinavir alone. No dose adjustment is required when the two medicinal products are co-administered.
Streptogramin antibiotics such as quinupristin/dalfopristin: Will inhibit CYP3A4 and may increase saquinavir concentrations. If these medicinal products are taken concomitantly with saquinavir, monitoring for saquinavir toxicity is recommended. The interaction between Invirase/ritonavir and quinupristin/dalfopristin has not been evaluated.
Antifungals:
Ketoconazole: Saquinavir/ritonavir: The interaction between Invirase/ritonavir and ketoconazole has not been evaluated. Saquinavir: Concomitant use of ketoconazole (200 mg once daily) and Invirase (600 mg three times daily) to 12 healthy volunteers led to an increase in saquinavir AUC by about 160 % at steady state (day 6 of treatment) with no increase in the elimination half-life or any change in the absorption rate. Ketoconazole pharmacokinetics were not affected by co-administration with saquinavir at a dose of 600 mg three times daily. No dose adjustment for either medicinal product is required when the two medicinal products are co-administered at the doses studied.
Itraconazole: Saquinavir/ritonavir: The interaction between Invirase/ritonavir and itraconazole has not been evaluated. Saquinavir: Like ketoconazole, itraconazole is a moderately potent inhibitor of the CYP3A4 isoenzyme and an interaction of similar magnitude is possible. If itraconazole is taken concomitantly with saquinavir, monitoring for saquinavir toxicity is recommended.
Fluconazole/miconazole: No specific drug interaction studies with either of these medicinal products have been performed.
Antimycobacterials:
Rifampicin: Saquinavir/ritonavir: In a study investigating the interaction of rifampicin 600 mg once daily and Invirase 1000 mg/ritonavir 100 mg given twice daily, 11 of 17 (65 %) healthy volunteers developed severe hepatocellular toxicity with transaminase elevations up to > 20-fold the upper limit of normal after 1 to 5 days of co-administration. Therefore, rifampicin is contraindicated in patients taking ritonavir boosted Invirase as part of an ART regimen (see section 4.3).
Rifabutin: Saquinavir/ritonavir: Concomitant administration of rifabutin with saquinavir/ritonavir 1000/100 mg twice daily has not been evaluated. A dosage reduction to rifabutin 150 mg every 3 days is recommended based on experience with low dose ritonavir boosted protease inhibitors. Patients receiving rifabutin with Invirase/ritonavir should be closely monitored for liver function test elevations and emergence of adverse events associated with rifabutin therapy. Further dosage reduction of rifabutin may be necessary. Therapeutic concentration monitoring for saquinavir is recommended.
Benzodiazepines:
Midazolam: Saquinavir/ritonavir: Co-administration of a single oral dose of midazolam 7.5 mg after 2 weeks of Invirase/ritonavir 1000/100 mg twice daily to 16 healthy volunteers in a cross-over study, increased midazolam Cmax by 4.3-fold and AUC by 12.4-fold. Invirase/ritonavir increased the elimination half-life of oral midazolam from 4.7 to 14.9 h. Therefore, the co-administration of Invirase/ritonavir with orally administered midazolam is contraindicated (see section 4.3), whereas caution should be used with co-administration of Invirase and parenteral midazolam. No data are available on concomitant use of ritonavir boosted saquinavir with intravenous midazolam; studies of other CYP3A modulators and i.v. midazolam suggest a possible 3-4 fold increase in midazolam plasma levels. If Invirase is co-administered with parenteral midazolam it should be done in an intensive care unit (ICU) or similar setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage adjustment should be considered, especially if more than a single dose of midazolam is administered.
Alprazolam, clorazepate, diazepam, flurazepam: Concentrations of these medicinal products may be increased when co-administered with Invirase/ritonavir. Careful monitoring of patients with regard to sedative effects is warranted, a decrease in the dose of the benzodiazepine may be required.
Triazolam: Concentrations of triazolam may be increased when co-administered with Invirase/ritonavir. Triazolam is contra-indicated with Invirase/ritonavir, due to the risk of potential for prolonged or increased sedation and respiratory depression (see section 4.3).
Calcium channel blockers:
Felodipine, nifedipine, nicardipine, diltiazem, nimodipine, verapamil, amlodipine, nisoldipine, isradipine: Concentrations of these medicinal products may be increased when co-administered with Invirase/ritonavir. Caution is warranted and clinical monitoring of patients is recommended.
Corticosteroids:
Dexamethasone: Will induce CYP3A4 and may decrease saquinavir concentrations. Use with caution, saquinavir may be less effective in patients taking these medicinal products concomitantly. The interaction between Invirase/ritonavir and dexamethasone has not been evaluated.
Fluticasone propionate (interaction with ritonavir): In a clinical study where ritonavir 100 mg capsules twice daily were co-administered with 50 µg intranasal fluticasone propionate (4 times daily) for 7 days in healthy subjects, the fluticasone propionate plasma levels increased significantly, whereas the intrinsic cortisol levels decreased by approximately 86 % (90 % confidence interval 82-89 %). Greater effects may be expected when fluticasone propionate is inhaled. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate; this could also occur with other corticosteroids metabolised via the P450 3A pathway e.g. budesonide. Consequently, concomitant administration of boosted saquinavir and these glucocorticoids is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects (see section 4.4). A dose reduction of the glucocorticoid should be considered with close monitoring of local and systemic effects or a switch to a glucocorticoid, which is not a substrate for CYP3A4 (e.g. beclometasone). Moreover, in case of withdrawal of glucocorticoids progressive dose reduction may have to be performed over a longer period. The effects of high fluticasone systemic exposure on ritonavir plasma levels is yet unknown.
Medicinal products that are substrates of P-glycoprotein:
Digitalis glycosides:
Digoxin: Saquinavir/ritonavir: Co-administration of a single oral dose of digoxin 0.5 mg after 2 weeks of Invirase/ritonavir 1000/100 mg twice daily to 16 healthy volunteers in a cross-over study, increased digoxin Cmax by 27% and AUC0-72 by 49%. Caution should be exercised when Invirase/ritonavir and digoxin are co-administered. The digoxin levels may differ over time, and large increments of digoxin may be expected when saquinavir/ritonavir is introduced in patients already treated with digoxin. The serum concentration of digoxin should be monitored and a dose reduction of digoxin should be considered if necessary.
Histamine H2-receptor antagonist:
Ranitidine: Saquinavir/ritonavir: The interaction between Invirase/ritonavir and ranitidine has not been evaluated. Saquinavir: In a study in 12 healthy male volunteers there was an increase in exposure of saquinavir when Invirase was dosed in the presence of both ranitidine and food, relative to Invirase dosed with food alone. This resulted in AUC values of saquinavir, which were 67 % higher. This increase is not thought to be clinically relevant and no dose adjustment of saquinavir is recommended.
HMG-CoA reductase inhibitors:
Pravastatin, fluvastatin: Are not metabolised by CYP3A4, and interactions are not expected with protease inhibitors including ritonavir. If treatment with a HMG-CoA reductase inhibitor is indicated, either pravastatin or fluvastatin are the products recommended.
Simvastatin, lovastatin: Are highly dependent on CYP3A4 metabolism, and plasma concentrations are markedly increased when co-administered with Invirase/ritonavir. Increased concentrations of these medicinal products have been associated with rhabdomyolysis and these medicinal products are contraindicated for use with Invirase/ritonavir (see section 4.3).
Atorvastatin: Is less dependent on CYP3A4 for metabolism. When used with Invirase/ritonavir, the lowest possible dose of atorvastatin should be administered and the patient carefully monitored for signs/symptoms of myopathy (muscle weakness, muscle pain, rising plasma creatinine kinase levels).
Immunosuppressants:
Ciclosporin, tacrolimus, rapamycin: Concentrations of these medicinal products increase several fold when co-administered with Invirase/ritonavir. Careful therapeutic drug monitoring is necessary for immunosuppressants when co-administered with Invirase/ritonavir.
Narcotic analgesic:
Methadone: Co-administration of saquinavir/ritonavir 1000/100 mg twice daily with methadone 60-120 mg once a day in 12 HIV negative methadone maintenance patients resulted in a 19 % (90 % confidence interval 9 % to 29 %) decrease in methadone AUC. None of the patients experienced withdrawal symptoms. No dosage adjustment is required when ritonavir boosted saquinavir is combined with methadone.
Neuroleptics:
Pimozide: Concentrations of pimozide may be increased when co-administered with Invirase/ritonavir. Due to a potential for life threatening cardiac arrhythmias, Invirase/ritonavir is contra-indicated in combination with pimozide (see section 4.3).
Oral contraceptives:
Ethinyl estradiol: Concentration of ethinyl estradiol may be decreased when co-administered with Invirase/ritonavir. Alternative or additional contraceptive measures should be used when oestrogen-based oral contraceptives are co-administered.
Phosphodiesterase type 5 (PDE5) inhibitors:
Sildenafil: The co-administration of saquinavir soft capsules at steady state (1200 mg three times daily) with sildenafil (100 mg single dose), a substrate of CYP3A4, resulted in a 140 % increase in sildenafil Cmax and a 210 % increase in sildenafil AUC. Sildenafil had no effect on saquinavir pharmacokinetics. Use sildenafil with caution at reduced doses of no more than 25 mg every 48 hours with increased monitoring of adverse events when administered concomitantly with Invirase/ritonavir.
Vardenafil: Concentrations of vardenafil may be increased when co-administered with Invirase/ritonavir. Use vardenafil with caution at reduced doses of no more than 2.5 mg every 72 hours with increased monitoring of adverse events when administered concomitantly with Invirase/ritonavir.
Tadalafil: Concentrations of tadalafil may be increased when co-administered with Invirase/ritonavir. Use tadalafil with caution at reduced doses of no more than 10 mg every 72 hours with increased monitoring of adverse events when administered concomitantly with Invirase/ritonavir.
Proton pump inhibitors:
Omeprazole: Concomitant administration of omeprazole (40 mg once daily) and Invirase/ritonavir (1000/100 mg twice daily) to 18 healthy volunteers resulted in steady-state saquinavir AUC and Cmax values which were 82% (90 % confidence interval 44-131 %) and 75% (90 % confidence interval 38-123 %) higher than those seen with Invirase/ritonavir alone. If omeprazole is taken concomitantly with Invirase/ritonavir, monitoring for potential saquinavir toxicities is recommended. The plasma levels of ritonavir did not change significantly after omeprazole use.
Others:
Ergot alkaloids (e.g. ergotamine, dihydroergotamine, ergonovine, and methylergonovine):
Invirase/ritonavir may increase ergot alkaloids exposure, and consequently, increase the potential for acute ergot toxicity. Thus, the concomitant use of Invirase/ritonavir and ergot alkaloids is contra-indicated (see section 4.3).
Grapefruit juice: Saquinavir/ritonavir: The interaction between Invirase/ritonavir and grapefruit juice has not been evaluated. Saquinavir: Co-administration of Invirase and grapefruit juice as single administration in healthy volunteers results in a 50 % and 100 % increase in exposure to saquinavir for normal and double strength grapefruit juice, respectively. This increase is not thought to be clinically relevant and no dose adjustment of Invirase is recommended.
Garlic capsules: Saquinavir/ritonavir: The interaction between Invirase/ritonavir and garlic capsules has not been evaluated. Saquinavir: Concomitant administration of garlic capsules (dose approx. equivalent to two 4 g cloves of garlic daily) and saquinavir soft capsules 1200 mg three times daily to nine healthy volunteers resulted in a decrease of saquinavir AUC by 51 % and a decrease of the mean trough levels at 8 hours post dose by 49 %. Saquinavir mean Cmax levels decreased by 54 %. Therefore patients on saquinavir treatment must not take garlic capsules due to the risk of decreased plasma concentrations and loss of virological response and possible resistance to one or more components of the antiretroviral regimen.
St. John’s wort (Hypericum perforatum): Saquinavir/ritonavir: The interaction between Invirase/ritonavir and St. John’s wort has not been evaluated. Saquinavir: Plasma levels of saquinavir can be reduced by concomitant use of the herbal preparation St. John’s wort (Hypericum perforatum). This is due to induction of drug metabolising enzymes and/or transport proteins by St. John’s wort. Herbal preparations containing St. John’s wort must not be used concomitantly with Invirase. If a patient is already taking St. John’s wort, stop St. John’s wort, check viral levels and if possible saquinavir levels. Saquinavir levels may increase on stopping St. John’s wort, and the dose of saquinavir may need adjusting. The inducing effect of St. John’s wort may persist for at least 2 weeks after cessation of treatment.
Other potential interactions
Medicinal products that are substrates of CYP3A4:
Although specific studies have not been performed, co-administration of Invirase/ritonavir with medicinal products that are mainly metabolised by CYP3A4 pathway (e.g. dapsone, disopyramide, quinine, fentanyl, and alfentanyl) may result in elevated plasma concentrations of these medicinal products. Therefore these combinations should be given with caution.
Medicinal products reducing gastrointestinal transit time:
It is unknown, whether medicinal products which reduce the gastrointestinal transit time (e.g. metoclopramide) could lead to lower saquinavir plasma concentrations.
5.1 Pharmacodynamic properties
Pharmaco-therapeutic group: Antiviral agent, ATC code J05A E01
Mechanism of action: The HIV protease is an essential viral enzyme required for the specific cleavage of viral gag and gag-pol polyproteins. Saquinavir selectively inhibits the HIV protease, thereby preventing the creation of mature infectious virus particles.The HIV protease carries out specific cleavages of viral precursor proteins as virions bud from infected cells. This is an essential step in the creation of fully formed, infectious virus particles. These viral precursor proteins contain a type of cleavage site which is recognised only by HIV and closely related viral proteases. Saquinavir is a mimetic of such cleavage sites and fits closely into the HIV‑1 and HIV‑2 protease active sites, acting as a reversible and selective inhibitor. Saquinavir has approximately 50,000-fold greater affinity for HIV protease than for human proteases. In in vitro antiviral assays saquinavir blocks the formation of infectious virus, and hence the spread of infection to naïve cells.
Antiviral activity in vitro: Saquinavir demonstrates antiviral activity against botha panel of laboratory strains and clinical isolates of HIV-1 with typical EC50 and EC90 values in the range 1-10 nM and 5-50 nM, respectively, with no apparent difference between subtype B and non-B clades. The corresponding serum (50% human serum) adjusted EC50 ranged from 25-250 nM. Clinical isolates of HIV-2 demonstrated EC50 values in the range of 0.3-2.4 nM.using acutely infected T cell lines or primary human lymphocytes/monocytes. In vitro antiviral activity was observed against a panel of HIV-1 group M non-clade B isolates (A, AE, C, D, F, G and H) and HIV-2 with EC50 values ranging from 0.9-2.5 nM. In the presence of 50% human serum or alpha-1 acid glycoprotein (1 mg/ml) the antiviral activity of saquinavir decreases by an average factor of 25-fold and 14-fold respectively.Saquinavir is active in lymphoblastoid and monocytic lines and in primary cultures of lymphocytes and monocytes infected with laboratory strains or clinical isolates of HIV‑1, typically displaying antiviral IC50 and IC90 values in the range 1–10 nM and 5–50 nM, respectively, depending on the cell type and virus isolate, in acutely infected cells. In common with other protease inhibitors, saquinavir binds extensively to plasma proteins, and its in vitro antiviral potency is markedly attenuated in the presence of human serum or its constituent proteins. Addition of 50% human serum or alpha-1 acid glycoprotein (1 mg/ml) to the cell culture resulted in 25-fold and 14-fold reductions, respectively, in activity against wild-type HIV, as well as 33-fold and 7-fold reductions, respectively, in activity against mutant HIV strains.Unlike nucleoside analogues (zidovudine, etc.), saquinavir acts directly on its viral target enzyme. It does not require metabolic activation. This extends its potential effectiveness into resting cells. Saquinavir is active at nanomolar concentrations in lymphoblastoid and monocytic lines and in primary cultures of lymphocytes and monocytes infected with laboratory strains or clinical isolates of HIV‑1. Experiments in cell culture show that saquinavir produces an additive to synergistic antiviral effect against HIV‑1 in double and triple combination with various reverse transcriptase inhibitors (including zidovudine, zalcitabine, didanosine, lamivudine, stavudine and nevirapine) without enhanced cytotoxicity, and clear synergy in double combination with lopinavir.
Pharmacodynamic effects: Early clinical studies assessed the effects in HIV-1 infected patients of unboosted saquinavir in combination with other antiretroviral agents on clinical endpoints and biological markers. Subsequently, the effects of boosted saquinavir in combination with other antiretroviral agents on biological markers (CD4 cell counts and plasma RNA) were evaluated in HIV‑1 infected patients.
Resistance
In vitro selection of resistance:
The most commonly reported mutations observed to develop during in vitro passage of HIV-1 wild type virus in the presence of increasing concentrations of saquinavir are G48V and L90M. Recombinant virus harbouring the G48V or L90M mutations respectively, exhibited 7.9 and 3.3-fold reduced susceptibility to saquinavir. Additional protease mutations observed to develop less frequently were M36I, I54V, K57R, and L63V.
In vivo selection of resistance:
Treatment naïve patients: Four studies have investigated ritonavir boosted saquinavir regimens in ART naïve patients (saquinavir/ritonavir 1600 mg/100 mg once daily n=349; 1000 mg/100 mg twice daily n=92). Baseline and on-therapy resistance analyses were available for 26 patients experiencing virological rebound, and not harbouring resistance mutations at baseline (n=1) or developing signature protease mutations associated with other PIs (n=1). Virus from two patients developed protease mutations (M36I and M46i/m respectively) not typically associated with saquinavir resistance. No saquinavir-associated protease mutations were observed to develop following virological failure.
Treatment experienced patients: Baseline and on-therapy genotype was available for 22 previously PI-experienced patients experiencing virological failure after receiving a ritonavir boosted saquinavir regimen (MaxCmin1 & 2 studies; 1000/100 mg twice daily, n=171). Virus from eight (8/22; 36%) patients developed additional protease mutations following virological failure. The relative incidence of each mutation was: I84V (n=4, 18%); F53L, A71V or G73S (n=2, 9%); L10V, M46I, I54V, V82A or L90M (n=1, 4.5%).
Antiviral activity according to baseline genotype and phenotype:
Genotypic and phenotypic clinical cut-offs predicting the clinical efficacy of ritonavir boosted saquinavir have been derived from retrospective analyses of the RESIST 1 and 2 clinical studies and analysis of a large hospital cohort (Marcelin et al 2007).
Baseline saquinavir phenotype (shift in susceptibility relative to reference, PhenoSense Assay) was shown to be a predictive factor of virological outcome. Virological response was first observed to decrease when the fold shift exceeded 2.3-fold; whereas virological benefit was not observed when the fold shift exceeded 12-fold.
Marcelin et al (2007) identified nine protease codons (L10F/I/M/R/V, I15A/V, K20I/M/R/T, L24I, I62V, G73S/T, V82A/F/S/T, I84V, L90M) that were associated with decreased virological response to saquinavir/ritonavir (1000/100 mg twice daily) in 138 saquinavir naive patients. The presence of 3 or more mutations was associated with reduced response to saquinavir/ritonavir. The association between the number of these saquinavir-associated resistance mutations and virological response was confirmed in an independent clinical study (RESIST 1 and 2) involving a more heavily treatment experienced patient population, including 54% who had received prior saquinavir (p=0.0133, see Table 3). The G48V mutation, previously identified in vitro as a saquinavir signature mutation, was present at baseline in virus from three patients, none of whom responded to therapy.
Table 3: Virological response to saquinavir/ritonavir stratified by the number of baseline saquinavir-associated resistance mutations
|
Number of Saquinavir Associated Resistance Mutations at Baseline*
|
Marcelin et al (2007)
|
RESIST 1 & 2
|
|
SQV Naive Population
|
SQV Naive/Experienced Population
|
|
N=138
|
Change in Baseline Plasma HIV-1 RNA at
Weeks 12-20
|
N=114
|
Change in Baseline Plasma HIV-1 RNA at
Week 4
|
|
0
|
35
|
-2.24
|
2
|
-2.04
|
|
1
|
29
|
-1.88
|
3
|
-1.69
|
|
2
|
24
|
-1.43
|
14
|
-1.57
|
|
3
|
30
|
-0.52
|
28
|
-1.41
|
|
4
|
9
|
-0.18
|
40
|
-0.75
|
|
5
|
6
|
-0.11
|
17
|
-0.44
|
|
6
|
5
|
-0.30
|
9
|
0.08
|
|
7
|
0
|
-
|
1
|
0.24
|
* Saquinavir Mutation Score Mutations: L10F/I/M/R/V, I15A/V, K20I/M/R/T, L24I, I62V, G73S/T, V82A/F/S/T, I84V, L90M
The association between the number of baseline saquinavir resistance-associated mutations and response was highly significant when the activity of the optimized background was taken into account (p=0.0011, see Table 3). The G48V mutation, previously identified in vitro as a saquinavir signature mutation, was present at baseline in virus from three patients, none of whom responded to therapy.
Table 3: Virological response at Week 4 stratified by the number of baseline saquinavir-associated resistance mutations and activity of optimized backbone therapy
|
PSS
of OBT
|
Number of Saquinavir-Associated Resistance Mutations at Baseline (N=114)
|
|
0
|
1
|
2
|
3
|
4
|
5
|
6
|
7
|
Total
|
|
0
|
-
|
-
|
-2.62
|
-0.32
|
-0.38
|
0.06
|
-0.51
|
0.24
|
-0.32
|
|
1
|
-
|
-
|
-1.44
|
-1.09
|
-0.32
|
-0.38
|
0.12
|
-
|
-0.44
|
|
2
|
-1.45
|
-0.92
|
-1.44
|
-1.58
|
-0.92
|
-0.79
|
0.16
|
-
|
-1.34
|
|
>2
|
-2.64
|
-1.78
|
-
|
-1.97
|
-2.05
|
-2.21
|
-0.94
|
-
|
-2.01
|
|
Total
|
-2.04
|
-1.69
|
-1.57
|
-1.41
|
-0.75
|
-0.44
|
0.08
|
0.24
|
-1.17
|
p-value = 0.0011 (model including PSS and saquinavir-associated resistance mutations)
PSS = Phenotypic sensitivity score
OBT = Optimised background treatment
Genotypic and phenotypic clinical cut-offs predicting the clinical efficacy of ritonavir boosted saquinavir have been derived from retrospective analysis of patients receiving saquinavir/ritonavir during the RESIST 1 and 2 studies and from two open label studies investigating the correlation between baseline genotype and virological response to saquinavir/ritonavir (1000/100 mg twice daily).
Baseline saquinavir phenotype (shift in susceptibility relative to reference) was shown to be a predictive factor of virological outcome. Virological response was first observed to decrease when the fold shift exceeded 2.3-fold; whereas virological benefit was not observed when the fold shift exceeded 12-fold.
The presence of 3 or more mutations from the saquinavir mutation score (see Table 2) or at least 6 PI resistance mutations were associated with reduced virological response.
Table 2: Response to Invirase co-administered with ritonavir (1000/100mg twice daily) by baseline genotype.
|
Number of Saquinavir Mutation Score Mutations at Baseline*
|
N
|
Change in Baseline Plasma HIV-1 RNA**
|
|
0
|
35
|
-2.24
|
|
1
|
29
|
-1.88
|
|
2
|
24
|
-1.43
|
|
3
|
30
|
-0.52
|
|
4
|
9
|
-0.18
|
|
5
|
6
|
-0.11
|
|
6
|
5
|
-0.30
|
|
* Saquinavir Mutation Score Mutations: L10F/I/M/R/V, I15A/V, K20I/M/R/T, L24I, I62V, G73S/T, V82A/F/S/T, I84V, L90M
** Log10 copies/ml decrease between day 0 and months 3-5
|
Genotypic and phenotypic clinical cut-offs predicting the clinical efficacy of ritonavir boosted saquinavir have been derived using different methodologies, patient populations and virological end-points (see Table 2).
Phenotypic clinical cut-offs predicting virological response have been established following retrospective analysis of patients receiving saquinavir/ritonavir during the RESIST 1 and 2 studies. Two open label studies have investigated the correlation between baseline genotype and virological response to saquinavir/ritonavir (1000/100 mg twice daily). The first study identified nine positions (L10F/I/M/R/V, I15A/V, K20I/M/R/T, L24I, I62V, G73S/T, V82A/T/S/F, I84V, L90M) associated with reduced virological response to ritonavir boosted saquinavir. The second study, identified a threshold of five protease inhibitor associated mutations as the maximal predictive number associated with virological response. In addition the presence of four amino acids (I54V, G73S, I84V and/or L90M) was associated with reduced virological response.
Table 2: Summary of phenotypic and genotypic predictors of virological response
|
|
N
|
Activity not affected
|
Decreased activity
|
Resistance
|
|
Baseline phenotype (fold change)
|
|
PhenoSense assay
|
87
|
< 2.3A
|
2.3-12.0
|
> 12.0B
|
|
Baseline genotype and virological response
|
|
SQV genotypic scoreC
|
138
|
0-2 mutations
(-2.24 to -1.43 log10 copies/ml)D
|
3 mutations
(-0.52 log10 copies/ml)
|
³ 4 mutations
(-0.11 to -0.3 log10 copies/ml)
|
|
Protease inhibitor associated mutationsE
|
139
|
5 mutations or less
(80% VRF at Week 24)
|
> 5 mutations
(29% VR at Wk 24)
|
|
A Fold change corresponding with first reduction in virological response at week 4
B Fold change above which the week 4 HIV-1 RNA reduction from baseline was < 0.3 log10 copies/ml
C Codons: L10F/I/M/R/V, I15A/V, K20I/M/R/T, L24I, I62V, G73S/T, V82A/T/S/F, I84V, L90M
D Viral load (log10 copies/ml) decrease from baseline after 3-5 months therapy
E Codons: L10, K20, L24, D30, V32, L33, M36, M46, I47, G48, I50, F53, I54, L63, A71, G73, V77, V82, I84, N88, L90
F Virological response defined as > 1 log reduction in viral load at week 24
|
Clinical results from studies with treatment naïve and experienced patientsClinical studies performed with boosted saquinavir soft capsules
Demographic characteristics for studies MaxCmin1 and MaxCmin2 are shown in Table 2 and the disposition and efficacy outcomes of studies MaxCmin 1 and MaxCmin 2 are shown in Table 3.
Table 2344: Subject Demographics MaxCmin1 and MaxCmin2†
|
|
MaxCmin1
|
MaxCmin2
|
|
|
SQV/r
|
IDV/r
|
SQV/r
|
LPV/r
|
|
|
N=148
|
N=158
|
N=161
|
N=163
|
|
Sex
Male
Female
|
82%
18%
|
74%
26%
|
81%
19%
|
76%
24%
|
|
Race (White/Black/Asian) %
White
Black
Asian
|
86/9/1
86%
9%
1%
|
82/12/4
82%
12%
4%
|
75/19/1
75%
19%
1%
|
74/19/2
74%
19%
2%
|
|
Age, median, yrs
(IQR)
|
39
(34-48)
|
40
(34-46)
|
40
(35-50)
|
40
(35-47)
|
|
CDC Category C (%)
|
32%
|
28%
|
32%
|
31%
|
|
Antiretroviral naïve (%)
|
28%
|
22%
|
31%
|
34%
|
|
PI naïve (%)
|
41%
|
38%
|
48%
|
48%
|
|
Median Baseline HIV-1 RNA, log10 copies/mL ml (IQR)
|
4.0
(1.7-5.1)
|
3.9
(1.7-5.2)
|
4.4
(3.1-5.1)
|
4.6
(3.5-5.3)
|
|
Baseline VL < 400 copies/mL
|
38%
|
39%
|
22%
|
21%
|
|
Median Baseline CD4+ Cell Count, cells/mm3 (IQR)
|
272
(135-420)
|
280
(139-453)
|
241
(86-400)
|
239
(95-420)
|
|
|
|
|
|
|
|
|
|
|
|
† data from clinical study report
Table 3455: Outcomes at Week 48 MaxCmin1 and MaxCmin2†
|
Outcomes
|
MaxCmin1
|
MaxCmin2
|
|
Status at week 48
|
SQV/r
|
IDV/r
|
SQV/r
|
LPV/r
|
|
Randomized
|
N=158
|
N=159
|
N=172
|
N=167
|
|
Initiated assigned treatment,
n (%)
|
148
(94%)
|
158
(99%)
|
161
(94%)
|
163
(98%)
|
|
Discontinued assigned treatment, n (%)
|
40
(27%)
|
64
(41%)
|
48
(30%)
|
23
(14%)
|
|
|
P=0.01
|
P=0.001
|
|
Reason for discontinuation n, (%)
|
|
|
|
|
|
Virological failure
|
2 (5%)
|
3 (5%)
|
3 (6%)
|
0
|
|
Death
|
1 (3%)
|
1 (2%)
|
3 (6%)
|
0
|
|
Clinical non-fatal adverse event
|
22 (55%)
|
45 (70%)
|
21 (44%)
|
12 (52%)
|
|
Laboratory adverse event
|
2 (5%)
|
4 (6%)
|
1 (2%)
|
1 (4%)
|
|
Patient choice
|
5 (13%)
|
3 (5%)
|
8 (17%)
|
7 (30%)
|
|
Lost to follow-up
|
3 (8%)
|
5 (8%)
|
4 (8%)
|
2 (9%)
|
|
Other
|
5 (13%)
|
3 (5%)
|
8 (17%)
|
1 (4%)
|
|
Completed 48 weeks of assigned treatment
|
108 (73%)
|
94 (59%)
|
113 (70%)
|
140 (86%)
|
|
Patients with outcome at week 48
|
137 (93%)
|
148 (94%)
|
146 (91%)
|
158 (97%)
|
|
|
|
|
|
|
|
|
|
|
|
† data from clinical study report
‡ includes patient choice and lost to follow-up
Table 3 (continued): Outcomes at Week 48 MaxCmin1 and MaxCmin2†
|
Outcomes
|
MaxCmin1
|
MaxCmin2
|
|
Status at week 48
|
SQV/r
|
IDV/r
|
SQV/r
|
LPV/r
|
|
Virological and Immunological Outcomes
|
|
|
|
|
|
Virological failure ITT/e*#
|
36/148 ( 24%)
|
41/158 (26%)
|
53/161 (33%)
|
29/163 (18%)
|
|
|
P=0.76
|
P=0.002
|
|
Virological failure, switch/discontinue = failure
|
51/148 (34%)
|
77/158 (49%)
|
63/161 (39%)
|
40/161 (25%)
|
|
|
P=0.01
|
P=0.005
|
|
Proportion with VL < 50 copies/mL ml at week 48, ITT/e#
|
97/144
(67%)
|
106/154
(69%)
|
90/158
(57%)
|
106/162
(65%)
|
|
|
P >0.05‡
|
P=0.12
|
|
Proportion with VL < 50 copies/mL at week 48, ITT/e/s##
|
82/144
(57%)
|
73/158
(46%)
|
84/158
(53%)
|
97/162
(60%)
|
|
|
P=0.048‡
|
P=0.23
|
|
Proportion with VL < 50 copies/mL ml at week 48,
On Treatment
|
82/104
(79%)
|
73/93
(78%)
|
84/113
(74%)
|
97/138
(70%)
|
|
|
P>0.05‡
|
P=0.48
|
|
Proportion with VL < 400 copies/mL at week 48, ITT/e#
|
118/148
(80%)
|
122/158
(77%)
|
108/158
(68%)
|
129/162
(80%)
|
|
|
P=NA
|
P=0.02
|
|
Proportion with VL < 400 copies/mL at week 48, ITT/e/s##
|
102/148 (69%)
|
84/158
(53%)
|
98/158
(62%)
|
120/162
(74%)
|
|
|
P=NA
|
P =0.02
|
|
Proportion with VL < 400 copies/mL at week 48,
On Treatment
|
102/108
(94%)
|
84/93
(90%)
|
100/113
(88%)
|
120/138
(87%)
|
|
|
P=NA
|
P=0.96
|
|
Median increase in CD4 cell count at week 48 (cells/mm3)
|
85
|
73
|
110
|
106
|
|
|
|
|
|
|
|
|
|
|
|
* For both studies: For patients entering study with VL < 200 copies/mLml, VF defined as > 200 copies/mLml. MaxCmin1: For those entering with VL > 200 copies/mLml, VF defined as any increase > 0.5 logs and/or VL > 50,000 copies/mL ml at week 4, > 5,000 copies/mL ml at week 12, or > 200 copies/mL ml at week 24 or thereafter. MaxCmin2: any rise > 0.5 log at a specific visit; < 0.5 log reduction if VL > 200 copies/mL ml at week 4; < 1.0 log reduction from base line if VL > 200 copies/mL ml at week 12; and a VL > 200 copies/mL ml at week 24.
# ITT/e = Intent-to-treat/exposed
## ITT/e/s = Intent-to-treat/exposed/switch/discontinue = failure
† Data from clinical study report
‡ Data from MaxCmin1 publication
NA= Not available
Potential for resistance and cross-resistance to saquinavir:
There are two primary protease mutations – L90M and G48V – associated with resistance to unboosted saquinavir. The G48V and L90M mutations give modest (typically less than 10-fold) reductions in susceptibility to saquinavir measured in vitro.
Selection of viral resistance during boosted saquinavir therapy:
In the Staccato study of 272 antiretroviral-naïve patients receiving boosted Invirase therapy (saquinavir/r 1600/100 mg once daily), no primary PI mutations were detected in virus isolated from the nine patients who experienced virological failure. Minor protease substitutions/natural polymorphisms were detected in two patients (one patient with missing baseline sample) experiencing virologic failure (M36I and L10I, respectively).
In the FOCUS study, 154 antiretroviral-naïve patients received either efavirenz or soft-capsule saquinavir/r (1600/100 mg once daily) together with two NRTIs. Resistance analysis of isolates from the ten patients in the saquinavir/r arm with virological failure (viral load > 1,000 copies/ml on two occasions during weeks 12–24) revealed no major PI resistance mutations; one patient at week 12 showed two minor mutations, V771 and N88D, resulting in intermediate-level resistance to nelfinavir.
In the MaxCmin1 and MaxCmin2 studies of 309 antiretroviral-naïve, PI-naïve and PI-experienced patients, isolates from 41 patients treated with saquinavir/r 1000/100 mg twice daily for ≥ 12 weeks with quantifiable (≥ 200 copies/ml) viral load and a matched baseline sample (or a missing baseline sample if PI naïve) were subjected to protease gene sequencing tests. This revealed an increase in the prevalence of primary PI mutations (at codons 30, 46, 48, 50, 82, 84 or 90) from 27% (11/41) at baseline to 32% (13/41) following boosted saquinavir therapy. New primary PI mutations (predominantly at codons 84, 90 or 46) were observed in 2/19 of PI-naïve patients and 5/22 of PI-experienced patients. The risk of developing a new primary PI mutation during ritonavir-boosted saquinavir treatment was positively correlated with the number of primary PI mutations present at baseline. Saquinavir mutations (mutations at codons 10, 48, 54, 71, 73, 77, 82, 84 or 90) developed on boosted saquinavir therapy in 17% (7/41) of patients overall (predominantly at codons 84, 10, 90 or 71).
Antiviral activity of boosted saquinavir in patients failing protease inhibitor therapy:
In a study of 139 PI-experienced patients experiencing virological failure, subsequent virological response to treatment with soft-capsule saquinavir/r 1000/100 mg twice daily at 12, 24 and 48 weeks was dependent on a threshold of five PI resistance mutations at baseline. Overall, 80% of patients with ≤ 5 PI resistance mutations achieved a virological response (< 50 copies/ml or > 1 log10-fold reduction in HIV RNA at week 24) with boosted saquinavir therapy, compared with 29% of patients who had > 5 such mutations.
In a retrospective analysis of 138 PI-experienced patients receiving a saquinavir/r 1000/100 mg twice daily-based regimen, the following nine baseline PI mutations were detected in more than 5% of patients and were identified as most strongly associated with reduced virological response: 10F/I/M/R/V, 15A/V, 20I/M/R/T, 24I, 62V, 73S/T, 82A/F/S/T, 84V and 90M. Among these PI-experienced patients, a significantly reduced virological response to boosted saquinavir therapy was predicted by isolates that had at least three to four of the nine mutations in this resistance score.Resistance: The objective of antiretroviral therapy is to suppress viral replication to below the limits of quantification. Incomplete viral suppression may lead to the development of drug resistance to one or more components of the regimen. Drug resistance is measured as the change in viral susceptibility to drug in culture (=”phenotypic resistance”) or in protease amino acid sequence (=”genotypic resistance”). Measurements of drug susceptibility in in vitro culture are conducted by determination of the IC50 of the active moiety, saquinavir, and may not be representative of the incidence or magnitude of resistance or cross-resistance in vivo, during the clinical use of boosted Invirase, where exposure to saquinavir is increased by the co-administration of low-dose ritonavir.
Two primary mutations in the viral protease (L90M and G48V, the former predominating and the combination rare even with saquinavir monotherapy) are found in isolates collected following failure of treatment with unboosted saquinavir regimens. The G48V and L90M mutations give modest (typically less than 10-fold) reductions in susceptibility to saquinavir measured in vitro. Secondary mutations (e.g. L10I/V, K20R, M36I/L, A71T, V82X) may accompany or precede the primary resistance mutations and give rise to greater reductions in susceptibility to saquinavir.
In one study, 24 clinical isolates containing G48V and/or L90M after therapy with unboosted Invirase showed a geometric mean reduction of susceptibility (increase in IC50) of 7.3-fold relative to baseline virus (range 1.2 to 97-fold). The overall incidence of protease genotypic resistance to saquinavir observed in a cohort of 51 antiretroviral naïve subjects after a mean of 46 weeks (range 15 to 50 weeks) treatment with unboosted saquinavir soft capsules 1200 mg three times daily in combination with 2 NRTIs was 4 %.
There are limited data on the development of resistance in viral isolates collected following the failure of treatment with boosted Invirase.
Cross-resistance: Resistance mutations selected by one drug can in principle also result in reduced susceptibility to other drugs, particularly those in the same drug class. When this occurs it is termed cross-resistance.
Cross-resistance can result in weakened virological response to drug therapy. The application of data from phenotypic and/or genotypic resistance testing following incomplete viral suppression or virological failure can improve the response to subsequent treatments.
Cross-resistance between saquinavir and reverse transcriptase inhibitors: Cross-resistance between saquinavir and reverse transcriptase inhibitors is unlikely because of their different enzyme targets. HIV isolates resistant to zidovudine are sensitive to saquinavir, and conversely, HIV isolates resistant to saquinavir are sensitive to zidovudine.
Cross-resistance to other protease inhibitors: In a study of virus isolates from four clinical trials with unboosted Invirase, 22 virus isolates were identified as being resistant to saquinavir following treatment for 24 - 147 weeks. Susceptibility in vitro of each isolate was assessed to indinavir, ritonavir, nelfinavir and amprenavir. Of the isolates, 6/22 did not show cross-resistance to the other inhibitors, while 4/22 showed broad cross-resistance. The remaining 12/22 retained activity against at least one other protease inhibitor.
Cross-resistance with lopinavir is as yet undetermined in clinical isolates, although laboratory strains with substitutions at residues 10, 84 and 90 or 10, 48, 82 and 90 did not show significant reduction in in vitro susceptibility to lopinavir.
Cross-resistance from other protease inhibitors: Viruses with high level resistance to other protease inhibitors do not necessarily show in vitro cross-resistance to saquinavir. Studies of molecular clones containing resistance mutations associated with ritonavir, nelfinavir or amprenavir showed significant resistance to these individual protease inhibitors, but not in all cases to saquinavir. In a clinical study of 32 individuals pre-treated with indinavir or ritonavir but naïve to saquinavir, 81 % showed reduced susceptibility to indinavir, 59 % showed reduced susceptibility to ritonavir and 40 % showed reduced susceptibility to saquinavir at baseline. Following 24 weeks of therapy with Invirase 1000 mg in combination with ritonavir 100 mg both two times daily, efavirenz and nucleoside analogues, the median decrease in plasma HIV-RNA was 0.9 log10 copies/ml for patients with phenotypic resistance to saquinavir versus 1.52 log10 copies/ml for those without resistance (p=0.03). HIV RNA levels below 50 copies/ml were achieved at week 24 for 58 % of those patients carrying saquinavir-sensitive virus and for 25 % of those carrying virus with reduced (> 10 fold) sensitivity to saquinavir. The median number of resistance mutations in the protease gene in individuals with phenotypic resistance to saquinavir was 5.5 (range 4 - 8), whereas it was 3 (range 0 - 6) in those sensitive to saquinavir (p=0.0003). However, extensive treatment of subjects with protease inhibitors after failure can lead to broad cross-resistance in a complex, dynamic process.
Using a linear regression model to analyse baseline phenotypic resistance and virological response from clinical observations derived from various clinical trials and patient cohorts, and following validation by bootstrapping, a baseline fold-change in saquinavir IC50 of 7.1 and 26.5, relative to wild type, was predicted to be associated with a 20% and 80% loss in maximum virological response at week 8, respectively, to boosted saquinavir therapy. Using linear regression to correlate the baseline fold change and absolute reduction in HIV RNA from baseline to week 4 from one trial, greater than a 12 fold change in IC50 of saquinavir in virus from highly experienced patients (3-class) was associated with no virologic response to SQV/r.
Hypersusceptibility to mutant virus: Some virus isolates with reduced susceptibility to other protease inhibitors can have enhanced susceptibility (hypersusceptibility) to inhibition with saquinavir, for example viruses containing the D30N substitution after nelfinavir therapy and viruses, carrying complex substitutions patterns including I50V. Many viruses with substitutions at residue 82, commonly selected by indinavir or ritonavir therapy, either retain, or show enhanced susceptibility to saquinavir. The clinical significance of hypersusceptibility to saquinavir has not been established.
|
