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Drug Interactions between ombitasvir / paritaprevir / ritonavir and saquinavir

This report displays the potential drug interactions for the following 2 drugs:

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Interactions between your drugs

Moderate

saquinavir ritonavir

Applies to: saquinavir and ombitasvir / paritaprevir / ritonavir

ADJUST DOSE: Coadministration with ritonavir (RTV) may significantly increase the bioavailability of saquinavir (SQV) from both the hard gelatin capsule (HGC) and soft gelatin capsule (SGC) formulations. The mechanism is RTV inhibition of CYP450 3A4 metabolism of SQV in the intestine and liver. In seven HIV+ patients stabilized on their antiretroviral regimen, addition of RTV (300 mg orally twice a day for 4 days) increased the median peak plasma concentration (Cmax) and 8-hour area under the concentration-time curve (AUC) of SQV (HGC 600 mg three times a day) by 30-fold and 58-fold, respectively, compared to baseline. In 57 healthy volunteers, escalating single doses of SQV (HGC) and RTV yielded comparable results, but increasing RTV dosages tended to produce less than proportional increases in SQV Cmax and AUC. The magnitude of the interaction is considerably less with the SGC formulation but still substantial. In individual groups of 8 healthy volunteers, various regimens of SQV (SGC 800 mg twice a day) and RTV (200 to 400 mg twice a day) for 14 days led to an approximate overall 9.6-fold increase in SQV Cmax and 20-fold increase in SQV AUC. RTV tended to reduce intersubject variability in SQV plasma levels. SQV had negligible effect on the pharmacokinetics of RTV.

MANAGEMENT: Based on the magnitude of interaction, SQV dosage should be reduced when coadministered with RTV. A regimen of (SQV HGC or SGC:RTV) 400:400 mg or 1000:100 mg twice daily is usually recommended based on their convenience and favorable safety-to-efficacy profile. Limited data suggest that dosages of 1200 to 2000:100 mg once daily may also be feasible and warrant further investigation. Patients receiving the combination should be closely monitored for toxicity including elevations in liver function tests and neutropenia.

References

  1. "Product Information. Invirase (saquinavir)." Roche Laboratories PROD (2001):
  2. "Product Information. Norvir (ritonavir)." Abbott Pharmaceutical PROD (2001):
  3. Fitzsimmons ME, Collins JM "Selective biotransformation of the human immunodeficiency virus protease inhibitor saquinavir by human small-intestinal cytochrome p4503a4 - potential contribution to high first-pass metabolism." Drug Metab Dispos 25 (1997): 256-66
  4. Merry C, Barry MG, Mulcahy F, Ryan M, Heavey J, Tjia JF, Gibbons SE, Breckenridge AM, Back DJ "Saquinavir pharmacokinetics alone and in combination with ritonavir in HIV-infected patients." AIDS 11 (1997): f29-33
  5. Kempf DJ, Marsh KC, Kumar G, et al. "Pharmacokinetic enhancement of inhibitors of the human immunodeficiency virus protease by coadministration with ritonavir." Antimicrob Agents Chemother 41 (1997): 654-60
  6. Angel JB, Kumar A, Parato K, Filion LG, DiazMitoma F, Daftarian P, Pham B, Sun E, Leonard JM, Cameron DW "Improvement in cell-mediated immune function during potent anti-human immunodeficiency virus therapy with ritonavir plus saquinavir." J Infect Dis 177 (1998): 898-904
  7. Hsu A, Granneman GR, Cao GL, Carothers L, ElShourbagy T, Baroldi P, Erdman K, Brown F, Sun E, Leonard JM "Pharmacokinetic interactions between two human immunodeficiency virus protease inhibitors, ritonavir and saquinavir." Clin Pharmacol Ther 63 (1998): 453-64
  8. Deeks SG, Grant RM, Beatty GW, Horton C, Detmer J, Eastman S "Activity of a ritonavir plus saquinavir-containing regimen in patients with virologic evidence of indinavir or ritonavir failure." AIDS 12 (1998): f97-102
  9. Tebas P, Patick AK, Kane EM, Klebert MK, Simpson JH, Erice A, Powderly WG, Henry K "Virologic responses to a ritonavir-saquinavir-containing regimen in patients who had previously failed nelfinavir." AIDS 13 (1999): f23-8
  10. Cameron DW, Japour AJ, Xu Y, Hsu A, Mellors J, Farthing C, Cohen C, Poretz D, Markowitz M, Follansbee S, Angel JB, McMahon D "Ritonavir and saquinavir combination therapy for the treatment of HIV infection." AIDS 13 (1999): 213-24
  11. Kirk O, Katzenstein TL, Gerstoft J, Mathiesen L, Nielsen H, Pedersen C, Lundgren JD "Combination therapy containing ritonavir plus saquinavir has superior short-term antiretroviral efficacy: a randomized trial." AIDS 13 (1999): f9-16
  12. "Product Information. Fortovase (saquinavir)." Roche Laboratories PROD (2001):
  13. Buss N, Snell P, Bock J, Hsu A, Jorga K "Saquinavir and ritonavir pharmacokinetics following combined ritonavir and saquinavir (soft gelatin capsules) administration." Br J Clin Pharmacol 52 (2001): 255-64
  14. Rathbun RC, Rossi DR "Low-dose ritonavir for protease inhibitor pharmacokinetic enhancement." Ann Pharmacother 36 (2002): 702-6
  15. Lu JF, Blaschke TF, Flexner C, Rosenkranz SL, Sheiner LB "Model-based Analysis of the Pharmacokinetic Interactions Between Ritonavir, Nelfinavir, and Saquinavir after Simultaneous and Staggered Oral Administration." Drug Metab Dispos 30 (2002): 1455-61
  16. Kilby JM, Sfakianos G, Gizzi N, et al. "Safety and pharmacokinetics of once-daily regimens of soft-gel capsule saquinavir plus minidose ritonavir in human immunodeficiency virus-negative adults." Antimicrob Agents Chemother 44 (2000): 2672-8
  17. Cooper CL, Van Heeswijk RP, Gallicano K, Cameron DW "A review of low-dose ritonavir in protease inhibitor combination therapy." Clin Infect Dis 36 (2003): 1585-92
  18. Boffito M, Dickinson L, Hill A, et al. "Saquinavir/ritonavir (SQV/r) pharmacokinetics (PKs) in HIV+ subjects: 1000/100 mg bid vs 1600/100 and 2000/100 mg once daily (OD) http://www.natap.org/2003/ICAAC/day7_1.htm" (2004):
  19. Developed by the panel of Clinical Practices for Treatment of HIV Infection convened by the Department of Health and Human Services (DHHS) "Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. http://AIDSinfo.nih.gov" (2004):
View all 19 references

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Moderate

saquinavir paritaprevir

Applies to: saquinavir and ombitasvir / paritaprevir / ritonavir

MONITOR: Coadministration with potent inhibitors of CYP450 3A4 may increase the plasma concentrations of paritaprevir, which is primarily metabolized by the isoenzyme. In 12 study subjects, ketoconazole 400 mg given once daily increased single-dose paritaprevir peak plasma concentration (Cmax) and systemic exposure (AUC) by approximately 37% and 98%, respectively. The risk of hyperbilirubinemia may be increased, as paritaprevir can cause elevations in indirect (unconjugated) bilirubin via inhibition of OATP1B1/1B3.

MANAGEMENT: Caution is advised if paritaprevir is prescribed in combination with potent CYP450 3A4 inhibitors. Patients should be monitored for signs and symptoms of hepatotoxicity (i.e., ALT and bilirubin elevations).

References

  1. Cerner Multum, Inc. "UK Summary of Product Characteristics." O 0
  2. "Product Information. Viekira Pak (dasabuvir/ombitasvir/paritaprev/ritonav)." AbbVie US LLC (2022):

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Drug and food interactions

Moderate

saquinavir food

Applies to: saquinavir

ADJUST DOSING INTERVAL: Food significantly increases the absorption of saquinavir.

MONITOR: Coadministration with grapefruit juice may increase the plasma concentrations of saquinavir. The primary mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. In eight healthy volunteers, ingestion of 400 mL of grapefruit juice prior to administration of a 600 mg dose of saquinavir mesylate increased the area under the plasma concentration-time curve and oral bioavailability of saquinavir by 50% and 100%, respectively, compared to water; however, the increase is not considered clinically relevant. A high degree of intersubject variability in the grapefruit juice effect was also observed. The extent to which this interaction may occur with the saquinavir free base soft gelatin capsule is unknown. However, the saquinavir soft gelatin capsule formulation is no longer commercially available.

MANAGEMENT: Saquinavir mesylate should be taken with meals or within 2 hours after eating to enhance bioavailability. Patients should be advised to avoid the consumption of large amounts of grapefruit and grapefruit juice during saquinavir therapy unless otherwise directed by their doctor, as the interaction is unreliable and subject to a high degree of interpatient variation.

References

  1. "Product Information. Invirase (saquinavir)." Roche Laboratories PROD (2001):
  2. Kupferschmidt HHT, Fattinger KE, Ha HR, Follath F, Krahenbuhl S "Grapefruit juice enhances the bioavailability of the HIV protease inhibitor saquinavir in man." Br J Clin Pharmacol 45 (1998): 355-9
  3. Bailey DG, Malcolm J, Arnold O, Spence JD "Grapefruit juice-drug interactions." Br J Clin Pharmacol 46 (1998): 101-10
  4. Eagling VA, Profit L, Back DJ "Inhibition of the CYP3A4-mediated metabolism and P-glycoprotein-mediated transport of the HIV-I protease inhibitor saquinavir by grapefruit juice components." Br J Clin Pharmacol 48 (1999): 543-52
  5. Cerner Multum, Inc. "UK Summary of Product Characteristics." O 0
  6. Cerner Multum, Inc. "Australian Product Information." O 0
View all 6 references

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Moderate

ritonavir food

Applies to: ombitasvir / paritaprevir / ritonavir

ADJUST DOSING INTERVAL: Administration with food may modestly affect the bioavailability of ritonavir from the various available formulations. When the oral solution was given under nonfasting conditions, peak ritonavir concentrations decreased 23% and the extent of absorption decreased 7% relative to fasting conditions. Dilution of the oral solution (within one hour of dosing) with 240 mL of chocolate milk or a nutritional supplement (Advera or Ensure) did not significantly affect the extent and rate of ritonavir absorption. When a single 100 mg dose of the tablet was administered with a high-fat meal (907 kcal; 52% fat, 15% protein, 33% carbohydrates), approximately 20% decreases in mean peak concentration (Cmax) and systemic exposure (AUC) were observed relative to administration after fasting. Similar decreases in Cmax and AUC were reported when the tablet was administered with a moderate-fat meal. In contrast, the extent of absorption of ritonavir from the soft gelatin capsule formulation was 13% higher when administered with a meal (615 KCal; 14.5% fat, 9% protein, and 76% carbohydrate) relative to fasting.

MANAGEMENT: Ritonavir should be taken with meals to enhance gastrointestinal tolerability.

References

  1. "Product Information. Norvir (ritonavir)." Abbott Pharmaceutical PROD (2001):

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Moderate

paritaprevir food

Applies to: ombitasvir / paritaprevir / ritonavir

ADJUST DOSING INTERVAL: Food enhances the oral bioavailability of ombitasvir, paritaprevir, ritonavir, and dasabuvir. Relative to fasting conditions, administration of ombitasvir, paritaprevir, ritonavir, and dasabuvir with a moderate-fat meal (approximately 600 Kcal; 20% to 30% calories from fat) increased the mean systemic exposure (AUC) by 82%, 211%, 49%, and 30%, respectively. Relative to fasting conditions, administration of ombitasvir, paritaprevir, ritonavir, and dasabuvir with a high-fat meal (approximately 900 Kcal; with 60% calories from fat) increased the mean AUC by 76%, 180%, 44%, and 22%, respectively.

MANAGEMENT: Ombitasvir/paritaprevir/ritonavir plus dasabuvir should always be administered with a meal. The fat or calorie content does not matter.

References

  1. "Product Information. Viekira Pak (dasabuvir/ombitasvir/paritaprev/ritonav)." AbbVie US LLC (2022):

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Therapeutic duplication warnings

Therapeutic duplication is the use of more than one medicine from the same drug category or therapeutic class to treat the same condition. This can be intentional in cases where drugs with similar actions are used together for demonstrated therapeutic benefit. It can also be unintentional in cases where a patient has been treated by more than one doctor, or had prescriptions filled at more than one pharmacy, and can have potentially adverse consequences.

Duplication

Protease inhibitors

Therapeutic duplication

The recommended maximum number of medicines in the 'protease inhibitors' category to be taken concurrently is usually one. Your list includes two medicines belonging to the 'protease inhibitors' category:

  • ombitasvir/paritaprevir/ritonavir
  • saquinavir

Note: In certain circumstances, the benefits of taking this combination of drugs may outweigh any risks. Always consult your healthcare provider before making changes to your medications or dosage.

See also

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Drug Interaction Classification

These classifications are only a guideline. The relevance of a particular drug interaction to a specific individual is difficult to determine. Always consult your healthcare provider before starting or stopping any medication.
Major Highly clinically significant. Avoid combinations; the risk of the interaction outweighs the benefit.
Moderate Moderately clinically significant. Usually avoid combinations; use it only under special circumstances.
Minor Minimally clinically significant. Minimize risk; assess risk and consider an alternative drug, take steps to circumvent the interaction risk and/or institute a monitoring plan.
Unknown No interaction information available.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

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