Drug interactions between Invirase and Norvir Soft Gelatin

saquinavir ↔ ritonavir

Applies to:Invirase (saquinavir) and Norvir Soft Gelatin (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.