Saquinavir pharmacokinetics alone and in combination with ritonavir in HIV-infected patients

Abstract

For some patients, administration of SQV 600 mg three times daily results in very low SQV plasma levels and possibly little antiviral effect. Combination of SQV with RIT results in a significant drug interaction mediated by enzyme inhibition which exposes patients to very high SQV concentrations and potential toxicity. If combination therapy with SQV plus RIT is considered then the dose of SQV should be greatly reduced.

Interaction of Ritonavir on Tissue Distribution of a [14C]L-Valinamide, a Potent Human Immunodeficiency Virus-1 Protease Inhibitor, in Rats Using Quantitative Whole-Body Autoradiography

“…Initial pharmacokinetic studies showed that upon pretreatment of rats with RTV, the AUC 0 -10h of DPC showed 2.5-fold enhancement. RTV is known to cause such effects by potent inhibition of the metabolizing isozyme CYP3A Merry et al, 1997;Koudriakova et al, 1998) and the transporter Pgp (Alsenz et al, 1998). DPC is indeed metabolized prominently by CYP3A4, like most other HIV protease inhibitors, and is also shown to be a good substrate for Pgp, as discussed below.…”

Infections in AIDS

“…Ritonavir is a potent inhibitor of CYP3A4 and coadministration of RTV and SQV results in increases in the C max and AUC of SQV [205,206]. The AUCs of the hard and soft gel formulations of SQV have been shown to increase in the presence of RTV .50-fold and 20-fold respectively [206,207].…”

“…The AUCs of the hard and soft gel formulations of SQV have been shown to increase in the presence of RTV .50-fold and 20-fold respectively [206,207]. Similarly, the protease inhibitors nel®navir and indinavir inhibit CYP3A4, increasing mean plasma concentrations and AUCs of SQV during co-administration.…”

“…Similarly, the protease inhibitors nel®navir and indinavir inhibit CYP3A4, increasing mean plasma concentrations and AUCs of SQV during co-administration. Indinavir and nel®navir increased the AUC of soft gel SQV by sixfold and ®ve-fold respectively [207,208]. These interactions are of clinical bene®t, as increased bioavailability results in enhanced antiviral activity and, perhaps, dose reduction.…”

“…Similarly, co-administration of NFV and RTV produced a 152% increase in the AUC 0-8h of NFV [218]. However, the plasma concentration of RTV is unaltered with IDV, NFV and SQV [217,219,220].…”