HIV-infected patients administered INVIRASE (600-mg tid) had AUC and maximum plasma concentration (Cmax) values approximately 2-2.5 times those observed in healthy volunteers receiving the same treatment regimen.

Similar bioavailability was demonstrated when INVIRASE 500 mg FCT (2 x 500 mg) and INVIRASE 200 mg capsule (5 x 200 mg) were administered with low-dose ritonavir (100 mg) under fed conditions. The ratio of mean exposures (90% confidence intervals) of tablets vs capsules were 1.10 (1.04-1.16) for AUC_0-∞ and 1.19 (1.14-1.25) for Cmax.

Absorption and Bioavailability in Adults

Absolute bioavailability of saquinavir administered as INVIRASE averaged 4% (CV 73%, range: 1% to 9%) in 8 healthy volunteers who received a single 600-mg dose (3 x 200 mg) of saquinavir mesylate following a high-fat breakfast (48 g protein, 60 g carbohydrate, 57 g fat; 1006 kcal). The low bioavailability is thought to be due to a combination of incomplete absorption and extensive first-pass metabolism.

INVIRASE in combination with ritonavir at doses of 1000/100 mg bid or 400/400 mg bid provides saquinavir systemic exposures over a 24-hour period similar to or greater than those achieved with saquinavir soft gel capsules 1200 mg tid (see Table 1).

Table 1 Pharmacokinetic Parameters of Saquinavir at Steady-State After Administration of Different Regimens in HIV-Infected Patients

Food Effect

No food effect data are available for INVIRASE in combination with ritonavir.

The mean 24-hour AUC after a single 600-mg oral dose (6 x 100 mg) in healthy volunteers (n=6) was increased from 24 ng·h/mL (CV 33%), under fasting conditions, to 161 ng·h/mL (CV 35%) when INVIRASE was given following a high-fat breakfast (48 g protein, 60 g carbohydrate, 57 g fat; 1006 kcal). Saquinavir 24-hour AUC and Cmax (n=6) following the administration of a higher calorie meal (943 kcal, 54 g fat) were on average 2 times higher than after a lower calorie, lower fat meal (355 kcal, 8 g fat). The effect of food has been shown to persist for up to 2 hours.

Saquinavir exposure was similar when saquinavir soft gel capsules plus ritonavir (1000-mg/100-mg bid) were administered following a high-fat (45 g fat) or moderate-fat (20 g fat) breakfast.

Distribution in Adults

The mean steady-state volume of distribution following intravenous administration of a 12-mg dose of saquinavir (n=8) was 700 L (CV 39%), suggesting saquinavir partitions into tissues. Saquinavir was approximately 98% bound to plasma proteins over a concentration range of 15 to 700 ng/mL. In 2 patients receiving saquinavir mesylate 600 mg tid, cerebrospinal fluid concentrations were negligible when compared to concentrations from matching plasma samples.

Metabolism and Elimination in Adults

In vitro studies using human liver microsomes have shown that the metabolism of saquinavir is cytochrome P450 mediated with the specific isoenzyme, CYP3A4, responsible for more than 90% of the hepatic metabolism. Based on in vitro studies, saquinavir is rapidly metabolized to a range of mono- and di-hydroxylated inactive compounds. In a mass balance study using 600 mg ¹⁴C-saquinavir mesylate (n=8), 88% and 1% of the orally administered radioactivity was recovered in feces and urine, respectively, within 5 days of dosing. In an additional 4 subjects administered 10.5 mg ¹⁴C-saquinavir intravenously, 81% and 3% of the intravenously administered radioactivity was recovered in feces and urine, respectively, within 5 days of dosing. In mass balance studies, 13% of circulating radioactivity in plasma was attributed to unchanged drug after oral administration and the remainder attributed to saquinavir metabolites. Following intravenous administration, 66% of circulating radioactivity was attributed to unchanged drug and the remainder attributed to saquinavir metabolites, suggesting that saquinavir undergoes extensive first-pass metabolism.

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