Dose-dependent increase of saquinavir bioavailability by the pharmaceutic aid cremophor EL

Abstract

Aims: Bioavailability of orally administered drugs depends on several factors including active excretion, e.g. by P-glycoprotein (PGP), and presystemic metabolism, e.g. by cytochrome P450 3A (CYP3A), in both gastrointestinal tract and liver. Many drugs including saquinavir are substrates of both PGP and CYP3A. It was the aim of this study to test whether the extremely low bioavailability of saquinavir can be increased dose-dependently in vivo by cremophor EL, an 'inactive' pharmaceutic aid known to inhibit PGP in vitro.

Methods: In a randomized, placebo-controlled, double-blind, four phase cross-over design single doses of oral saquinavir (Invirase, 600 mg, without food) were administered with increasing single doses of oral cremophor EL (up to 5000 mg) to eight healthy, male individuals. Saquinavir plasma concentrations were determined by LC/MS/MS up to 48 h after intake. Main outcome measures were area under the plasma concentration time curve (AUC), peak concentration (Cmax), time to reach Cmax (tmax) and terminal elimination half-life (t(1/2)).

Results: Cremophor EL dose-dependently increased Cmax, AUC(0,4 h), and AUC(0,infinity) of saquinavir. As compared with placebo, the increment observed after 5000 mg cremophor EL was 13-fold for both Cmax and AUC(0,4 h) and 5-fold for AUC(0,infinity). The terminal half-life and the time to reach Cmax (tmax) were unchanged.

Conclusions: Cremophor EL increased the systemic availability of saquinavir without affecting its elimination suggesting that cremophor EL is not devoid of pharmacological action and acts as a modulator of the absorption process, probably by inhibiting intestinal PGP.

Figure 1

Average plasma concentration – time curves of a single dose of saquinavir (Invirase®, 600 mg orally) after administration with increasing single oral doses of cremophor EL (○ mg; ▴ 100 mg; ▪ 1000 mg; • 5000 mg) in eight healthy volunteers. Data are presented as mean ± s.e.mean.

Figure 2

Mean values of C_max (•), AUC(0,4 h) (▴), and AUC(0,∞) (▪) of a single dose of saquinavir (Invirase®, 600 mg p.o.) after administration with increasing single oral doses of cremophor EL in eight healthy volunteers. Data are presented as mean ± s.e.mean.