Cytochrome P450 3A Inhibition by Atazanavir and Ritonavir, but Not Demography or Drug Formulation, Influences Saquinavir Population Pharmacokinetics in Human Immunodeficiency Virus Type 1-Infected Adults

Abstract

Inadequate concentrations of the human immunodeficiency virus (HIV) protease inhibitor saquinavir jeopardize individual therapy success or produce side effects despite treatment according to the current guidelines. We performed a population pharmacokinetic analysis with NONMEM and determined that the steady-state pharmacokinetics of saquinavir in 136 HIV type 1-infected adults was modulated by a decrease in saquinavir CL following coadministration of the cytochrome P450 3A inhibitors ritonavir and atazanavir. In contrast, age, sex, weight, pregnancy, and the pharmaceutical formulation exerted only minor, nonsignificant effects.The human immunodeficiency virus type 1 (HIV-1) protease inhibitor saquinavir (1,000 mg twice daily) is a well-established component of antiretroviral therapy (3, 7). Antiretrovirally effective plasma concentrations above the in vitro 90% inhibitory concentration of 5 to 80 nM (12) are clinically obtained by decreasing saquinavir's metabolic clearance (CL) following coadministration of 100 mg of the cytochrome P450 3A (CYP3A) blocking agent ritonavir (4,7,8). However, too-low or too-high concentrations jeopardize the therapy success or produce side effects, respectively (10, 13). Therefore, factors affecting plasma saquinavir concentrations are of clinical relevance.(A subset of these data was published previously [10].) Population pharmacokinetics is receiving increasing acceptance for exploration and definition of relevant sources of variation in drug exposure and responses (1). We used it to assess the relative contributions of ritonavir and atazanavir coadministration (2,5,14), of demographic factors, and of the pharmaceutical formulation (9) to the modulation of plasma saquinavir concentrations. HIV-1-infected patients (n ϭ 136) received 1,000 mg saquinavir twice daily, either as soft gel capsules (Fortovase; n ϭ 52) or hard gel capsules (Invirase; n ϭ 84) containing 200 mg saquinavir mesylate (Hoffmann-La Roche, Basel, Switzerland) together with 100 mg ritonavir (Norvir; Abbot GmbH, Wiesbaden, Germany). Atazanavir (300 mg once daily; Reyataz; Bristol Myers Squibb GmbH, Baar, Switzerland) was administered to 49 patients (43 men, 6 nonpregnant women) in whom reverse transcriptase inhibitors had had toxic effects or were ineffective due to viral resistance.Nucleosidic reverse transcriptase inhibitors were administered to the other 87 patients.The study cohort comprised 104 HIV-1-infected men, aged 20 to 71 years (median, 41.5 years) and weighing 51 to 116 kg (median, 74 kg), and 32 HIV-1-infected women, aged 19 to 64 years (median, 32.5 years) and weighing 42 to 100 kg (median, 68.5 kg), of which 13 were pregnant (mean ϭ 32 weeks ϩ 4 days, range ϭ 24 weeks ϩ 3 days to 36 weeks ϩ 5 days). Subjects with any CD4 cell count or viral load at baseline of therapy were included. Patients with functional impairment of the liver (Child-Pugh classification B or C [11]) and patients taking CYP3A4-modulating cotherapies other than the presented antiretrovirals were excluded.A 12-h plasma drug concen...

Chronic exposure to nicotine and saquinavir decreases endothelial Notch‐4 expression and disrupts blood‐brain barrier integrity

“…Using reverse phase HPLC, the daily Intraperitoneal dosing of saquinavir and ritonavir also provided C max concentrations (1.8 ± 0.4 μM) which are in general agreement with previously published human plasma concentrations ranging from 1 to 5 μM (Barry et al. 1997; von Hentig and Lotsch 2009). After 28 days, the animal underwent a brief vascular perfusion (120 s) with 14 C‐sucrose to remove vascular contents and determine BBB integrity.…”

Genetic variability of CYP3A4 in a heterogeneous Brazilian population from Maranhão

“…CYP3A4 is responsible for the metabolism of over 50% of all clinically used drugs, including commonly used antidepressants, antibiotics, antihypertensives, steroids, and immunosuppressants (Von Hentig and Lötsch, 2009). Thus, polymorphisms in the CYP family may have a majority impact on the fate of these drugs, and other therapeutic drugs whose metabolism they regulate (Evans and Relling, 1999).…”

Unique CYP3A4 genetic variant in Brazilian tuberculosis patients with/without HIV

“…In this way, CYP3A4-V may damage the metabolism of anticancer drugs, reducing the production of potentially DNA-damaging reactive intermediates (47). Beyond the suggested roles in cancer response and TB immune response, the CYP3A4 gene may be explored in approaches for the prediction of therapy response in AIDS and TB, since CYP3A4 demonstrates a role in the metabolism of anti-HIV and anti-TB drugs (2)(3)(4)(5)(6)(7)(8).…”

“…Rifampicin, an antibiotic commonly used for tuberculosis (TB) treatment (2,3), protease inhibitors and non-nucleoside reverse transcriptase inhibitors used for human immunodeficiency virus (HIV) therapy (4,5), and many medicines from the anti-inflammatory and antibiotic classes (2-6) have been described as inhibitors or inductors of CYP3A gene expression (3,(6)(7)(8).…”