Intracellular and Plasma Pharmacokinetics of Saquinavir-Ritonavir, Administered at 1,600/100 Milligrams Once Daily in Human Immunodeficiency Virus-Infected Patients

Abstract

Ritonavir-boosted saquinavir (SQV/r) is currently licensed as a twice-daily regimen. Reducing the pill burden with once-daily dosing may improve adherence. Intracellular concentrations of drugs must be related to the clinical efficacy of protease inhibitors. The aims of the study were to determine the cellular and plasma saquinavir and ritonavir concentrations, to determine the half-lives (t 1/2 s) of the drugs in each compartment, and to examine relationships between drug accumulation and lymphocyte subset P glycoprotein (P-gp) expression. Venous blood samples from 12 human immunodeficiency virus-infected patients receiving a hard-gel formulation of SQV/r (1,600/100 mg once daily) were collected at 2, 6, 12, and 24 h after dosing. Peripheral blood mononuclear cells were separated by density gradient centrifugation, and P-

Clinical and Pharmacokinetic Data Support Once-Daily Low-Dose Boosted Saquinavir (1,200 Milligrams Saquinavir with 100 Milligrams Ritonavir) in Treatment-Naive or Limited Protease Inhibitor-Experienced Human Immunodeficiency Virus-Infected Patients

“…All of these values are concurrent with previously reported data (17,26) and suggest that intracellular SQV levels may be sufficient even when concentrations in plasma are below the minimum effective concentration. No significant differences could be found between plasma SQV levels and gender, weight, or the presence of hepatitis and/or cirrhosis, except for a slight trend toward higher SQV C min levels in cirrhotic patients.…”

“…As expected, this 1,200/100-mg SQVr regimen has yielded C max and AUC 0-24 values that are considerably lower than those observed with higher doses of once-daily SQVr, whereas the C min values are within the range of previously reported levels (6,11,13,21,22,24,27,34), being higher than the IC 95 value (25 ng/ml) for wild HIV-1 isolates and the estimated trough level required to obtain the half-maximal antiviral response (50% effective concentration ϭ 50 ng/ml). In addition, the SQV AUC 0-24 values in our patients were Ͼ20,000 ng/ml ⅐ h, the cutoff at which 85% of the maximum antiviral effect is expected in patients without protease gene mutations (17,18). The observed interindividual variability in SQV concentrations, both in plasma and intracellularly, was considerable, although within the range of other studies on SQV and other PIs (3,4,5,6,7,11,13,17,19,21,25,26,30,31,34).…”

“…In addition, the SQV AUC 0-24 values in our patients were Ͼ20,000 ng/ml ⅐ h, the cutoff at which 85% of the maximum antiviral effect is expected in patients without protease gene mutations (17,18). The observed interindividual variability in SQV concentrations, both in plasma and intracellularly, was considerable, although within the range of other studies on SQV and other PIs (3,4,5,6,7,11,13,17,19,21,25,26,30,31,34).…”

Intracellular and plasma steady‐state pharmacokinetics of raltegravir, darunavir, etravirine and ritonavir in heavily pre‐treated HIV‐infected patients

“…Intracellular accumulation of antiretroviral drugs may depend on the presence of other agents, as previously seen with lopinavir, saquinavir and nelfinavir [26,28,29]. Studies investigating the intracellular accumulation of raltegravir, etravirine, darunavir and rironavir in patients taking different combinations therefore seem warranted.…”

Quantification of Cell-Associated Atazanavir, Darunavir, Lopinavir, Ritonavir, and Efavirenz Concentrations in Human Mononuclear Cell Extracts

“…The method has many potential areas of use, from investigating ART pharmacokinetics-pharmacodynamics in viral reservoirs of HIV to determining long-term patient medication compliance, as intracellular half-lives of many antiretrovirals are longer than plasma half-lives (17)(18)(19)(20)(21). The ability to use a small sample aliquot of 20 l and cell numbers as low as 50,000 cells allows studies in human subjects that might not otherwise be possible because of the limited size and number of biopsy specimens in, for example, lymphatic tissues which can be obtained.…”