Pharmacokinetics of Once-Daily Darunavir-Ritonavir and Atazanavir-Ritonavir over 72 Hours following Drug Cessation

Abstract

The object of this study was to investigate the pharmacokinetics of darunavir-ritonavir and atazanavirritonavir once-daily dosing over 72 h (h) following drug intake cessation. Volunteers received darunavirritonavir at 800 and 100 mg, respectively, once daily for 10 days, followed by a 7-day washout period, and atazanavir-ritonavir at 300 and 100 mg, respectively, once daily for 10 days. Full pharmacokinetic profiles were assessed for each phase for the 72 h following day 10. Pharmacokinetic parameters were determined over 24 h and to the last measurable concentration by noncompartmental methods. Seventeen subjects completed the study. The geometric mean (GM) terminal elimination half-life to 72 h of darunavir was 6.48 h, which was lower than the 0-to 24-h half-life (10.70 h). The terminal elimination half-life of atazanavir was 6.74 h, which was lower than the 0-to 24-h half-life (13.72 h). All subjects but one had darunavir concentrations higher than the target of 550 ng/ml for protease-resistant HIV isolates (equivalent to 10 times the protein-binding-corrected 50% inhibitory concentration [IC 50 ] for wild-type virus) at 24 h postdose, and 14 out of 17 had concentrations higher than the target at 30 h postdose (GM of 1,088 and 851 ng/ml). All subjects had atazanavir concentrations above the suggested minimum effective concentration of 150 ng/ml (equivalent to 10 times the proteinbinding-corrected IC 50 for wild-type virus) at 24 and 30 h postdose (GM of 693 and 392 ng/ml). Two of 17 and 5 of 17 subjects were above target at 48 h postdose while on darunavir-ritonavir and atazanavir-ritonavir. Ritonavir half-life to 72 h was 6.84 h with darunavir and 6.07 with atazanavir. This study investigated the pharmacokinetic forgiveness of two boosted protease inhibitors. Although the rates of decline of darunavir and atazanavir slightly increased as ritonavir concentrations declined, most individuals had concentrations 6 h after the end of the ideal dosing interval of 24 h which were above the cutoff used to define therapeutic concentrations.The combination of a ritonavir-boosted protease inhibitor and two nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs) has shown sustained suppression of plasma HIV replication and continued immunological recovery in naïve and experienced HIV-infected individuals (11).The advantages associated to ritonavir boosting are a consequence of the increased drug exposure and prolonged halflife that allow reducing the pill burden and dosing frequency and lead to the achievement of a high genetic barrier to resistance (11, 16).Drug persistence (the presence of drug at a detectable level high enough to exert an effect) in plasma mainly depends on the half-life (which itself is dependent on clearance and volume of distribution). Long-half-life antiretroviral agents may allow for forgotten doses, especially if they are able to delay the decline in drug concentration to a subtherapeutic level for a period of time that is long enough for the concentrations to be above target until th...

Placental Transfer of Darunavir in an Ex Vivo Human Cotyledon Perfusion Model

“…The mean trough level in the fetal compartment was 140 ng/ml, near the suggested minimum effective concentration for darunavir, reported to be 150 ng/ml (22). Clinical data on darunavir use in pregnant women are still limited to small case series, but the available pharmacological data are compatible with our findings.…”

Dysregulation of Endoplasmic Reticulum Stress and Autophagic Responses by the Antiretroviral Drug Efavirenz

“…Cells were exposed to the following combinations of ARVds: cART1 (10 mM efavirenz, 5 mM emtricitabine, and 1 mM tenofovir) or cART2 (1 mM atazanavir, 60 nM ritonavir, 5 mM emtricitabine, and 1 mM tenofovir) in serum-free and antibioticfree EBM-2 basal media. These concentrations reflect the physiologic level of the drugs (Marzolini et al, 2001;Stahle et al, 2004;Droste et al, 2005;Boffito et al, 2011;Valade et al, 2014). For example, successful therapy was observed in patients with plasma concentrations of efavirenz between 1000 and 4000 mg/l, which translates to 3.17 and 12.67 mM.…”

Comparative Single Dose Pharmacokinetics and Bioavailability Studies of Saquinavir, Ritonavir and their Optimized Cyclodextrin Complexes after Oral Administration into Rats using LC-MS/MS.

“…Pure RTV also exhibited slightly variable bioavailability, which is commonly observed with protease inhibitors. 21 However, with RTV-RMβCD complex, such phenomenon was not observed. The T max values were unchanged and found to be 2 h for both groups.…”