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Tenofovir alafenamide (TAF) is an oral prodrug of tenofovir (TFV) that has greater stability in plasma than TFV disoproxil fumarate (TDF) and circulates as intact TAF, resulting in the direct and higher lymphatic loading of and exposure to TFV diphosphate, the active moiety. Unlike TFV, TAF is minimally eliminated in urine. The pharmacokinetics (PK) of TAF and TFV in HIVuninfected subjects with severe renal impairment and matched healthy controls were evaluated. Subjects with severe renal impairment (RI; estimated glomerular filtration rate [eGFR], 15 to 29 ml/min) and controls (eGFR, >90 ml/min) matched for age, gender, and body mass index received a single dose of TAF at 25 mg. Blood and urine samples for TAF and TFV PK determinations were collected over 7 days postdosing, and subjects were followed up at 14 days. A total of 14 renally impaired subjects and 13 control subjects enrolled and completed the study. The TAF maximum observed concentration in plasma (C max ) and the area under the concentration-versus-time curve (AUC) extrapolated to infinite time (AUC inf ) were 79% and 92% higher, respectively, in subjects with severe RI than the controls, primarily due to higher absorption. The TFV C max and AUC inf were 2.8-fold and 5.7-fold higher, respectively, in subjects with severe RI than the controls. In subjects with severe RI, TAF at 25 mg provided a TFV AUC 10 to 40% lower than that from historical TDF-based TFV exposures in subjects with normal renal function. There were no discontinuations due to adverse events. In subjects with severe RI receiving TAF at 25 mg, TAF exposures were higher than those for the controls; these differences are unlikely to be clinically meaningful. TFV exposures were higher than those for the controls but lower than the exposures in nonrenally impaired subjects on TDF-based regimens.T he availability of efficacious and well-tolerated antiretroviral agents and their coformulation into a single-tablet regimen (STR) for convenient dosing have transformed the treatment landscape and rendered HIV into a manageable disease (1). Indeed, several STRs have been approved for HIV treatment, including efavirenz (EFV)-emtricitabine (FTC)-tenofovir disoproxil fumarate (TDF), rilpivirine (RPV)-FTC-TDF, elvitegravir (EVG)-cobicistat (COBI)-FTC-TDF, and, recently, abacavir (ABC)-dolutegravir (DTG)-lamivudine (3TC). Although STRs have been beneficial to a large number of HIV-infected patients, their use in special populations, such as those with end-organ dysfunction, has been limited due to the inability to alter the dose and the discordance in the doses of the various components with the different routes of elimination needed. Specifically, one or more components of the STRs mentioned above are predominantly if not exclusively renally eliminated [i.e., the nucleos(t)ide reverse transcriptase inhibitors TDF, FTC, and 3TC], necessitating dose reductions in patients with certain levels of renal impairment that is incompatible with fixed-dose-strength STR dosage forms. Therefore, patients with m...

Rat liver cytochrome P-450 hydroxylates toluene to benzyl alcohol plus o-, m-, and p-cresol. Deuterated toluenes (CeD5CH3, C6D6CD3, PhCDnH3_") were incubated under saturating conditions with liver microsomes from phenobarbital-pretreated rats, and product yields and ratios were measured. Stepwise deuteration of the methyl leads to stepwise decreases in the alcohol/cresol ratio without changing the cresol isomer ratios. Extensive deuterium retention in the benzyl alcohols from PhCH2D and PhCHD2 suggests there is a large intrinsic isotope effect for benzylic hydroxylation. After replacement of the third benzylic H by D, the drop in the alcohol/cresol ratio was particularly acute, suggesting that metabolic switching from D to H within the methyl group was easier them switching from the methyl to the ring. Comparison of the alcohol/cresol ratio for PhCH3 vs PhCD3 indicated a net isotope effect of 6.9 for benzylic hydroxylation. From product yield data for PhCH3 and PhCD3, DV for benzyl alcohol formation is only 1.92, whereas DV for total product formation is 0.67 (i.e., inverse). These observations can be explained by postulating that product release is partly rate limiting in turnover when the product is benzyl alcohol but not when it is cresol; thus, deuterium-induced metabolic switching directs the substrate to a pathway (ring hydroxylation) that is intriniscally harder to enter but ultimately faster to traverse. Quantitative fitting (1) Financial support for this study was provided in part by the National Institutes of Health (Grant GM-31910).(2) Ling, K.-H.

SOF/VEL and ARV regimens including ATV, COBI, DRV, DTG, EVG, FTC, LPV, RAL, RPV, RTV, TAF, or TDF may be coadministered without dose adjustment. Use of SOF/VEL with EFV-containing regimens is not recommended due to an approximate 50% reduction in VEL exposure.

Elvitegravir (EVG) is an HIV strand transfer integrase inhibitor approved for the treatment of HIV infection as a part of antiretroviral regimens containing cobicistat (COBI) or ritonavir (RTV) as a booster. The population pharmacokinetics of EVG in treatment-naive and -experienced HIV patients was determined, and the effects of demographic, biometric, and formulation covariates on EVG pharmacokinetics (PK) were evaluated. Data from 31 clinical studies (25 in healthy subjects, 6 phase 1b to phase 3 in HIV-1-infected patients) with COBI-boosted EVG studies (as EVG/co or EVG/COBI/FTC/TDF single-tablet regimen) or RTV-boosted EVG studies (EVG/r) were analyzed using NONMEM. The effect of the covariates age, sex, race, health status (healthy volunteers vs HIV patients), weight, body mass index (BMI), body surface area (BSA), creatinine clearance (estimated GFR), and formulation were evaluated. EVG PK, with COBI or RTV, was described by a 2-compartment model, with first-order absorption and elimination and an absorption lag time. A statistically significant, but not clinically relevant, effect of BSA on EVG clearance (CL) was observed. Coadministration of atazanavir or lopinavir with EVG/r had an effect on EVG CL consistent with the known interaction with these agents. No other covariate had a meaningful effect on EVG PK. EVG PK was well described in a population PK model with HIV-infected patients, with low PK variability and no relevant effect of demographic or biometric covariates.

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Statins are commonly used medications by HIV-1 patients. Elvitegravir/cobicistat/emtricitabine/tenofovir DF is a single tablet regimen for the treatment of HIV. The pharmacokinetic interaction between cobicistat-boosted elvitegravir (EVG/co) and rosuvastatin was evaluated. Breast cancer resistance protein (BCRP) and organic anion transporting polypeptide (OATP) 1B1 and 1B3 inhibition were assessed in vitro. Healthy subjects (N = 12) received a single dose of rosuvastatin 10 mg alone and in combination with EVG/co. Intensive pharmacokinetic sampling was conducted and safety was assessed throughout the study. Rosuvastatin pharmacokinetic exposure parameters were evaluated using 90% confidence intervals (CI) of the geometric mean ratio (GMR) of the test (combination) versus reference (rosuvastatin alone) using equivalence boundaries of 70-143% for AUCinf and 70-175% for Cmax . Elvitegravir and cobicistat inhibited BCRP and OATP in vitro, emtricitabine and TDF did not. Clinically, study treatments were well tolerated, with adverse events generally mild. Upon coadministration, rosuvastatin plasma concentrations increased (Cmax 89% higher), while AUCinf changes were modest (38% higher) and clinically nonrelevant, potentially driven by moderate inhibition of intestinal efflux by BCRP, and/or hepatic uptake by OATPs by EVG/co. Elvitegravir and cobicistat pharmacokinetics were comparable to historical data. Rosuvastatin may be coadministered with EVG/COBI/FTC/TDF without dose adjustment.

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