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Linking the population pharmacokinetics of tenofovir and its metabolites with its cellular uptake and metabolism.

ABSTRACT: Empirical pharmacokinetic models are used to explain the pharmacokinetics of the antiviral drug tenofovir (TFV) and its metabolite TFV diphosphate (TFV-DP) in peripheral blood mononuclear cells. These empirical models lack the ability to explain differences between the disposition of TFV-DP in HIV-infected patients vs. healthy individuals. Such differences may lie in the mechanisms of TFV transport and phosphorylation. Therefore, we developed an exploratory model based on mechanistic mass transport principles and enzyme kinetics to examine the uptake and phosphorylation kinetics of TFV. TFV-DP median Cmax from the model was 38.5?fmol/10(6) cells, which is bracketed by two reported healthy volunteer studies (38 and 51?fmol/10(6) cells). The model presented provides a foundation for exploration of TFV uptake and phosphorylation kinetics for various routes of TFV administration and can be updated as more is known on actual mechanisms of cellular transport of TFV.

SUBMITTER: Madrasi K

PROVIDER: S-EPMC4260001 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Linking the population pharmacokinetics of tenofovir and its metabolites with its cellular uptake and metabolism.

Madrasi K K Burns R N RN Hendrix C W CW Fossler M J MJ Chaturvedula A A

CPT: pharmacometrics & systems pharmacology 20141112

Empirical pharmacokinetic models are used to explain the pharmacokinetics of the antiviral drug tenofovir (TFV) and its metabolite TFV diphosphate (TFV-DP) in peripheral blood mononuclear cells. These empirical models lack the ability to explain differences between the disposition of TFV-DP in HIV-infected patients vs. healthy individuals. Such differences may lie in the mechanisms of TFV transport and phosphorylation. Therefore, we developed an exploratory model based on mechanistic mass transp ...[more]

PMID: 25390686

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Project description:Background and objectivesCariprazine, a dopamine D3-preferring D3/D2 receptor partial agonist, is approved for the treatment of adults with schizophrenia (1.5-6 mg/day) and manic/mixed (3-6 mg/day) episodes associated with bipolar I disorder. This population pharmacokinetic analysis describes the concentration-time profiles of cariprazine and its two major active metabolites, desmethyl-cariprazine (DCAR) and didesmethyl-cariprazine (DDCAR). Additionally, the potential impact of patient characteristics, creatinine clearance, and cytochrome P450 2D6 (CYP2D6) metabolizer status on the pharmacokinetics of cariprazine and its metabolites was evaluated.MethodsData from three phase 1 and ten phase 2/3 studies in adult patients with schizophrenia or bipolar mania were included. Nonlinear mixed-effects pharmacokinetic modeling was performed using the NONMEM software package. Compartmental modeling was performed sequentially with the cariprazine elimination rate used as the DCAR formation rate and likewise the elimination rate of DCAR used with a delay as the DDCAR formation rate.ResultsCariprazine pharmacokinetics were described by a three-compartment model with zero-order input of the dose to a depot compartment followed by first-order absorption and first-order elimination. DCAR and DDCAR pharmacokinetics were described by two-compartment models with linear elimination. Statistically significant predictors of pharmacokinetic parameters included weight, sex, and race, though differences in exposures were not large enough to require an adjustment in dose. Creatinine clearance was not a statistically significant predictor of drug clearance, and a post hoc analysis found that CYP2D6 metabolizer status was not associated with changes in exposure levels for cariprazine, DCAR, or DDCAR. The median time to 90% of steady state was approximately 1 week for cariprazine and DCAR and 3 weeks for DDCAR.ConclusionsPopulation pharmacokinetic modeling provided a quantitative description of the concentration-time profile of cariprazine and its metabolites.

Project description:Recent data support that the vaginal microbiota may alter mucosal pharmacokinetics (PK) of topically delivered microbicides. Our team developed an intravaginal ring (IVR) that delivers tenofovir (TFV) (8-10 mg/day) alone or with levonorgestrel (LNG) (20 ug/day). We evaluated the effect of IVRs on the vaginal microbiota, and describe how the vaginal microbiota impacts mucosal PK of TFV. CONRAD A13-128 was a randomized, placebo controlled phase I study. We randomized 51 women to TFV, TFV/LNG or placebo IVR. We assessed the vaginal microbiota by sequencing the V3-V4 regions of 16S rRNA genes prior to IVR insertion and after approximately 15 days of use. We measured the concentration of TFV in the cervicovaginal (CV) aspirate, and TFV and TFV-diphosphate (TFV-DP) in vaginal tissue at the end of IVR use. The change in relative or absolute abundance of vaginal bacterial phylotypes was similar among active and placebo IVR users (all q values >0.13). TFV concentrations in CV aspirate and vaginal tissue, and TFV-DP concentrations in vaginal tissue were not significantly different among users with community state type (CST) 4 versus those with Lactobacillus dominated microbiota (all p values >0.07). The proportions of participants with CV aspirate concentrations of TFV >200,000 ng/mL and those with tissue TFV-DP concentrations >1,000 fmol/mg were similar among women with anaerobe versus Lactobacillus dominated microbiota (p = 0.43, 0.95 respectively). There were no significant correlations between the CV aspirate concentration of TFV and the relative abundances of Gardnerella vaginalis or Prevotella species. Tissue concentrations of TFV-DP did not correlate with any the relative abundances of any species, including Gardnerella vaginalis. In conclusion, active IVRs did not differ from the placebo IVR on the effect on the vaginal microbiota. Local TFV and TFV-DP concentrations were high and similar among IVR users with Lactobacillus dominated microbiota versus CST IV vaginal microbiota. Trial registration: ClinicalTrials.gov NCT02235662.

Dataset Information

Linking the population pharmacokinetics of tenofovir and its metabolites with its cellular uptake and metabolism.

Publications

Linking the population pharmacokinetics of tenofovir and its metabolites with its cellular uptake and metabolism.

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