Biphasic Elimination of Tenofovir Diphosphate and Nonlinear Pharmacokinetics of Zidovudine Triphosphate in a Microdosing Study

Abstract

Objective Phase 0 studies can provide initial pharmacokinetics (PK) data in humans and help to facilitate early drug development, but their predictive value for standard dosing is controversial. To evaluate the prediction of microdosing for active intracellular drug metabolites, we compared the PK profile of two antiretroviral drugs, zidovudine (ZDV) and tenofovir (TFV), in microdose and standard dosing regimens. Study Design We administered a microdose (100 μg) of 14C-labeled drug (ZDV or tenofovir disoproxil fumarate (TDF)) with or without a standard unlabelled dose (300 mg) to healthy volunteers. Both the parent drug in plasma and the active metabolite, ZDV-triphosphate (ZDV-TP) or TFV-diphosphate (TFV-DP) in PBMCs and CD4+ cells were measured by AMS. Results The intracellular ZDV-TP concentration increased less than proportionally over the dose range studied (100 μg to 300 mg), while the intracellular TFV-DP PK were linear over the same dose range. ZDV-TP concentrations were lower in CD4+ cells versus total peripheral blood mononuclear cells (PBMCs), while TFV-DP concentrations were not different in CD4+ cells and PBMCs. Conclusion Our data were consistent with a rate-limiting step in the intracellular phosphorylation of ZDV but not TFV. AMS shows promise for predicting the PK of active intracellular metabolites of nucleosides, but nonlinearity of PK may be seen with some drugs.

Microdosing and drug development: past, present and future

“…Measurement of the parent drug in plasma does not correlate well with efficacy, and assays for the phosphorylated drug in peripheral blood mononuclear cells (PBMCs) are required. In a series of studies, the degree of phosphorylation of zidovudine and tenofovir was demonstrated in human microdose studies using 14 C drug and highly sensitive AMS [66-68]. Interestingly, one paper indicated that intracellular zidovudine concentrations showed linear pharmacokinetics between a microdose and a therapeutic dose [67], whilst the other paper reported non-linear intracellular pharmacokinetics [66].…”

“…[49] ‡ The dose range is given between a microdose and a therapeutic dose in the study cited or for a typical therapeutic dose if compared to the literature (see comment column). § Summarised mean parameters. ¶ Data for zidovudine were ambiguous in that one publication reported scalable pharmacokinetics in PBMCs [65], whilst the other reported non-linear pharmacokinetics [66]. Since the plasma pharmacokinetics for both papers reported saleable pharmacokinetics, zidovudine has been included with those drugs where microdosing was predictive within a factor of 2.…”

“…¶ Data for zidovudine were ambiguous in that one publication reported scalable pharmacokinetics in PBMCs [65], whilst the other reported non-linear pharmacokinetics [66]. Since the plasma pharmacokinetics for both papers reported saleable pharmacokinetics, zidovudine has been included with those drugs where microdosing was predictive within a factor of 2.…”

Intravaginal ring eluting tenofovir disoproxil fumarate completely protects macaques from multiple vaginal simian-HIV challenges

“…This notion is supported by the higher cell permeability and at least 100 times greater potency of TDF compared with TFV against HIV in vitro (13). The bioactive form, TFV diphosphate (TFV-DP), has the further advantage of a long intracellular half-life (60-150 h) (14,15) that could mitigate lapses in adherence and may prove advantageous compared with antiretrovirals (e.g., dapivirine) that can readily diffuse from the intracellular to the extracellular compartments in response to drug concentration gradients in time and space (16).…”

Use of Microdosing and Accelerator Mass Spectrometry To Evaluate the Pharmacokinetic Linearity of a Novel Tricyclic GyrB/ParE Inhibitor in Rats

“…Key to the use of microdose studies is establishing a correlation between the PKs at the microdose and the pharmacological dose. Although the published data are limited, studies that have compared data obtained with the microdose and the therapeutic dose have shown that the microdose data are predictive of the therapeutic dose in more than 80% of the cases (6,8,11,25,26). One approach for establishing dose linearity is to validate the approach in an animal model prior to initiating a human microdosing study (8,11).…”