Population Pharmacokinetic Parent-Metabolite Modeling of Tenofovir Alafenamide in Healthy Korean Volunteers

Background: Tenofovir alafenamide (TAF) is widely used drug as a first-line drug for managing hepatitis B virus infection. TAF was developed as the prodrug of tenofovir (TFV) to decrease renal and bone toxicities through lower dose administration and sufficient systemic exposures than other salt forms of TFV. TAF is also a highly variable drug in which within-subject variabilities are greater than 30%. However, there are still rack of knowledge to understand the pharmacokinetics of TAF and TFV in various races including Korean as well.

Obgectives: This study aims to establish a population pharmacokinetic (pop PK) model for TAF and TFV in healthy adult Korean volunteers and evaluate factors influencing the pharmacokinetics (PK).

Methods: A total of 1368 TAF and 1888 TFV plasma concentration data were collected from a randomized, open-label, 2-sequence, 4-period, cross-over trial with 56 healthy volunteers who were orally administered by TAF 25 mg under fasting conditions (NCT05189288). The pop PK model was developed using first-order conditional estimation with interaction (FOCE-I) in NONMEM 7.4 assisted by Perl-speaks-NONMEM 4.9.0. Under the assumption that the whole TAF is irreversibly converted into TVF, the structural model was parameterized and various covariates such as demographics and clinical laboratory tests were explored. Bootstrap (n=1000) as internal evaluation of final model was applied.

Results: The one-compartment model incorporating first-order absorption and first-order elimination of TAF and TFV through the complete and rapid metabolization into TFV better described TAF and TFV PK. The absorption rate constant of TAF was 3 h-1 without lag time, and metabolic elimination rate from TAF to TFV was 6 h-1. The apparent clearance and the apparent volume of distribution for TVF were 111 L/h and 3840 L. Although body weight may affect the distribution of TAF and TFV, clinically significant covariates were not found.

Conclusions: The combining TAF and TFV in one model could well explain the metabolic process in terms of pharmacokinetics. The rapid metabolic rate of TAF to TFV can make the inter-individual variability of TFV much smaller and provide the stable exposure of TFV for Korean patients without kidney diseases. This research could serve as a basis for more extensive and in-depth studies targeting patients with different ethnics or diseases.