Student School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, United States
Disclosure(s):
Weihua Jiang, PharmD/MS Candidate: No financial relationships to disclose
Objectives: Tenofovir alafenamide (TAF) holds promise in HIV prevention and treatment. TAF functions as a prodrug, rapidly hydrolyzed by specific esterases—CES1 in hepatocytes and CatA in lymphoid cells—to generate tenofovir (TFV). This activation process triggers its target-specific pharmacodynamic effect, facilitating potent antiviral activity with low systemic toxicity. TAF exhibits a complex disposition, characterized by transient plasma pharmacokinetics (PK) that render it undetectable approximately 4 hours post oral administration, while its active metabolite, tenofovir diphosphate (TFVdp), sustains prolonged activity for 6-7 days within peripheral blood mononuclear cells (PBMCs). However, existing models primarily focus on the PK of its metabolite TFV alone. This study aims to develop a minimal physiologically based pharmacokinetic (mPBPK) model for TAF and its metabolites in humans.
Methods: The PK model was developed using human PK data of TAF, TFV, and TFVd obtained from 4 clinical trials. These clinical trials encompassed diverse drug regimens, including intravenous TFV (1 & 3 mg/kg) administered to HIV-infected adults and oral TAF (5, 10, 25, 40, 120 mg) administered to both HIV-infected adults and healthy seronegative women. PK profiles included measurements of both TAF and TFV plasma concentrations, as well as TFVdp levels in PBMCs. The model integrates mechanisms for the cellular uptake of TAF, the conversion of TAF to TFV, and subsequent metabolism to TFVdp in both PBMCs and hepatocytes. In-vitro studies were incorporated to determine TAF's conversion rates in both hepatocytes and PBMCs. Model verification was conducted using data from 3 additional clinical studies, evaluating predictive performance across diverse populations, including healthy seronegative women, non-cirrhotic adults with chronic hepatitis B, and HIV-infected adults in an African population.
Results: The final model integrates an mPBPK model for TAF with a two-compartmental model for TFV, utilizing a permeability-limited structure for TAF tissue distribution. The hybrid mPBPK model effectively characterized the plasma profiles of TAF and TFV, along with the PBMC profiles of TFVdp, demonstrating good agreement between predicted and observed data. Additionally, the model also successfully predicted the validation datasets, aligning 95% of the steady-state concentrations of TFV in an HIV-infected African population.
Conclusions: This hybrid mPBPK model represents a valuable tool for predicting the plasma profiles of TAF, TFV, and the PBMC profile of TFVdp. It has the potential to optimize dosing regimens and improve the efficacy and safety of TAF-based therapies for HIV prevention and treatment, such as the development of long-acting formulations.
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