New article: BJCP - Physiologically based pharmacokinetic modelling to inform lenacapavir dose regimen when co-administered with rifamycins in participants with tuberculosis
Introduction:
There is a global need to ensure tuberculosis treatments using rifamycins can be safely administered to individuals receiving lenacapavir (LEN), a potent HIV-1 capsid inhibitor used for multidrug-resistant HIV and as PrEP. LEN is metabolized by CYP3A, UGT1A1, and P-glycoprotein (P-gp), all of which are induced by rifamycins. A physiologically based pharmacokinetic (PBPK) model was developed to guide LEN dosing when co-administered with rifampin (strong CYP3A inducer) or rifabutin (moderate CYP3A inducer).
Methods:
A full-body PBPK model for LEN was built using GastroPlus®. It included LEN distribution and elimination via intestinal secretion, liver metabolism, and P-gp-mediated transport. Kinetic parameters were calibrated using human data. The model was validated against clinical data involving LEN co-administered with various CYP3A and P-gp modulators. Simulations were run to test LEN dosing regimens that maintain plasma levels above the inhibitory threshold (15.5 ng/mL) during six-month intervals, even when rifampin or rifabutin treatment begins.
Results:
The PBPK model accurately predicted LEN concentrations, with simulated Cmax and AUC values within 1.5-fold of observed data. Prediction errors were mostly within accepted criteria for drug–drug interaction modeling. Based on simulations, specific supplemental LEN doses are recommended when co-administered with rifamycins:
- For strong CYP3A inducers (e.g., rifampin), administer 927 mg LEN SC and 600 mg orally on the day of inducer initiation, followed by 600 mg orally the next day.
- For moderate CYP3A inducers (e.g., rifabutin), administer 463.5 mg LEN SC on the day of initiation.
Conclusions:
With appropriate supplemental dosing, LEN can be safely co-administered with strong or moderate CYP3A inducers, including rifampin and rifabutin, during tuberculosis treatment.
Additional information to the following link: Physiologically based pharmacokinetic modelling to inform lenacapavir dose regimen when co‐administered with rifamycins in participants with tuberculosis - Salerno - 2025 - British Journal of Clinical Pharmacology - Wiley Online Library