PHYSIOLOGICALLY BASED PHARMACOKINETIC MODELING OF LONG-ACTING CABOTEGRAVIR AND RILPIVIRINE IN SPECIAL POPULATIONS AND DRUG–DRUG INTERACTION SCENARIOS
DOI:
https://doi.org/10.65327/hsn.v12i2.2483Keywords:
Cabotegravir, Rilpivirine, PBPK modeling, Drug–drug interactions, Long-acting antiretroviral therapyAbstract
This study compared physiologically based pharmacokinetic (PBPK) models of long acting cabotegravir (CAB) and rilpivirine (RPV) to describe exposure at regular dosing, special population conditions and clinically relevant drug–drug interaction scenarios. The modeling framework included the modeling of intramuscular depot release, the modeling of the physicochemical and metabolic properties of the drugs, population physiology, and enzyme-mediated interactions. Model verification results indicated good agreement with the observed pharmacokinetic parameters with 73% of simulated parameters within 1.25-fold, 83% within 1.5-fold and 100% within twofold of observed values. Predicted RPV reduction was less than that predicted for progressive reductions in CAB, with the greatest reduction seen for greater BMI categories. The exposure of the CAB and RPV generally increased with age. Drug-drug interaction simulations showed that the strongest inducer was rifampicin, for which the fold reduction in the AUC of CAB and RPV was around 61% and 38%, respectively, while the fold reduction for rifabutin was moderate. The decreases in exposure were small and brief with residual induction with efavirzen. Alternative dosing simulations indicated that some loss of activity with rifabutin was countered with dosing changes; induction by rifampicin was potentially problematic. Sensitivity analysis revealed that solubility, viscosity, thickness of the diffusion layer and related depot properties were found to be significant factors for the long-acting pharmacokinetics. Overall, PBPK modeling was used to provide a mechanistic framework to assess exposure variability and to support tailored dosing strategies for CAB/RPV.
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