Abstract
Aim: The pharmacokinetics of doravirine have been studied in clinical
trials, but not in real-world settings. Our study aims to characterize
and identify factors influencing doravirine pharmacokinetics (a CYP3A4
substrate) in real-world people with HIV (PWH). Methods: A total of 174
doravirine concentrations measured in 146 PWH followed up in the
therapeutic drug monitoring (TDM) program at the University Hospital of
Lausanne (Switzerland) between 2019 and 2023 were included in the
analysis. Population pharmacokinetic analysis and Monte Carlo
simulations to investigate the clinical significance of the covariates
retained in the final model were performed using NONMEM. Results: A
one-compartment model with first-order absorption and linear elimination
best described doravirine pharmacokinetics. Potent CYP3A4 inhibitors
and, to a lesser extent age, were the only tested covariates to
significantly impact doravirine clearance (CL). Potent CYP3A4 reduced CL
by 50%, and a 30% decrease in CL was observed in an 80-year-old
compared to a 55-year-old PWH. The effect of potent CYP3A4 inhibitors
was prominent, explaining 59% of between-subject variability in CL.
Model-based simulations predicted 2.8-fold and 1.6-fold increases in
median steady-state trough and maximum doravirine concentrations,
respectively, when a potent CYP3A4 inhibitor was co-administered.
Conclusion: Our findings show that potent CYP3A4 inhibitors and age
influence doravirine pharmacokinetics. However, given the good
tolerability of doravirine, dosing adjustment of doravirine is probably
not mandatory in those situations. TDM remains useful essentially in
specific clinical situations, such as hepatic impairment, suspected
non-adherence or pregnancy.