Physiologically based pharmacokinetic modelling prediction of the effects of dose adjustment in drug-drug interactions between levonorgestrel contraceptive implants and efavirenz-based ART.

摘要: Background HIV-positive women receiving efavirenz-based ART and levonorgestrel contraceptive implants are at risk of low exposure unintended pregnancy. Objectives To investigate clinically applicable dose-adjustment strategies to overcome the known drug-drug interaction (DDI) between efavirenz, using a physiologically based pharmacokinetic (PBPK) modelling-based approach. Methods A PBPK model was qualified against clinical data predict plasma concentrations when standard-dose (150 mg) were administered alone (control group), as well or increased-dose (300 coadministered with either 600 400 mg efavirenz. Results No difference seen in vivo PBPK-model-simulated (P > 0.05). Simulated ∼50% lower 48 weeks post-implant-placement virtual individuals efavirenz compared control group (efavirenz:control geometric mean ratio = 0.42 0.49, respectively). Conversely, combination sufficient restore levels similar those observed 150 0.86 1.03, Conclusions These results suggest that significant DDI is likely persist despite dose reduction, whereas escalation implantable may represent successful strategy circumvent efavirenz-levonorgestrel DDIs will be use inform trial design assess coadministration implants.