PA-727 Physiologically-based pharmacokinetic modelling of drug-drug interactions between ritonavir-boosted atazanavir and rifampicin in pregnancy

<h3>Background</h3> Ritonavir-boosted atazanavir (ATV/r) and rifampicin are mainstays of second-line antiretroviral and multiple anti-TB regimens, respectively. Rifampicin is a strong inducer of CYP3A4, the main enzyme involved in atazanavir metabolism, causing drug-drug interaction (DDI) in those co-infected with HIV and TB, which might be exaggerated in pregnancy. We employed physiologically-based pharmacokinetic (PBPK) modelling to investigate atazanavir pharmacokinetics during coadministration of rifampicin and ATV/r in pregnancy. <h3>Methods</h3> A pregnancy PBPK model was developed from a published adult PBPK model by incorporating pregnancy-induced biological changes. Predicted pharmacokinetic parameters in pregnancy were validated with published clinical datasets for once daily (OD) rifampicin 600 mg and clinical data for ATV/r (300/100 mg) in pregnancy (NCT03923231). Predicted atazanavir Ctrough was compared against its protein-adjusted IC90 (14 ng/ml) when simulating the coadministration of ATV/r 300/100 mg OD and rifampicin 600 mg OD in pregnancy. Alternative dosing regimens were also explored. <h3>Results</h3> The pregnancy model was considered validated when the absolute average fold error (AAFE) for Ctrough and AUC0–24 of ATV/r 300/100 mg OD and for Cmax and AUC0–24 for rifampicin 600 mg OD were &lt;2, when comparing predicted vs observed data. Similarly, comparison of predicted and observed plasma concentrations of atazanavir and ritonavir in the sparse pregnancy data (NCT03923231) gave AAFE values &lt;2. Pregnancy was predicted to increase the rifampicin DDI effect on atazanavir. For the dosing regimens of ATV/r 300/100 mg OD, ATV/r 300/200 mg OD and ATV/r 300/100 mg BD (all with rifampicin 600 mg OD), predicted atazanavir Ctrough was above 14 ng/ml in 29%, 71% and 100%; and 32%, 73% and 100% of the population in second and third trimesters, respectively. <h3>Conclusion</h3> PBPK modelling suggests ATV/r 300/100 mg BD could maintain antiviral efficacy when co-administered with rifampicin 600 mg OD in pregnancy. Clinical studies are warranted to confirm safety and efficacy in pregnancy.