Background Fetal drug exposure during pregnancy can be a determinant of fetal drug toxicity or efficacy. Fetal exposure is usually derived from the cord-to-maternal (ctm) concentration ratio. This static parameter does not provide information on the pharmacokinetics in utero, limiting the assessment of a fetal exposure-effect relationship. Pregnancy physiologically-based pharmacokinetic (p-PB-PK) modelling could provide a solution, although incor-poration of placental transfer remains challenging. Here, we aimed to include placental transfer parameters de-rived from an ex vivo human cotyledon perfusion model into a p-PBPK model, to quantitatively simulate fetal ex-posure to the antiretroviral agent darunavir, co-adminis-tered with ritonavir, at term.
Methods An existing and validated p-PBPK model of ma-ternal darunavir/ritonavir exposure was coded in Berkeley Madonna syntax to allow expansion with a feto-placental unit. Bidirectional placental transport of darunavir at term was included. In order to parameterize the model, we determined maternal-to-fetal (mtf) and fetal-to-maternal (ftm) darunavir/ritonavir placental clearances with an ex vivo human cotyledon perfusion model. Simulated ma-ternal PK profiles were compared with observed clinical data to verify the validity of the maternal model aspect. Next, population fetal PK profiles were simulated for different darunavir/ritonavir dosing regimens. These profiles were compared with available cord blood concen-trations in vivo. Additionally, we explored the influence of different DRV/r dosing regimens on fetal exposure and antiviral effects.
Results An average (±SD) mtf cotyledon clearance of 0.91±0.11 mL/min and ftm of 1.6±0.3 mL/min was de-termined (n=6 perfusions). Scaled placental transfer was included into a feto-placental unit and integrated in the p-PBPK model. For darunavir 600/100 mg twice daily, the simulated fetal plasma Cmax, Ctrough, Tmax and T1/2 at steady state were; 1.1 mg/L, 0.57 mg/L, 3 hours, and 21 hours, respectively. This indicates that the fetal population Ctrough is above the protein-adjusted EC90 for inhibit-ing the replication of wild type (0.20 mg/L) and around the EC90 for resistant virus (0.55 mg/L). The simulated ftm plasma concentration ratio (range) over a dosing interval was 0.30 (0.16–0.37), compared to a median (range) ratio for observed darunavir ctm plasma ratio of 0.18 (0–0.82; 0 reported if cord blood concentrations were below the lower limit of quantification [<0.09 mg/L] and hence no ratio could be determined).
Conclusion A p-PBPK model for maternal darunavir exposure was extended with a feto-placental unit. The simulated fetal darunavir plasma concentrations were in the range of observed cord blood concentrations. This advanced model provides a valuable tool in assessing the implications of new dosing regimens, optimising the safety of maternal pharmacotherapy and fetal antiretro-viral treatment.
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