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O-1 Dosing for two: placental transfer and fetal darunavir exposure
  1. Greupink,
  2. Schalkwijk,
  3. Buaben,
  4. Freriksen,
  5. Colbers,
  6. Burger,
  7. Russel
  1. Radboud University Medical Centre, NIJMEGEN, Nederland

Abstract

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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