Estimation of Fetal-to-Maternal Unbound Steady-State Plasma Concentration Ratio of P-Glycoprotein and/or Breast Cancer Resistance Protein Substrate Drugs Using a Maternal-Fetal Physiologically Based Pharmacokinetic Model

Abstract

Pregnant women are frequently prescribed drugs to treat chronic diseases such as human immunodeficiency virus infection, but little is known about the benefits and risks of these drugs to the fetus that are driven by fetal drug exposure. The latter can be estimated by fetal-to-maternal unbound plasma concentration at steady state (K_p,uu,fetal). For drugs that are substrates of placental efflux transporters [i.e., P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP)], K_p,uu,fetal is expected to be <1. Here, we estimated the in vivo K_p,uu,fetal of selective P-gp and BCRP substrate drugs by maternal-fetal physiologically based pharmacokinetic (m-f-PBPK) modeling of umbilical vein (UV) plasma and maternal plasma (MP) concentrations obtained simultaneously at term from multiple maternal-fetal dyads. To do so, three drugs were selected: nelfinavir (P-gp substrate), efavirenz (BCRP substrate), and imatinib (P-gp/BCRP substrate). An m-f-PBPK model for each drug was developed and validated for the nonpregnant population and pregnant women using the Simcyp simulator (v20). Then, after incorporating placental passive diffusion clearance, the in vivo K_p,uu,fetal of the drug was estimated by adjusting the placental efflux clearance until the predicted UV/MP values best matched the observed data (K_p,uu,fetal) of nelfinavir = 0.41, efavirenz = 0.39, and imatinib = 0.35. Furthermore, K_p,uu,fetal of nelfinavir and efavirenz at gestational weeks (GWs) 25 and 15 were predicted to be 0.34 and 0.23 (GW25) and 0.33 and 0.27 (GW15). These K_p,uu,fetal values can be used to adjust dosing regimens of these drugs to optimize maternal-fetal drug therapy throughout pregnancy, to assess fetal benefits and risks of these dosing regimens, and to determine if these estimated in vivo K_p,uu,fetal values can be predicted from in vitro studies. SIGNIFICANCE STATEMENT: The in vivo fetal-to-maternal unbound steady-state plasma concentration ratio (K_p,uu,fetal) of nelfinavir [P-glycoprotein (P-gp) substrate], efavirenz [breast cancer resistance protein (BCRP) substrate], and imatinib (P-gp and BCRP substrate) was successfully estimated using maternal-fetal physiologically based pharmacokinetic (m-f-PBPK) modeling. These K_p,uu,fetal values can be used to adjust dosing regimens of these drugs to optimize maternal-fetal drug therapy throughout pregnancy, to assess fetal benefits and risks of these dosing regimens, and to determine if these estimated in vivo K_p,uu,fetal values can be predicted from in vitro studies.

Fig. 1.

Workflow for estimation of in vivo K_p,uu,fetal using the Simcyp m-f-PBPK model. A PBPK model for each drug was developed for the nonpregnant population using the Simcyp simulator (v20), and the predicted PK profiles of these drugs were validated with data after intravenous (i.v.) and oral administration as well as drug-drug interaction studies (step 1). Systemic maternal PK of drugs in the second trimester, third trimester, and postpartum was predicted using the pregnant population of the Simcyp simulator and validated with the observed data (step 2). Then, using the estimated passive diffusion clearance (CL_PD) of the drugs, the magnitude of the placental efflux clearance (CL_{efflux,placenta}) and the K_p,uu,fetal were estimated by adjusting the CL_{efflux,placenta} until the predicted UV/MP values best matched the observed data (step 3).

Fig. 2.

Predicted and observed plasma concentration-time (C-T) profiles of nelfinavir, efavirenz, and imatinib in the nonpregnant adults. (A) Observed (geometric mean) and predicted plasma C-T profile after single oral dose of nelfinavir (1250 mg) in nonpregnant adults (Sarapa et al., 2005; Damle et al., 2006); (B) Observed (mean) and predicted plasma C-T profile of 600 mg efavirenz (once daily by mouth) at steady state in nonpregnant adults (Villani et al., 1999); and (C) Observed (median) and predicted plasma C-T profile after single dose of 100 mg imatinib in nonpregnant adults (Ostrowicz et al., 2014). The observed data (open circles) fell within the 5th and 95th percentiles (dashed lines) of the predicted data (continuous black line). The predicted PK endpoints (AUC and C_max) also fell within 0.80- to 1.25-fold of the observed data (Tables 2 and 3).

Fig. 3.

Predicted and observed plasma concentration-time (C-T) profiles of nelfinavir in pregnant women throughout pregnancy for several studies. Observed (geometric) (Fang et al., 2012) and predicted steady-state plasma C-T profile of nelfinavir (1250 mg, twice daily by mouth) in (A) postpartum, (B) second trimester, and (C) third trimester women; observed (median) (Read et al., 2008) and predicted steady-state plasma C-T profile of nelfinavir (1250 mg, twice daily by mouth) in (D) postpartum, (E) second trimester, and (F) third trimester women; and observed (geometric mean) (Van Heeswijk et al., 2004) and predicted steady-state plasma C-T profile of nelfinavir (1250 mg, twice daily by mouth) in (G) postpartum and (H) third trimester women (second trimester data are not available). The observed data (open circles) fell within the 5th and 95th percentiles (dashed lines) of the predicted data (continuous black line). The predicted PK endpoints (AUC and C_max) also fell within 0.80- to 1.25-fold of the observed data (Table 4).

Fig. 4.

Predicted and observed plasma concentration-time (C-T) profile of efavirenz in pregnant women throughout pregnancy for several studies. Observed (median) (Kreitchmann et al., 2019) and predicted plasma C-T profile of efavirenz (600 mg, once daily by mouth) at steady state in (A) postpartum, (B) second trimester, and (C) third trimester, respectively; observed (geometric mean) (Lamorde et al., 2018) and predicted plasma C-T profile of efavirenz (400mg, once daily by mouth) at steady state in (D) postpartum and (E) third trimester (second trimester data are not available), respectively; and observed (median) (Cressey et al., 2012) and predicted plasma C-T profile of efavirenz (600 mg, once daily by mouth) in (F) postpartum and (G) third trimester (second trimester data are not available), respectively. The observed data (open circles) fell within the 5^th and 95^th percentiles (dashed lines) of the predicted data (continuous black line). The predicted PK endpoints (AUC and C_max) also fell within 0.80- to 1.25-fold of the observed data (Table 4).

Fig. 5.

Predicted and observed (pooled) steady-state (A, D, and G) maternal plasma (MP) concentration-time profiles; (B, E, and H) umbilical vein (UV) plasma concentration-time profiles; and (C, F, and I) UV/MP profiles of the drugs with (black line) or without (blue line) in vivo placental efflux clearance. (A–C) Nelfinavir (1250 mg, twice daily) was administered (by mouth, fed) for at least 15 days, followed by 1250 mg (by mouth, fasted) on the day of delivery, between 31 and 41 weeks of gestation (Hirt et al., 2007); (D–F) efavirenz (600 mg, once daily) was administered between 37 and 41 weeks of gestation (Cressey et al., 2012); and (G–I) imatinib (400 mg daily) was administered between 35 and 41 weeks of gestation (Chelysheva et al., 2018). The x-axis is the time between the last dose and delivery. Dashed lines represent the 5th and 95th percentiles of the predicted data in the presence of CL_{efflux,placenta}; open circles represent observed data. K_p,uu,fetal values for nelfinavir, efavirenz, and imatinib estimated from the UV/MP data were 0.41, 0.39, and 0.35, respectively.

Fig. 6.

Simulated steady-state (A and D) maternal plasma (MP) concentrations; (B and E) umbilical vein (UV) plasma concentrations; and (C and F) the UV/MP profiles of (A–C) nelfinavir or (D–F) efavirenz at varying gestational ages. Profiles were simulated after administration of (A–C) nelfinavir (1250 mg, twice daily in fed state for 15 days) and (D–F) efavirenz (600 mg, once daily for 15 days). K_p,uu,fetal values for nelfinavir were 0.41, 0.34, and 0.23 at GWs 38, 25, and 15, respectively. K_p,uu,fetal values for efavirenz were 0.39, 0.33, and 0.27 at GWs 39, 25, and 15, respectively.