Physiologically Based Pharmacokinetic Models to Predict Maternal Pharmacokinetics and Fetal Exposure to Emtricitabine and Acyclovir

Abstract

Pregnancy is associated with physiological changes that may impact drug pharmacokinetics (PK). The goals of this study were to build maternal-fetal physiologically based pharmacokinetic (PBPK) models for acyclovir and emtricitabine, 2 anti(retro)viral drugs with active renal net secretion, and to (1) evaluate the predicted maternal PK at different stages of pregnancy; (2) predict the changes in PK target parameters following the current dosing regimen of these drugs throughout pregnancy; (3) evaluate the predicted concentrations of these drugs in the umbilical vein at delivery; (4) compare the model performance for predicting maternal PK of emtricitabine in the third trimester with that of previously published PBPK models; and (5) compare different previously published approaches for estimating the placental permeability of these 2 drugs. Results showed that the pregnancy PBPK model for acyclovir predicted all maternal concentrations within a 2-fold error range, whereas the model for emtricitabine predicted 79% of the maternal concentrations values within that range. Extrapolation of these models to earlier stages of pregnancy indicated that the change in the median PK target parameters remained well above the target threshold. Concentrations of acyclovir and emtricitabine in the umbilical vein were overall adequately predicted. The comparison of different emtricitabine PBPK models suggested an overall similar predictive performance in the third trimester, but the comparison of different approaches for estimating placental drug permeability revealed large differences. These models can enhance the understanding of the PK behavior of renally excreted drugs, which may ultimately inform pharmacotherapeutic decision making in pregnant women and their fetuses.

Keywords: PBPK modeling; acyclovir; drug development; emtricitabine; pregnancy.

Conflict of interest statement

Conflicts of Interest

The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Dr André Dallmann is an employee of Bayer AG, a company that is part of the Open Systems Pharmacology (OSP) member team and involved in OSP software development. The results from this study were presented in part at the American College of Clinical Pharmacology Annual Meeting, Washington, DC, September 2018.

© 2019, The American College of Clinical Pharmacology.

Figures

Figure 1.

Pregnancy PBPK model structure. Thick arrows represent drug transport via blood flow, and thin arrows via other pathways (eg, via passage in the gastrointestinal tract, biliary excretion through the gallbladder, and diffusive transfer in the placenta). Compartments that are exclusively part of the pregnancy PBPK model structure are shown in italics with dashed borders and dashed arrows for drug transfer via the blood flow.

Figure 2.

Goodness-of-fit plot for plasma concentrations of acyclovir (upper panels) and emtricitabine (lower panels) in nonpregnant subjects (left panels) and pregnant women (right panels). The solid line represents the line of identity, and the dotted lines the 2-fold error range. Upper left panel: Acyclovir plasma concentrations in nonpregnant subjects; black circles indicate concentrations for the suspension, and gray circles indicate concentrations in steady state for the suspension. Upper right panel: Acyclovir plasma concentrations in pregnant women,; black circles indicate concentrations after a single dose, and gray circles indicate concentrations in steady state., Lower left panel: Emtricitabine plasma concentrations in nonpregnant subjects; black circles indicate the concentrations after a single dose, gray circles indicate concentrations at steady state, gray squares indicate concentrations after a single dose, black squares indicate concentrations after a single dose, and black triangles indicate concentrations at steady state. Lower right panel: Emtricitabine plasma concentrations in pregnant women; black circles indicate concentrations in women at gestational age 23–30 weeks, gray circles indicate concentrations in women at gestational age 31–35 weeks, and black squares indicate concentrations in women at gestational age 36–42 weeks.

Figure 3.

Plasma concentration-time profiles of acyclovir following oral administration of 400 mg in pregnant women. Semi-log scale figures are given as inset figures in the top right corners. Observed in vivo data were taken from published studies.–A, Single dose in pregnant women with an average gestational age of 36 weeks. Empty circles represent individual concentrations taken from Frenkel et al, and closed circles represent mean concentrations in the maternal plasma taken from Kimberlin et al; the solid line represents the predicted mean concentration, and the shaded area the predicted 5th to 95th percentile range. B, Multiple doses in steady state in pregnant women with an average gestational age of 38 weeks. Empty circles represent individual concentrations taken from Frenkel et al, and closed circles represent mean concentrations in the maternal plasma taken from Kimberlin et al; the solid line represents the predicted mean concentration, and the shaded area the predicted 5th to 95th percentile range. C, Multiple doses in steady state in pregnant women with an average gestational age of 40 weeks. Empty circles represent individual concentration data in the maternal plasma, and closed circles individual concentration data in the umbilical vein taken from Leung et al; the solid and dashed lines represent the predicted mean concentration in the maternal plasma and umbilical vein, respectively, and the shaded areas the predicted 5th to 95th percentile ranges.

Figure 4.

Plasma concentration-time profiles of emtricitabine following oral administration of 200 mg in pregnant women in steady state. Semi-log scale figures are given as inset figures in the top right corners. Observed in vivo data were taken from the described clinical study and from another study published in the literature.A, Pregnant women with a gestational age of 23–30 weeks; empty circles represent individual concentrations, and closed circles the geometric concentrations in the maternal plasma; the green line represents the predicted geometric mean concentration, and the shaded area the predicted 5th to 95th percentile range. B, Pregnant women with a gestational age of 31–35 weeks; empty circles represent individual concentrations, and closed circles the geometric concentrations in the maternal plasma; the green line represents the predicted geometric mean concentration, and the shaded area the predicted 5th to 95th percentile range. C, Pregnant women with a gestational age of 36–42 weeks; empty circles represent individual concentrations, and closed circles the geometric concentrations in the maternal plasma; the green line represents the predicted geometric mean concentration, and the shaded area the predicted 5th to 95th percentile range. D, Empty circles represent individual concentration data in the maternal plasma, and gray circles individual concentration data in the umbilical vein; the solid and dashed lines represent the predicted mean concentration in the maternal plasma and umbilical vein, respectively, and the shaded areas the predicted 5th to 95th percentile ranges.

Figure 5.

Predicted changes in PK target parameters of acyclovir (upper panels) and emtricitabine (lower panels) during pregnancy. A, The dashed line represents the reported half-maximal inhibitory concentration (IC50), the solid line the predicted median trough level (Cmin), and the shaded area the predicted 5th to 95th percentile range. B, The dashed line represents the reported average exposure (AUC) in nonpregnant subjects,,– the solid line the predicted AUC, and the shaded area the predicted 5th to 95th percentile range. C, The upper and lower dashed lines represent the reported IC50 and 90% of maximal inhibitory concentration (IC90), respectively, the solid line the predicted Cmin, and the shaded area the predicted 5th to 95th percentile range. D, The dashed line represents the reported target AUC in pregnant subjects,, the solid line the predicted AUC, and the shaded area the predicted 5th to 95th percentile range. ACV indicates acyclovir; AUC, area under the concentration-time curve; Cmin, trough drug concentration; FTC, emtricitabine; GA, gestational age; IC50, drug concentration that produced 50% inhibition; PK, pharmacokinetics.

Figure 6.

Emtricitabine plasma concentration-time profile in pregnant women around gestational week 33 following oral administration of 200 mg in steady state. Empty circles indicate individual observed plasma concentration data obtained from the publication of Mendes et al, black circles indicate the mean values of these data; the dashed line indicates mean plasma concentrations predicted by Mendes et al, the dotted line indicates mean plasma concentrations predicted by Xia et al, and the solid line indicates mean plasma concentrations predicted by the model presented here. Data from Mendes et al and Xia et al were extracted from the published figures.