Development of a Novel Maternal-Fetal Physiologically Based Pharmacokinetic Model I: Insights into Factors that Determine Fetal Drug Exposure through Simulations and Sensitivity Analyses

Abstract

Determining fetal drug exposure (except at the time of birth) is not possible for both logistical and ethical reasons. Therefore, we developed a novel maternal-fetal physiologically based pharmacokinetic (m-f-PBPK) model to predict fetal exposure to drugs and populated this model with gestational age-dependent changes in maternal-fetal physiology. Then, we used this m-f-PBPK to: 1) perform a series of sensitivity analyses to quantitatively demonstrate the impact of fetoplacental metabolism and placental transport on fetal drug exposure for various drug-dosing regimens administered to the mother; 2) predict the impact of gestational age on fetal drug exposure; and 3) demonstrate that a single umbilical venous (UV)/maternal plasma (MP) ratio (even after multiple-dose oral administration to steady state) does not necessarily reflect fetal drug exposure. In addition, we verified the implementation of this m-f-PBPK model by comparing the predicted UV/MP and fetal/MP AUC ratios with those predicted at steady state after an intravenous infusion. Our simulations yielded novel insights into the quantitative contribution of fetoplacental metabolism and/or placental transport on gestational age-dependent fetal drug exposure. Through sensitivity analyses, we demonstrated that the UV/MP ratio does not measure the extent of fetal drug exposure unless obtained at steady state after an intravenous infusion or when there is little or no fluctuation in MP drug concentrations after multiple-dose oral administration. The proposed m-f-PBPK model can be used to predict fetal exposure to drugs across gestational ages and therefore provide the necessary information to assess the risk of drug toxicity to the fetus.

Fig. 1.

Schematic diagram of the full m-f-PBPK model. Solid arrows indicate tissue blood flows, whereas dashed arrows indicate clearances. f/F, fetal; PD, passive diffusion; M, maternal; P, placental; A, amniotic fluid; met, metabolism; renal, renal excretion; reabsorp, amniotic fluid swallowing. CL_PF/FP and CL_PM/MP represent unidirectional transporter-mediated clearances.

Fig. 2.

Impact of changes in CL_m0 on fetal and maternal drug X plasma concentration and UV/MP ratio. Changes in CL_m0 of drug X significantly influenced maternal-fetal drug X plasma C-T profiles at week 40. (a) After infusion (16.7 mg/h, i.v.) at week 40, decreasing CL_m0 from 45 l/h (red) to 4.5 l/h (blue) increased the steady-state maternal (solid lines) and fetal (dashed lines) plasma concentration of drug X as well as the time to reach steady state. Inset shows the curves on a semilogarithmic scale. (b) The corresponding UV/MP ratios indicate that at steady state_inf these ratios do not change with changes in CL_m0 (45 l/h, red; 4.5 l/h, blue). (c) After a single oral dose (400 mg), increasing CL_m0 from 4.5 l/h (blue) to 45 l/h (red) resulted in lower MP drug concentrations (solid lines) and subsequently lower fetal plasma drug X concentrations (dashed lines). (d) Corresponding changes in UV/MP ratio indicate that higher CL_m0 (red) led to greater time-dependent fluctuations in the UV/MP ratio as well as a lager UV/MP ratio at distributional equilibrium. (e) Under a multiple oral dosing regimen (133.3 mg; τ = 8 hours) lower CL_m0 (blue) not only prolonged the time to reach steady state but also resulted in greater extent of drug accumulation. (f) In addition, lower CL_m0 (blue) led to fewer fluctuations in UV/MP ratio within a dosing interval compared with higher CL_m0 (red). When the dosing interval was increased (400 mg; τ = 24 hours), the effect of reduction in CL_m0 on drug accumulation (g) or variation in UV/MP ratio (h) was dampened. In panels (e) and (g), the predicted F/M AUC ratio remained at unity despite the changes in CL_m0. See Table 3 for the clearance values used in these simulations.

Fig. 3.

Impact of changes in CL_m0 on fetal and maternal drug Y plasma concentration and UV/MP ratio. Changes in CL_m0 of drug Y significantly influenced maternal-fetal drug Y plasma C-T profiles at week 40. After infusion (0.625 mg/h, i.v.) at week 40, a 10-fold decrease in maternal hepatic intrinsic clearance (from 3327 to 332.7 l/h) resulted in a decrease in CL_m0 from 43 l/h (red) to 12 l/h (blue). (a) The resultant steady-state_inf maternal (solid lines) and fetal (dashed lines) plasma concentration of drug Y as well as the time to reach steady state increased. (b) The corresponding UV/MP ratios indicate that at steady state_inf these ratios stay at 1.2 and do not change with varying CL_m0 values (43 l/h, red; 12 l/h, blue). (c) After a single oral dose (15 mg), increasing CL_m0 from 12 l/h (blue) to 43 l/h (red) resulted in lower MP drug concentrations (solid lines) and subsequently lower fetal plasma drug X concentrations (dashed lines). (d) Corresponding changes in UV/MP ratio indicate that higher CL_m0 (red) led to greater fluctuations in the UV/MP ratio as well as a larger UV/MP ratio at distributional equilibrium. (e) After multiple oral doses (3.75 mg; τ = 4 hours), lower CL_m0 (blue) not only prolonged the time to reach steady state but also resulted in much greater drug accumulation. (f) In addition, lower CL_m0 values (blue) led to fewer fluctuations in UV/MP ratio (within a dosing interval) when compared with higher CL_m0 values (red). When the dosing interval was increased (15 mg; τ = 24 hours), the effect of reduction in CL_m0 on dose accumulation (g) or variations in UV/MP ratio (h) was dampened. The inset shows the curves on a semilogarithmic scale. In panels (e) and (g), the predicted unbound F/M AUC ratio remained at unity despite the changes in CL_m0. See Table 4 for the clearance values used in these simulations.

Fig. 4.

Impact of changes in CL_PD on fetal and maternal drug X plasma concentration and UV/MP ratio. Changes in CL_PD of drug X significantly influenced the fetal (dashed lines) but not the maternal (solid lines) drug X plasma C-T profile at week 40. (a) After infusion (16.7 mg/h, i.v.) at week 40, decreasing CL_PD from 18 l/h (red) to 1.8 l/h (blue) did not affect the maternal (the red and blue solid lines overlap) or fetal steady-state_inf plasma concentrations of the drug. (a and b) The corresponding UV/MP ratios indicate that at steady state_inf these ratios do not change with alterations in CL_PD (18 l/h, red; 1.8 l/h, blue), but the time to reach the steady-state ratio was prolonged. (c) After a single oral dose (400 mg), increasing CL_PD from 1.8 l/h (blue) to 18 l/h (red) significantly modified the shape of fetal plasma C-T curves (dashed lines) but not MP drug concentrations (solid lines; blue and red lines overlap). (d) Corresponding changes in UV/MP ratio indicate that higher CL_PD values (red) not only shortened the time to reach distributional equilibrium but also reduced distributional equilibrium UV/MP ratio compared with lower CL_PD (blue). After multiple oral doses (400 mg; τ = 24 hours), alterations in CL_PD did not affect the MP drug X C-T curve but significantly changed the shape of fetal plasmas in the drug X C-T profile. (e) Higher CL_PD values (red) resulted in greater fluctuations in fetal plasma drug X concentration within a dosing interval compared with lower CL_PD values (blue). (f) In contrast, higher CL_PD (red) produced fewer fluctuations in UV/MP ratio within a dosing interval compared with lower CL_PD (blue). Insets in (d) and (f) show the F/M AUC ratios at lower CL_PD (blue) or higher CL_PD (red). The predicted F/M AUC ratio remained at unity despite changes in CL_PD after single (c) or multiple (e) oral doses of drug X. See Table 3 for the clearance values used in these simulations.

Fig. 5.

Impact of changes in CL_PD on fetal and maternal drug Y plasma concentration and UV/MP ratio. Changes in CL_PD of drug Y significantly influenced drug Y fetal (dashed lines), but not maternal (solid lines), plasma C-T profile at week 40. (a) After infusion (0.625 mg/h, i.v.) at week 40, decreasing CL_PD values from 22.5 l/h (red) to 2.25 l/h (blue) did not affect the maternal (the red and blue solid lines overlap) or fetal steady state_inf plasma concentration of the drug. (b) The corresponding UV/MP ratios indicate that at steady-state_inf these ratios do not change with alterations in CL_PD (22.5 l/h, red; 2.25 l/h, blue), but the time to reach the steady-state ratio was prolonged. (c) After a single oral dose (15 mg), decreasing CL_PD from 22.5 l/h (red) to 2.25 l/h (blue) significantly modified the shape of fetal plasma C-T curve (dashed lines) but not MP drug concentrations (solid lines; blue and red lines overlap). (d) Corresponding changes in UV/MP ratio indicate that higher CL_PD values (red) not only shortened the time to reach distributional equilibrium but also reduced distributional equilibrium UV/MP ratio compared with lower CL_PD (blue). Under a multiple oral dosing regimen (15 mg; τ = 24 hours), alterations in CL_PD values did not affect the MP drug Y C-T curve but significantly changed the shape of the fetal plasma drug Y C-T profile. (e) Higher CL_PD values (red) resulted in greater fluctuations in fetal plasma drug Y concentration within a dosing interval compared with lower CL_PD values (blue). (f) In contrast, higher CL_PD values (red) produced fewer fluctuations in UV/MP ratio within a dosing interval compared with lower CL_PD values (blue) as transplacental distributional equilibirum of drug Y was quickly attained after an oral dose. Insets in (d) and (f) show the unbound F/M AUC ratios at lower CL_PD (blue) or higher CL_PD (red). The predicted unbound F/M AUC ratio remained at unity despite changes in CL_PD after single (c) or multiple (e) oral doses of drug Y. See Table 4 for the clearance values used in these simulations.

Fig. 6.

Impact of changes in feto-placental metabolism and placental transport on fetal plasma and placental drug X concentration, P/M AUC, F/M AUC, and UV/MP ratios after a single 400-mg oral dose of drug X. Changes in fetoplacental clearance pathways differentially impacted fetal exposure to drug X, P/M plasma AUC ratio (hatched bar), F/M plasma AUC ratio (solid bar), and the UV/MP ratio after a single 400-mg oral dose of drug X at week 40. The CL_PD of drug X was held at 1.8 l/h. The clearance pathway variance is indicated at the extreme left of the first panel of each row. The indicated clearance was set at 0, 0.18, 0.9, or 1.8 l/h, respectively (0%, 10%, 50%, or 100% of CL_PD; black, red, green, and blue lines, respectively). Other than CL_MP (d1), increasing any of the indicated clearance pathways resulted in lower fetal plasma drug X concentrations (a1–c1 and e1). When CL_f0 was present, the resultant F/M plasma AUC ratio was lower (b2 and c2) than when only CL_P0 was present (a2). In all cases, the predicted UV/MP ratio at distributional equilibrium was significantly greater than its steady-state_inf value (Supplemental eq. 1). The UV/MP ratio at distributional equilibrium decreased with an increase in CL_p0, CL_f0,CL_f0 plus CL_p0, or CL_PM (a3, b3, c3, and e3, respectively) and increased with an increase in CL_MP (d3). See Table 3 for the clearance values used in these simulations.

Fig. 7.

Impact of changes in fetoplacental metabolism and placental transport on fetal plasma and placental drug Y concentrations, and P/M AUC, F/M AUC, and UV/MP ratios after a single 15-mg oral dose of drug Y. Changes in fetoplacental clearance pathways differentially impacted fetal exposure to drug Y, P/M plasma unbound AUC ratio (hatched bar), F/M plasma unbound AUC ratio (solid bar), and the UV/MP ratio after a single 15-mg oral dose of drug Y at week 40. The CL_PD of drug Y was held at 22.5 l/h. The clearance pathway varied is indicated at the extreme left of the first panel of each row. The indicated clearance was set at 0, 2.25, 11.3, or 22.5 l/h, respectively (0%, 10%, 50%, or 100% of CL_PD; black, red, green, and blue lines, respectively). Other than CL_MP (d1), increasing any of the indicated clearance pathways resulted in lower fetal plasma drug X concentrations (a1–c1 and e1). When CL_f0 was present, the F/M plasma unbound AUC ratio was lower (b2 and c2) than when only CL_P0 was present (a2). In all cases, the predicted UV/MP ratio at distributional equilibrium was greater than its expected steady-state_inf value (Supplemental eq. 1). The UV/MP ratio at distributional equilibrium decreased with an increase in CL_p0, CL_f0, CL_f0 plus CL_p0, or CL_PM (a3, b3, c3, and e3, respectively) and increased with an increase in CL_MP (d3). See Table 4 for the clearance values used in these simulations.

Fig. 8.

Impact of GA on maternal and fetal drug X plasma concentration and F/M AUC ratio after a single 400-mg oral dose of drug X at week 20 (red) or week 40 (blue). The effect of GA on fetal exposure to drug X varies with fetoplacental clearance mechanisms involved. Maternal (solid) and fetal (dashed) C-T profiles as well as F/M plasma AUC ratios were simulated after a single 400 mg oral dose of drug X at week 20 (red) and week 40 (blue) under different scenarios. In scenario 1, where no irreversible loss of drug X occurred in the fetoplacental unit, the advancement of GA did not significantly affect fetal-maternal drug disposition (a) or the F/M plasma AUC ratio of unity (b). In scenario 2, the addition of fetal metabolism (increased proportionally with the fetal body volume as GA increased) significantly reduced fetal plasma drug concentrations (c versus a) and resulted in an ∼50% decrease in F/M AUC plasma ratio at both GAs (d). In scenario 3, placental P-gp efflux clearance decreased with GA (based on reported P-gp expression and changes in placental volume with GA). Consequently, fetal exposure to drug X increased with GA, reflected by higher fetal plasma drug concentrations (e) and increased F/M plasma AUC ratios (f). Finally, in scenario 4, where both fetal metabolism and placental efflux were present, a further reduction in fetal exposure was observed at both GAs (g and h). See Table 3 and Table 5 for the clearance values used in these simulations.

Fig. 9.

Impact of GA on maternal and fetal drug Y plasma concentration and F/M AUC ratio after a single 15-mg oral dose of drug Y at week 20 (red) and week 40 (blue). The effect of GA on fetal exposure to drug Y varies with the fetoplacental clearance mechanisms involved. Maternal (solid) and fetal (dashed) C-T profiles, maternal (solid) and fetal (hatched) plasma AUCs, as well as F/M [total (solid) and unbound (hatched)] AUC ratios were simulated after a single 15-mg oral dose of drug Y at week 20 (red) and week 40 (blue) under different scenarios. In scenario 1, where no irreversible loss of drug Y occurred in the fetoplacental unit under a constant maternal hepatic unbound intrinsic clearance (CL_int,u,hep), the advancement of GA resulted in an increased fetal plasma AUC despite the decrease in MP AUC (a and b) but did not affect the F/M plasma AUC unbound ratio of unity (c). In scenario 2, the assumed 100% higher CL_int,u,hep at week 40 compared with week 20 significantly decreased maternal-fetal plasma drug Y concentrations (hence, AUCs) at term (d versus a; e versus b), whereas F/M AUC plasma ratios at both GAs were identical to those in scenario 1 (f versus c). In scenario 3, placental P-gp–mediated efflux clearance decreased with GA. Consequently, fetal exposure to drug Y increased with GA, which is reflected by higher fetal plasma drug concentrations (g) and increased F/M plasma AUC ratios (i). Finally, in scenario 4, the increase in fetal exposure from week 20 to week 40 persisted in the presence of both a decrease in placental efflux and an increase in CL_m0 with GA, but to a smaller extent compared with scenario 3 (k versus h). Note that F/M AUC plasma ratios at both GAs were identical to those in scenario 3 (l versus i). See Table 4 and Table 5 for the clearance values used in these simulations.