Application of a Physiologically Based Pharmacokinetic Approach to Predict Theophylline Pharmacokinetics Using Virtual Non-Pregnant, Pregnant, Fetal, Breast-Feeding, and Neonatal Populations

Abstract

Perinatal pharmacology is influenced by a myriad of physiological variables that are changing dynamically. The influence of these covariates has not been assessed systemically. The objective of this work was to use theophylline as a model drug and to predict its pharmacokinetics before, during (including prediction of the umbilical cord level), and after pregnancy as well as in milk (after single and multiple doses) and in neonates using a physiological-based pharmacokinetic (PBPK) model. Neonatal theophylline exposure from milk consumption was projected in both normal term and preterm subjects. Predicted infant daily doses were calculated using theophylline average and maximum concentration in the milk as well as an estimate of milk consumption. Predicted concentrations and parameters from the PBPK model were compared to the observed data. PBPK predicted theophylline concentrations in non-pregnant and pregnant populations at different gestational weeks were within 2-fold of the observations and the observed concentrations fell within the 5th-95th prediction interval from the PBPK simulations. The PBPK model predicted an average cord-to-maternal plasma ratio of 1.0, which also agrees well with experimental observations. Predicted postpartum theophylline concentration profiles in milk were also in good agreement with observations with a predicted milk-to-plasma ratio of 0.68. For an infant of 2 kg consuming 150 ml of milk per day, the lactation model predicted a relative infant dose (RID) of 12 and 17% using predicted average (C_avg,ss) and maximum (C_max,ss) concentration in milk at steady state. The maximum RID of 17% corresponds to an absolute infant daily dose of 1.4 ± 0.5 mg/kg/day. This dose, when administered as 0.233 mg/kg every 4 h, to resemble breastfeeding frequency, resulted in plasma concentrations as high as 3.9 (1.9-6.8) mg/L and 2.8 (1.3-5.3) (5th-95th percentiles) on day 7 in preterm (32 GW) and full-term neonatal populations.

Keywords: PBPK model; breastfeeding; feto-placenta; infant dose; lactation; pregnancy; preterm; theophylline.

Figure 1

Workflow of the implemented perinatal theophylline physiological-based pharmacokinetic (PBPK) model. The neonatal model includes caffeine PBPK as a formed metabolite.

Figure 2

Plasma concentration profiles after intravenous infusion and oral administration in the non-pregnant population. Solid lines, predicted means; Dashed lines, 5th and 95th centiles; Circles, observed means. (A) Trial design NP1 (24), (B) Trial design NP2 (19), (C) Trial design NP3 (29), (D) Trial design NP4 (30), (E) Trial design NP5 (31), (F) Trial design NP6 (32), (G) Trial design NP7 (33), (H) Trial design NP8 (19), and (I1–I4) Trial design NP9 (34). See the Method section for trial settings.

Figure 3

Plasma concentration profiles after multiple oral administration in pregnant population during pregnancy and at delivery. Solid lines, predicted means; Dashed lines, 5th and 95th centiles; Circles, individual observations (open, maternal; filled, umbilical cord). Plots representing the following trials: (A) Trial design P1 (45), (B) Trial design P2 (45), (C) Trial design P3 (45), (L1) Trial design L1 (45) added here for comparison (see lactation section), (D1,D2) Trial design P4 (46), (E1–E3) Trial design P5 (47), and (F1–F3) Trial design P6 (48). See the Method section for trial settings.

Figure 4

Theophylline concentration profiles in maternal plasma (left) and the milk (right). Milk exposure was predicted using the average predicted M/P ratio from both lactation models (see Method section). Solid lines, predicted means; Dashed lines, 5th and 95th centiles; Circles, individual observations (open, maternal; filled, milk). (A1,A2) Trial design L1 (45), (B1,B2) Trial design L2 (51), and (C1,C2) Trial design L3 (52). See the Method section for trial settings.

Figure 5

Theophylline (and formed caffeine) concentration profiles in neonates after intravenous (A–C) and oral (D–H) administration of theophylline. Solid lines, predicted means; Dashed lines, 5th and 95th centiles; closed circles, individual observations; closed circles (D,E), mean; dashes associated with observations in (D) represent reported ranges, and bars [(E); till 12 h] represent SD. (A1,A2) Trial design N1 (28), (B) Trial design N2 (48), (C) Trial design N3 (57), (D) Trial design N4 (55), (E) Trial design N5 (58), (F1,F2) Trial design N6 (58) subject-Sch, (G1,G2) Trial design N6 (58) subject-C, and (H1,H2) Trial design N7 (27). See the Method section for trial settings.

Figure 6

Predicted mean (5th−95th percentiles) neonatal theophylline (and formed caffeine) concentration during the first 2 weeks of life with different gestational weeks. Predicted scenarios: The first three plots show, respectively, theophylline exposure in neonates at birth using a dosage of 30-min infusion of 5 mg/kg as a loading dose followed by 1 h-infusion of 1.1 mg/kg/12 h in 28 (A), 32 (B), and 38 (C) GWs according to a clinical study (28). Exposure after oral administration of the calculated theophylline infant dose using milk C_avg,ss are shown for 28 (D), 32 (E), and 38 (F) GW considering the cord level at birth as a baseline. Exposure after oral administration of the calculated theophylline infant dose using milk C_max,ss are shown for 28 (G), 32 (H), and 38 (I) GW considering the cord level at birth as a baseline. Exposure after oral administration of the calculated theophylline infant dose using milk C_max,ss are shown for 28 (J), 32 (K), and 38 (L) GW without considering the cord level at birth as a baseline. (A–D) Trial design N8, (D–F) Trial design N9, (G–I) Trial design N10, and plo (J–L) Trial design N11. See the Method section for trial settings. Dashed horizontal lines represent the theophylline therapeutic window for apnea. InfDs, infant dose predicted using the lactation model; GWs, gestational weeks; PNA, postnatal age. The lowest profiles in each plot represent the mean (5th−95th percentiles) for the formed caffeine.