An Application of a Physiologically Based Pharmacokinetic Approach to Predict Ceftazidime Pharmacokinetics in a Pregnant Population.

Physiological changes during pregnancy can alter maternal and fetal drug exposure. The objective of this work was to predict maternal and umbilical ceftazidime pharmacokinetics during pregnancy. Ceftazidime transplacental permeability was predicted from its physicochemical properties and incorporated into the model. Predicted concentrations and parameters from the PBPK model were compared to the observed data. PBPK predicted ceftazidime concentrations in non-pregnant and pregnant subjects of 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 calculated transplacental clearance (0.00137 L/h/mL of placenta volume) predicted an average umbilical cord-to-maternal plasma ratio of 0.7 after the first dose, increasing to about 1.0 at a steady state, which also agrees well with clinical observations. The developed maternal PBPK model adequately predicted the observed exposure and kinetics of ceftazidime in the pregnant population. Using a verified population-based PBPK model provides valuable insights into the disposition of drug concentrations in special individuals that are otherwise difficult to study and, in addition, offers the possibility of supplementing sparse samples obtained in vulnerable populations with additional knowledge, informing the dosing adjustment and study design, and improving the efficacy and safety of drugs in target populations.

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

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 (Cavg,ss) and maximum (Cmax,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.

Placental weight centiles adjusted for age, parity and fetal sex.

INTRODUCTION: The weight of the placenta can be indicative of efficacy in nutrient and oxygen supply. Furthermore, it has been suggested that a measure of the placenta's ability to adequately supply nutrients to the fetus can be found in the relationship between birth weight and placental weight expressed as a ratio. Our aim was to develop age adjusted placenta weight and birth weight to placenta weight ratio reference curves that are stratified by maternal parity and fetal sex. METHODS: We included singleton, non-anomalous births with a gestational age inclusive of 28 + 0 weeks to 42 + 6 weeks. Excluded were pregnancies of multiplicity, fetuses with congenital abnormalities, stillbirths and pregnancies that had placental complications (ie placenta previa or abruption). Generalised additive model for location, shape and scale (GAMLSS) was used to fit reference curves. RESULTS: We stratified 97,882 pregnancies by maternal nulliparity status and fetal sex. Extensive assessment model goodness-of-fit showed appropriate modeling and accurate fit to the four parameters of distribution. Our results show accurate model fit of the reference curves to the data. We demonstrated that the influence that parity has on the placenta weight is far greater than that exerted by fetal sex, and that the difference is dependent on gestational age. DISCUSSION: This is the largest presentation of age and parity adjusted placenta weight and feto-placental weight ratio reference ranges to date. The difference observed between nulliparous and multiparous pregnancies could be explained by biological memory and the remnants of maternal endo-myometrial vascularity after the first pregnancy.