Prediction of maternal pharmacokinetics using physiologically based pharmacokinetic models: assessing the impact of the longitudinal changes in the activity of CYP1A2, CYP2D6 and CYP3A4 enzymes during pregnancy

Abduljalil, Khaled; Pansari, Amita; Jamei, Masoud

doi:10.1007/s10928-020-09711-2

Cited by 36 publications

(56 citation statements)

References 64 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…13 Beyond inducer drugs, the regulation of P450 expression during pregnancy has also been the topic of numerous clinical studies and physiologically-based pharmacokinetic (PBPK) modelling exercises. [14][15][16] For instance, there are reports describing changes in CYP3A4 and CYP2D6 trait measures consistent with their induction during preganancy. 15,[17][18][19] To date, however, there are no reports describing tissue biopsy profiling of pregnant subjects.…”

mentioning

confidence: 99%

Exploring the Use of Serum‐Derived Small Extracellular Vesicles as Liquid Biopsy to Study the Induction of Hepatic Cytochromes P450 and Organic Anion Transporting Polypeptides

Rodrigues

Dyk

Sorich

et al. 2021

Clin Pharma and Therapeutics

124

View full text Add to dashboard Cite

Liver‐derived small extracellular vesicles (sEVs), prepared from small sets of banked serum samples using a novel two‐step protocol, were deployed as liquid biopsy to study the induction of cytochromes P450 (CYP3A4, CYP3A5, and CYP2D6) and organic anion transporting polypeptides (OATP1B1 and OATP1B3) during pregnancy (nonpregnant (T0), first, second, and third (T3) trimester women; N = 3 each) and after administration of rifampicin (RIF) to healthy male subjects. Proteomic analysis revealed induction (mean fold‐increase, 90% confidence interval) of sEV CYP3A4 after RIF 300 mg × 7 days (3.5, 95% CI = 2.5–4.5, N = 4, P = 0.029) and 600 mg × 14 days (3.7, 95% CI = 2.1–6.0, N = 5, P = 0.018) consistent with the mean oral midazolam area under the plasma concentration time curve (AUC) ratio in the same subjects (0.28, 95% CI = 0.22–0.34, P < 0.0001; and 0.17, 95% CI = 0.13–0.22, P < 0.0001). Compared with CYP3A4, liver sEV CYP3A5 protein (subjects genotyped CYP3A5*1/*3) was weakly induced (≤ 1.5‐fold). It was also possible to measure liver sEV‐catalyzed dextromethorphan (DEX) O‐demethylation to dextrorphan (DXO), correlated with sEV CYP2D6 expression (r = 0.917, P = 0.0001; N = 10) and 3‐hour plasma DXO‐to‐DEX concentration ratio (r = 0.843, P = 0.002, N = 10), and show that CYP2D6 was not induced by RIF. Nonparametric analysis of liver sEV revealed significantly higher CYP3A4 (3.2‐fold, P = 0.003) and CYP2D6 (3.7‐fold, P = 0.03) protein expression in T3 vs. T0 women. In contrast, expression of both OATPs in liver sEV was unaltered by RIF administration and pregnancy.

show abstract

mentioning

confidence: 99%

Exploring the Use of Serum‐Derived Small Extracellular Vesicles as Liquid Biopsy to Study the Induction of Hepatic Cytochromes P450 and Organic Anion Transporting Polypeptides

Rodrigues

Dyk

Sorich

et al. 2021

Clin Pharma and Therapeutics

124

View full text Add to dashboard Cite

show abstract

“…Despite the high prevalence of drug use in pregnancy (~80% of pregnant women using at least one drug (Scaffidi et al, 2017)), 90% of drugs on the market still lack guidance on their administration in this population, leaving both mother and her fetus "drug orphans". Although we have some understanding of maternal drug exposure (and changes therein) during pregnancy (Abduljalil, Furness, Johnson, Rostami-Hodjegan, & Soltani, 2012;Abduljalil, Pansari, & Jamei, 2020;Anderson, 2005;Hebert et al, 2008), this is not the case for fetal drug exposure which is related to fetal drug efficacy and toxicity. This study is the first to address this significant gap in health care knowledge, that is development of a method to successfully predict fetal exposure to drugs irrespective of whether they are transported or not.…”

Section: B-d 3 B-d)mentioning

confidence: 99%

Successful Prediction of Human Fetal Exposure to P-Glycoprotein Substrate Drugs Using the Proteomics-Informed Relative Expression Factor Approach and PBPK Modeling and Simulation

2021

View full text Add to dashboard Cite

5 th percentile: 5 th percentile confidence value; 95 th percentile: 95 th percentile confidence value; AAFE: absolute average fold error; AUC f : area under the curve of total fetal plasma concentration-time profile; AUC m : area under the curve of total maternal plasma concentration-time profile; BCRP: breast cancer resistance protein; BID: Bis in die, twice daily; CI 90% : 90% confidence interval spanning between 5th and 95th percentiles; CL int,PD,placenta : intrinsic placental passive diffusion clearance; CL int,Pgp,placenta : In vivo P-gp mediated efflux clearance from the placenta; C max : maximum plasma drug concentration; C-T profile: drug plasma concentration-time profile; CYP: cytochrome P450; DEX: dexamethasone; DRV: darunavir; ER: This article has not been copyedited and formatted. The final version may differ from this version.

show abstract

“…Pharmacokinetics (PK) are typically influenced by a variety of physiological variables and also can be altered in different pathological states ( 1 , 2 ). During the perinatal period, drug PK can be affected by a variety of time-varying physiological parameters in the mother and the unborn fetus ( 3 ). Immediately after birth few physiological parameters are reverting to the pre-pregnancy status and can affect the maternal drug exposure ( 4 ).…”

Section: Introductionmentioning

confidence: 99%

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

2022

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Prediction of maternal pharmacokinetics using physiologically based pharmacokinetic models: assessing the impact of the longitudinal changes in the activity of CYP1A2, CYP2D6 and CYP3A4 enzymes during pregnancy

Cited by 36 publications

References 64 publications

Exploring the Use of Serum‐Derived Small Extracellular Vesicles as Liquid Biopsy to Study the Induction of Hepatic Cytochromes P450 and Organic Anion Transporting Polypeptides

Exploring the Use of Serum‐Derived Small Extracellular Vesicles as Liquid Biopsy to Study the Induction of Hepatic Cytochromes P450 and Organic Anion Transporting Polypeptides

Successful Prediction of Human Fetal Exposure to P-Glycoprotein Substrate Drugs Using the Proteomics-Informed Relative Expression Factor Approach and PBPK Modeling and Simulation

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

Contact Info

Product

Resources

About