College of Medicine and Public Health, Flinders University, Flinders Medical Centre, Bedford Park, Adelaide, SA, 5042, Australia.
ADME Sciences, Medicine Design, Pfizer Worldwide Research & Development, Groton, CT, USA.
AAPS J. 2021 Jan 6;23(1):15. doi: 10.1208/s12248-020-00541-1.
Guidance regarding the effect of codeine and its metabolites on foetal development is limited by small studies and inconsistent findings. The primary objective was to use physiologically based pharmacokinetic modelling to investigate the impact of gestational stage and maternal CYP2D6 phenotype on foetal morphine exposure following codeine administration. Full body physiologically based pharmacokinetic models were developed and verified for codeine and morphine using Simcyp (version 19.1). The impact of gestational age and maternal CYP2D6 phenotype on foetal and maternal morphine and codeine exposure following oral codeine administration was modelled in a cohort of 250 pregnant females and foetuses at gestational weeks 0 (mothers only), 6, 12, 24 and 36. Consistent with the known effect on codeine metabolism, a clinically meaningful (> 1.65-fold) increase in foetal morphine AUC was observed in the CYP2D6 UM phenotype cohort compared to the CYP2D6 EM and PM phenotype cohorts. The mean (95% CI) foetal morphine AUC in the CYP2D6 UM cohort of 0.988 (0.902 to 1.073) ng/mL.h was 1.8-fold higher than the CYP2D6 EM cohort of 0.546 (0.492 to 0.600) ng/mL.h (p < 0.001). Despite a 2.8-fold increase in maternal CYP2D6 protein abundance between gestational weeks 6 and 36, the mean foetal morphine AUC in the CYP2D6 EM and UM phenotype cohorts reduced by 1.55- and 1.75-fold, respectively, over this period. Maternal CYP2D6 phenotype is a significant determinant of foetal morphine AUC. Simulations suggest that the greatest risk with respect to foetal morphine exposure is during the first trimester of pregnancy, particularly in CYP2D6 UM phenotype mothers.
关于可待因及其代谢物对胎儿发育影响的指导意见受到小型研究和不一致发现的限制。主要目的是使用基于生理的药代动力学模型来研究母体 CYP2D6 表型和妊娠阶段对可待因给药后胎儿吗啡暴露的影响。使用 Simcyp（版本 19.1）为可待因和吗啡开发并验证了全身基于生理的药代动力学模型。在 250 名孕妇和胎儿的队列中，对口服可待因给药后，妊娠周 0（仅母亲）、6、12、24 和 36 时胎儿和母亲的吗啡和可待因暴露情况进行了基于生理的药代动力学模型研究。与可待因代谢的已知作用一致，与 CYP2D6 EM 和 PM 表型队列相比，CYP2D6 UM 表型队列的胎儿吗啡 AUC 增加了一个有临床意义的（>1.65 倍）。CYP2D6 UM 队列中胎儿吗啡 AUC 的平均值（95%CI）为 0.988（0.902 至 1.073）ng/mL.h，是 CYP2D6 EM 队列的 1.8 倍，后者为 0.546（0.492 至 0.600）ng/mL.h（p<0.001）。尽管在妊娠第 6 周至第 36 周期间，母体 CYP2D6 蛋白丰度增加了 2.8 倍，但在 CYP2D6 EM 和 UM 表型队列中，胎儿吗啡 AUC 的平均值分别减少了 1.55 倍和 1.75 倍。母体 CYP2D6 表型是胎儿吗啡 AUC 的重要决定因素。模拟表明，在妊娠早期（尤其是 CYP2D6 UM 表型母亲），胎儿吗啡暴露的风险最大。
