Risk to the Breast-Fed Neonate From Codeine Treatment to the Mother: A Quantitative Mechanistic Modeling Study

Abstract

Administering codeine to breast-feeding mothers had been considered safe until the recent death of a breast-fed neonate whose mother had been prescribed codeine. We investigated the risk of opioid poisoning to breast-fed neonates using coupled physiologically based pharmacokinetic models for the mother and child. Neonatal morphine plasma concentrations were simulated for various combinations of cytochrome P450 2D6 (CYP2D6) genotype and morphine clearance, assuming typical breast-feeding schedules and maternal codeine doses of <or=2.5 mg/kg/day. The simulations demonstrated that the mother's codeine and morphine clearances and the neonate's morphine clearance are the most critical determinants of morphine accumulation in the neonate. The cumulative doses ingested by the neonate over 14 days were 0.38 mg/kg codeine and 0.17 mg/kg morphine. Given the added effect of low neonatal elimination capacity for morphine, potentially toxic morphine plasma concentrations can be reached within 4 days in the neonate after repeated codeine dosing to the mother. Importantly, neonates of mothers with the ultrarapid CYP2D6 genotype and neonates of mothers who are extensive metabolizers have comparable risks of opioid poisoning.

Medication Use in Pregnancy; Treating the Mother: Protecting the Unborn

“…Codeine in Breastfeeding Maternal treatment by oral opioids during breastfeeding can cause central nervous system depression and even death in the neonate, with mothers who are ultra rapid metabolizers of CYP 2D6 at higher risk (Willmann et al 2009;Nauta et al 2009). Newborn infants appear to be especially sensitive to the effects of even modest doses of narcotic analgesics.…”

Prediction of a potentially effective dose in humans for BAY 60–5521, a potent inhibitor of cholesteryl ester transfer protein (CETP) by allometric species scaling and combined pharmacodynamic and physiologically‐based pharmacokinetic modelling

“…PK-Sim® is part of a larger SystemsBiology software platform. PK-Sim® has been able to predict and simulate the pharmacokinetic behaviour of a variety of structurally different drugs [23][24][25][26][27][28][29][30][31][32]. A description of the PBPK model structure implemented in PK-Sim® has been described elsewhere [33].…”

“…It is well documented that PK-Sim® is able to predict and simulate the pharmacokinetic behaviour of a variety of structurally different drugs [28][29][30][31][32][33][34][35][36][37]. The PBPK model behind PK-Sim® describes 17 organs plus several other containers (arterial and venous blood pool, portal vein, bile, urine, etc), each organ consisting of three to four subcompartments, leading to a total number of >70 compartments that are pre-parameterized according to their physiology [38,39].…”

Pharmacogenetics and Obstetric Anesthesia and Analgesia

“…In light of these findings, it has been suggested that codeine be avoided in breastfeeding mothers with a CYP2D6 extensive or ultra-rapid metabolism genotype. Reports followed that studied the rates of codeine and morphine clearance in breastfeeding mothers and their relation to CYP2D6 genotypes [56][57][58] . Other life-threatening adverse events have been reported in individuals who are CYP2D6 ultra-rapid metabolizers 59,60 .…”