Influence of OCT 1 Ontogeny and Genetic Variation on Morphine Disposition in Critically Ill Neonates: Lessons From PBPK Modeling and Clinical Study

Morphine is commonly used for analgesia in the neonatal intensive care unit ( NICU ) despite having highly variable pharmacokinetics (PKs) between individual patients. The pharmacogenetic (PG) effect of variants at the loci of organic cation transporter 1 ( OCT 1 ) and UDP‐glucuronosyltransferase 2B7 ( UGT 2B7 ) on age‐dependent morphine clearance were evaluated in a cohort of critically ill neonatal patients using an opportunistic sampling design. Our primary results demonstrate the significant influence of OCT 1 genotype ( P  < 0.05) and gestational age ( P  ≤ 0.005) on morphine PKs. A physiologically based pharmacokinetic ( PBPK ) model for morphine that accounted for OCT 1 ontogeny and PG effect in post‐term neonates adequately described the clinically observed variability in morphine PKs. This study serves as a proof of concept for genotype‐dependent drug transporter ontogeny in neonates.