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

Hahn David | Zendy; Emoto Chie | Zendy; Euteneuer Joshua C. | Zendy; Mizuno Tomoyuki | Zendy; Vinks Alexander A. | Zendy; Fukuda Tsuyoshi | Zendy

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

Author(s) -

Hahn David,

Emoto Chie,

Euteneuer Joshua C.,

Mizuno Tomoyuki,

Vinks Alexander A.,

Fukuda Tsuyoshi

Publication year - 2019

Publication title -

clinical pharmacology and therapeutics

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 1.941

H-Index - 188

eISSN - 1532-6535

pISSN - 0009-9236

DOI - 10.1002/cpt.1249

Subject(s) - morphine , neonatal intensive care unit , pharmacogenetics , pharmacokinetics , physiologically based pharmacokinetic modelling , ontogeny , organic cation transport proteins , gestational age , genotype , pharmacology , transporter , critically ill , medicine , anesthesia , biology , pediatrics , gene , genetics , pregnancy

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.

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