Age related changes in fractional elimination pathways for drugs: Assessing the impact of variable ontogeny on metabolic drug-drug interactions

Farzaneh Salem, Trevor N. Johnson, Zoe E. Barter, J. Steven Leeder, Amin Rostami-hodjegan

    Research output: Contribution to journalArticlepeer-review

    Abstract

    The magnitude of any metabolic drug-drug interactions (DDIs) depends on fractional importance of inhibited pathway which may not necessarily be the same in young children when compared to adults. The ontogeny pattern of cytochrome P450 (CYP) enzymes (CYPs 1A2, 2B6, 2C8, 2C9, 2C18/19, 2D6, 2E1, 3A4) and renal function were analyzed systematically. Bootstrap methodology was used to account for variability, and to define the age range over which statistical differences existed between each pair of specific pathways. A number of DDIs were simulated (Simcyp Pediatric v12) for virtual compounds to highlight effects of age on fractional elimination and consequent magnitude of DDI. For a theoretical drug metabolized 50% by each of CYP2D6 and CYP3A4 pathways at birth, co-administration of ketoconazole (3 mg/kg) resulted in a 1.65-fold difference between inhibited versus uninhibited AUC compared to 2.4-fold in 1 year olds and 3.2-fold in adults. Conversely, neonates could be more sensitive to DDI than adults in certain scenarios. Thus, extrapolation from adult data may not be applicable across all pediatric age groups. The use of pediatric physiologically based pharmacokinetic (p-PBPK) models may offer an interim solution to uncovering potential periods of vulnerability to DDI where there are no existing clinical data derived from children. © The Author(s) 2013.
    Original languageEnglish
    Pages (from-to)857-865
    Number of pages8
    JournalJournal of Clinical Pharmacology
    Volume53
    Issue number8
    DOIs
    Publication statusPublished - Aug 2013

    Keywords

    • Drug-drug interaction
    • Ontogeny
    • Pediatric

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