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Review
. 2019 Sep:59 Suppl 1:S33-S41.
doi: 10.1002/jcph.1483.

Ontogeny of Phase I Metabolism of Drugs

Karel Allegaert  1   2 , John van den Anker  3   4   5
Affiliations
Review

Ontogeny of Phase I Metabolism of Drugs

Karel Allegaert et al. J Clin Pharmacol. 2019 Sep.

Abstract

Capturing ontogeny of enzymes involved in phase I metabolism is crucial to improve prediction of dose-concentration and concentration-effect relationships throughout infancy and childhood. Once captured, these patterns can be integrated in semiphysiologically or physiology-based pharmacokinetic models to support predictions in specific pediatric settings or to support pediatric drug development. Although these translational efforts are crucial, isoenzyme-specific ontogeny-based models should also incorporate data on variability of maturational and nonmaturational covariates (eg, disease, treatment modalities, pharmacogenetics). Therefore, this review provides a summary of the ontogeny of phase I drug-metabolizing enzymes, indicating current knowledge gaps and recent progresses. Furthermore, we tried to illustrate that straightforward translation of isoenzyme-specific ontogeny to predictions does not allow full exploration of scenarios of potential variability related to maturational (non-age-related variability, other isoenzymes or transporters) or nonmaturational (disease, pharmacogenetics) covariates, and necessitates integration in a "systems" concept.

Keywords: developmental pharmacology; drug-metabolizing enzymes; ontogeny; phase I metabolism.

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References

    1. Holford NH, Buclin T. Safe and effective variability-a criterion for dose individualization. Ther Drug Monit. 2012;34(5):565-568.
    1. van den Anker J, Reed MD, Allegaert K, Kearns GL. Developmental changes in pharmacokinetics and pharmacodynamics. J Clin Pharmacol. 2018;58(suppl 10):S10-S25.
    1. Allegaert K, van den Anker J. Neonatal drug therapy: the first frontier for therapeutics for children. Clin Pharmacol Ther. 2015;98(3):288-297.
    1. Krekels EHJ, van Hasselt JGC, van den Anker JN, Allegaert K, Tibboel D, Knibbe CAJ. Evidence-based drug treatment for special patient populations through model-based approaches. Eur J Pharm Sci. 2017;109S:S22-S26.
    1. Allegaert K, Simons SHP, Tibboel D, Krekels EH, Knibbe CA, van den Anker JN. Non-maturational covariates for dynamic systems pharmacology models in neonates, infants, and children: filling the gaps beyond developmental pharmacology. Eur J Pharm Sci. 2017;109S:S27-S31.

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