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Understanding drug–drug interaction and pharmacogenomic changes in pharmacokinetics for metabolized drugs

Abstract

Here we characterize and summarize the pharmacokinetic changes for metabolized drugs when drug–drug interactions and pharmacogenomic variance are observed. Following multiple dosing to steady-state, oral systemic concentration–time curves appear to follow a one-compartment body model, with a shorter rate limiting half-life, often significantly shorter than the single dose terminal half-life. This simplified disposition model at steady-state allows comparisons of measurable parameters (i.e., area under the curve, half-life, maximum concentration and time to maximum concentration) following drug interaction or pharmacogenomic variant studies to be utilized to characterize whether a drug is low versus high hepatic extraction ratio, even without intravenous dosing. The characteristics of drugs based on the ratios of area under the curve, maximum concentration and half-life are identified with recognition that volume of distribution is essentially unchanged for drug interaction and pharmacogenomic variant studies where only metabolic outcomes are changed and transporters are not significantly involved. Comparison of maximum concentration changes following single dose interaction and pharmacogenomic variance studies may also identify the significance of intestinal first pass changes. The irrelevance of protein binding changes on pharmacodynamic outcomes following oral and intravenous dosing of low hepatic extraction ratio drugs, versus its relevance for high hepatic extraction ratio drugs is re-emphasized.

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Acknowledgements

The authors thank the UCSF PharmD Class of 2021 for their understanding, questions and patience in the presentation of the material presented here. This work was supported in part by a Mary Ann Koda-Kimble Seed Award for Innovation. Dr. Benet is a member of the UCSF Liver Center supported by NIH grant P30 DK026743. Ms. Bowman was supported by the National Science Foundation Graduate Research Fellowship Program (Grant 1144247) and a Pharmaceutical Research and Manufacturers of America Foundation Pre-doctoral Fellowship in Pharmaceutics. Ms. Koleske was supported in part by NIGMS grant R25 GM56847. Ms. Rinaldi was supported by the National Science Foundation Graduate Research Fellowship Program (Grant 1650113). Ms. Sodhi was supported in part by an American Foundation for Pharmaceutical Education Predoctoral Fellowship and NIGMS grant R25 GM56847.

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Correspondence to Leslie Z. Benet.

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Benet, L.Z., Bowman, C.M., Koleske, M.L. et al. Understanding drug–drug interaction and pharmacogenomic changes in pharmacokinetics for metabolized drugs. J Pharmacokinet Pharmacodyn 46, 155–163 (2019). https://doi.org/10.1007/s10928-019-09626-7

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  • DOI: https://doi.org/10.1007/s10928-019-09626-7

Keywords

  • Drug-drug interactions
  • Pharmacogenomics
  • Area under the curve
  • Operational half-lives
  • Maximum systemic concentrations