A Simple Methodology to Differentiate Changes in Bioavailability From Changes in Clearance Following Oral Dosing of Metabolized Drugs.

Clinical Pharmacology and Therapeutics
Jasleen K Sodhi, Leslie Z Benet

Abstract

Accurately discriminating changes in clearance (CL) from changes in bioavailability (F) following an oral drug-drug interaction is difficult without carrying out an intravenous interaction study. This may be true for drugs that are clinically significant transporter substrates; however, for interactions that are strictly metabolic, it has been recognized that volume of distribution remains unchanged between both phases of the interaction study. With the understanding that changes in volume of distribution will be minimal for metabolized drugs, the inverse of the change in apparent volume of distribution can provide adequate estimates of the change in bioavailability alone. Utilization of this estimate of F change in tandem with the observed apparent clearance (CL/F) change in an oral drug-drug interaction can provide an estimate of the change in clearance alone. Here, we examine drug-drug interactions involving five known inhibitors and inducers of cytochrome P450 3A4 isozyme on victim drugs midazolam and apixaban for which the interaction was carried out both orally and intravenously, allowing for evaluation of this methodology. Predictions of CL and F changes based on oral data were reasonably close to observed changes based ...Continue Reading

References

Aug 1, 1979·Journal of Pharmaceutical Sciences·L Z Benet, R L Galeazzi
Jan 1, 1989·European Journal of Clinical Pharmacology·A Wahlländer, G Paumgartner
Sep 5, 1998·Clinical Pharmacology and Therapeutics·J C GorskiS D Hall
Feb 20, 2002·British Journal of Clinical Pharmacology·Eleonora L SwartMeindert Danhof
Dec 29, 2006·Clinical Pharmacology and Therapeutics·Y Y LauL Z Benet
Apr 29, 2009·The AAPS Journal·Anita Grover, Leslie Z Benet
Mar 17, 2011·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Brian J KirbyJashvant D Unadkat
Jan 11, 2016·American Journal of Cardiovascular Drugs : Drugs, Devices, and Other Interventions·Blisse VakkalagaddaFrank LaCreta
Oct 24, 2018·Pharmaceutical Research·Leslie Z BenetJasleen K Sodhi
Mar 27, 2019·Journal of Pharmacokinetics and Pharmacodynamics·Leslie Z BenetJasleen K Sodhi
Mar 28, 2019·Clinical Pharmacology and Therapeutics·Aleksi TornioJanne T Backman
Sep 5, 2019·The AAPS Journal·Leslie Z BenetJasleen K Sodhi

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Citations

Jul 30, 2020·Clinical Pharmacokinetics·Jasleen K SodhiLeslie Z Benet
Oct 1, 2020·Pharmaceutical Research·Jasleen K SodhiLeslie Z Benet

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