title: Pharmacokinetic simulations to explore dissolution criteria of BCS I and III biowaivers with and without MDR-1 efflux transporter.
abstract: In this study, a pharmacokinetic simulation model was used to explore the dissolution acceptance criteria for BCS I and III biowaivers and to examine the risk of MDR-1 efflux transporter on bioequivalence of substrates. The compartmental absorption and transit (CAT) model with one- or two systemic compartments was used. The parameter values used in the simulations were based on the pharmacokinetics of existing 70 BCS I and III drugs. Based on the simulations BCS I drug products with Tmax of >0.9 h, both dissolution criteria "very rapid" and "rapid and similar" were acceptable. For rapidly absorbed and distributed BCS I drug products with Tmax of 0.6-0.9 h, the dissolution criterion "very rapid" is preferred. If Tmax is less than 0.6 h there is a risk of bioinequivalence for the BCS I drug products regardless of the dissolution criteria. Based on the simulations, all BCS III drug products were good biowaiver candidates with both dissolution criteria. Almost all the BCS III drug products (>89%) and many BCS I products (9-57%) showed risks of bioinequivalence, if an excipient in either product inhibits MDR1-efflux transport of the drug. To eliminate these risks excipients with prior use in bioequivalent products should be used for MDR-1 efflux substrates.
authors.affiliation: Division of Biopharmaceutics and Pharmacokinetics, Faculty of Pharmacy, P.O. Box 56, 00014 University of Helsinki, Finland. Electronic address: hanna.kortejarvi@helsinki.fi.
authors.forename: H
authors.initials: H
authors.lastname: Kortejärvi
authors.affiliation: Research & Development, Orion Pharma, P.O. Box 65, 02101 Espoo, Finland.
authors.forename: J
authors.initials: J
authors.lastname: Malkki
authors.affiliation: Division of Biopharmaceutics and Pharmacokinetics, Faculty of Pharmacy, P.O. Box 56, 00014 University of Helsinki, Finland; Department of Pharmacy, The Islamia University of Bahawalpur, Pakistan; Inserm 705, CNRS 8206, University Paris Descartes, Department of Pharmaceutical Sciences, Faculty of Pharmacy, 4 avenue de l'Observatoire, FR-75006 Paris, France.
authors.forename: R
authors.initials: R
authors.lastname: Shawahna
authors.affiliation: Inserm 705, CNRS 8206, University Paris Descartes, Department of Pharmaceutical Sciences, Faculty of Pharmacy, 4 avenue de l'Observatoire, FR-75006 Paris, France.
authors.forename: J-M
authors.initials: JM
authors.lastname: Scherrmann
authors.affiliation: Centre for Drug Research, Faculty of Pharmacy, P.O. Box 56, 00014 University of Helsinki, Finland.
authors.forename: A
authors.initials: A
authors.lastname: Urtti
authors.affiliation: Division of Biopharmaceutics and Pharmacokinetics, Faculty of Pharmacy, P.O. Box 56, 00014 University of Helsinki, Finland.
authors.forename: M
authors.initials: M
authors.lastname: Yliperttula
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors / Q000378:metabolism; D065567:Absorption, Physiological; D001692:Biological Transport; D001702:Biopharmaceutics / Q000145:classification*; D006801:Humans; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D010599:Pharmacokinetics; D013810:Therapeutic Equivalency
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D004364:Pharmaceutical Preparations
keywords: BCS; Bioequivalence; Biowaiver; Compartmental absorption and transit model; Drug dissolution; Pharmacokinetic simulation