title: Evaluation of Normalization Methods To Predict CYP3A4 Induction in Six Fully Characterized Cryopreserved Human Hepatocyte Preparations and HepaRG Cells.
abstract: Prediction of drug-drug interactions due to cytochrome P450 isoform 3A4 (CYP3A4) overexpression is important because this CYP isoform is involved in the metabolism of about 30% of clinically used drugs from almost all therapeutic categories. Therefore, it is mandatory to attempt to predict the potential of a new compound to induce CYP3A4. Among several in vitro-in vivo extrapolation methods recently proposed in the literature, an approach using a scaling factor, called a d factor, for a given hepatocyte batch to provide extrapolation between in vitro induction data and clinical outcome has been adopted by leading health authorities. We challenged the relevance of the calibration factor determined using a set of 15 well-known clinical CYP3A4 inducers or the potent CYP3A4 inducer rifampicin only. These investigations were conducted using six batches of human hepatocytes and an established HepaRG cell line. Our findings show that use of a calibration factor is preferable for clinical predictions, as shown previously by other investigators. Moreover, the present results also suggest that the accuracy of prediction through calculation of this factor is sufficient when rifampicin is considered alone, and the use of a larger set of fully characterized CYP3A4 clinical inducers is not required. For the established HepaRG cell line, the findings obtained in three experiments using a single batch of cells show a good prediction accuracy with or without the d factor. Additional investigations with different batches of HepaRG cell lines are needed to confirm these results.
authors.affiliation: Drug Disposition Domain, Disposition, Safety and Animal Research Scientific Core Platform (H.V., N.R., R.N., S.K., G.F., X.B.); Biostatistics and Programming, Clinical Sciences & Operations, Scientific Core Platform (L.E.), Sanofi Recherche & Développement, Montpellier, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Vermet
authors.affiliation: Drug Disposition Domain, Disposition, Safety and Animal Research Scientific Core Platform (H.V., N.R., R.N., S.K., G.F., X.B.); Biostatistics and Programming, Clinical Sciences & Operations, Scientific Core Platform (L.E.), Sanofi Recherche & Développement, Montpellier, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Raoust
authors.affiliation: Drug Disposition Domain, Disposition, Safety and Animal Research Scientific Core Platform (H.V., N.R., R.N., S.K., G.F., X.B.); Biostatistics and Programming, Clinical Sciences & Operations, Scientific Core Platform (L.E.), Sanofi Recherche & Développement, Montpellier, France.
authors.forename: Robert
authors.initials: R
authors.lastname: Ngo
authors.affiliation: Drug Disposition Domain, Disposition, Safety and Animal Research Scientific Core Platform (H.V., N.R., R.N., S.K., G.F., X.B.); Biostatistics and Programming, Clinical Sciences & Operations, Scientific Core Platform (L.E.), Sanofi Recherche & Développement, Montpellier, France.
authors.forename: Luc
authors.initials: L
authors.lastname: Esserméant
authors.affiliation: Drug Disposition Domain, Disposition, Safety and Animal Research Scientific Core Platform (H.V., N.R., R.N., S.K., G.F., X.B.); Biostatistics and Programming, Clinical Sciences & Operations, Scientific Core Platform (L.E.), Sanofi Recherche & Développement, Montpellier, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Klieber
authors.affiliation: Drug Disposition Domain, Disposition, Safety and Animal Research Scientific Core Platform (H.V., N.R., R.N., S.K., G.F., X.B.); Biostatistics and Programming, Clinical Sciences & Operations, Scientific Core Platform (L.E.), Sanofi Recherche & Développement, Montpellier, France.
authors.forename: Gérard
authors.initials: G
authors.lastname: Fabre
authors.affiliation: Drug Disposition Domain, Disposition, Safety and Animal Research Scientific Core Platform (H.V., N.R., R.N., S.K., G.F., X.B.); Biostatistics and Programming, Clinical Sciences & Operations, Scientific Core Platform (L.E.), Sanofi Recherche & Développement, Montpellier, France xavier.boulenc@sanofi.com.
authors.forename: Xavier
authors.initials: X
authors.lastname: Boulenc
mesh_terms: D000328:Adult; D000368:Aged; D002460:Cell Line; D048430:Cell Shape / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015925:Cryopreservation; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis* / Q000235:genetics; D065701:Cytochrome P-450 CYP3A Inducers / Q000494:pharmacology* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004790:Enzyme Induction; D005260:Female; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D012333:RNA, Messenger / Q000096:biosynthesis; D012293:Rifampin / Q000494:pharmacology
chemical_list: D065701:Cytochrome P-450 CYP3A Inducers; D012333:RNA, Messenger; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D012293:Rifampin