title: Comparison of prediction methods for in vivo clearance of (S,S)-3-[3-(methylsulfonyl)phenyl]-1-propylpiperidine hydrochloride, a dopamine D2 receptor antagonist, in humans.
abstract: The purpose of this study is to investigate reliable prediction methods for in vivo pharmacokinetics and the likelihood of drug interactions with several cytochrome P450 inhibitors in humans for (S,S)-3-[3-(methylsulfonyl)phenyl]-1-propylpiperidine (PNU-96391). By allometric scaling of in vivo animal data, clearance of PNU-96391 in humans was over-predicted by 4-fold, half-life was under-predicted by 3-fold, and volume of distribution was accurately predicted. High correlation coefficients (>0.99) were observed for these parameters. Neither the in vitro-in vivo correlation approach nor the modified allometric scaling with maximum life span potential or brain weight accurately provided the predicted clearance value. Using an alternative method, based on normalization of in vitro human data with the ratio of in vivo to in vitro animal data, the in vivo clearance in humans was predicted to be 0.39 l/h/kg. This value correlated well with the in vivo value (0.43 l/h/kg). Regarding the interactions of PNU-96391 with cytochrome P450 inhibitors, only quinidine, haloperidol, and ketoconazole showed significant inhibition on the metabolic clearance of PNU-96391 in human hepatocytes. By comparing in vitro K(i) values with in vivo maximum unbound concentrations of the inhibitor, the increases in systemic exposure of PNU-96391 by coadministration of the inhibitors were estimated to be less than 1.5-fold. A preliminary comparison of pharmacokinetics of PNU-96391 between CYP2D6 extensive and poor metabolizers in the clinical study showed only a slight increase in systemic exposure in poor metabolizers (approximately 1.4-fold as area under the concentration-time curve). Therefore, clinically significant drug-drug interactions of PNU-96391 would be unlikely to occur with coadministration of CYP2D6 inhibitors.
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism, La Jolla Laboratories, Pfizer Inc., 10724 Science Center Drive, San Diego, CA 92121, USA. shinji.yamazaki@pfizer.com
authors.forename: Shinji
authors.initials: S
authors.lastname: Yamazaki
authors.forename: Lisa N
authors.initials: LN
authors.lastname: Toth
authors.forename: Meredith L
authors.initials: ML
authors.lastname: Black
authors.forename: J Neil
authors.initials: JN
authors.lastname: Duncan
mesh_terms: D000328:Adult; D000818:Animals; D002853:Chromatography, Liquid / Q000379:methods; D019389:Cytochrome P-450 CYP2D6 / Q000493:pharmacokinetics; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004285:Dogs; D065127:Dopamine D2 Receptor Antagonists; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004347:Drug Interactions; D005260:Female; D006220:Haloperidol / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007275:Injections, Intravenous; D007654:Ketoconazole / Q000494:pharmacology; D008252:Macaca fascicularis; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects* / Q000502:physiology; D008875:Middle Aged; D010880:Piperidines / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D011802:Quinidine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D013045:Species Specificity; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods; D013450:Sulfones / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology
chemical_list: C486876:3-(3-(methylsulfonyl)phenyl)-1-propylpiperidine; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D065127:Dopamine D2 Receptor Antagonists; D010880:Piperidines; D017448:Receptors, Dopamine D2; D013450:Sulfones; D019389:Cytochrome P-450 CYP2D6; D011802:Quinidine; D006220:Haloperidol; D007654:Ketoconazole