title: Statistical methods for analysis of time-dependent inhibition of cytochrome p450 enzymes.
abstract: Time-dependent inhibition (TDI) of cytochrome P450 (P450) enzymes, especially CYP3A4, is an important attribute of drugs in evaluating the potential for pharmacokinetic drug-drug interactions. The analysis of TDI data for P450 enzymes can be challenging, yet it is important to be able to reliably evaluate whether a drug is a TDI or not, and if so, how best to derive the inactivation kinetic parameters K(I) and k(inact). In the present investigation a two-step statistical evaluation was developed to evaluate CYP3A4 TDI data. In the first step, a two-sided two-sample z-test is used to compare the k(obs) values measured in the absence and presence of the test compound to answer the question of whether the test compound is a TDI or not. In the second step, k(obs) values are plotted versus both [I] and ln[I] to determine whether a significant correlation exists, which can then inform the investigator of whether the inactivation kinetic parameters, K(I) and k(inact), can be reliably estimated. Use of this two-step statistical evaluation is illustrated with the examination of five drugs of varying capabilities to inactivate CYP3A4: ketoconazole, erythromycin, raloxifene, rosiglitazone, and pioglitazone. The use of a set statistical algorithm offers a more robust and objective approach to the analysis of P450 TDI data than frequently employed empirically derived or heuristic approaches.
authors.affiliation: PharmaTherapeutics Statistics, Pfizer Inc., Groton, CT 06340, USA. pyatesgene@gmail.com
authors.forename: Phillip
authors.initials: P
authors.lastname: Yates
authors.forename: Heather
authors.initials: H
authors.lastname: Eng
authors.forename: Li
authors.initials: L
authors.lastname: Di
authors.forename: R Scott
authors.initials: RS
authors.lastname: Obach
mesh_terms: D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003627:Data Interpretation, Statistical; D004347:Drug Interactions; D005260:Female; D006801:Humans; D007266:Inhibition, Psychological; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D013997:Time Factors
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human