title: Quantitation of the impact of CYP3A5 A6986G polymorphism on quetiapine pharmacokinetics by simulation of target attainment.
abstract: The aim of this study was to evaluate whether genetic polymorphisms in CYP3A5 and ABCB1 are responsible for the interindividual variability observed in quetiapine pharmacokinetics. Pharmacokinetic data from a randomized crossover study evaluating 2 quetiapine 25 mg immediate-release tablets after single oral dose were used to develop a population pharmacokinetic model. The single nucleotide polymorphisms (SNPs) evaluated for the genotype effects of quetiapine pharmacokinetics were CYP3A5 A6986G and ABCB1 C3435T, along with other demographic variables and formulations. A one-compartment distribution model with linear elimination plus four transit compartments for the delayed absorption adequately described quetiapine disposition. CYP3A5 *1/*1 individuals (n = 3) had 29% increased clearance compared to *1/*3 and *3/*3 individuals. The impact of an increased clearance was evaluated by simulations. By computing the probability of target attainment (PTA) of steady-state therapeutic goal at 1-hour and 12-hour time points after 50-400 mg twice-daily regimens, the results indicated that CYP3A5 genotype has minimal impact on the PTA of the 1-hour concentrations but a significant impact on the 12-hour concentrations. The interpretation based on the simulations does not call for a genotype-based dosing scheme and is consistent with consensus guidelines for quetiapine that therapeutic drug monitoring is considered useful. Clinical Pharmacology in Drug Development.
authors.affiliation: Pharmacy Practice Department, Pharmacy College, Princess Nourah Bint Abdul Rahman University, Riyadh, Saudi Arabia.
authors.forename: Sireen A R
authors.initials: SA
authors.lastname: Shilbayeh
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, USA.
authors.forename: Sherwin K B
authors.initials: SK
authors.lastname: Sy
authors.affiliation: Institute of Clinical Pharmacodynamics, Latham, NY, USA.
authors.forename: Murad
authors.initials: M
authors.lastname: Melhem
authors.affiliation: ICU Clinical Pharmacy Services, King Saud Medical City, Riyadh, Saudi Arabia.
authors.forename: Rawan
authors.initials: R
authors.lastname: Zmeili
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, USA.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Derendorf
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D000328:Adult; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D003198:Computer Simulation; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A / Q000235:genetics* / Q000378:metabolism; D005838:Genotype; D064368:Healthy Volunteers; D006801:Humans; D007597:Jordan; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009010:Monte Carlo Method; D017711:Nonlinear Dynamics; D010597:Pharmacogenetics; D000071184:Pharmacogenomic Variants; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D000069348:Quetiapine Fumarate / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D014150:Antipsychotic Agents; D000069348:Quetiapine Fumarate; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A
keywords: ABCB1; CYP3A5; pharmacokinetics; polymorphisms; quetiapine