Quantitation of the impact of CYP3A5 A6986G polymorphism on quetiapine pharmacokinetics by simulation of target attainment

Sireen A.R. Shilbayeh, Sherwin K.B. Sy, Murad Melhem, Rawan Zmeili, Hartmut Derendorf

Research output: Contribution to journalArticleResearchpeer-review

2 Citations (Scopus)

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 25mg 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 50-400mg 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

Original languageEnglish
Pages (from-to)387-394
Number of pages8
JournalClinical Pharmacology in Drug Development
Volume4
Issue number5
DOIs
Publication statusPublished - 1 Jan 2015

Fingerprint

Cytochrome P-450 CYP3A
Pharmacokinetics
Genotype
Clinical Pharmacology
Drug Monitoring
Genetic Polymorphisms
Cross-Over Studies
Tablets
Single Nucleotide Polymorphism
Linear Models
Demography
Quetiapine Fumarate
Guidelines
Pharmaceutical Preparations
Population

Keywords

  • ABCB1
  • CYP3A5
  • Pharmacokinetics
  • Polymorphisms
  • Quetiapine

Cite this

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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 25mg 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 50-400mg 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",
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Quantitation of the impact of CYP3A5 A6986G polymorphism on quetiapine pharmacokinetics by simulation of target attainment. / Shilbayeh, Sireen A.R.; Sy, Sherwin K.B.; Melhem, Murad; Zmeili, Rawan; Derendorf, Hartmut.

In: Clinical Pharmacology in Drug Development, Vol. 4, No. 5, 01.01.2015, p. 387-394.

Research output: Contribution to journalArticleResearchpeer-review

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