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The Effect of CYP2D6 Phenotypes on the Pharmacokinetics of Propafenone: A Systematic Review and Meta-Analysis

ABSTRACT: Propafenone (PPF) is a class 1C antiarrhythmic agent mainly metabolized by cytochrome (CYP) 2D6, CYP1A2, and CYP3A4. Previous studies have shown that CYP2D6 polymorphism influences the pharmacokinetics (PK) of PPF. However, the small sample sizes of PK studies can lead to less precise estimates of the PK parameters. Thus, this meta-analysis was performed to merge all current PK studies of PPF to determine the effects of the CYP2D6 phenotype more accurately on the PPF PK profile. We searched electronic databases for published studies to investigate the association between the PPF PK and CYP2D6 phenotype. Four PK-related outcomes were included: area under the time–concentration curve (AUC), maximum concentration (Cmax), apparent clearance (CL/F), and half-life (t1/2). A total of five studies were included in this meta-analysis (n = 56). Analyses were performed to compare PK parameters between poor metabolizers (PMs) versus extensive metabolizers (EMs). PPF has a non-linear pharmacokinetics; therefore, analyses were performed according to dose (300 mg and 400 mg). At 300 mg, the AUC mean (95% CI), Cmax, and t1/2 of PPF in PMs were 15.9 (12.5–19.2) µg·h/mL, 1.10 (0.796–1.40) µg/mL, and 12.8 (11.3–14.3) h, respectively; these values were 2.4-, 11.2-, and 4.7-fold higher than those in the EM group, respectively. At 400 mg, a comparison was performed between S- and R-enantiomers. The CL/F was approximately 1.4-fold higher for the R-form compared with the S-form, which was a significant difference. This study demonstrated that CYP2D6 metabolizer status could significantly affect the PPF PK profile. Adjusting the dose of PPF according to CYP2D6 phenotype would help to avoid adverse effects and ensure treatment efficacy.

SUBMITTER: Tran Q

PROVIDER: S-EPMC9324789 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectiveTo evaluate evidence on the association between CYP2D6 genotype and tamoxifen response through.DesignSystematic review and meta-analysis of prospective, cross-sectional and case-control studies published to 2012. For each study, relative risks and 95% confidence intervals were extracted and pooled with a fixed and random effects model. Heterogeneity, publication bias, subgroup, and meta-regression analyses were performed.Data sourcesPubMed (inception-2012) and EMBASE (inception-2012).Eligibility criteria for selecting studiesCriteria for inclusion were studies reporting breast cancer outcomes in patients treated with tamoxifen and genotyped for polymorphisms in the CYP2D6 gene.ResultsTwenty-five studies of 13,629 individuals were identified, of which 22 investigated the association of CYP2D6 genotype with outcomes in breast cancer women all receiving tamoxifen treatment ("treatment-only" design). Three randomized trials evaluated the effect of CYP2D6 genotype on tamoxifen response ("effect modification" design). In analysis of treatment-only studies, the relative risk (RR) of all-cause mortality (>307 events in 4,936 patients) for carriers of a CYP2D6 reduced function allele was 1.11 (95% confidence interval (CI): 0.94 to 1.31) compared to individuals with normal/increased function CYP2D6 alleles. When we investigated a composite outcome including all-cause mortality and surrogate endpoints for overall survival (>307 events in 6,721 patients), carriers of a CYP2D6 reduced function allele had a RR of 1.27 (95% CI: 1.11 to 1.45). From two randomized trials that permitted effect-modification analysis, one had only 154 patients and showed evidence of effect modification of tamoxifen by CYP2D6 genotype for distant recurrence but was directionally opposite to that predicted, whereas a larger trial of 2,537 patients failed to show evidence of effect modification for breast cancer-free interval (P values for interaction 0.02 and 0.44, respectively).ConclusionsBased on these findings, there is insufficient evidence to recommend CYP2D6 genotyping to guide tamoxifen treatment.

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The Effect of CYP2D6 Phenotypes on the Pharmacokinetics of Propafenone: A Systematic Review and Meta-Analysis

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