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 (C_max), apparent clearance (CL/F), and half-life (t_1/2). 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), C_max, and t_1/2 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.

Keywords: CYP2D6; pharmacokinetics; phenotype; precision medicine; propafenone.

Figure 1

Flow chart of the selection process of all articles included in this meta-analysis.