Quyen Thi Tran (1), Ngoc Anh Thi Vu (1), In-hwan Baek (2), Na-young Han (3), Hwi-yeol Yun (1), Jung-woo Chae (1)
(1) College of Pharmacy, Chungnam National University, Republic of Korea, (2) College of Pharmacy, Kyungsung University, Republic of Korea, (3) College of Pharmacy, Jeju National University, Republic of Korea
Objectives: Propafenone (PPF) is a class 1C antiarrhythmic agent mainly metabolized to 5-hydroxypropafenone by cytochrome (CYP) 2D6 and norpropafenone by CYP1A2 and CYP3A4 [1]. Previous studies reported that the polymorphism of CYP2D6 has an effect on the pharmacokinetics (PK) of PPF [2], [3]. Those studies have small sample sizes, which could be estimated its conclusion with less precision. Therefore, this study aims to merge all current PK studies of propafenone to determine overall effects of CYP2D6 phenotype on propafenone PK.
Methods: This study followed the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-analysis) guideline [4]. We searched five electronic databases for studies published, including Pubmed, Google scholar, Embase, Web of Science, and Cochrane Library, to investigate the association between PPF PK and CYP2D6 phenotypes. Genotype and/or phenotype information was extracted. The association between PK parameters of PPF and CYP2D6 phenotype was analyzed. Four outcomes were tested in our study, including area under the time-concentration curve (AUC), the maximum concentration (Cmax), the apparent oral clearance (CL/F) and/or half-life (t1/2). Meta-analyses were performed to compare poor metabolizers (PMs) versus (vs.) extensive metabolizers (EMs), and intermediate metabolizers (IMs) vs. very extensive metabolizers (VEMs) for each outcome. Furthermore, as PPF is clinically used as a racemic mixture of S-PPF and R-PPF, we compared PK parameters in EMs between S- and R-form as well.
Results: A total of 7 studies were included in this study (n = 84). As PPF follows non-linear pharmacokinetics [5], analyses were performed at 300 mg and 400 mg, respectively. At 300 mg, mean (95% CI) of AUC, Cmax, and t1/2 of PPF in PMs were 15.9 (12.5 – 19.2) ug*h/mL, 1.10 (0.796 – 1.40) ug/mL, 12.8 (11.3 – 14.3) h, respectively, and it was 2.4-, 14.5-, and 4.7-fold higher than those in EMs group. At 400 mg, as data was collected in each enantiomer of PPF (S- and R-enantiomer), analyses were performed in each S- and R-form. All comparisons showed a significant difference between IMs and VEMs in each PK parameter (p < 0.0001). In IMs, AUC, Cmax, CL/F were 2.96 (2.55 – 3.36) ug*h/mL, 0.512 (0.478 – 0.545) ug/mL, 64.2 (56 – 72.4) L/h in S-enantiomer, and 2.17 (1.88 – 2.45) ug*h/mL, 0.360 (0.332 – 0.388) ug/mL, 87.6 (76.3 – 98.9) L/h in
R-enantiomer, respectively. In IMs, AUC and Cmax are 1.6-fold and 1.8-fold higher than those in VEMs at both racemic forms. CL/F of VEMs was 1.9-fold and 2.1-fold higher than that of IM in S-form and R-form, respectively. In addition, AUC and Cmax of S-PPF were significantly higher than those in R-PPF, and CL/F of S-PPF was significantly lower than R-PPF (all p < 0.0001).
Conclusions: This study demonstrated that CYP2D6 metabolizer status could have a significant effect on propafenone pharmacokinetics. Adjustment dose of PPF according to CYP2D6 phenotype would be necessary to avoid adverse effects or ensure treatment efficacy.
References:
[1] S.-F. Zhou, “Polymorphism of human cytochrome P450 2D6 and its clinical significance: Part I.,” Clin. Pharmacokinet., vol. 48, no. 11, pp. 689–723, 2009, doi: 10.2165/11318030-000000000-00000.
[2] TS. F. Zhou, “Polymorphism of human cytochrome P450 2D6 and its clinical significance: Part II,” Clin. Pharmacokinet., vol. 48, no. 12, pp. 761–804, 2009, doi: 10.2165/11318070-000000000-00000.
[3] C. Bing and C. A. I. Wei-min, “Influence of CYP2D6 * 10B genotype on pharmacokinetics of propafenone enantiomers in Chinese subjects,” Acta Pharmacol. Sin., vol. 24, no. 12, pp. 1277–1280, 2003.
[4] D. Moher, A. Liberati, J. Tetzlaff, and D. G. Altman, “Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement,” BMJ, vol. 339, no. 7716, pp. 332–336, 2009, doi: 10.1136/bmj.b2535.
[5] S. Vozeh, W. Haefeli, H. R. Ha, J. Vlcek, and F. Follath, “Nonlinear kinetics of propafenone metabolites in healthy man,” Eur. J. Clin. Pharmacol., vol. 38, no. 5, pp. 509–513, 1990, doi: 10.1007/BF02336693.
Reference: PAGE 29 (2021) Abstr 9712 [www.page-meeting.org/?abstract=9712]
Poster: Methodology - Other topics