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European Journal of Drug Metabolism and Pharmacokinetics

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01-02-2018 | Original Research Article

Population Pharmacokinetic Modeling of Diltiazem in Chinese Renal Transplant Recipients

Authors: Xiao-feng Guan, Dai-yang Li, Wen-jun Yin, Jun-jie Ding, Ling-yun Zhou, Jiang-lin Wang, Rong-Rong Ma, Xiao-cong Zuo

Published in: European Journal of Drug Metabolism and Pharmacokinetics | Issue 1/2018

Abstract

Background and Objectives

Diltiazem is a benzothiazepine calcium blocker and widely used in renal transplant patients since it improves the level of tacrolimus or cyclosporine A concentration. Several population pharmacokinetic (PopPK) models had been established for cyclosporine A and tacrolimus but no specific PopPK model was established for diltiazem. The aim of the study is to develop a PopPK model for diltiazem in renal transplant recipients and provide relevant pharmacokinetic parameters of diltiazem for further pharmacokinetic interaction study.

Methods

Patients received tacrolimus as primary immunosuppressant agent after renal transplant and started administration of diltiazem 90 mg twice daily on 5th day. The concentration of diltiazem at 0, 0.5, 1, 2, 8, and 12 h was measured by high-performance liquid chromatography–tandem mass spectrometry (HPLC–MS/MS). Genotyping for CYP3A4*1G, CYP3A5*3, and MDR1 3435 was conducted by polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP). 25 covariates were considered in the stepwise covariate model (SCM) building procedure.

Results

One-compartment structural pharmacokinetic model with first-order absorption and elimination was used to describe the pharmacokinetic characteristics of diltiazem. Total bilirubin (TBIL) influenced apparent volume of distribution (V/F) of diltiazem in the forward selection. The absorption rate constant (K _a), V/F, and apparent oral clearance (CL/F) of the final population pharmacokinetic (PopPK) model of diltiazem were 1.96/h, 3550 L, and 92.4 L/h, respectively.

Conclusion

A PopPK model of diltiazem is established in Chinese renal transplant recipients and it will provide relevant pharmacokinetic parameters of diltiazem for further pharmacokinetic interaction study.

al Edreesi M, Caille G, Dupuis C, Theoret Y, Paradis K. Safety, tolerability, and pharmacokinetic actions of diltiazem in pediatric liver transplant recipients on cyclosporine. Liver Transpl Surg. 1995;1:383–8.CrossRefPubMed

Kurokawa T, Fukami T, Nakajima M. Characterization of species differences in tissue diltiazem deacetylation identifies Ces2a as a rat-specific diltiazem deacetylase. Drug Metab Dispos. 2015;43:1218–25.CrossRefPubMed

Echizen H, Eichelbaum M. Clinical pharmacokinetics of verapamil, nifedipine and diltiazem. Clin Pharmacokinet. 1986;11:425–49.CrossRefPubMed

Piepho RW, Bloedow DC, Lacz JP, et al. Pharmacokinetics of diltiazem in selected animal species and human beings. Am J Cardiol. 1982;49:525–8.CrossRefPubMed

Booker B, Magee M, Blum R, Lates C, Jusko W. Pharmacokinetic and pharmacodynamic interactions between diltiazem and methylprednisolone in healthy volunteers. Clin Pharmacol Ther. 2002;72:370–82.CrossRefPubMed

Manitpisitkul P, Curtin CR, Shalayda K, et al. Pharmacokinetic interactions between topiramate and diltiazem, hydrochlorothiazide, or propranolol. Clin Pharmacol Drug Dev. 2014;3:378–87.CrossRefPubMed

Friedman EJ, Fraser IP, Wang Y, et al. Effect of different durations and formulations of diltiazem on the single-dose pharmacokinetics of midazolam: how long do we go? J Clin Pharmacol. 2011;51:1561–70.CrossRefPubMed

Hermann P, Rodger SD, Remones G, et al. Pharmacokinetics of diltiazem after intravenous and oral administration. Eur J Clin Pharmacol. 1983;24:349–52.CrossRefPubMed

Zhang X, Quinney SK, Gorski JC, Jones DR, Hall SD. Semiphysiologically Based pharmacokinetic models for the inhibition of midazolam clearance by diltiazem and its major metabolite. Drug Metab Dispos. 2009;37:1587–97.CrossRefPubMed

10.

Rovei V, Gomeni R, Mitchard M, et al. Pharmacokinetics and metabolism of diltiazem in man. Acta Cardiol. 1980;35:35–45.PubMed

11.

Molden E, Johansen PW, Bøe GH, et al. Pharmacokinetics of diltiazem and its metabolites in relation to CYP2D6 genotype*. Clin Pharmacol Ther. 2002;72:333–42.CrossRefPubMed

12.

Zheng T, Su CH, Zhao J, Zhang XJ, Zhang TY. Effects of CYP3A5 and CYP2D6 genetic polymorphism on the pharmacokinetics of diltiazem and its metabolites in Chinese subjects. Pharmazie. 2013;68:257–60.PubMed

13.

Jones D, Morris RG. Pharmacokinetic interaction between tacrolimus and diltiazem. Clin Pharmacokinet. 2002;41:381–8.CrossRefPubMed

14.

Zhou LY, Zuo XC, Chen K, et al. Significant impacts of CYP3A4*1G and CYP3A5*3 genetic polymorphisms on the pharmacokinetics of diltiazem and its main metabolites in Chinese adult kidney transplant patients. J Clin Pharm Ther. 2016;41:341–7.CrossRefPubMed

15.

Wang YX, Li JL, Wang XD, et al. Diltiazem augments the influence of MDR1 genotype status on cyclosporine concentration in Chinese patients with renal transplantation. Acta Pharmacol Sin. 2015;36:855–62.CrossRefPubMedPubMedCentral

16.

Jones TE, Morris RG, Mathew TH. Diltiazem-cyclosporin pharmacokinetic interaction-dose-response relationship. Br J Clin Pharmacol. 1997;44:499–504.CrossRefPubMedPubMedCentral

17.

Zuo X, Ng CM, Barrett JS, et al. Effects of CYP3A4 and CYP3A5 polymorphisms on tacrolimus pharmacokinetics in Chinese adult renal transplant recipients. Pharmacogenet Genom. 2013;23:251–61.CrossRef

18.

Dingemanse J, Nicolas LB, van Bortel L. Effect of Multiple-Dose Diltiazem on the Pharmacokinetics of the Renin Inhibitor ACT-077825. Clin Pharmacol Drug Dev. 2013;2:113–9.CrossRefPubMed

19.

Chen YH, Liang YX, Chen LQ, et al. [Nephrotoxicity of tacrolimus and preventive effect of diltiazem: experiment with rats]. Zhonghua Yi Xue Za Zhi. 2009;89:704–8.PubMed

20.

Dasandi B, Shah S, Shivprakash. Development and validation of a high throughput and robust LC-MS/MS with electrospray ionization method for simultaneous quantitation of diltiazem and its two metabolites in human plasma: application to a bioequivalence study. J Chromatogr B Analyt Technol Biomed Life Sci. 2009;877:791–8.CrossRefPubMed

21.

Gao Y, Zhang L, Fu Q. CYP3A4*1G polymorphism is associated with lipid-lowering efficacy of atorvastatin but not of simvastatin. Eur J Clin Pharmacol. 2008;64:877–82.CrossRefPubMed

22.

Pérez-Blanco JS, Santos-Buelga D, Fernández De Gatta MDM, et al. Population pharmacokinetic of doxorubicin and doxorubicinol in patients diagnosed with non-Hodgkin´s lymphoma. Br J Clin Pharmacol. 2016;82:1517–27.CrossRefPubMedPubMedCentral

23.

Zuo X, Ng CM, Barrett JS, et al. Effects of CYP3A4 and CYP3A5 polymorphisms on tacrolimus pharmacokinetics in Chinese adult renal transplant recipients. Pharmacogenet Genom. 2013;23:251–61.CrossRef

24.

Fu M, Hung JS, Yeh SJ, et al. Pharmacokinetics and pharmacodynamic effects of aqueous diltiazem in healthy humans. J Clin Pharmacol. 1987;27:106–10.CrossRefPubMed

25.

Kurosawa S, Kurosawa N, Owada E, Soeda H, Ito K. Pharmacokinetics of diltiazem in patients with liver cirrhosis. Int J Clin Pharmacol Res. 1990;10:311–8.PubMed

26.

Yamamoto T, Kubota T, Ozeki T, et al. Effects of the CYP3A5 genetic polymorphism on the pharmacokinetics of diltiazem. Clin Chim Acta. 2005;362:147–54.CrossRefPubMed

27.

Dong H, Huang H, Yun X, et al. Bilirubin increases insulin sensitivity in leptin-receptor deficient and diet-induced obese mice through suppression of ER stress and chronic inflammation. Endocrinology. 2014;155:818–28.CrossRefPubMedPubMedCentral

28.

Vogel ME, Zucker SD. Bilirubin acts as an endogenous regulator of inflammation by disrupting adhesion molecule-mediated leukocyte migration. Inflamm Cell Signal. 2016;3:e1178.PubMedPubMedCentral

29.

Peng YF, Wang JL, Pan GG. The correlation of serum bilirubin levels with disease activity in patients with rheumatoid arthritis. Clin Chim Acta. 2017;469:187–90.CrossRefPubMed

30.

Hamur H, Duman H, Demirtas L, et al. Total bilirubin levels predict subclinical atherosclerosis in patients with prediabetes. Angiology. 2016;67:909–15.CrossRefPubMed

31.

Hinds TD, Adeosun SO, Alamodi AA, Stec DE. Does bilirubin prevent hepatic steatosis through activation of the PPARα nuclear receptor? Med Hypotheses. 2016;95:54–7.CrossRefPubMedPubMedCentral

32.

Moon JS. Role of bilirubin in diabetic vascular complications: can bilirubin predict more than just liver disease? Diabetes Metab J. 2015;39:384–6.CrossRefPubMedPubMedCentral

33.

Zhang W, Chang YZ, Kan QC, et al. CYP3A4*1G genetic polymorphism influences CYP3A activity and response to fentanyl in Chinese gynecologic patients. Eur J Clin Pharmacol. 2010;66:61–6.CrossRefPubMed

34.

Miura M, Satoh S, Kagaya H, et al. Impact of the CYP3A4*1G polymorphism and its combination with CYP3A5 genotypes on tacrolimus pharmacokinetics in renal transplant patients. Pharmacogenomics. 2011;12:977–84.CrossRefPubMed

35.

Zuo X, Zhang W, Yuan H, et al. ABCB1 polymorphism and gender affect the pharmacokinetics of amlodipine in Chinese patients with essential hypertension: a population analysis. Drug Metab Pharmacokinet. 2014;29:305–11.CrossRefPubMed

Title: Population Pharmacokinetic Modeling of Diltiazem in Chinese Renal Transplant Recipients
Authors: Xiao-feng Guan
Dai-yang Li
Wen-jun Yin
Jun-jie Ding
Ling-yun Zhou
Jiang-lin Wang
Rong-Rong Ma
Xiao-cong Zuo
Publication date: 01-02-2018
Publisher: Springer International Publishing
Published in: European Journal of Drug Metabolism and Pharmacokinetics / Issue 1/2018
Print ISSN: 0378-7966
Electronic ISSN: 2107-0180
DOI: https://doi.org/10.1007/s13318-017-0425-y

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Population Pharmacokinetic Modeling of Diltiazem in Chinese Renal Transplant Recipients

Abstract

Background and Objectives

Methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background and Objectives

Methods

Results

Conclusion

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