Pharmacokinetics and bioequivalence study of two digoxin formulations after single-dose administration in healthy Chinese male volunteers

Abstract

The pharmacokinetics and relative bio-availability/bioequivalence of two formulations of digoxin (CAS 20830-75-5) were assessed in this paper. The study was conducted in 20 healthy Chinese male volunteers according to an open, randomized, single-blind, 2-way crossover study design with a wash-out phase of 14 days. Blood samples for pharmacokinetic profiling were taken up to 72 h post-dose and digoxin plasma concentrations were determined by a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Based on the plasma concentration-time data of each individual during two periods, pharmacokinetic parameters, C_max, AUC_0–τ, AUC_0–∞ and t_1/2, were calculated by applying non-compartmental analysis. Pharmacokinetic data for test and reference formulations were analyzed statistically to evaluate bioequivalence of the two formulations. After oral administration, the values of C_max, T_max, t_1/2, AUC_0–τ, AUC_0–∞ for test and reference formulations were 2.61 ± 0.98 and 2.68 ± 1.09 ng/mL, 1.0 ± 0.4 and 1.0 ± 0.4 h, 27.94 ± 3.14 and 27.56 ± 3.86 h, 28.57 ± 4.99 and 28.77 ± 6.53 ng · h/mL, 33.44 ± 4.85 and 33.63 ± 7.57 ng · h/mL, respectively. Both primary target parameters, AUC_0–∞ and AUC_0–τ, were tested parametrically by analysis of variance (ANOVA). Relative bioavailabilities were 102.5 ± 19.2% for AUC_0–∞, 102.0 ± 19.3% for AUC_0–τ. Bioequivalence between test and reference formulations was demonstrated for both parameters, AUC_0–∞ and AUC_0–τ. The 90% confidence intervals of the T/R-ratios of logarithmically transformed data were in the generally accepted range of 80%–125%, which means that the test formulation is bioequivalent to the reference formulation of digoxin.

Key words

Bioequivalence - Cardiac glycoside - Digoxin - Pharmacokinetics

• References

• 1 Mackstaller LL, Alpert JS. Atrial fibrillation: a review of mechanism, etiology, and therapy. Clin Cardiol. 1997; Jul 20 (7) 640-50
• 2 Cobbe SM. Using the right drug. A treatment algorithm for atrial fibrillation. Eur Heart J. 1997; May (Suppl C) C33-9
• 3 de Lannoy IA, Silverman M. The MDR1 gene product, P-glycoprotein, mediates the transport of the cardiac glycoside, digoxin. Biochem Biophys Res Commun. 1992; Nov 189 (1) 551-7
• 4 Okamura N, Hirai M, Tanigawara Y, Tanaka K, Yasuhara M, Ueda K et al. Digoxin-cyclosporin A interaction: modulation of the multidrug transporter P-glycoprotein in the kidney. J Pharmacol Exp Ther. 1993; Sep 266 (3) 1614-9
• 5 Ben-Itzhak J, Bassan HM, Shor R, Lanir A. Digoxin quinidine interaction: a pharmacokinetic study in the isolated perfused rat liver. Life Sci. 1985; Aug 37 (5) 411-5
• 6 Reitman ML, Chu X, Cai X, Yabut J, Venkatasubramanian R, Zajic S et al. Rifampin’s acute inhibitory and chronic inductive drug interactions: experimental and model-based approaches to drug-drug interaction trial design. Clin Pharmacol Ther. 2011; Feb 89 (2) 234-42
• 7 Friedrich C, Ring A, Brand T, Sennewald R, Graefe-Mody EU, Woerle HJ. Evaluation of the pharmacokinetic interaction after multiple oral doses of linagliptin and digoxin in healthy volunteers. Eur J Drug Metab Pharmacokinet. 2011; Mar 36 (1) 17-24
• 8 Nakade S, Ohno T, Nakayama K, Kitagawa J, Hashimoto Y, Ohnishi A et al. No effect of imidafenacin, a novel anti-muscarinic drug, on digoxin pharmacokinetics in healthy subjects. Drug Metab Pharmacokinet. 2008; 23 (2) 95-100
• 9 Higashi Y, Ikeda Y, Yamamoto R, Yamashiro M, Fujii Y. Pharmacokinetic interaction with digoxin and glucocorticoids in rats detected by radio-immunoassay using a novel specific antiserum. Life Sci. 2005; 77: 1055-67
• 10 Jedliĉka A, Grafnetterová T, Miller V. HPLC method with UV detection for evaluation of digoxin tablet dissolution in acidic medium after solid-phase extraction. J Pharm Biomed Anal. 2003; Sep 33 (1) 109-15
• 11 Varma MV, Kapoor N, Sarkar M, Panchagnula R. Simultaneous determination of digoxin and permeability markers in rat in situ intestinal perfusion samples by RP-HPLC. J Chromatogr B Analyt Technol Biomed Life Sci. 2004; Dec 813 (l – 2) 347-52
• 12 Li S, Liu G, Jia J, Miao Y, Gu S, Miao P et al. Therapeutic monitoring of serum digoxin for patients with heart failure using a rapid LC-MS/MS method. Clin Biochem. 2010; Feb 43 (3) 307-13
• 13 US Department of Health and Human Services. Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Guidance for Industry, Bioanalytical Method Validation. 2001.