Inter- and Intra-individual Variability in the Pharmacokinetics of Agomelatine Tablets in Chinese Healthy Male Subjects

Abstract

Agomelatine is an antidepressant with a unique action mechanism differing from conventional antidepressants. The high inter- and intra-individual variability of agomelatine was previously reported, but no exact data values about the inter- and intra-individual variability in AUC and C_max were mentioned. The current study aimed to determine and evaluate the inter- and intra-individual variability in AUC and C_max of agomelatine tablets in Chinese healthy male subjects, providing useful information for designing bioequivalence studies of agomelatine. Each of 12 Chinese healthy male subjects received a 25-mg agomelatine tablet on 2 separate periods, and plasma samples were collected up to 24 h after dose and analyzed for agomelatine. Inter- and intra-individual variability in the pharmacokinetic parameters (C_max, AUC_0–t and AUC_0–∞) of agomelatine was assessed. High variations in the plasma concentrations of agomelatine could be observed at each sampling time between the different subjects and in one subject on different periods. The inter-individual CVs of C_max, AUC_0–t and AUC_0–∞ were 102.20%, 131.74% and 130.59%, respectively. The intra-individual CVs of C_max, AUC_0–t and AUC_0–∞ were 84.34%, 49.61% and 50.83%, respectively. The results showed high inter- and intra-individual variability in the pharmacokinetics of agomelatine in Chinese healthy male subjects, and the intra-individual variability at CV>80% should be considered in the design of bioequivalence studies.

Key words

agomelatine - individual variability - pharmacokinetics - highly variable drugs

• References

• 1 Kasper S, Hajak G. The efficacy of agomelatine in previously-treated depressed patients. Eur Neuropsychopharmacol 2013; 23: 814-821
• 2 Pecenak J, Novotny V. Agomelatine as monotherapy for major depression: an outpatient, open-label study. Neuropsychiatr Dis Treat 2013; 9: 1595-1604
• 3 Dolder CR, Nelson M, Snider M. Agomelatine treatment of major depressive disorder. Ann Pharmacother 2008; 42: 1822-1831
• 4 European Medicines Agency CHMP Assessment Report for Valdoxan. 2008. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/000915/WC500046226.pdf Accessed June 18, 2014
• 5 Kobayashi H. Inter- and intra-individual variations of heart rate variability in Japanese males. J Physiol Anthropol 2007; 26: 173-177
• 6 Tothfalusi L, Endrenyi L. Sample sizes for designing bioequivalence studies for highly variable drugs. J Pharm Pharm Sci 2012; 15: 73-84
• 7 Bogaards JJ, Hissink EM, Briggs M et al. Prediction of interindividual variation in drug plasma levels in vivo from individual enzyme kinetic data and physiologically based pharmacokinetic modeling. Eur J Pharm Sci 2000; 12: 117-124
• 8 Howland RH. Critical appraisal and update on the clinical utility of agomelatine, a melatonergic agonist, for the treatment of major depressive disease in adults. Neuropsychiatr Dis Treat 2009; 5: 563-576
• 9 Song L, Du Q, Jiang X et al. Effect of CYP1A2 polymorphism on the pharmacokinetics of agomelatine in Chinese healthy male volunteers. J Clin Pharm Ther 2014; 39: 204-209
• 10 Wang X, Zhang D, Liu M et al. LC-MS/MS method for the determination of agomelatine in human plasma and its application to a pharmacokinetic study. Biomed Chromatogr 2014; 28: 218-222
• 11 Health Canada, Health Products and Food Branch Conduct and Analysis of Comparative Bioavailability Studies. 2012. Available from: http://www.hc-sc.gc.ca/dhp-mps/alt_formats/pdf/prodpharma/applic-demande/guide-ld/bio/gd_cbs_ebc_ld-eng.pdf Accessed June 18, 2014
• 12 Tothfalusi L, Endrenyi L, Arieta AG. Evaluation of bioequivalence for highly variable drugs with scaled average bioequivalence. Clin Pharmacokinet 2009; 48: 725-743