Bioequivalence Studies of Tacrolimus Capsule under Fasting and Fed Conditions in Healthy Male and Female Subjects

Abstract

The bioequivalence of tacrolimus (CAS 104987–11–3) 5 mg capsules was assessed in two single-dose, open-label, randomized 2-way crossover trials with a minimum washout period of 14 days; one trial was conducted under fasting condition (n = 44) and the other one under fed condition (n = 48). Blood samples were collected over a 120-h period and concentrations were assayed using a liquid chromatography tandem mass spectrometry (LC-MS/MS) method. A non-compartmental method was used for calculation of pharmacokinetic parameters. Under fasting conditions, mean AUC_0–t, AUC_0–inf and C_max were comparable between the test (296 ng · h/mL, 318 ng · h/mL and 32 ng/mL, respectively) and the reference formulations (289 ng · h/mL, 309 ng · h/mL and 33 ng/mL, respectively). T_max was reached between 1.5 and 2 h post-dose. Mean AUC_0–t, AUC_0–inf and C_max were also comparable under fed conditions (154 ng · h/mL, 169 ng · h/mL and 7.6 ng/mL, respectively, for the test and 161 ng · h/mL, 176 ng · h/mL and 7.5 ng/mL, respectively, for the reference formulation). Under fed conditions, T_max was reached between 5 and 6 h post-dose. 90 % geometric confidence intervals were all within the acceptable 80–125% limit, suggesting bioequivalence between the generic product and the innovator product.

Key words

CAS 104987–11–3 - Immunosuppressants - Tacrolimus, bioequivalence, fasting and fed condition, male and females volunteers, pharmacokinetics

• References

• 1 Prograf (tacrolimus) prescribing information. Deerfield (IL): Astellas Pharma US, Inc.; revised Apr 2006
• 2 Scott LI, McKeage K, Keam SI, Plosker GL. Tacrolimus: a further update of its use in the management of organ transplantation. Drugs. 2003; 63: 1247-97
• 3 Plosker GL, Foster RH. Tacrolimus: A further update of its pharmacology and therapeutic use in the management of organ transplantation. Drugs. 2002; (5) 323-89
• 4 Staatz CE, Tett SE. Clinical pharmacokinetics and pharmacodynamics of tacrolimus in solid organ transplantation. Clin Pharmacokinet. 2004; 43: 623-53
• 5 Venkataramanan R, Swaminathan A, Prasad T, Jain A, Zuckerman S, Warty V et al. Clinical pharmacokinetics of tacrolimus. Clin Pharmacokinet. 1995; 29: 404-30
• 6 Zahir H, McLachlan AJ, Nelson A, McCaughan G, Gleeson M, Akhlaghi F. Population pharmacokinetic estimation of tacrolimus apparent clearance in adult liver transplant recipients. Ther Drug Monit. 2005; 27: 422-30
• 7 Sabatini S, Ferguson RM, Helderman JH, Hulla R, Kirkpatrick BS, Barr WH. Drug substitution in transplantation: a National Kidney Foundation white paper. Am J Kidney Dis. 1999; 33: 389-397
• 8 Committee for Proprietary Medicinal Products. Note for guidance on investigation of bioavailability and bioequivalence (CPMP/EWP/QWP/1401/98). London, 26 Jul 2001. Available at: http://www.emea.europa.eu/pdfs/human/ewp/140198en.pdf
• 9 Center for Drug Evaluation and Research (CDER), US FDA. Industry Guidance, Bioavailability and Bioequivalence Studies for Orally Administered Drug Products - General Considerations. Rockville, Mar 2003. Available at: http://www.fda.gov/cder/guidance/5356fnl.pdf
• 10 Bekersky I, Dressier D, Colburn W, Mekki Q. Bioequivalence of 1 and 5 mg tacrolimus capsules using a replicate study design. Clin Pharmacol. 1999; 39: 1032-1037
• 11 Bekersky I, Dressler D, Boswell GW, Fergen B, Tracewell W, Mekki Q. Bioequivalence of a New Strength Tacrolimus Capsule under Development. Transplant Proc. 1998; 30: 1457-1459
• 12 Christians U, Jacobsen W, Serkova N, Benet LZ, Vidal C, Sewing KF et al. Automated, fast and sensitive quantification of drugs in blood by liquid chromatography-mass spectrometry with on-line extraction: immunosuppressants. J Chromatogr B Biomed SciAppl. 2000; 748: 41-53
• 13 Lee JW, Sukovaty RL, Farmen RH, Dressler DE, Alak A, Bekersky I. Tacrolimus (FK506): validation of a sensitive enzyme-linked immunosorbent assay kit for and application to a clinical pharmacokinetic study. Ther Drug Monit. 1997; 19: 201-207
• 14 Mancinelli LM, Frassetto L, Floren LC, Dressier D, Carrier S, Bekersky I et al. The pharmacokinetics and metabolic disposition of tacrolimus: a comparison across ethnic groups. Clin Pharmacol Ther. 2001; 69: 24-31
• 15 Nightengale SL, Morrison JC. Generic drugs and the prescribing physician. JAMA. 1987; 258: 1200-1204
• 16 American Pharmaceutical Association. Substitution of Critical Dose Drugs: Issues, Analysis, and Decision Making 2000 Available at: http://www.pharmacist.com/pdf/critical_dose.pdf