How Improved Sensitivity of Bioassays and Terminal Half-Life of Drugs Impact on Bioequivalence Trials

Abstract

In planning comparative bioavailability and bioequivalence trials, the half-life of the parent compound and metabolites included in the active moiety requires careful attention. Drugs cleared with long or very long half-lives, mainly in cases of clearance from a deep compartment, could suffer from an inappropriate prevision of the half-life. Prevision of a too short half-life would produce shorter blood sampling and wash-out periods with critical consequences on the extrapolation of AUC to infinity and on a possible carryover effect of the circulating concentration of analytes in the pre-dose sample of the second study period. This problem is further complicated by the evidence that half-lives are influenced by the low limit of quantification of the bioassay method (inverse correlation) and by the blood sampling period (direct correlation). Examples of tamoxifen (CAS 10540-29-1) and its active metabolite desmethyl-tamoxifen and ramipril (CAS 87333-19-5) and its active metabolite ramiprilat are described on the basis of experimental data, focusing on the clearance from a deep compartment occurring with ramiprilat.

Key words

Bioassay - Bioequivalence - Clearance - Guidelines - Terminal half-life

• References

• 1 US Dept of Health and Human Services. Guidance for industry. Bioavailability and bioequivalence studies for orally administered drug products: general conditions – Draft guidance; 2002.
• 2 Note for guidance on the investigation of bioavailability and bioequivalence. CPMP/EWP/QWP/1401/98; 2001.
• 3 Draft Guideline on the investigation of bioequivalence. Doc. Ref. CPMP/EWP/QWP/1401/98 Rev. 1.
• 4 Marzo A. Pharmacokinetic analysis, bioavailability and operating guidelines. J Pharm Pharmacol. 1997; 49: 1259-60
• 5 Marzo A. Open questions in bioequivalence: an updated reappraisal. Curr Clin Pharmacol. 2007; 2: 179-89
• 6 Marzo A, Ceppi Monti N, Vuksic D. Experimental, extrapolated and truncated areas under the concentration-time curve in bioequivalence trials. Eur J Clin Pharmacol. 1999; 55: 627-31
• 7 Marzo A. Crossover design in tamoxifen bioequivalence: a borderline situation. J Pharm Pharmacol. 1998; 50: 1433-4
• 8 Lonning PE, Lien EA, Lundgren S, Kvinnsland S. Clinical pharmacokinetics of endocrine agents used in advanced breast cancer. Clin Pharmacokinet. 1992; 22: 327-58
• 9 Marzo A, Dal Bo L. Tandem mass spectrometry (LC-MS-MS): a predominant role in bioassays for pharmacokinetic studies. Arzneimittelforschung. 2007; 57: 122-8
• 10 Thuillez C, Richer C, Giudicelli JF. Pharmacokinetics, converting enzyme inhibition and peripheral arterial hemodynamics of ramipril in healthy volunteers. Am J Cardiol. 1987; 59: 38D-44D
• 11 Witte PU, Irmisch R, Hajdú P, Metzger H. Pharmacokinetics and pharmacodynamics of a novel orally active angiotensin converting enzyme inhibitor (HOE 498) in healthy subjects. Eur J Clin Pharmacol. 1984; 27: 577-81
• 12 Gilchrist WJ, Beard K, Manhem P, Thomas EM, Robertson JI, Ball SG. Pharmacokinetics and effects on the renin-angiotensin system of ramipril in elderly patients. Am J Cardiol. 1987; 59: 28D-32D
• 13 Lu XY, Shen-Tu JZ, Liu J. High-performance liquid chromatography-mass spectrometric analysis of ramipril and its active metabolite ramiprilat in human serum: application to a pharmacokinetic study in the Chinese volunteers. J Pharm Biomed Anal. 2006; 40: 478-83
• 14 Mendes GD, Dantas ATSanfelice, do Carmo NCBorges, Cavedal LE, Sverdloff C, Prado MGaluppo et al. Comparative bioavailability of two ramipril formulations after single-dose administration in healthy volunteers. Int J Clin Pharmacol Ther. 2006; 44: 93-8
• 15 Eckert HG, Badian MJ, Gantz D, Kellner HM, Volz M. Pharmacokinetics and biotransformation of 2-[N-[(S)-l-ethoxy-carbonyl-3-phenylpropyl]-L-alanyl]-(lS,3S,5S)-2-azabicyclo-[3.3.0] octane-3-carboxylic acid (Hoe 498) in rat, dog and man. Arzneimittelforschung. 1984; 34: 1435-47