Bioequivalence trials simulation to select the best analyte for acetylsalicylic acid
Cuesta-Gragera, A(1); Mangas-Sanjuan, V(2); Navarro-Fontestad, C(1); Gonzalez-Alvarez, I(2); Bermejo, M(2); Casabó, VG(1)
(1) Pharmaceutics and Pharmaceutical Technology Departament, University of Valencia. (2) Department of Engineering, Pharmaceutics and Pharmaceutical Technology Area. University Miguel Hernández, Elche.
Introduction: The analyte (parent drug or metabolite) to be evaluated in bioequivalence trials is still today a controversial issue, with different solutions in EMA and FDA guidance:
- FDA: Measurement of a metabolite may be preferred when parent drug levels are too low to allow reliable analytical measurement. Measurement of metabolite(s) is required in addition to the parent drug when metabolite(s) contributes meaningfully to safety and/or efficacy and is(are) formed as a result of pre-systemic metabolism [1].
- EMA: When an inactive pro-drug have low plasma concentrations and is quickly eliminated, it is acceptable to demonstrate bioequivalence for the main active metabolite instead of parent compound. The use of a metabolite as a surrogate for an active parent compound can only be considered if it is not possible to reliably measure the parent compound, and if the metabolite formation is not saturated at therapeutic doses [2].
The EMA and FDA guidelines generally recommended measuring the parent drug bioequivalence, but the situations in which are recommended the measurement of metabolite are different. The objective is to evaluate which analyte (parent drug or metabolites) is more sensitive to detect changes in the quality of the problem medicinal product.
Materials and methods: The pharmacokinetic model used represents the LADME process of ASA administered orally in a solid dosage form for immediate release. Different scenarios depending on the in vivo dissolution constant of the problem formulation and dose have been considered.A semi-physiological model was used including pre-systemic intestinal and hepatic metabolism and Michaelis-Menten elimination with two metabolites (first and second-generation metabolites of ASA) [3].The studies were simulated using NONMEM VI.
Results: The plasma concentration-time population fit the experimental curves of the literature [4], so the model is considered validated. The analyte sensitive to decline in quality is the ASA, and the decrease of ratios of AUC and Cmax is more noticeable with increasing dose. The percentages of bioequivalence when drugs are not bioequivalent is lower for the parent drug, and this percentage decreases with increasing dose.
Conclusions: The ASA is more sensitive than its metabolites to detect the decrease in pharmaceutical quality. The measurement of metabolites of first and second generation does not provide any additional information to the parent drug.
References:
[1] FDA. Guidance for industry. Bioavailability and bioequivalence studies for orally administered drug products- General considerations. Center for Drug Evaluation and Research (CDER) (2003).
[2] EMA. Guideline on the investigation of bioequivalence. Committee for Medicinal Products for Human Use (CHMP) (2010)
[3] C. Fernandez-Teruel et al. Computer simulations of bioequivalence trials: selection of design and analyte in BCS drugs with first-pass hepatic metabolism: Part II. Non-linear kinetics. Eur J Pharm Sci. 36:147-156 (2009).
[4] Brantmark B et al. Bioavailability of acetylsalicylic acid and salicylic acid from rapid-and slow-release formulations, and in combination with dipyridamol. Eur J Clin Pharmacol. 22: 309-314 (1982)
Acknowledgements: This work is supported by project SAF-2009-12768 funded by Spanish Ministry of Science and Innovation.