Cuesta-Gragera, A(1); Mangas-Sanjuan, V(2); Navarro, C(1); Gonzalez-Alvarez, I(2); Bermejo, M(2); Casabó, VG(1).
(1) Pharmaceutics and Pharmaceutical Technology Department, University of Valencia. (2) Department of Engineering, Pharmaceutics and Pharmaceutical Technology Area. University Miguel Hernández, Elche.
Iintroduction: 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 guidances [1], [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: 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]. Different scenarios depending on the in vivo dissolution rate constant of the problem formulation and dose have been considered, in order to evaluate the loss of sensitivity of parent drug to detect differences between formulations. 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 in most of cases but not all of them: when there is a large difference between reference and test dissolution rate constant values, in case of 1000 mg of administered dose, SA becomes more sensitive than ASA.
Conclusions: The ASA is more sensitive than its metabolites to detect the decrease in pharmaceutical quality, but not in all cases. The measurement of first generation metabolite could 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.
Reference: PAGE 21 () Abstr 2443 [www.page-meeting.org/?abstract=2443]
Poster: Absorption and Physiology-Based PK