J. D. Gómez-Mantilla(1), U. F. Schäfer(1), T. Lehr(2) ,V. G. Casabó(3), C. M. Lehr(4)
(1) Biopharmaceutics and Pharmaceutical Technology, Saarland University, Saarbruecken, Germany; (2) Clinical Pharmacy, Saarland University, Saarbruecken, Germany; (3)Department of Technological Pharmacy, University of Valencia, Burjassot, Spain; (4) Helmholtz-Institute for Pharmaceutical Research (HIPS), Helmholtz Center for Infection Research (HZI), Saarbruecken, Germany
Objectives: Current alternatives for performing dissolution profile comparisons are limited to mathematical distances in which limits for declaring similarity or non-similarity are fixed, drug-unspecific and not based in any biopharmaceutical criteria. This study is aimed to develop drug-specific Dissolution Profile Comparisons able to detect the differences in release profiles between different formulations that can lead to differences in the in-vivo performance (Bioequivalence) of the formulations, using IVIVc models, computer simulated bioequivalence trials and permutation tests.
Methods: Extended release formulations of Metformin, Diltiazem and Pramipaxole were included in the study [1,2]. Available published differential equations based IVIVc models were employed using one (Metformin and Diltiazem) or two (Pramipaxole) compartment models. Release profiles were modelled using Hill and Weibull equations; Bio-relevant limits in the dissolution profiles were detected identifying the change in Hill or Weibull parameters necessary to produce non-bioequivalent formulations. Bioequivalence cross over studies were simulated with 12 healthy volunteers and Intra Individual Variability was described to fit available population data. Customization of dissolution profiles comparisons was made by adjusting the delta of a recently described Tolerated Difference Test (TDT)[3], this delta value was tailored for each formulation to detect the differences in release profiles identified as bio-relevant limits with the IVIVc models. Effect of Number of patients, Number of time points and drug properties (ka, kel) were studied in these customizations.
Results: Bio-relevant limits in release profiles differences were identified for all three formulations. Delta values for TDT were tailored for each formulation as follows: 3.8 for Metformin, 5.8 for Diltiazem and 3.5 for pramipaxole, this value represents the average tolerated difference (in Percentage) between two formulations at any time point to produce bio-equivalent formulations under both criteria AUC and Cmax. Total overlap of zones was not possible, but safe zones (Bioequivalent formulations under Cmax or AUC criteria) were totally identified. The studied variables had a greater impact in the bioequivalence decisions made by Cmax than by AUC, especially Ka and kel.
Conclusion: TDT test allows customization of formulation-specific dissolution profile comparisons of extended released formulations with bio-relevant limits.
References
[1] P. Buchwald, Direct, differential-equation-based in-vitro-in-vivo correlation (IVIVC) method, J Pharm Pharmacol, 55 (2003) 495-504.
[2] E. Soto, S. Haertter, M. Koenen-Bergmann, A. Staab, I.F. Troconiz, Population in vitro-in vivo correlation model for pramipexole slow-release oral formulations, Pharm Res, 27 (2010) 340-349.
[3] J.D. Gomez-Mantilla, V.G. Casabo, U.F. Schaefer, C.M. Lehr, Permutation Test (PT) and Tolerated Difference Test (TDT): Two new, robust and powerful nonparametric tests for statistical comparison of dissolution profiles, Int J Pharm, 441 (2013) 458-467.
Reference: PAGE 22 (2013) Abstr 2677 [www.page-meeting.org/?abstract=2677]
Poster: Other Modelling Applications