PHARMACOKINETIC AND MATHEMATICAL
OUTLIERS FOR DRUGS WITH ACTIVE
METABOLITES. NOTE I. MODEL INDEPENDENT
ANALYSES FOR PENTOXIFYLLINE.
CONSTANTIN MIRCIOIU1*, GEORGETA IONICA1, ALA
DANILCEAC1, DALIA MIRON1, IONUT MIRCIOIU2, FLAVIAN
RADULESCU1
1University of Medicine and Pharmacy “Carol Davila”, Bucharest,
Romania, Faculty of Pharmacy, 6 Traian Vuia st.
2Biopharmacy & Pharmacol Research, Bucharest, Romania
*corresponding author: constantin.mircioiu@yahoo.com
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Abstract:

The paper presents the difficulties in establishing the bioequivalence of formulations containing pentoxifylline, following a high variability of both absorption and metabolism.
The paper presents the case of two true outliers giving discordant results even after the evaluation of the sum of active substances (i.e parent drug and metabolites). Examined parameters included C_max (maximum concentration), AUC (area under the curve) after single dose and in steady-state after multiple doses, and their ratios. The comparison was made both intra and inter- subjects.
The result was that two subjects were essentially outliers, but only a part of parameters or combinations of parameters showed discordant values.
The conclusion was that the evaluation of bioequivalence would be more efficient or rational starting from the sum of active entities, than separately, as they are required by the current EMEA (European Medicines Agency) Regulations.

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