Existing and new criteria for bioequivalence evaluation of new controlled release (CR) products of carbamazepine

Bialer, M; Arcavi, L; Sussan, S; Volosov, A; Yacobi, A; Moros, D; Levitt, B; Laor, A

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Volume 32, Issue 3 , Pages 371-378, November 1998

Existing and new criteria for bioequivalence evaluation of new controlled release (CR) products of carbamazepine

M Bialer
- Department of Pharmaceutics, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, PO Box 12065, Jerusalem 91120, Israel
- David R. Bloom Centre for Pharmacy, School of Pharmacy, Faculty of Medicine, The Hebrew University of JerusalemPO Box 12065, Jerusalem 91120, Israel
- Corresponding author. Tel.: +972 2 6758610; fax: +972 2 6436246; e-mail: bialer@md2.huji.ac.il
L Arcavi
- Clinical Pharmacology Unit, Department of Internal Medicine, Kaplan Hospital, Rehovot, Israel
S Sussan
- Department of Pharmaceutics, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, PO Box 12065, Jerusalem 91120, Israel
A Volosov
- Department of Pharmaceutics, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, PO Box 12065, Jerusalem 91120, Israel
A Yacobi
- Taro Pharmaceuticals, New York, USA
D Moros
- Taro Pharmaceuticals, New York, USA
- Department of Neurology, Mount Sinai Medical School, New York, USA
B Levitt
- Taro Pharmaceuticals, New York, USA
- Department of Medicine, Albert Einstein Medical School, New York, USA
A Laor
- Department of Internal Medicine, Lady Davis Carmel Hospital, Haifa, Israel

Received 11 February 1998; accepted 5 May 1998.

Abstract

While the three classical pharmacokinetic (PK) parameters, AUC, C_max and t_max are adequate to assess bioequivalence of immediate release (IR) formulations, they are not designed to fully characterize the pharmacokinetic (PK) performance of controlled release (CR) formulations and provide only limited insight into the function of carbamazepine (CBZ) CR products. Thus, for reliable assessment of bioequivalence in CR formulations, there is a role for the use of additional criteria (parameters). The following are the proposed new parameters: MRT (mean residence time), C_max/AUC, plateau time or POT (the time span associated with the concentrations within 25% of C_max), tapical (the arithmetic mean of the times associated with POT) and Capical (the arithmetic mean of the concentrations within 25% of C_max). The above proposed parameters, were utilized in a recent PK study of new CR products of CBZ (600 mg) designed for once daily dosing. The comparative PK analysis was conducted in a three-way crossover single dose studies of three CBZ CR formulations (Teril 600 CR tablet, CBZ 600 granulate and Timonil 600 Retard tablet). Teril 600 CR was found to be bioequivalent to Timonil 600 Retard while CBZ 600 granulate was not. This conclusion was reached utilizing both the classical and the proposed new parameters. The new parameters showed that CBZ 600 granulate has similar rate of absorption as the two 600 mg CR tablets, but its extent of absorption was lower. The new parameters examined in this paper are more attractive than the single point parameters, C_max and t_max, for assessment of rate of absorption and the flatness of the plasma concentration versus time curve. Their potential benefit and practical utility was confirmed in this study, which demonstrated bioequivalence between a new CR and an innovator CBZ (600 mg) tablet. Absorption rate assessment is important in light of concentration-related side effects associated with CBZ therapy and the impact of fluctuations and the flatness of the CBZ plasma concentration curve on the drug efficacy and tolerability.