Exposure-response analysis reveals that clinically important toxicity difference can exist between bioequivalent carbamazepine tablets.
OBJECTIVE
To assess whether, using the current regulatory criteria, therapeutically important differences can exist between bioequivalent carbamazepine (CBZ) tablets. A secondary goal was to demonstrate quantitatively the relationship between the risk of neurological adverse effects to orally ingested CBZ and the rate of absorption.


METHODS
Results of a bioequivalence study by Olling et al. (Biopharm Drug Dispos 1999; 20: 19-28) were reanalysed. Following an exploratory data analysis step, a mixed-effect pharmacokinetic-pharmacodynamic (PK-PD) model was built to describe the dependence of adverse events on the CBZ concentration.


RESULTS
Rapid development of tolerance was demonstrated for most neurological adverse effects, with a characteristic half-life of 02.29 h and an initial EC50 of 2.33 mg l(-1). The resulting tolerance PK-PD model was characterized further using the tools and terminology of sensitivity analysis. It was demonstrated that the maximum concentration (C(max)) exhibits poor PK and PD sensitivities, and that clinically significant differences can exist between formulations which otherwise comply with the bioequivalence requirements. In contrast, another PK metric, the partial AUC, was a much better marker of the early neurological adverse events observable during the absorption phase of the drug.


CONCLUSIONS
In clinical and regulatory considerations, the development of acute tolerance for adverse effects of CBZ must be taken into account. Partial AUC reflects more sensitively the risk of adverse events than C(max). Instead of the current trend of tightening of the bioequivalence criteria for narrow therapeutic index drugs, the use of alternative, more sensitive PK metrics is proposed.
Tothfalusi
Laszlo
L
Department of Pharmacodynamics, Semmelweis University, Budapest, Hungary.
Speidl
Szilvia
S
Endrenyi
Laszlo
L
D000927:Anticonvulsants / Q000009:adverse effects* / Q000493:pharmacokinetics; D019540:Area Under Curve; D002220:Carbamazepine / Q000009:adverse effects* / Q000493:pharmacokinetics; D002490:Central Nervous System / Q000187:drug effects*; D006801:Humans; D012016:Reference Values; D013810:Therapeutic Equivalency; D013997:Time Factors
D000927:Anticonvulsants; D002220:Carbamazepine
Eur J Pharm Sci. 2003 May;19(1):45-56
12729861
J Psychopharmacol. 2003 Sep;17(3):269-72
14513917
Acta Neurol Scand. 2004 Jun;109(6):374-7
15147458
Acta Pharmacol Toxicol (Copenh). 1978 Oct;43(4):306-10
362821
Eur J Clin Pharmacol. 1979 Jul;15(6):421-5
583039
Epilepsia. 1980 Aug;21(4):341-50
7398602
Epilepsia. 1984 Aug;25(4):476-81
6540170
Int J Clin Pharmacol Ther Toxicol. 1985 Apr;23(4):226-32
3997307
Int J Clin Pharmacol Ther Toxicol. 1991 Oct;29(10):394-9
1748540
Arzneimittelforschung. 1992 Mar;42(3):284-8
1497685
Pharm Res. 1992 Nov;9(11):1380-5
1475222
Pharm Res. 1995 Jun;12(6):937-42
7667204
Seizure. 1996 Mar;5(1):1-5
8777549
Pharm Res. 1995 Dec;12(12):1845-55
8786955
Pharm Res. 1996 Mar;13(3):453-6
8692741
Ther Drug Monit. 1998 Feb;20(1):56-9
9485555
Drug Saf. 2000 Sep;23(3):173-82
11005701
Pharmacol Ther. 2000 Oct;88(1):33-58
11033383
Pharm Res. 1998 Mar;15(3):399-404
9563068
Epilepsia. 1998 May;39(5):513-9
9596204
Eur J Clin Pharmacol. 1998 Apr;54(2):185-92
9626926
Pharm Res. 1998 Nov;15(11):1787-91
9834004
Biopharm Drug Dispos. 1999 Jan;20(1):19-28
10086834
Clin Pharmacol Ther. 1999 Apr;65(4):389-94
10223775
Transplant Proc. 1999 May;31(3):1642-4; discussion 1675-84
10331032
Neurology. 1999 Oct 12;53(6):1170-4
10522867
Curr Top Med Chem. 2005;5(1):3-14
15638774
J Heart Lung Transplant. 2005 Aug;24(8):1076-80
16102443
J Pharmacokinet Pharmacodyn. 2005 Apr;32(2):185-97
16283534
AAPS J. 2005;7(3):E503-12
16353928