An investigation into the bioequivalency of four carbamazepine tablet formulations available in Kenya

Abstract

Carbamazepine is the first choice anti-epileptic drug for the control of partial and generalized tonic - clonic seizures and the treatment of trigeminal neuralgia. It exhibits variable and incomplete absorption probably due to limited aqueous solubility. Carbamazepine has a narrow therapeutic index (therapeutic concentrations of 4 - 8 ug/ml) and concentrations above 12 ug/ml lead to symptoms of toxicity. Since its therapeutic and adverse effects are closely related to its plasma levels, the bioavailability of the various formulations of carbamazepine tablets is of clinical concern. There have been reports of therapeutic failure following the substitution of the innovator product with a generic product or a change from one generic product to another. The objective of this study was to investigate the bioequivalency of four formulations of carbamazepine tablets available in the Kenyan market and to evaluate the influence of physico - chemical properties on bioavailability. The four products were: the innovator brand TegretolR (CIBA), TemporolR (Orion), TaverR (Medochemie) and Carbamazepine Lincoln. The first study involved evaluation of some physico - chemical characteristics of the tablets that may affect drug bioavailability. These included potency, content uniformity, friability, disintegration and dissolution profile. These determinations were performed according to specifications in official Compendia. The potency of Tegretol and Temporol was within the limits specified in the British Pharmacopoeia (BP) (95 - 105)% while those of Taver (90.9)% and Carbamazepine Lincoln (9l.2)% were below the BP limits. All the four products met compendial requirements for content uniformity (85 - 115)%. The friability of Tegretol and Taver was within the acceptable limits (0.8 - 1%) while that of Temporal and Carbamazepine Lincoln were not,(1.6% and 2.87% respectively). Tegretol and Temporal disintegrated rapidly «1 min.) while Taver disintegrated in 4.45 minutes, all of which were within compendial requirements, (:S15 min). Carbamazepine Lincoln failed to disintegrate (>15 min.). The dissolution profiles of Temporol and Taver were similar to that of Tegretol and met the USP requirements (:::75% in 1 hr), with over 75% of labelled dose dissolving in 45 minutes (P>0.05) while less than 40% of the labelled dose of Carbamazepine Lincoln was released within 60 minutes (P<0.05). The second study involved the determination of carbamazepine in plasma samples following oral administration of the various products according to a randomized cross-over study design. Extent of bioavailability (with reference to innovator's product) was evaluated from areas under the plasma concentration - time curves (AUCs), maximum plasma dmg concentrations (Cmax) and time to maximum plasma concentrations (Tmax). Statistical analysis (ANOVA) was used to define significant differences (P<O.05). In addition, 90% confidence intervals (CI) were calculated to determine whether the differences were clinically relevant, (80 -120% of reference product). Temporol exhibited the highest relative bioavailability (101.2%). There was no significant difference (P>0.05) between its mean AUC (197.6 ± 33.5 ug-hr/ml) and that of Tegretol (195.3 ±49.9 ug-hr/ml). The mean Cmax (4.12 ± 1.14 ug/ml) was not statistically different (P>0.05) from that of Tegretol(4.02 ±0.96j.lg/ml) while the Tmax (median, 6hr; range, 3 - 8hr) was also comparable to that of Tegretol. Taver had a relative bioavailability of 82%,mean AUC of 160.6 ± 31.2 ug-hr/ml and mean Cmax of (3.37 ± 0.46 ug/ml). The 90% percent CI of the AUC (64 -114%) and of the Cmax (0.7- 1.0) were below the official bioeqiuvalence interval(80 - 120%). The Tmax (median, 6hr; range, 4 -1Ohr) was however, comparable to that of Tegretol. Carbamazepine Lincoln exhibited the lowest relative bioavailability (72%). There was a significant difference (P<0.05) between mean Cmax (2.38 ± 0.2j.lg/ml) and that of Tegretol (4.02 ± 0.96flg/ml).Its Mean AUC (139.9 ± 16flghr/ ml) had a 90% CI of 55 - 107% which was below the official bioequivalence interval(80 - 120%). The mean Tmax of Carbamazepine Lincoln of 13.7hrs (median, 10 hr, range, 8-24hr) was approximately double that of Tegretol. The bioavailability of the four products was highly correlated to their dissolution profiles (r = 0.946). The results of this study suggest that Temporol is bioequivalent to Tegretol and could safely serve as a generic substitute in the control of epilepsy and other neurological conditions. Taver and Carbamazepine Lincoln were not bioequivalent to Tegretol and their use could result in therapeutic failure.