| dc.description.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. | en |
