METHODS: The intrasubject coefficient of variation was estimated from the residual mean square error obtained from analysis of variance of the parameters AUC0-infinity, Cmax and Cmax/AUC0-infinity after logarithmic transformation. The test power in the analyses of the above parameters was subsequently estimated using nomograms provided by Diletti et al. [1991].
RESULTS AND CONCLUSION: Thirty products covering 16 drugs were studied in which 22 were immediate-release (including one dispersible tablet) and 8 were sustained-release formulations. The intrasubject coefficient of variation for the parameter AUC0-infinity was smaller than Cmax, and hence considerably more studies were able to attain a power of greater than 80% using 12 volunteers for the AUC0-infinity, compared to the Cmax. However, the variability in the Cmax could be reduced by using the parameter Cmax/ AUC0-infinity, and thus, provide a more realistic estimation of sample size, since the latter reflects only the rate of absorption and not both the rate and extent as in the case of Cmax [Endrenyi et al. 1991].
METHODS: Xenical 120 mg capsules (Roche, Basel, Switzerland) were used as reference material. Generic products were from India, Malaysia, Argentina, Philippines, Uruguay, and Taiwan. Colour, melting temperature, crystalline form, particle size, capsule fill mass, active pharmaceutical ingredient content, amount of impurities, and dissolution were compared. Standard physical and chemical laboratory tests were those developed by Roche for Xenical.
RESULTS: All nine generic products failed the Xenical specifications in four or more tests, and two generic products failed in seven tests. A failure common to all generic products was the amount of impurities present, mostly due to different by-products, including side-chain homologues not present in Xenical. Some impurities were unidentified. Two generic products tested failed the dissolution test, one product formed a capsule-shaped agglomerate on storage and resulted in poor (=15%) dissolution. Six generic products were powder formulations.
CONCLUSIONS: All tested generic orlistat products were pharmaceutically inferior to Xenical. The high levels of impurities in generic orlistat products are a major safety and tolerability concern.
MATERIALS AND METHODS: A randomized, 2-treatment, 2-period, 2-sequence, single dose, crossover with a washout period of 2 weeks, was conducted in 24 healthy Thai male volunteers. Blood samples were collected at 0, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24, 36, 48, 72 and 96 h following drug administration. Plasma concentrations of risperidone and 9-hydroxyrisperidone were determined using a validated LC-MS-MS method. The pharmacokinetic parameters of risperidone and 9-hydroxyrisperidone were determined using a non-compartmental model.
RESULTS: The geometric means ratios (%) and 90% confidence interval (CI) of the test and reference products for the log-transformed pharmacokinetic parameters, Cmax, AUC0-t and AUC0-inf of risperidone were 104.49 % (92.79% - 117.66%), 100.96 % (92.15% - 110.61 %) and 97.99 % (90.72% - 105.85%). The 90% CI of geometric means ratios of the test and reference products for the log-transformed pharmacokinetic parameters, Cmax, AUC0-t and AUC0-inf of 9-hydroxyrisperidone were 97.00%, 96.97% and 97.49%.
CONCLUSIONS: The 90% CI for the geometric means ratios (test/reference) of the log-trasformed Cmax, AUC0-t and AUC0-inf of risperidone and its major active metabolite were within the bioequivalence acceptance criteria of 80% - 125% of the US-FDA.
SETTING: A sample of 1419 Malaysian community pharmacies with resident pharmacists.
METHOD: A cross-sectional nationwide survey using a self-completed mailing questionnaire.
MAIN OUTCOME MEASURE: Pharmacists' views on generic medicines including issues surrounding efficacy, safety, quality and bioequivalence.
RESULTS: Responses were received from 219 pharmacies (response rate 15.4%). Only 50.2% of the surveyed pharmacists agreed that all products that are approved as generic equivalents can be considered therapeutically equivalent with the innovator medicines. Around 76% of respondents indicated that generic substitution of narrow therapeutic index medicines is inappropriate. The majority of the pharmacists understood that a generic medicine must contain the same amount of active ingredient (84.5%) and must be in the same dosage form as the innovator brand (71.7%). About 21% of respondents though that generic medicines are of inferior quality compared to innovator medicines. Most of the pharmacists (61.6%) disagreed that generic medicines produce more side-effects than innovator brand. Pharmacists graduated from Malaysian universities, twinning program and overseas universities were not differed significantly in their views on generic medicines. Additionally, the respondents appeared to have difficulty in ascertaining the bioequivalent status of the marketed generic products in Malaysia.
CONCLUSION: The Malaysian pharmacists' have lack of information and/or trust in the generic manufacturing and/or approval system in Malaysia. This issue should be addressed by pharmacy educators and relevant government agencies.