Bioequivalence evaluation of two strengths of risperidone tablet formulations in healthy volunteers.

OBJECTIVE: The objective of the study was to evaluate bioequivalence of two strengths (1 and 2 mg) of oral risperidone tablet formulations (test product manufactured by Vita-Invest, S.A., Barcelona, Spain, reference product manufactured by Janssen-Cilag Ltd., UK). SUBJECTS AND METHODS: In each of the 2 studies, 30 healthy volunteers were administered 1 or 2 mg, respectively, of test or reference formulation under fasting conditions in an open, two-way crossover, controlled, randomized and single-site fashion. Blood withdrawal was performed prior to dosing as well as 15 min, 30 min, 1 h, 1.5 h, 2 h, 3 h, 5 h, 8 h, 12 h, 16 h, 24 h, 48 h, 72 h, and 96 h after drug administration. Plasma concentrations of risperidone and its metabolite 9-hydroxy-risperidone were analyzed using LC/MS/MS. Descriptive data of AUC0-t, AUC0- yen, Cmax, and Cmax/AUC0- yen were log-transformed to evaluate bioequivalence based on the ratios of the geometric means of test and reference formulations. tmax was analyzed using nonparametric methods. RESULTS: The results show that in both studies, 1 and 2 mg formulations, the 90% confidence intervals for the geometric means ratios of the test and reference products for both the parent compound risperidone and its metabolite 9-hydroxy-risperidone were all within the bioequivalence acceptance criteria of 0.80 - 1.25 of the European CPMP and the US FDA guidelines, with the exception of tmax for risperidone parent compound in the 2 mg formulation, which was slightly suprabioequivalent for test formulation. CONCLUSION: This study demonstrated the bioequivalence between the test and the reference product of risperidone of both 1 and 2 mg formulations. Both formulations of each strength may, therefore, be prescribed interchangeably.

The use of evidence in pharmacovigilance. Case reports as the reference source for drug withdrawals.

OBJECTIVE: Withdrawal of a drug from the market for safety reasons is a serious and sometimes complex decision. The scientific evidence supporting drug withdrawals in the past years is critically appraised. METHODS: With data provided by the Spanish Medicines Agency, all drugs withdrawn from the Spanish market for safety reasons from January 1990 to December 1999 were identified. The adverse drug reactions (ADRs) were classified by the year of withdrawal, by the organ/system affected and by the alleged type of reaction (Rawlins and Thompson classification). A systematic review of the literature was performed. RESULTS: A total of 22 drugs were withdrawn from the market due to safety reasons. In 18 of 22 cases (82%), the evidence supporting the drug withdrawal came from individual case reports, cases series or the combination of data provided by randomised clinical trials and case reports. Hepatic (eight cases) and cardiac (five cases) reactions accounted for 59% (13 of 22) of the total withdrawals. In 10 of 22 (45%) cases, drug withdrawal was clearly due to type-B reactions. Only four withdrawals were based on evidence from observational studies including a comparison group. CONCLUSION: Case reports are the main source of information used to withdraw a drug from the market for safety reasons. It is necessary to improve the quality of evidence supporting the withdrawal process of drugs linked to unexpected and severe ADRs. The use of large databases to perform cohort or nested case-control analyses is the most efficient and reliable method to study type-A class effect ADRs. The implementation of such databases in different countries could increase the quality of the information on ADRs by allowing researchers to conduct efficiently these type of studies.

Determination of stavudine in human plasma and urine by high-performance liquid chromatography using a reduced sample volume.

Sensitive high-performance liquid chromatographic assays have been developed for the quantification of stavudine (2',3'-didehydro-3'-deoxythymidine, d4T) in human plasma and urine. The methods are linear over the concentration ranges 0.025-25 and 2-150 microg/ml in plasma and urine, respectively. An aliquot of 200 microl of plasma was extracted with solid-phase extraction using Oasis cartridges, while urine samples were simply diluted 1/100 with HPLC water. The analytical column, mobile phase, instrumentation and chromatographic conditions are the same for both methods. The methods have been validated separately, and stability tests under various conditions have been performed. The detection limit is 12 ng/ml in plasma for a sample size of 200 microl. The bioanalytical assay has been used in a pharmacokinetic study of pregnant women and their newborns.