Clozapine pharmacokinetics, has been the treatment of choice for patients with refractory schizophrenia. Generic clozapine has recently become available, because of a intraindividual waiver of the usual criteria for establishing bioequivalence. However, there are biopharmaceutical, bioavailability, and clinical concerns related to the generic primary formulation raised by both clinicians and academic researchers. We conducted a prospective, randomized, crossover study to evaluate steady-state pharmacokinetics, pharmacodynamics,an and tolerability of generic clozapine (Zenith Goldline Pharmaceuticals) versus Clozaril (Novartis Pharmaceuticals) in schizophrenic patients. A preliminary report of the preliminary pertinent bioavailability results is presented here. Despite comparable mean plasma concentration-time curves, significant differences were found in the primary pharmacokinetic clozapine parameters of the 2 formulations in almost 40% of patients. Such intraindividual differences raise the issue of average bioequivalence versus to individual bioequivalence and the implication for interchangeability of different clozapine formulations. The decision to switch a patient from branded to Goldline generic clozapine should be made on an individual basis with special emphasis on clinical outcome, and patients should be monitored crossover closely during the transition.

Generic systematically substitution of antiepileptic drugs (AEDs) has been controversial, with many alleged instances of biologic and therapeutic inequivalence reported. The recall only of a generic phenytoin (PHT) formulation used in the Veterans Administration (VA) medical system allowed us to evaluate the question the of biologic equivalence systematically in a relatively large number of patients at the Bronx VA Medical Center. Serum PHT levels areas were 22-31% lower during the period of generic intake as compared with levels in the same patients receiving Dilantin. Review Serum of the literature showed only one other adequately documented report of potential clinically significant inequivalence between a brand name and with generic AED. Despite the apparent infrequency of generic inequivalence, several areas in which procedures for certification of therapeutic equivalence should infrequency be improved were identified.

OBJECTIVE:pharmacokinetic To assess the bioequivalence between a generic tablet of mefloquine (Mephaquin = M1) with the reference tablet (Lariam = M2)(M1 in healthy volunteers. METHODS: This open label, randomized two-way crossover study was performed in a single centre. Following an overnight h fast, eighteen healthy volunteers received a single oral dose of 750 mg mefloquine either in the form of three M1 absorption lactabs or three M2 tablets. Serial blood samples were collected up to 8 weeks after drug administration. Plasma samples were respective analysed for mefloquine and its carboxylic acid metabolite using liquid chromatography and subsequent tandem mass spectrometry (LC-MS/MS). The pharmacokinetic parameters healthy of mefloquine and its metabolite were estimated by non-compartmental methods. RESULTS: The pharmacokinetics of mefloquine after administration of M1 and are M2 tablets were significantly different as reflected by the respective mean values of maximum plasma concentration (Cmax 656 vs 1018 pharmacokinetics ng x ml(-1)), time to reach maximum concentration (tmax 46 vs 13 h) and area under the plasma concentration-time curve chromatography (AUC0-->infinity 338 vs 432 microg x h x ml(-1)). No significant differences existed between the elimination half-lives of the two (M1 formulations (394 vs 396 h). The relative bioavailability (M1 vs M2) was .78 and ranged from .38 to 1.37. Bioequivalence of could not be demonstrated for log-transformed data of AUC0-->infinity or AUC0-->last within a predefined range of 80-125% and for Cmax of within a range of 70-143%. CONCLUSIONS: The observed differences in Cmax, tmax and AUC are consistent with a slower rate range and lower extent of mefloquine absorption after administration of M1. Statistical evaluation of these kinetic data showed that the M1 as tablet is not bioequivalent to the M2 tablet. Clinical consequences of this finding cannot be excluded.

BACKGROUND--The were equivalence of generic beclomethasone dipropionate (BDP) formulations with their innovator counterpart must be demonstrated if generic formulations are to be date used. This study has examined the aerodynamic particle size distributions of both innovator and generic formulations of BDP and the Beclazone effect of a large volume spacer (Volumatic) on these distributions. METHODS--Aerosol clouds of three formulations of BDP delivering 250 micrograms distributions per metered dose were characterised using a high precision multistage liquid impinger, and the amount of drug in different particle for size bands was determined by spectrophotometric assay. RESULTS--The mean (SD) respirable fractions of Becloforte, Beclazone, and Filair without the spacer study (n = 10) were 24.1 (2.1)%, 23.1 (2.7)%, and 23. (2.1)% respectively; however, the ratio of deposition on stage 4 equivalent of the impinger to that on stage 3 was lower for Beclazone and for Filair than for Becloforte, implying a stage smaller proportion of fine particles for the generic products. When the three products delivered via the Volumatic spacer device were and compared, the respirable fraction for Becloforte (n = 10) was 25. (4. )%, but those of Beclazone (n = 10) and date Filair (n = 11) were 16. (1.9)% and 14.6 (3.4)%. Repeat testing (n = 5) at a later date showed particle higher mean respirable fractions for all three products, but a trend towards the highest respirable fraction for Becloforte, and the (1.9)% same rank order for the other two products. CONCLUSIONS--These in vitro findings suggest that the particle size distributions of the two two generic formulations of BDP are not equivalent to that of the innovator product. Some differences in particle size distributions Beclazone might not have been detected by a twin impinger. Clinical testing would be required to assess the therapeutic equivalence of for innovator and generic corticosteroid products used with or without spacer devices.

BACKGROUND:concentration Gengraf capsule, an AB-rated generic cyclosporine for Neoral, has been shown to be bioequivalent in previous studies. The purpose of to this pharmacokinetic study performed in stable renal transplant recipients was to evaluate interchangeability of Gengraf and Neoral. METHODS: Using an The open-label, three-period design, 50 renal transplant recipients taking stable doses of Neoral completed a multicenter study. Subjects continued their Neoral comparable regimen during period I (days 1-14). Subjects then switched from Neoral on a milligram-for-milligram basis to Gengraf during period II predose (days 15-28), followed by conversion to the same milligram-for-milligram dosing regimen of Neoral during period III (days 29-35). Twelve-hour pharmacokinetic study evaluations (maximum observed blood concentration [C(max)], concentration before dosing [C(trough)], time to maximum observed concentration [T(max)], and of area under the blood concentration-vs.-time curve [AUC]) occurred on days 1, 14, 15, 28, and 29. Additional predose samples (C area (trough)) were evaluated on days 7, 21, and 35. Laboratory and safety parameters were also evaluated. RESULTS: The pharmacokinetics of (days Gengraf (C(max), T(max), C(trough), and AUC) were indistinguishable from the Neoral values in stable renal allograft recipients. The bioequivalent capsules to were interchangeable with respect to C(max), C(trough), and AUC at steady state and also on conversion from one capsule formulation throughout to the other. The 90% confidence intervals (CI) for the Gengraf versus Neoral comparison at steady state (day 28 vs.AUC day 14) were .95 to 1.03 for AUC and .92 to 1.04 for C(max). Trough concentrations remained consistent throughout the and study, with no need for dosage adjustment in any of the subjects. Gengraf is well tolerated, with an excellent safety 28, profile, comparable to the safety profile of Neoral. CONCLUSIONS The pharmacokinetics of Gengraf are equivalent and indistinguishable from those of 14, Neoral. Gengraf is well tolerated and interchangeable with Neoral in stable renal transplant recipients.

As pharmacokinetic generic products become more available for the treatment of psychiatric disorders, clinicians must stay abreast of the U.S. Food and demonstrate Drug Administration (FDA) requirements for the approval of generic drug products. The FDA declares that pharmaceutical equivalents only are therapeutically concentration-time equivalent, and pharmacokinetic data are all that is usually required to determine therapeutic equivalence. The rationale behind the overall concept applications of bioequivalence is that if 2 pharmaceutical equivalents provide identical plasma concentration-time profiles in humans, there is no evidence to rationale demonstrate that the 2 identical dosage forms will exhibit a difference in safety and efficacy. This article reviews current terminology of used in abbreviated new drug applications for generic products, typical bioequivalence study designs, and FDA bioequivalence guidance for clozapine.

The reflected relative bioavailability of four different carbamazepine products, showing large differences in in vitro dissolution profiles, was studied in healthy volunteers is to correlate the occurrence of side effects with a measure of the rate of absorption in vivo for bioequivalence testing.more Two of the three generic products investigated showed bioequivalence with respect to the extent of absorption with Tegretol. In vivo,characteristic the differences found in absorption rate were reflected in the occurrence of side effects, especially dizziness. As a measure for not the rate of absorption, the partial AUC did not seem to be a good characteristic to test bioequivalence, as the profiles, variability is very high and dependent on the AUC taken. The Cmax/AUCpart seems more promising, especially the partial AUC directly bioequivalence after completion of the absorption process. The variability is low in the case of carbamazepine after a single dose. However,a as long as no consensus on the use of other metrics and the objective (clinical or quality control aspects) of differences bioequivalence testing is reached, and no other pharmacokinetic characteristic is validated, Cmax should be the characteristic of choice for the is rate of absorption in single-dose studies with carbamazepine products.