Methylphenidate bioavailability from two extended-release formulations.

OBJECTIVE: The objective of these studies was to compare the rate and extent of absorption of d,l-threo-methylphenidate (MPH) from two extended-release products--a capsule formulation containing coated beads and an OROS tablet formulation--in healthy male and female subjects under fasted conditions. MATERIALS: Metadate CD (methylphenidate HCl, USP) Extended-Release Capsules and Concerta (methylphenidate hydrochloride) Extended-Release Tablets. METHODS: Two studies were conducted: (1) A single dose, randomized, two-way crossover study in 36 adults comparing a 20 mg capsule and an 18 mg tablet, and (2) a single dose, randomized, four-way crossover study in 24 adults comparing 2 x 20 mg capsules, one 36 mg tablet, 3 x 20 mg capsules and one 54 mg tablet. Blood samples were collected over 24 hours and MPH plasma concentrations were used to calculate pharmacokinetic parameters for each treatment. Equivalence of pharmacokinetic parameters for comparable doses of the formulations was concluded if the 90% confidence intervals (CI) for the ratio between test and reference means were within the 80-125% equivalence criterion. RESULTS: Both formulations exhibited biphasic plasma concentration-time profiles and were equivalent in terms of total exposure (AUC(0-last) and AUC(0-infinity)). However, early exposure (AUC(0-4) and AUC(0-6), the first maximum measured plasma concentration (C(max-1), and early plasma MPH concentrations (1.5, 3 and 4 hours) were greater with the capsule formulation, while later plasma MPH concentrations (8, 10 and 12 hours) were greater with the tablet formulation (the CIs were outside the 80-125% required for equivalence and p < 0.001 for all). Similar results were obtained whether or not the data were normalized for the difference in total dose. CONCLUSIONS: The two formulations are not bioequivalent. The capsule fonnulation produces greater exposure to MPH and higher MPH concentrations during the first 6 hours following dosing. MPH is frequently used in school children, and this period would correspond to a major part of the school day.

Effect of albumin on the estimation, in vitro, of phenytoin Vmax and Km values: implications for clinical correlation.

The effect of bovine serum albumin (BSA) on human liver metabolism, in vitro, of 14C-phenytoin (PHT) was studied. Michaelis Menten parameters were determined for the conversion of PHT to p-hydroxy phenytoin in seven different microsomal preparations with the addition of 0, 2, and 4% BSA. The unbound Km (Kmu) values were 30.8 +/- 18.6, 1.57 +/- 0.21 and 1.50 +/- 0.17 microM (mean +/- S.D.), respectively; however, there was excellent agreement among the Vmax values (29.1, 31.8 and 31.5 pmol/min/mg). With intact tissue slices, BSA (4%) added to incubations of PHT had a minimal effect on the Vmax values in two of the four livers studied and resulted in a mean Kmu value of 2.20 +/- 0.59 microM, although the Kmu in the absence of BSA was 6.64 +/- 3.17. In scaling-up to the whole body, Vmax values were 3.9 and 1.0 mg/kg/day for microsomes and slices, respectively, compared to 5.9 mg/kg/day, in vivo. The Kmu values determined in the presence of albumin in both microsomes and slices were similar to those based on in vivo human steady state data (Kmu = 2-3 microM), and the intersubject variation, in vitro, was decreased in the presence of BSA. These findings for phenytoin metabolism suggest that the addition of albumin to incubation media for slices or microsome experiments may yield Km estimates that are more representative of in vivo values.

The effect of food on the bioavailability of ebastine.

Two studies were performed to characterize the influence of food on the bioavailability of the current formulation of ebastine tablets. Study 1 was an open label, randomized, three-period, crossover food effect study where 18 healthy male volunteers received 10 mg ebastine after an overnight fast, a low-fat breakfast, and a high-fat breakfast. Study 2 was an open label, randomized, two period crossover food effect study where 12 healthy male volunteers received 20 mg ebastine after both an overnight fast and a high-fat breakfast. Plasma samples were obtained at selected times and analyzed for ebastine and carebastine, the active metabolite of ebastine, using a validated high-performance liquid chromatography assay. Biopharmaceutic parameters for carebastine, area under the plasma concentration-time curves (AUC (0-infinity)), and maximum plasma concentrations (C ( max ) ), were estimated using noncompartmental techniques and analyzed for statistical differences. AUC (0-infinity) and C(max estimates were 40%-50% and 30%-40% higher under fed conditions as compared with fasting conditions. The time to reach maximum concentrations (T(max)), the terminal elimination rate (K(e) ), and the half-life (t(1/2) ) were not significantly altered by the ingestion of a low-fat or high-fat meal. Statistical analyses of the natural logarithmic transformed data for AUC ((0-infinity) and C(max) also demonstrated significant differences between fasted and fed (low-fat and high-fat) conditions. This indicates that food had a statistically significant effect on the rate and extent of carebastine formation. Therefore, it may be concluded that administration with food maximizes the bioavailability of carebastine.

Bioequivalence: individual and population compartmental modeling compared to the noncompartmental approach.

PURPOSE: The purpose of this study were to evaluate the use of individual compartmental and population compartmental methods for bioequivalence determination, and to determine their utility as adjuncts to the current methods used for bioequivalence assessment. METHODS: Data from three bioequivalence studies of chlorthalidone were analyzed with PCNONLIN using individual compartmental modeling and NONMEM for population analyses. These results were compared with results obtained from the traditional noncompartmental or SHAM (slopes, heights, areas, and moments) approach for bioequivalence assessment and the 90% confidence interval procedure. RESULTS: Individual compartmental modeling and population compartmental modeling techniques performed well on this routine set of bioequivalence data which displayed simple pharmacokinetic properties. A direct assessment of the analysis methods was made by comparing the final estimates and 90% confidence intervals for the test to reference ratios (T/R) of AUC and CMAX. The final estimates and 90% confidence intervals for AUC T/R and CMAX T/R were similar and suggest consistency of results, independent of the method used. CONCLUSIONS: These results demonstrate the utility of modeling techniques as adjuncts to the traditional noncompartmental approach for bioequivalence determination.