Pedro Guerra

Acceptability and characteristics of 124 human bioequivalence studies with active substances classified according to the Biopharmaceutic Classification System

AIM The aim of this study was to evaluate the acceptability of 124 bioequivalence (BE) studies with 80 active substances categorized according to the Biopharmaceutics Classification System (BCS) in order to establish if there were different probabilities of proving BE between the different BCS classes. METHODS We evaluated the differences between pharmaceutical products with active substances from different BCS classes in terms of acceptability, number of subjects in the study (n), the point estimates, and intra- and inter-subject coefficients of variation data from BE studies with generic products. RESULTS Out of 124 BE studies 89 (71.77%) were performed with pharmaceutical products containing active substances classified by the BCS. In all BCS classes there were non-bioequivalent pharmaceutical products: 4 out of 26 (15.38%) in class 1, 14 out of 28 (50%) in class 2, 3 out of 22 (13.63%) in class 3 and 1 out of 13 (7.69%) in class 4. When we removed those pharmaceutical products in which intra-subject variability was higher than predicted (2 in class 1 active substances, 9 in class 2 and 2 in class 3) there were still non-BE pharmaceutical products in classes 1, 2 and 3. CONCLUSIONS Comparisons between pharmaceutical products with active substances from the four BCS classes have not allowed us to define differential characteristics of each class in terms of n, inter and intra-subject variability for C(max) or AUC. Despite the usually employed test dissolution methodology proposed as quality control, pharmaceutical products with active substances from the four classes of BCS showed non-BE studies.

Evaluation of the influence of sex and CYP2C19 and CYP2D6 polymorphisms in the disposition of citalopram.

We investigate the impact of sex and genotype on citalopram disposition in 35 healthy volunteers who received an oral dose of 20mg citalopram within a single-dose bioequivalence study. CYP2C19*2 and *3, and CYP2D6*4 mutations were determined by Real-Time PCR. The influence of sex and genotype was analyzed by a linear mixed model for repeated measures, including formulation, period, sequence, sex, CYP2C19 and CYP2D6 as fixed effects and subject nested sequence*sex*CYP2C19*CYP2D6 as the random one. Pharmacokinetic parameters were log-transformed and AUC(infinity) and C(max) adjusted to the administered dose/weight. The model yields a statistical significance in AUC(infinity) and CL/F for CYP2C19 and CYP2D6. Gender, formulation, sequence or period effects were not statistically significant. AUC(infinity) of CYP2C19*1/*2 and CYP2C19*2/*2 carriers is 44% and 118% higher than wild type, respectively; CYP2D6 volunteers carrying 1/4 have an AUC 23% higher than wild type. Our data also suggest that the influence of CYP2D6 on AUC(infinity) is very low when it is in association with CYP2C19*1/*1 while its influence is more apparent in association with CYP2C19*1/*2. In conclusion, we demonstrate the influence of CYP2C19 and CYP2D6 in the disposition of citalopram, and we suggest that the influence of CYP2D6 is more probable in volunteers with at least one defective allele of CYP2C19.

Evaluation of sex differences in the pharmacokinetics of ranitidine in humans.

A bioequivalence study of two oral formulations of 300 mg ranitidine was carried out in 16 healthy volunteers (8 men and 8 women), and the pharmacokinetics in both sexes were compared. There was bioequivalence of both formulations. The terminal half‐life of ranitidine was 7% shorter and the oral apparent clearance 10.5% higher in women (1.44 L/h/kg) than in men (1.29 L/h/kg), although this difference did not reach statistical significance. No differences were observed in maximum concentration (Cmax) or the time of its occurrence (tmax). Sex, age, and weight did not correlate significantly with oral clearance. These results suggest that there are no sex differences in the pharmacokinetics of ranitidine, or that any differences would not be of clinical relevance. It also should be emphasized that bioequivalence trials also can be used to study other pharmacokinetic or pharmacodynamic characteristics of drugs without damaging the main endpoint of the study.

The importance of sample size, log-mean ratios, and intrasubject variability in the acceptance criteria of 108 bioequivalence studies

PurposeFulfilling bioequivalence criteria with highly variable drugs is difficult. The aim of this study was to compare the importance of sample size, intrasubject variability, and the point estimate of test and reference formulations with regard to meeting bioequivalence (BE) criteria [maximum observed plasma concentration (Cmax) and area under the concentration-time curve (AUC)].MethodsWe compared 137 pairs of data from BE studies with a conventional number of subjects, approximately 31–32 volunteers, developed in the last 10 years.ResultsThe third part of the studies failed to demonstrate BE, in part due to an unacceptable difference between the mean ratios (T/R) (18) but also due to high variability with small differences between formulations (17). Increasing the number of subjects is hard to justify, and expanding the confidence interval (CI) was insufficient for the most highly variable drugs.ConclusionsTherefore, for low-variable drugs, the difference between formulations was the cornerstone of the fulfillment of BE criteria, but for highly variable drugs, the intrasubject coefficient of variability (ICV) was decisive. Our proposal is that for highly variable drugs that fall outside BE 90% CI limits could result in BE in the absence of formulation effect and maximal differences between formulations below 20%.

Comparative Bioavailability of Two Oral 875/125mg Sachet Formulations of Amoxicillin/Clavulanic Acid in Healthy Volunteers

AbstractObjectives and Design: The aim of this single-dose, randomised, two-sequence, crossover study in 24 healthy volunteers was to establish the bioequivalence of two different sachet formulations of amoxicillin/clavulanic acid 875/125mg (Augmentine® and Duonasa®). Patients and Methods: Twenty-four healthy volunteers aged 18 to 30 years fasted from 10 hours before until 2.5 hours after administration of each sachet. Venous blood samples were taken prior to each administration and at 14 different times within 24 hours after the dose, and plasma concentrations of amoxicillin and clavulanic acid were determined by high performance liquid chromatography. Clinical adverse events were recorded after an open question and a symptoms checklist during the study. Main Outcome Measures: For the purpose of bioequivalence analysis, area under the curve (AUC) and peak plasma concentration (Cmax) were considered to be primary variables and time to Cmax (tmax) a secondary one. Cmax and tmax were obtained directly from plasma data, the elimination rate constant (kel) was estimated by log-linear regression, and AUC was calculated by the trapezoidal rule. AUC and Cmax were tested for bioequivalence after log-transformation of data. Results: The 90% standard confidence intervals (CI) of the mean AUC values for the test/reference ratios were 1.01 to 1.18 for amoxicillin and 0.87 to 1.06 for clavulanic acid. There was no significant difference in the bioavailability of either product judged from Cmax ratios for amoxicillin (90% CI 1.01 to 1.16) and clavulanic acid (90% CI 0.90 to 1.12). These results were within the bioequivalence acceptable range of 90% CI 0.80 to 1.25. Overall, disposition parameters for these formulations were roughly proportional to those found in the literature after single-dose administration of other formulations with different strengths and amoxicillin/clavulanic acid ratios. Importantly, interindividual variability values were consistent with those previously reported. Conclusions: The two formulations were found to be bioequivalent and, therefore, interchangeable.

A Preliminary Model to Avoid the Overestimation of Sample Size in Bioequivalence Studies

Often the only available data in literature for sample size estimations in bioequivalence studies is intersubject variability, which tends to result in overestimation of sample size. In this paper, we proposed a preliminary model of intrasubject variability based on intersubject variability for Cmax and AUC data from randomized, crossovers, bioequivalence (BE) studies. From 93 Cmax and 121 AUC data from test-reference comparisons that fulfilled BE criteria, we calculated intersubject variability for the reference formulation and intrasubject variability from ANOVA. Lineal and exponential models (y=a(1-e-bx)) were fitted weighted by the inverse of the variance, to predict the intrasubject variability based on intersubject variability. To validate the model we calculated the coefficient of cross-validation of data from 30 new BE studies. The models fit very well (R2=0.997 and 0.990 for Cmax and AUC respectively) and the cross-validation correlation were 0.847 for Cmax and 0.572 for AUC. A preliminary model analyses allow us to estimate the intrasubject variability based on intersubject variability for sample size calculation purposes in BE studies. This approximation provides an opportunity for sample size reduction avoiding unnecessary exposure of healthy volunteers. Further modelling studies are desirable to confirm these results especially suggestions of the higher intersubject variability range.

Comparison of Lormetazepam Solution and Capsules in Healthy Volunteers

ObjectiveThe aim of this study was to demonstrate a faster absorption and disposition rate for a solution formulation of lormetazepam, comparing the bio-availability of two different oral formulations (tablets and solution), in healthy volunteers.Study design, methods and participants24 healthy volunteers (12 male, 12 female) were included in the study. Venous blood samples were taken prior to each administration and at 20 different times within 72 hours after the dose. Plasma concentrations of lormetazepam were determined in a blinded fashion by means of high-resolution gas chromatography. Clinical adverse events were recorded after open-ended questioning. For the purpose of statistical analysis, area under the concentration-time curve (AUC), early exposure AUC (AUCearly), maximum plasma concentration (Cmax) and time to Cmax(tmax) of lormetazepam were considered as the primary variables, and half-life and clearance as secondary ones. Both Cmax and tmax were obtained directly from plasma data, the slope of least-square regression of the terminal elimination phase was estimated by log-linear regression, and the AUC and AUCearly were calculated by the trapezoidal rule.ResultsThe standard 90% CI for the log-transformed data was 0.86–1.05 for AUC from time zero to infinity. The relative bioavailability of the solution was 97% compared with that of the tablets. The Cmax standard 90% CI was 1.25–1.72, and the relative Cmax ratio of the lormetazepam solution was 138.1%. The median lormetazepam tmax was 30 minutes for the solution and 1.5 hours for the tablet formulation, the median difference for tmax was —1.17h. The early exposure 90% CI was 1.64–2.48. Comparing both formulations, in terms of early exposure AUC, relative bioavailability was 173% in favour of the solution formulation of lormetazepam.ConclusionsThe pharmacokinetic profile of the solution formulation showed a faster and higher disposition rate than the tablet formulation, and we can thus assume a more rapid onset of hypnotic effect for the solution. This can be useful for patients who have difficulty in falling asleep.

Average bioequivalence of two oral formulations of ticlopidine in healthy volunteers

Abstract Objective The aim of the study was to describe the pharmacokinetic properties and compare the rate and extent of absorption of ticlopidine from a new generic tablet formulation compared with the reference formulation. Methods In this single-dose, open-label, 2-sequence, 2-period, randomized crossover study, all 24 subjects received one 250-mg dose of ticlopidine. Subjects were assigned to treatment sequences in groups of 4 by block randomization. They fasted from 10 hours before until 5 hours after administration of the medication. Venous blood samples were taken before each administration and at 14 different times within 48 hours after administration, and plasma concentrations of ticlopidine were determined by high-performance liquid chromatography. Clinical adverse events were recorded after an open-ended question and a symptom checklist during the study. For the purpose of bioequivalence analysis, area under the plasma concentrationtime curve from zero to infinity (AUC o−∞ ) and maximum concentration (C max ) were considered as the primary variables and time to C max (T max ) as the secondary variable. C max and T max were obtained directly from plasma data, the elimination constant was estimated by log-linear regression, and AUC was calculated by the trapezoidal rule. AUC and C max were tested for bioequivalence after logtransformation of data. Results The 90% standard CIs of the mean values for the test/ reference ratios were 0.80 to 1.10 for AUC and 0.87 to 1.17 for C max . The point estimate was 92.7% for AUC and 102% for C max . No significant period effects were obtained. Mean T max was 1.9 hours for the test formulation (range, 0.5 to 3.0 hours) and 2.5 hours for the reference formulation (range, 1.0 to 4.0 hours). Conclusions Our results are within the acceptable bioequivalence range of 0.80 to 1.25. We conclude that the 2 formulations are bioequivalent and, therefore, interchangeable.