Pharmacokinetics and pharmacodynamics of tiotropium solution and tiotropium powder in chronic obstructive pulmonary disease

The aim of the study was to characterize pharmacokinetics of tiotropium solution 5 µg compared to powder 18 µg and assess dose-dependency of tiotropium solution pharmacodynamics in comparison to placebo. In total 154 patients with chronic obstructive pulmonary disease (COPD) were included in this multicenter, randomized, double-blind within-solution (1.25, 2.5, 5 µg, and placebo), and open-label powder 18 µg, crossover study, including 4-week treatment periods. Primary end points were peak plasma concentration (Cmax,ss ), and area under the plasma concentration-time profile (AUC0-6h,ss ), both at steady state. The pharmacodynamic response was assessed by serial spirometry (forced expiratory volume in 1 second/forced vital capacity). Safety was evaluated as adverse events and by electrocardiogram/Holter. Tiotropium was rapidly absorbed with a median tmax,ss of 5-7 minutes postdosing for both devices. The gMean ratio of solution 5 µg over powder 18 µg was 81% (90% confidence interval, 73-89%) for Cmax,ss and 76% (70-82%) for AUC0-6h,ss , indicating that bioequivalence was not established. Dose ordering for bronchodilation was observed. Powder 18 µg and solution 5 µg were most effective, providing comparable bronchodilation. All treatments were well tolerated with no apparent relation to dose or device. Comparable bronchodilator efficacy to powder18 µg at lower systemic exposure supports tiotropium solution 5 µg for maintenance treatment of COPD

Statistical analysis of bioequivalence studies

A Research Report submitted to the Faculty of Science in partial fulfilment of the requirements for the degree of Master of Science. 26 October 2016.The cost of healthcare has become generally expensive the world over, of which the greater part of the money is spent buying drugs. In order to reduce the cost of drugs, drug manufacturers came up with the idea of manufacturing generic drugs, which cost less as compared to brand name drugs. The challenge which arose was how safe, effective and efficient the generic drugs are compared to the brand name drugs, if people were to buy them. As a consequence of this challenge, bioequivalence studies evolved, being statistical procedures for comparing whether the generic and brand name drugs are similar in treating patients for various diseases. This study was undertaken to show the existence of bioequivalence in drugs. Bioavailability is considered in generic drugs to ensure that it is more or less the same as that of the original drugs by using statistical tests. The United States of America’s Food and Agricultural Department took a lead in the research on coming up with statistical methods for certifying generic drugs as bioequivalent to brand name drugs. Pharmacokinetic parameters are obtained from blood samples after dosing study subjects with generic and brand name drugs. The design for analysis in this research report will be a 2 2 crossover design. Average, population and individual bioequivalence is checked from pharmacokinetic parameters to ascertain as to whether drugs are bioequivalent or not. Statistical procedures used include confidence intervals, interval hypothesis tests using parametric as well as nonparametric statistical methods. On presenting results to conclude that drugs are bioequivalent or not, in addition to hypothesis tests and confidence intervals, which indicates whether there is a difference or not, effect sizes will also be reported. If ever there is a difference between generic and brand name drugs, effect sizes then quantify the magnitude of the difference. KEY WORDS: bioequivalence, bioavailability, generic (test) drugs, brand name (reference) drugs, average bioequivalence, population bioequivalence, individual bioequivalence, pharmacokinetic parameters, therapeutic window, pharmaceutical equivalence, confidence intervals, hypothesis tests, effect sizes.TG201

A comparison of classical bioequivalence analysis techniques with simulated annealing algorithm optimised sampling times and population pharmacokinetic modelling

A Dissertation submitted to the Faculty of Science, University of the Witwatersrand, Johannesburg, in fulfillment of the requirements for the degree of Master of Science October, 2017Bioequivalence (BE) studies are conducted to demonstrate that two drug for- mulations produce similar bioavalabilities or therapeutic e ect and safety when used. During this study, drug concentrations are obtained several times over a given period of time and a concentration vs. time graph is constructed. For a generic drug to be approved, this BE studies are conducted and the generic drug must be demonstrated to be therapeutically equivalent to the innovator drug. This study utilised a standard 2 2 crossover design to randomly assign sub- jects to each of the two sequences. Statistical methods such as con dence in- tervals, Schuirmann's two one-sided and Wilcoxon-Mann-Whitney tests were used to assess average bioequivalence (ABE). However, there are concerns that the use of ABE alone is not appropriate for drugs with high intra-subject and inter-subject variabilities. Under such a circumstance, population bioequiv- alence (PBE) and individual bioequivalence (IBE) are proposed. This study employs the PBE approach but not the IBE as it is not possible to perform IBE on the available data. Results indicated that the generic drug is average bioequivalent to the innovator drug although Cmax was outside the regulatory range set by the Food and Drug Administration (FDA). Most biological data are modelled using nonlinear xed e ect models. Popula- tion pharmacokinetic (PK) modelling has been used in clinical pharmacology to identify the sources of PK variability in the target population. This study was conducted to determine the characteristics of the PK parameters of the orally administered antibiotic given to pigs using a population approach. A population PK model was developed using a nonlinear mixed e ects model (NLMEM) with a one-compartment model using di erent residuals. For the NLMEM, the stochastic approximation expectation maximisation (SAEM) al- gorithm was implemented in MONOLIX. The models were used to estimate the population PK parameters and diagnostic plots obtained for model eval- uation. The results showed that the combined residual error model tted the data better than the constant error model. In addition, this study sought to nd optimal sampling times which will min- imise the number of blood samples required for pharmacokinetic study. The optimal sampling times were generated from a one compartment model and implemented in MATLAB. The parameters used in the optimisation were es- timated from the population PK model. These sampling times were generated using the simulated annealing (SA) algorithm. Keywords: Bioavailability, Bioequivalence, generic drugs, reference drugs, average bioequivalence, population bioequivalence, individual bioequivalence, pharmacokinetics, pharmacodynamics, therapeutic window, con dence inter- val, nonlinear xed e ects model, two one-sided tests, maximum likelihood, population parameters, optimal sampling design, concentration-time curve, model evaluation, Visual predictive checks (VPC), Normalised prediction dis- tribution errors (NPDE), Stochastic approximation expectation maximisation (SAEM) algorithm.MT 201

New and alternative approaches to the assessment of pharmacokinetic and pharmacodynamic equivalence

La bioéquivalence, une mesure de substitution de l'innocuité et de l'efficacité à différents stades du processus de développement des médicaments, est tout particulièrement importante lors du développement d'un médicament générique. Entre autres critères, la bioéquivalence garantit que les médicaments génériques sont équivalents aux produits innovateurs ou de références approuvés en termes d’efficacité clinique et d’innocuité tout en contournant le long cours et le coût élevé des essais chez les animaux et des essais cliniques chez les patients exigés pour les médicaments innovants. Malgré les avancées dans le développement d'approches robustes au cours des dernières décennies, la pratique actuelle de la bioéquivalence fait toujours l'objet de controverses. Le but de cette thèse est d'explorer certaines de ces controverses et de les aborder en proposant des approches nouvelles et alternatives. L'une des questions les plus controversées dans la pratique actuelle de la bioéquivalence est l'extrapolation des résultats d'études de bioéquivalence d'une population à une autre. La majorité des études de bioéquivalence portant sur des formes pharmaceutiques orales efficaces par voie systémique reposent sur les critères de pharmacocinétique obtenus chez des sujets sains, alors que la population cible est constituée de patients. Ceci est basé sur l'hypothèse que si deux produits sont bioéquivalents dans une population, ils devraient l'être dans une autre. L'extrapolation des résultats des études de bioéquivalence ne se limite pas à celle des sujets sains aux patients. Depuis 2007, une proportion croissante d'études de bioéquivalence pharmacocinétique portant sur des soumissions génériques nord-américaines ou européennes a été réalisée auprès de populations géographiques/ethniques autres que celles visées, en raison du coût moins élevé de ces études en dehors de l'Amérique du Nord et de l'Europe. Dans le premier volet de cette thèse, nous avons examiné si les résultats de la bioéquivalence obtenus dans une population géographique ou ethnique pouvaient être extrapolés à une autre. À cette fin, nous avons extrait les résultats des études de bioéquivalence pharmacocinétique disponibles publiquement et provenant de soumissions génériques à Santé Canada et à la Food and Drug Administration des États-Unis. Pour dix médicaments différents, nous avons calculé l'effet d’un repas normalisé sur le produit de référence et comparé les résultats obtenus chez deux populations ethniques, les indiens et les nord-américains. Cette approche novatrice est basée sur le raisonnement suivant: si l'effet d’un repas sur le produit de référence est le même chez les populations indienne et nord-américaine, le produit générique et sa référence qui se sont révélés bioéquivalents dans la population indienne devraient également l'être dans la population nord-américaine. Pour 90% des médicaments à l'étude, une différence statistiquement significative a été détectée entre les deux populations après un repas. Pour 30% de ces médicaments, la différence s'est révélée d'une pertinence clinique possible. Les résultats de cette étude ont mis en évidence que l’extrapolation des résultats de bioéquivalence d’une population à l’autre devrait possiblement être reconsidérée pour certains médicaments. Les défis dans le contexte de la bioéquivalence ne se limitent pas toujours aux études pivots où la performance d’un produit générique est comparée à celle de la référence. En effet, une étude pilote peut être menée afin d’établir un protocole d’étude approprié pour cette étude pivot. Par conséquent, les résultats inexacts provenant d'une étude pilote, tels qu'une estimation imprécise du moment ou de la durée d’administration optimale de la dose lors de la comparaison du produit testé par rapport à la référence, pourront affecter négativement les résultats de l’étude de bioéquivalence. Ceci est particulièrement crucial pour les produits indiqués pour un usage topique dermatologique dont les corticostéroïdes constituent un cas d’espèce. En effet, leur bioéquivalence est démontrée par une mesure pharmacodynamique, le blanchiment cutané, à différents temps après application topique. L’intensité du blanchiment est comparée entre le produit générique et le produit de référence à une durée d’administration spécifique d’une dose donnée, la DD50, soit la durée associée à 50% de l’effet maximal observé. Par conséquent, cette durée d’administration de la dose doit d’abord être déterminée dans le cadre d’une étude pilote. L’agence réglementaire américaine recommande l’utilisation d’une approche populationnelle basée sur la modélisation non linéaire à effets mixtes pour l'estimation de la DD50 et ce, quelle que soit la méthode d'analyse. Étant donné qu’il existe différents types de méthodes d’analyse non linéaire à effets mixtes, chaque commanditaire peut en choisir une différente. Dans le deuxième volet de cette thèse, nous avons examiné si les mêmes estimations de DD50 pouvaient être obtenues en utilisant différentes méthodes non linéaires à effets mixtes. À cette fin, nous avons ajusté les données de blanchiment de la peau d’onze études avec deux méthodes non linéaires à effets mixtes différentes : le maximum de vraisemblance avec maximisation de l’espérance (MLEM) et l'estimation conditionnelle de premier ordre (FOCE). Les résultats ont favorisé MLEM, compte tenu d’une meilleure puissance discriminative pour l’estimation de la DD50 de population et d’une meilleure minimisation de la variabilité interindividuelle. Bien que l'approche de la bioéquivalence fondée sur la pharmacocinétique ait contribuée de manière significative au développement de versions génériques de haute qualité des formes pharmaceutiques orales indiquées pour un effet systémique, la disponibilité de versions génériques pour les produits dermatologiques topiques demeure limitée et ce, par manque de méthodes acceptées par les agences réglementaires pour l'évaluation de la bioéquivalence de ces produits. Dans le troisième volet de cette thèse, une nouvelle approche pour l’évaluation de la bioéquivalence de formulations de crème topique d’acyclovir a été développée en utilisant une analyse basée sur un modèle de données d’exposition locales récupérées à partir d’échantillons de peau abrasée prélevés à une seule durée d’administration de la dose, la DD50 à l’aide de bandes adhésives. Un seul échantillonnage de peau effectué à la DD50 a non seulement assuré que les données pharmacocinétiques étaient recueillies à la durée d’administration de la dose ayant le meilleur pouvoir discriminant pour détecter une différence au niveau des formulations, mais a également permis de diminuer considérablement le nombre d'échantillons à analyser. Et surtout, cette nouvelle approche a permis de générer un profil pharmacocinétique au niveau même de la peau. Ce faisant, nous avons pu utiliser l'analyse compartimentale populationnelle et contourner les nombreuses hypothèses et calculs sophistiqués requis par les méthodes précédentes. Notre approche a également permis de générer de nouveaux paramètres pharmacocinétiques permettant de décrire la vitesse et le degré d’exposition cutanée pour l'évaluation de la biodisponibilité et de la bioéquivalence topiques. Finalement, cette méthode a le potentiel de discerner une formulation bioéquivalente d’une autre qui ne l’est pas.Bioequivalence is a surrogate measure of safety and efficacy in different stages of drug development process with the most pronounced significance in the development of generic drugs. Bioequivalence, among other standards, ensures that generic drugs are equivalent to their approved innovator or reference products in terms of clinical efficacy and safety while circumventing the lengthy-time course and high cost of animal and clinical trials in patients required for innovator drugs. Despite the advancements in development of robust bioequivalence approaches over the past decades, there are still controversies in the current practice of bioequivalence. The aim of this thesis is to explore some of these controversies and address them by putting forward new and alternative approaches. One of the most controversial issues in the current practice of bioequivalence is the extrapolation of bioequivalence study results from one population to another. The majority of bioequivalence studies for systemic effective oral dosage forms are conducted based on pharmacokinetic endpoints in healthy volunteers whilst the targeted population is patients. This is based on the assumption that if two products are bioequivalent in one population, they should be bioequivalent in another one. The extrapolation of bioequivalence study results is not limited to that from healthy volunteers to patients. Since 2007, an ever-increasing proportion of pharmacokinetic bioequivalence studies for North American or European generic submissions have been performed in geographical/ethnic populations other than the intended ones, due to the lower cost of these studies outside North America and Europe. In the first part of this thesis, we investigated whether the bioequivalence results obtained in one geographical or ethnic population can be extrapolated to another one. To this purpose, we extracted pharmacokinetic bioequivalence studies results from generic submissions to Health Canada and the US Food and Drug Administration. We calculated food effect for ten different reference drug products and compared the results for each product between two ethnic populations, Indians and North Americans. This is based on the reasoning that if food effect is found to be the same between the Indian and North American populations, then the generic product and its reference that were found to be bioequivalent in the Indian population should also be bioequivalent in North American population. For 90% of the study drugs, statistically significant difference was detected in the food effect between two populations. For 30% of these drugs, the difference was found to be of possible clinical relevance. The results of this study raised a flag for extrapolating the bioequivalence results from one population to another. Challenges in the context of bioequivalence are not always limited to the pivotal studies where the performance of a generic product is compared to that of Reference. Prior to pivotal bioequivalence studies, a pilot study may be conducted to establish an appropriate study design for the pivotal bioequivalence study. Therefore, inaccurate results from a pilot study, such as inaccurate estimation of time point or dose duration for comparison of test versus reference, can affect the bioequivalence outcomes adversely. An example to this case is the comparison of the extent of skin blanching, the pharmacological effect of generic versus reference products of topical dermatological corticosteroids at specific dose duration, DD50, where the effect is half maximal. This dose duration should initially be determined in a pilot study. The US FDA 1995 Guidance document recommends the use of non-linear mixed effect population modeling for the estimation of DD50, irrespective of the method of analysis. Given the availability of different types of non-linear mixed effect modeling methods, each sponsor could choose a different one. In the second part of this thesis we investigated whether the same DD50 estimates can be obtained when different non-linear mixed effect modeling methods are used. To this purpose, we fitted the skin blanching data from eleven studies with two different non-linear mixed effect modeling methods, the Maximum Likelihood Expectation Maximization (MLEM) and the First Order Conditional Estimation (FOCE). The results favored MLEM given its lower population DD50 estimates that would locate in a more discriminative portion of the Emax curve and better minimization of inter-individual variability. Although the pharmacokinetic-based bioequivalence approach has contributed significantly to the development of high-quality generic versions of systemic effective oral dosage form, the availability of generic versions of topical dermatological products remains constrained due to the limited methods accepted for bioequivalence evaluation of these products. In the third part of this thesis, a novel approach for the bioequivalence assessment of topical acyclovir cream formulations was developed based on the model-based analysis of local exposure data recovered from tape stripping of the skin at a single dose duration, DD50. Conducting the stripping procedure only at DD50 not only ensured that the PK data was collected at the dose duration that is most discriminative of formulation differences, but it also decreased the number of samples to be analyzed significantly. More importantly, our novel approach in generating the local PK profile in the skin (dermatopharmacokinetic profile) and the implementation of population compartmental analysis circumvented the numerous assumptions and sophisticated calculations that were inherent to previous methods, while yielding the PK parameters relevant for topical bioavailability and bioequivalence assessment (rate and extent of exposure to the skin). This method successfully concluded bioequivalence and its absence

BIOAVAILABILITY AND CV COMPONENT COMPARISON IN A CROSSOVER

Two medication formulations are compared using noncompartmental pharmacokinetic (PK) variables. However, more than the ratio of mean effects is of interest. A difference in formulation coeficients of varication (CV), within- or between-subject, is sought. The experimental design chosen is a 2 sequence crossover design of the form ABBA and BAAB, where A and B are two medication formulations. A mixed linear model is defined that contains random effects for subjects and for subject by formulation interactions. The model has fixed effects for the average formulation effects and period effects. The 2 formulations are assumed to have different error terms. The average formulation effect ratios and within-subject CVs may be compared by usual methods. An approximate Z-statistic is computed to compare the between-subject CVs. This statistic assumes a correlation of the 2 between-subject CV estimates. In addition, a tractable variance ratio is defined to indicate the extent to which the average effects ratio is applicable to each subject

Carryover negligibility and relevance in bioequivalence studies

The carryover effect is a recurring issue in the pharmaceutical field. It may strongly influence the final outcome of an average bioequivalence study. Testing a null hypothesis of zero carryover is useless: not rejecting it does not guarantee the non-existence of carryover, and rejecting it is not informative of the true degree of carryover and its influence on the validity of the final outcome of the bioequivalence study. We propose a more consistent approach: even if some carryover is present, is it enough to seriously distort the study conclusions or is it negligible? This is the central aim of this paper, which focuses on average bioequivalence studies based on 2×2 crossover designs and on the main problem associated with carryover: type I error inflation. We propose an equivalence testing approach to these questions and suggest reasonable negligibility or relevance limits for carryover. Finally, we illustrate this approach on some real datasets

MIXED SCALING APPROACH TO ESTABLISH BIOEQUIVALENCE OF LANSOPRAZOLE DELAYED RELEASE CAPSULE IN FASTING SPRINKLE WITH APPLE SAUCE STUDY IN HEALTHY SUBJECTS

Objective: The aim of the present study was to establish bioequivalence of highly variable generic lansoprazole (LSP) delayed release (DR) capsule,exploring minimal number of healthy volunteers by mixed scaling approach as oppose to average bioequivalence approach.Methods: This was an open-labeled, three-treatment, three-periods, three-sequences, single-dose, partial replicate crossover trial conducted in 36 +4 (stand by) healthy adult human subject in Indian origin.Results: Non-parametric Wilcoxon sign rank test at 95% confidence interval failed to conclude significance difference in T and t1/2 between theformulations. The intra subject standard deviation of the reference formulation was 0.340 for C, 0.249 for area under curve up to last measurabletime point (AUCT) and 0.244 for area under curve up to infinity time (AUCI) parameters. The reference scaling as proposed by Haider et al., 2008, wasapplied for Cmax, maxand constant scaling was applied for AUCT and AUCI metrics. No significance difference between two formulations were observedwhen data were analyzed by Analysis of Variance (p<0.05). Westlake 90% confidence limit, as well as two one-sided t-test as proposed by Schurimanand the Anderson-Hauck power analysis all fell under the predefine bioequivalence criteria for mixed scaling.Conclusion: The generic LSP DR capsules were found to bioequivalent with reference drug under fasting study with apple sauce with respect to rateand extent of absorption. The mixed scaling statistical analysis approach used to establish bioequivalence with a minimum number of subjects wasfound reliable and utilize 40 subjects as opposed to 110 subjects need to establish bioequivalence in traditional average bioequivalence approach.Keywords: Mixed scaling, Techniques, Non-parametric, Bioequivalence, Delayed release

Assessing the Effect of Prior Distribution Assumption on the Variance Parameters in Evaluating Bioequivalence Trials

Bioequivalence determines if two drugs are alike. The three kinds of bioequivalence are Average, Population, and Individual Bioequivalence. These Bioequivalence criteria can be evaluated using aggregate and disaggregate methods. Considerable work assessing bioequivalence in a frequentist method exists, but the advantages of Bayesian methods for Bioequivalence have been recently explored. Variance parameters are essential to any of theses existing Bayesian Bioequivalence metrics. Usually, the prior distributions for model parameters use either informative priors or vague priors. The Bioequivalence inference may be sensitive to the prior distribution on the variances. Recently, there have been questions about the routine use of inverse gamma priors for variance parameters. In this paper we examine the effect that changing the prior distribution of the variance parameters has on Bayesian models for assessing Bioequivalence and the carry-over effect. We explore our method with some real data sets from the FDA

An Example of How to Write the Statistical Section of a Bioequivalence Study Protocol for FDA Review

This paper provides a detailed example of how one should write the statistical section of a bioequivalence study protocol for FDA review. Three forms of bioequivalence are covered: average bioequivalence (ABE), population bioequivalence (PBE) and individual bioequivalence (IBE). The method of analysis is based on Jones and Kenward (2003) and a modification of their SAS Macro is provided