Bioequivalence Assessment Research Articles

Topical ketoprofen nanogel: artificial neural network optimization, clustered bootstrap validation, and in vivo activity evaluation based on longitudinal dose response modeling

Objectives: This work aimed at investigating the potential of solid lipid nanoparticles (SLN) as carriers for topical delivery of Ketoprofen (KP); evaluating a novel technique incorporating Artificial Neural Network (ANN) and clustered bootstrap for optimization of KP-loaded SLN (KP-SLN); and demonstrating a longitudinal dose response (LDR) modeling-based approach to compare the activity of topical non-steroidal anti-inflammatory drug formulations.Methods: KP-SLN was fabricated by a modified emulsion/solvent evaporation method. Box–Behnken design was implemented to study the influence of glycerylpalmitostearate-to-KP ratio, Tween 80, and lecithin concentrations on particle size, entrapment efficiency, and amount of drug permeated through rat skin in 24 hours. Following clustered bootstrap ANN optimization, the optimized KP-SLN was incorporated into an aqueous gel and evaluated for rheology, in vitro release, permeability, skin irritation and in vivo activity using carrageenan-induced rat paw edema model and LDR mathematical model to analyze the time course of anti-inflammatory effect at various application durations.Results: Lipid-to-drug ratio of 7.85 [bootstrap 95%CI: 7.63–8.51], Tween 80 of 1.27% [bootstrap 95%CI: 0.601–2.40%], and Lecithin of 0.263% [bootstrap 95%CI: 0.263–0.328%] were predicted to produce optimal characteristics. Compared with profenid® gel, the optimized KP-SLN gel exhibited slower release, faster permeability, better texture properties, greater efficacy, and similar potency.Conclusions: SLNs are safe and effective permeation enhancers. ANN coupled with clustered bootstrap is a useful method for finding optimal solutions and estimating uncertainty associated with them. LDR models allow mechanistic understanding of comparative in vivo performances of different topical formulations, and help design efficient dermatological bioequivalence assessment methods.

Batch-to-batch pharmacokinetic variability confounds current bioequivalence regulations: A dry powder inhaler randomized clinical trial.

Current pharmacokinetic (PK) bioequivalence guidelines do not account for batch‐to‐batch variability in study design or analysis. Here we evaluate the magnitude of batch‐to‐batch PK variability for Advair Diskus 100/50. Single doses of fluticasone propionate and salmeterol combinations were administered by oral inhalation to healthy subjects in a randomized clinical crossover study comparing three different batches purchased from the market, with one batch replicated across two treatment periods. All pairwise comparisons between different batches failed the PK bioequivalence statistical test, demonstrating substantial PK differences between batches that were large enough to demonstrate bio‐inequivalence in some cases. In contrast, between‐replicate PK bioequivalence was demonstrated for the replicated batch. Between‐batch variance was ∼40–70% of the estimated residual error. This large additional source of variability necessitates re‐evaluation of bioequivalence assessment criteria to yield a result that is both generalizable and consistent with the principles of type I and type II error rate control.

THE ROLL OF GENERIC DRUGS– QUALITY AND ECONOMIC ASPECT IN TREATMENT

Generic drugs have an important role in ensuring the efficacy, safety, and especially the economic aspect of drug use. A generic drug is a pharmaceutical product, usually intended to be interchangeable with an innovator product manufactured without a licence from the innovator company and marketed after the expiry date of the patent or other exclusive rights. At present, unlikely FDA’s regulations, Vietnam’s law does not require all generic drugs launching in the market to prove the bioequivalence, the same efficient and safe as innovator drugs. Because of the rapid growth of the domestic pharmaceutical market, the standard and quality of generic drugs compared with innovator drugs have to be consolidated and proved through trials of bioequivalence, then building the faith of professionals and patients in using generic drugs. Thus the expansion of number and improving quality of the bioequivalence assessment centers become an important task of Vietnam pharmaceutical industry in the context of integration with the global pharmaceutical industry. Key words: generic drugs, innovator drugs, patent, bioequivalence, treatment.

Sex-related in vitro/in vivo and PK/PD correlations after oral single dose furosemide administration

Abstract Background: The goal of this study was to develop an in vivo-in vitro (IVIV) correlation, both in men and women, which allows constructing a model to predict bioequivalence assessments for

Оценка биоэквивалентности препарата BCD-022 (трастузумаб производства ЗАО «Биокад», Россия) по сравнению с препаратом Герцептин® (Ф.Хоффманн-Ля Рош Лтд., Швейцария), применяемых в сочетании с паклитакселом у больных метастатическим раком молочной железы

Оценка биоэквивалентности препарата BCD-022 (трастузумаб производства ЗАО «Биокад», Россия) по сравнению с препаратом Герцептин® (Ф.Хоффманн-Ля Рош Лтд., Швейцария), применяемых в сочетании с паклитакселом у больных метастатическим раком молочной железы

Dermal Open Flow Microperfusion (dOFM) for the bioequivalence assessment of topical products based on skin PK

Dermal Open Flow Microperfusion (dOFM) for the bioequivalence assessment of topical products based on skin PK

Fed and Fasted Single-dose Assessment of Bioequivalence of Dapagliflozin and Metformin Extended-release Fixed-dose Combination Tablets Relative to Single-component Dapagliflozin and Metformin Extended-release Tablets in Healthy Subjects

PurposeIn patients with type 2 diabetes mellitus, fixed-dose combinations (FDCs) of antihyperglycemic medications may provide complementary efficacy while reducing tablet burden and improving compliance. The aim of this study was to assess the bioequivalence and tolerability of 2 FDCs of dapagliflozin and metformin extended-release (XR) versus their individual component (IC) tablets. MethodsAn open-label, balanced, randomized, 2-way crossover, 4-arm study was conducted in 129 healthy Brazilian subjects (aged 18–55 years). Two oral doses of the FDCs (5 mg dapagliflozin and 500 mg metformin XR, and 10 mg dapagliflozin and 1000 mg metformin XR) were evaluated in fed and fasted states. FindingsUnder fed and fasted conditions the 5 mg dapagliflozin and 500 mg metformin XR FDC showed bioequivalence to its ICs. The 10 mg dapagliflozin and 1000 mg metformin XR FDC was bioequivalent to its ICs in fed subjects. Although AUC for the 10 mg dapagliflozin and 1000 mg metformin XR FDC was bioequivalent in fasted subjects, the Cmax for metformin was not bioequivalent to its ICs in fasted subjects (upper 90% CI was 127.5%, and thus outside the 80%–125% bioequivalence interval). The small increase in the fasted state is not considered clinically meaningful due to the small magnitude of the difference (9.2%), the lack of metformin Cmax being associated with efficacy or tolerability concerns, and the fasted state not being the recommended state for dosing of metformin XR. The safety profile and tolerability of the FDCs were similar to those of their ICs and no deaths or serious adverse events were reported. ImplicationsBoth FDCs of dapagliflozin and metformin XR were bioequivalent to their ICs in fed and fasted subjects, except for the metformin Cmax from the 10 mg dapagliflozin and 1000 mg metformin XR FDC in fasted subjects. These data support the use of a dapagliflozin and metformin XR FDC in patients with type 2 diabetes mellitus.

Терапевтическая эквивалентность и взаимозаменяемость лекарственных препаратов

Обзорная статья посвящена концепции взаимозаменяемости лекарственных препаратов, разработка которой является актуальной задачей отечественной клинической фармакологии. Представлены результаты обобщения принятых за рубежом и рекомендуемых международными организациями принципов оценки взаимозаменяемости лекарственных средств синтетического и биологического происхождения, на основании анализа которых авторами предложены подходы к разработке условий успешного внедрения концепции взаимозаменяемости лекарственных препаратов в России. Обсуждается выбор оптимальных подходов к оценке терапевтической эквивалентности, биоэквивалентности, взаимозаменяемости и сопоставимости лекарственных препаратов с учетом опыта международных, зарубежных и отечественных регуляторных органов.

Some thoughts on drug interchangeability

Current regulation for generic approval is based on the assessment of average bioequivalence. As indicated by the United States Food and Drug Administration (FDA), an approved generic drug can be used as a substitute for the innovative drug. FDA does not indicate that two generic copies of the same innovative drug can be used interchangeably even though they are bioequivalent to the same brand-name drug. In practice, bioequivalence between generic copies of an innovative drug is not required. However, as more generic drug products become available, it is a concern whether the approved generic drug products have the same quality and therapeutic effect as the brand-name drug product and whether they can be used safely and interchangeably. In this article, several criteria including a newly proposed criterion for assessing drug interchangeability are studied. In addition, comments on possible study designs and power calculation for sample size under a specific design are also discussed.

Single-Dose, Randomized, Open-Label, Two-Way, Crossover Bioequivalence Study of Two Formulations of Pregabalin 300 mg Hard Capsules in Healthy Volunteers Under Fasting Conditions.

AimsThis bioequivalence study was conducted to assess the bioequivalence of two formulations, test and reference, of pregabalin 300 mg hard capsules, under fasting conditions.MethodsThis was a single-center, randomized, single-dose, open-label, laboratory-blinded, two-way crossover study, with a minimum washout period of 7 days. Plasma samples were collected prior to and up to 36 h after dosing. Pregabalin plasma concentrations were determined, using a validated method, by reversed phase high performance liquid chromatography coupled to a tandem mass spectrometry detector (LC–MS–MS). Pharmacokinetic metrics used for bioequivalence assessment were the AUC(0–t) (area under the plasma concentration–time curve from time zero to time of last observed non-zero plasma concentration) and the Cmax (maximum observed plasma concentration). These parameters were determined from the pregabalin plasma concentration data using noncompartmental analysis.ResultsForty healthy subjects, age ranging from 18 to 43 years old, were enrolled and randomized, of whom 39 completed the study. The ratio of geometric least square means for Cmax was 99.29 % (90 % confidence interval [CI] 93.29–105.67). The ratio of geometric least square means for AUC(0–t) was 101.54 % (90 % CI 100.13–102.98). The 90 % CIs were within the predefined range (80.00–125.00).ConclusionsBioequivalence between test and reference formulations, under fasting conditions, was concluded both in terms of rate and extent of absorption.

The similarity question for biologicals and non-biological complex drugs

For small – low molecular weight – molecule medicines a robust regulatory system has evolved over the years. This system guarantees high and constant quality of our (generic) medicines. Pharmaceutical equivalence and bioequivalence assessment are the pillars under that system. But there are complex medicines where the question of equivalence is more challenging to answer. For biologicals the paradigm of similarity rather than equality (the emergence of ‘biosimilars’) was developed in the past decade. This has been a program where an evolutionary, science based approach has been chosen by the frontrunner regulatory body, the EMA, with a ‘learn and confirm’ character.In addition, there is another group of complex drugs, the non-biological complex drugs, NBCDs, where the generic paradigm can be challenged as well. The NBCDs are defined as: 1. consisting of a complex multitude of closely related structures; 2. the entire multitude is the active pharmaceutical ingredient; 3. the properties cannot be fully characterized by physicochemical analysis and 4. the consistent, tightly controlled manufacturing process is fundamental to reproduce the product. NBCDs encompass product families such as the glatiramoids, liposomes, iron–carbohydrate colloids and many candidates of the group of the upcoming nanoparticulate systems. Following the main principles of regulatory pathways for biologicals (with appropriate product-by-product adjustments), instead of that for small molecules, would be the more logical strategy for these NBCDs.The status and outstanding regulatory issues for biosimilars and NBCD-similars/follow on versions were discussed at a conference in Budapest, Hungary (October 2014) and this commentary touches upon the issues brought up in the presentations, deliberations and conclusions.

Nanoemulsion formulation of florfenicol improves bioavailability in pigs.

Nanotechnology applications in medicine have seen a tremendous growth in the past decade and are being employed to enhance the stability and bioavailability of lipophilic substances, such as florfenicol. This study aimed to examine the pharmacokinetic properties of the formulated oil-in-water florfenicol-loaded nanoemulsion (FF-NE). FF-NE and florfenicol control (Nuflor) were administered to the pigs at a dose of 20 mg/kg. Nanoemulsion formulation of florfenicol was highly influenced in vivo plasma profile. The in vivo absorption study in pigs indicated that Cmax (14.54 μg/mL) was significantly higher in FF-NE, 3.42 times higher than the marketed formulation. In comparison with the control group, the relative bioavailability of formulated nanoemulsion was up to 134.5%. Assessment of bioequivalence using log-transformed data showed that the 90% confidence intervals (90% CI) of Cmax and AUC₀-∞ were 2.48-4.60 and 1.21-1.72, respectively.

Regulatory and clinical aspects of psychotropic medicinal products bioequivalence

Introduction of generic medicinal products to the market has increased access to modern therapies but also enabled significant reduction in their cost, leading to containment of public expenditures on medicinal products reimbursement. The critical assessment of bioequivalence of any reference medicinal product and its counterpart is based on comparison of their rate and extent of absorption. It is assumed that two medicinal products are bioequivalent when their rate and extent of absorption do not show significant differences when administered at the same dose under similar experimental conditions. Bioequivalent medicinal products are declared to be also therapeutically equivalent and can be used interchangeably. However, despite regulatory declaration, switching from reference to generic drugs is often associated with concerns of healthcare providers about decreased treatment effectiveness or occurrence of adverse drug reactions. The aim of this article is to provide a description of rules that guide registration of generic medicinal products in the European Union and to analyze specific examples from the scientific literature concerning therapeutic equivalence of reference and generic antidepressant and antipsychotic medicinal products.

Bioequivalence and Therapeutic Equivalence of Psychotropic Drugs.

Introduction to the market of generic drugs has increased access to modern therapies and enabled significant reduction of their cost, leading to containment of public expenditures on drug reimbursement. The assessment of bioequivalence of reference and generic drugs is based on the assumption that two different drug products are equivalent when their rate and extent of absorption do not show significant differences when administered at the same dose under similar experimental conditions. However, despite regulatory declaration, switching from reference to generic drugs is often associated with concerns of healthcare providers about decreased treatment effectiveness or occurrence of adverse drug reactions. The aim of the present research was to retrospectively study therapeutic equivalence of selected reference and generic psychotropic drugs. In our preliminary data we show, that no significant differences in clinical outcome was observed in patients after the switch. It indicates, that bioequivalent drugs are also therapeutically equivalent and can be used interchangeably.

Fluorescence detection of tramadol in healthy Chinese volunteers by high-performance liquid chromatography and bioequivalence assessment.

This study developed a revised high-performance liquid chromatography fluorescence method to determine plasma tramadol concentration, and thereby to examine the bioequivalence of two tramadol formulations among healthy male Chinese volunteers. The study used a double-blind, randomized, 2×2 crossover-design principle. Calculated pharmacokinetic parameters for both formulations were consistent with previous reports. According to the observation of vital signs and laboratory measurement, no subjects had any adverse reactions. The geometric mean ratios (90% confidence interval) of the test drug/reference drug for tramadol were 100.2% (95.3%–103.4%) for the area under the plasma concentration–time curve (AUC) from time zero to the last measurable concentration, 99.6% (94.2%–102.7%) for the AUC from administration to infinite time, and 100.8% (93.1%–106.4%) for maximum concentration. For the 90% confidence intervals of the test/reference AUC ratio and maximum concentration ratio of tramadol, both were in the acceptance range for bioequivalence. According to the two preparations by pharmacokinetic parameter statistics, the half-life, mean residence time, and clearance values showed no significant statistical differences. Therefore, the conclusion of this study was that the two tramadol formulations (tablets and capsules) were bioequivalent.

Low within- and between-day variability in exposure to new insulin glargine 300 U/ml.

AimsTo characterize the variability in exposure and metabolic effect of insulin glargine 300 U/ml (Gla-300) at steady state in people with type 1 diabetes (T1DM).MethodsA total of 50 participants with T1DM underwent two 24-h euglycaemic clamps in steady-state conditions after six once-daily administrations of 0.4 U/kg Gla-300 in a double-blind, randomized, two-treatment, two-period, crossover clamp study. Participants were randomized to receive Gla-300 as a standard cartridge formulation in the first treatment period, and as a formulation with enhanced stability through polysorbate-20 addition in the second treatment period, or vice versa. This design allowed the assessment of bioequivalence between formulations and, subsequently, within- and between-day variability.ResultsThe cumulative exposure and effect of Gla-300 developed linearly over 24 h, and were evenly distributed across 6- and 12-h intervals. Diurnal fluctuation in exposure (within-day variability) was low; the peak-to-trough ratio of insulin concentration profiles was <2, and both the swing and peak-to-trough fluctuation were <1. Day-to-day reproducibility of exposure was high: the between-day within-subject coefficients of variation for total systemic exposure (area under the serum insulin glargine concentration time curve from time 0 to 24 h after dosing) and maximum insulin concentration were 17.4% [95% confidence interval (CI) 15–21] and 33.4% (95% CI 28–41), respectively. Reproducibility of the metabolic effect was lower than that of exposure.ConclusionsGla-300 provides predictable, evenly distributed 24-h coverage as a result of low fluctuation and high reproducibility in insulin exposure, and appears suitable for effective basal insulin use.

The Role of Metabolite in Bioequivalence Decision Making

Purpose: To investigate whether the combined concentrations of the parent drug and its corresponding metabolite impacts the experimental design of bioequivalence studies. Methods: Enalpril and sildenafil were selected to assess bioequivalence as both drugs have active metabolites. The bioequivalence study of enalpril was conducted under fasting conditions, while the bioequivalence assessment of sildenafil was conducted under both fasting and fed conditions. For the three studies, the bioequivalence criteria of 80-125% was applied to assess the parent compounds alone, the active metabolites alone, and both the parent drugs and the active metabolites. Results: Similar statistical results to assess bioequivalence were obtained for the parent drug, metabolite, and the sum of the parent drug and metabolite for AUC. In the case of Cmax, the intra subject variability of the bioequivalence statistical results with regards to the metabolite and the sum of the parent and the metabolite was lower than that for the parent drug while the power of the bioequivalence decision was higher for the metabolite and the sum of the parent drug and the metabolite. Conclusions: An improved intra subject variability resulted in higher power with a smaller sample size in the Cmax values with regards to decision making in bioequivalence studies.

Bioequivalence studies in Europe before and after 2010

AbstractRegulatory guidelines are necessary to standardize the evaluation procedure in bioequivalence. Revisions in the guidelines occur in order to resolve any previously unclear issues and to address new needs. In this paper, the authors discuss the major regulatory requirements for bioequivalence assessment before and after the EMA guidelines of 2010 and unveil their differences. The authors compiled this review following the critical exploration of literature articles and regulatory guidance documents. This was achieved through searching MEDLINE, Scopus, and the official EMA site. The authors found, in the post-2010 era, that the major differences in the regulatory framework refer to: the choice of clinical designs, the assessment of highly variable drugs, biowaivers, the pharmacokinetics parameters used, and the explicit definition for the use of metabolite data, enantiomers, and endogenous substances. Also, product-specific guidelines have started to be issued, while recommendations are now provided...

Model-Based Bioequivalence assessment of a commercial Azithromycin Capsule against Pfizer Zithromax® Tablet marketed in Jamaica

Clinical evidence indicated that effective substitution of azithromycin capsule with a tablet dosage form should be based on evidence of providing equivalent in vivo AUC/MIC ratio at the site of infection. This study was designed to compare the bioavailability of a generic azithromycin capsule and assess its bioequivalence with Zithromax tablets marketed in Jamaica. Healthy adult volunteers were recruited following official institutional protocols and randomly assigned to pre- and post wash-over periods of the tests. Sampled plasma levels were analyzed using validated HPLC method. Drug’s bio-disposition mechanism in the subjects was determined using the Gastroplus® pharmacokinetics software. Model evaluation with Akaike Information Criterion (AIC) and Schwarz Criterion (SC) indicated one-compartment and two-compartment open models as the best for modeling azithromycin bioavailability from tablets and capsules respectively. However, statistical analysis showed no statistical significance between the respective bioavailability parameters of capsules and tablets, and they fell generally within the US FDA acceptance range of -20% to +25 % of reference product. Azithromycin release from tablets fits one-compartment while from capsules fits the two-compartment open models respectively. Azithromycin capsules were bioequivalent to its proprietary tablets and can be substituted in black male subjects if administered at least two hours before meals.

Evaluation of the highly variable agomelatine pharmacokinetics in Chinese healthy subjects to support bioequivalence study.

ObjectivesWe aim to obtain the intra-subject coefficient of variability of a highly variable antidepressant agomelatine in humans, and propose an adjusted bioequivalence assessment strategy.MethodsA single-dose, randomized crossover design was conducted in four periods (reference administered thrice, placebo administered once) separated by seven days. A validated LC-MS/MS assay was used to measure drug concentrations in serial blood samples.ResultsThe intra-subject coefficient of variability was calculated using the residual variance of ANOVA analysis, and the results for Cmax and AUC0-t was 78.34% and 43.52%, respectively, in Chinese healthy subjects. The sample size required for standard BE study were 124(192, 340) if the expected deviation between the reference and generic products was set to 0 (5%, 10%).ConclusionsAgomelatine meets the criteria for highly variable drug in Chinese healthy male subjects, and the traditional BE criteria for agomelatine needs to be adjusted to alleviate the resource and ethical burden of using a large numbers of subjects in clinical trials. Our clinical data on the intra-subject variability of agomelatine PK in Chinese healthy population enables to adjust bioequivalence (BE) assessment approach for agomelatine based on the RSABE approaches recommended by regulatory agencies.Trial RegistrationChiCTR.org ChiCTR-TTRCC-13003835