Assessment of comparative bioavailability of Itraconazole capsule 100 mg under fasting conditions by average bioequivalence (ABE), population bioequivalence (PBE) and individual bioequivalence (IBE) approaches

The assessment of interchangeability (prescribability and switchability) is one of the debatable topics in the generic drug industry. Currently, the question is whether we have an adequate assessment system for the evaluation of generic drug products. The objective of the study is to assess the comparative oral bioavailability of Itraconazole capsule 100mg after administering single dose to adult, healthy, human subjects in fasted state by different bioequivalence approaches like average bioequivalence (ABE), population bioequivalence (PBE) and individual bioequivalence (IBE) and to monitor the safety of study subjects. An open-label, balanced, randomized, two-treatment, two-sequence, four-period, crossover, single-dose comparative oral bioavailability study was conducted in sixteen healthy, adult, human subjects in a fasted state. Test formulation, Itraconazole capsule 100mg, and reference formulation, SPORANOX® (Itraconazole) capsule 100mg, were administered in a fasted state. The test formulation, Itraconazole capsule 100mg, showed bio-inequivalent against reference SPORANOX® (Itraconazole) capsule 100mg in study subjects under a fasted state. Also, the test formulation exhibited a similar safety and tolerability profile compared to the reference formulation. There was no report of serious adverse events (SAEs) and deaths in the study. The test formulation was found to be bio-inequivalent to reference formulation in the study subjects under a fasted state by estimating different bioequivalence approaches like average bioequivalence, population bioequivalence, and individual bioequivalence.

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Has the Time Come to Employ Population and Individual Bioequivalence for the Evaluation of Generics?

Current Drug Metabolism ◽

10.2174/1389200221666200401105119 ◽

2020 ◽

Vol 21 (2) ◽

pp. 112-125

Author(s):

Francis Micheal ◽

Mohanlal Sayana ◽

Rajendra Prasad ◽

Balamurali Musuvathi Motilal

Keyword(s):

Therapeutic Index ◽

Bioequivalence Study ◽

Open Label ◽

Statistical Parameters ◽

Population Mean ◽

Average Bioequivalence ◽

Individual Bioequivalence ◽

Population Bioequivalence ◽

Enteric Coated ◽

Bioequivalence Assessment

Background: Bioequivalence studies are a vital part of drug development. The average bioequivalence approach is the standard method of assessment to conclude whether the generic product is bioequivalent to the innovator product. Of late, debates are on whether the average bioequivalence approach adequately addresses drug interchangeability as it considers only population mean for the evaluation especially when highly variable drug products and narrow therapeutic index drugs are dealt with. Hence, the alternative approaches like population bioequivalence and individual bioequivalence assessment approaches emerge as they consider inter/intra-subject variance and subject- by-formulation variance along with population mean. Objectives: The objective of the study was to apply different bioequivalence assessment approaches in a replicate bioequivalence study to evaluate the drug interchangeability. Methods: This was an open-label, single-dose, randomized, balanced, two-treatment, three-period, three-sequence, partial replicate crossover bioequivalence study of omeprazole enteric-coated tablet 20 mg conducted on 48 normal healthy subjects under fed conditions. The plasma concentration of omeprazole was analyzed by a validated bioanalytical method to determine the pharmacokinetic and statistical parameters to assess average bioequivalence, population bioequivalence, and individual bioequivalence. Results: In this study, test formulation was shown to be bio-inequivalent to the reference formulation by average bioequivalence, population bioequivalence, and individual bioequivalence approaches. Conclusion: The outcome of the evaluation clearly states that the bioequivalence outcome of all these approaches are the same. Obviously, it does not mean that these three approaches provide the same outcome though the consideration of variances varies. Certainly, population bioequivalence and individual bioequivalence approach will be more accurate for the assessment of drug interchangeability.

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Bioequivalence of levamlodipine besylate tablets in healthy Chinese subjects: A single-dose and two-period crossover randomized study

10.21203/rs.3.rs-47842/v1 ◽

2020 ◽

Author(s):

Li Xin ◽

Chenjing Wang ◽

Ting Li ◽

Yanping Liu ◽

Shuqin Liu ◽

...

Keyword(s):

Single Dose ◽

Randomized Study ◽

Pharmacokinetic Parameters ◽

Reference Formulation ◽

High Fat ◽

Fasting Condition ◽

Test Formulation ◽

Healthy Chinese ◽

Chinese Subjects ◽

Fat Meal

Abstract Background: Levamlodipine, a calcium channel blocker, is used in treatment of hypertension. To compare the pharmacokinetic parameters between levamlodipine test formulation at a single dose of 5 mg and amlodipine reference formulation at a single dose of 10 mg, the bioequivalence study was carried out.Methods: A single-dose randomized, open-label, two-period crossover study was designed in healthy Chinese subjects. 48 subjects were divided into fasting and high-fat meal group equally. The subjects randomly received the test or reference formulations at the rate of 1:1. Following a 21-day washout period, the alternative formulations were received. The blood samples were collected at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 24, 36, 48, 72, 96, 120, 144, 168 hours later. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was applied to determine levamlodipine in the plasma samples.Results: Within equivalence limits between 80 ~ 125%, the test formulation and the reference formulation were bioequivalent, with the 90% confidence intervals (CIs) for the ratio of geometric means of Cmax, AUC0-t, and AUC0-∞. The data were shown as Cmax (89.59% ~ 101.61%), AUC0-t (87.83% ~ 94.87%) and AUC0-∞ (86.28% ~ 93.49%) under fasting condition, Cmax (90.93% ~ 102.37%), AUC0–t (95.75% ~ 104.93%) and AUC0–∞ (95.36% ~ 105.33%) under high-fat meal condition. Serious adverse event was not observed.Conclusions: The trial confirmed that levamlodipine at a single dose of 5 mg and amlodipine at a single dose of 10 mg were bioequivalent under both fasting condition and high-fat meal condition.Trial registration: Cinicaltrials, NCT04411875. Registered 3 June 2020 - Retrospectively registered, https://register.clinicaltrials.gov/prs/app/action/SelectProtocol?sid=S0009W1Q&selectaction=Edit&uid=U00050YQ&ts=3&cx=-6iqkm8

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Current Regulatory Standpoint on Evaluating the Bioequivalence of Different Classes of Generic Drugs - Is the Evaluation in the Right Direction?

Current Drug Metabolism ◽

10.2174/1389200220666191007152542 ◽

2019 ◽

Vol 20 (10) ◽

pp. 835-844 ◽

Cited By ~ 1

Author(s):

Francis Micheal ◽

Mohanlal Sayana ◽

Balamurali Musuvathi Motial

Keyword(s):

Generic Drugs ◽

Bibliographic Databases ◽

Eligibility Criteria ◽

Individual Bioequivalence ◽

Population Bioequivalence ◽

Standard Tool ◽

Review Question ◽

Guidance Documents ◽

The Right

Background: The concept of evaluating bioequivalence has changed over a period of time. Currently, the Average Bioequivalence approach (ABE) is the gold standard tool for the evaluation of generics. Of late, many debates had arisen about employing ABE approach for the appraisal of all drug categories. This review aims to examine the limitations of ABE approach and the significances of Population Bioequivalence (PBE) and Individual Bioequivalence (IBE) approach, current regulatory thinking for assessing different categories of the drug, whether they are adequately assessed, and the evaluation is in the right direction. Methods: We carried out an organized search of bibliographic databases for peer-reviewed research literatures, regulatory recommendations, guidance documents using a focused review question and eligibility criteria. The standard tools were used to appraise the quality of retrieved documents and to make sure the authenticity of the data. Results: In total 73 references were used in the review, the majority of the references (guidance documents) were from the different regulatory agencies and product-specific guidance. There were 29 product-specific guidance from USFDA and EMA. The limitations of the ABE approach were discussed in detail along with the significances of Population Bioequivalence (PBE) approach and Individual Bioequivalence (IBE) approaches. Conclusion: It is apparent from the review that IBE approach is a precise method for evaluating the drugs as it answers drug interchangeability (prescribability and switchability). IBE approach is followed by PBE approach and ABE approach for the evaluation of different categories of drugs in terms of precision.

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Fiber-Reinforced-Phospholipid Vehicle-Based Delivery of l-Ascorbic Acid: Development, Characterization, ADMET Profiling, and Efficacy by a Randomized, Single-Dose, Crossover Oral Bioavailability Study

ACS Omega ◽

10.1021/acsomega.0c05963 ◽

2021 ◽

Author(s):

Joby Jacob ◽

Nimisha Pulikkal Sukumaran ◽

Shintu Jude

Keyword(s):

Ascorbic Acid ◽

Single Dose ◽

Oral Bioavailability ◽

Fiber Reinforced ◽

Bioavailability Study

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The fate of cyclamate in man and other species

Biochemical Journal ◽

10.1042/bj1290869 ◽

1972 ◽

Vol 129 (4) ◽

pp. 869-879 ◽

Cited By ~ 60

Author(s):

A. G. Renwick ◽

R. T. Williams

Keyword(s):

Single Dose ◽

Gastrointestinal Tract ◽

Biliary Excretion ◽

Guinea Pigs ◽

Human Subjects ◽

Gut Flora

1. 14C-labelled cyclamate has been administered to guinea pigs, rabbits, rats and humans. When given orally to these species on a cyclamate-free diet, cyclamate is excreted unchanged. In guinea pigs some 65% of a single dose is excreted in the urine and 30% in the faeces, the corresponding values for rats being 40 and 50%, for man, 30–50% and 40–60%, and for rabbits, 90 and 5%, the excretion being over a period of 2–3 days. 2. Cyclamate appears to be readily absorbed by rabbits but less readily by guinea pigs, rats and humans. 3. If these animals, including man, are placed on a diet containing cyclamate they develop the ability to convert orally administered cyclamate into cyclohexylamine and consequently into the metabolites of the latter. The extent to which this ability develops is variable, the development occurring more readily in rats than in rabbits or guinea pigs. In three human subjects, one developed the ability quite markedly in 10 days whereas two others did not in 30 days. Removal of the cyclamate from the diet caused a diminution in the ability to convert cyclamate into the amine. 4. In rats that had developed the ability to metabolize orally administered cyclamate, intraperitoneally injected cyclamate was not metabolized and was excreted unchanged in the urine. The biliary excretion of injected cyclamate in rats was very small, i.e. about 0.3% of the dose. 5. The ability of animals to convert cyclamate into cyclohexylamine appears to depend upon a continuous intake of cyclamate and on some factor in the gastrointestinal tract, probably the gut flora.

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BIOANALYTICAL METHOD DEVELOPMENT AND VALIDATION OF MICRONIZED GLICLAZIDE IN HUMAN PLASMA BY LC-MS/MS AND ITS PHARMACOKINETIC STUDIES

INDIAN DRUGS ◽

10.53879/id.55.09.11405 ◽

2018 ◽

Vol 55 (09) ◽

pp. 24-33

Author(s):

R. Bose ◽

◽

S Dan ◽

P. Mandal ◽

P. Sarkar ◽

...

Keyword(s):

Single Dose ◽

Oral Bioavailability ◽

Method Development ◽

Test Preparation ◽

Pharmacokinetic Parameters ◽

Pharmacokinetic Studies ◽

Particle Size Reduction ◽

Male Adult ◽

Minimum Effective Concentration ◽

Reference Preparation

Drugs having poor oral bioavailability, fail to reach the minimum effective concentration required to achieve pharmacological action. Improvement of the oral bioavailability of the drug is the most realistic approach, as it is the most preferred and convenient route of administration. Besides numerous techniques to improve oral bioavailability of the drugs, particle size reduction leads to increase in the effective surface area, resulting in enhancement of solubility and dissolution velocity of the drug. In the present study a sustained release tablet formulation containing 60mg micronized gliclazide was attempted to develop and a randomized, two period, two treatment crossover, single dose, pilot study of test preparation along with a marketed sample of Gliclazide 60mg was carried out on 6 healthy male, adult, human volunteers under fasting condition to establish the bioequivalence of the new formulation with a washout period of one week. The developed method was found to be simple, reproducible, sensitive, and specific for the determination of gliclazide from plasma and was also applied to study the pharmacokinetic parameters of gliclazide. The mean peak plasma levels of gliclazide with the reference preparation on the study day ranged between 2562.27–2823.61ng/mL, while the test preparation ranged between 3091.24–3467.66ng/mL. On the basis of comparison of the AUC0-t for gliclazide after single dose administration, the relative bioavailability of the test preparation was 109.96% of that of the reference preparation.

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Assessment of prescribability and switchability by using multiple bioequivalence assessment approaches

Drug Metabolism Letters ◽

10.2174/1872312814666210319124659 ◽

2021 ◽

Vol 14 ◽

Author(s):

Francis Micheal ◽

Mohanlal Sayana ◽

Rajendra Prasad ◽

Balamurali Musuvathi Motiala

Keyword(s):

Single Dose ◽

Assessment Methods ◽

Coefficient Of Determination ◽

Adult Males ◽

Time Data ◽

Open Label ◽

Gold Standard Method ◽

Population Mean ◽

Average Bioequivalence ◽

Bioequivalence Assessment

Background: In the drug development process, an assessment of bioequivalence is an integral part. For the evaluation of generics against the comparator, average bioequivalence approach is the gold standard method. In the recent past, there were many discussions on whether we have the adequate tool to evaluate generics and thereby drug interchangeability (prescribability and switchability) issue is addressed as average bioequivalence approach just considers population mean. Hence, the alternative approaches like population bioequivalence and individual bioequivalence assessment approaches arise as different variances like inter/ intra-subject variance and subject-by-formulation variance along with population mean are considered. Objectives: Methoxsalen, in combination with long-wave UVA radiation, is used in the symptomatic management certain psoriasis. The study was aimed to establish the bioequivalence (BE) of a newly developed methoxsalen capsule (MTX test) with that of a reference methoxsalen capsule (MTX reference) using multiple BE methods (i.e., average [ABE], population [PBE], and individual [IBE]) by utilizing a new LC–MS/MS method. Methods: This is an open-label, randomized, balanced, two-treatment, three-period, three-sequence, crossover, single-dose (20 mg, 2 × 10 mg capsules), comparative, oral BE study conducted in 52 healthy, adult males under fasting conditions. Along with various pharmacokinetic (PK) parameters ABE, PBE, and IBE were also determined in the single study. Results: : A non-compartmental model best described the concentration–time data of both MTX test and reference. Both the formulations demonstrated nearly similar values of BE parameters (i.e., AUCo–t, AUC0–∞, Cmax, Tmax, and t1/2). For MTX test, the observed Cmax, AUC0–t, and AUC0–∞ were 125.16±81.53 ng/mL, 313.73±260.86 ng h/mL, and 321.25±271.85 ng h/mL, respectively. For MTX reference, the values were 127.63±71.60 ng/mL, 329.11±252.91 ng h/mL, and 335.48±264.54 ng h/mL, respectively. The bioanalytical method was validated over the concentration range 0.100–100.00ng/mL and the coefficient of determination (r2) was ≥ 0.9991. The sensitivity of the method was 0.100 ng/mL with the accuracy and precision values of 115% and 10.54%, respectively. Conclusion: A single dose of MTX test met the ABE criteria of 80.00% –125.00% for Cmax, AUCo–t, and AUC0–∞, against MTX reference. The study outcome by PBE and IBE approaches proved that MTX Test was bio-inequivalent to MTX reference. Using multiple BE assessment methods in a single BE study is a novel approach and may overcome shortcomings of conventional bioequivalence assessment methods.

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