Individual Bioequivalence Research Articles

Interchangeability between Generic and Reference Products: Limits of Average Bioequivalence Methodology.

Marketing authorisation of generic drugs is based on a demonstration of the "average" bioequivalence (ABE), with acceptance limits of 0.8-1.25 for the 90% confidence interval (CI) of the ratio (generic versus reference) of geometric means of exposure (whole blood, serum or plasma drug concentration). However, when interchangeability of reference by one generic is considered during treatment of a given patient, such methodology cannot guarantee the lack of therapeutic impact especially for drugs with narrow therapeutic index. This review article describes the basis and limits of ABE methodology, and the adaptations that have been proposed by regulatory agencies. For highly variable drugs, given their large therapeutic margin, regulatory agencies even allow widening of the bioequivalence acceptance limits. For drugs with a narrow therapeutic index, the average bioequivalence methodology has been amended differently by regulatory agencies. The European Medicine Agency only requires the narrowing of the ABE acceptance limits to the 0.9-1.10 range. The US Food and Drug Administration (FDA) has proposed to narrow the ABE acceptance limits according to the reference within-subject variance. The FDA requires a fully replicate cross-over study (with four periods) which allows one to compare the within-subject variance between generic and reference drug, and to detect any subject-by-formulation interaction. Indeed, any within-subject variance difference or subject by formulation interactionis an obstacle to interchangeability at the individual level. These amendments for the ABE do not fundamentally change the fact that individual ratios of exposure (generic/reference) will vary to a larger extent than the ratio of their means. For these reasons, since true individual bioequivalence studies cannot be performed for practical reasons and statistical issues, one can suggest that, in addition to the usual average bioequivalence criteria, the limits of the 95% confidence interval of the individual generic/reference exposure ratios could be used to allow interchangeability during treatment (at least for narrow therapeutic index drugs). Limit values of such CI for interchangeability acceptance should be scaled to the therapeutic margin of the reference drug. Regulatory agencies could conduct calculations based on real datasets of bioequivalence studies to determine if such criteria could be acceptable to allow interchangeability.

Assessment of Prescribability and Switchability by Using Multiple Bioequivalence Assessment Approaches.

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. 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. 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. 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. 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.

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

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. The objective of the study was to apply different bioequivalence assessment approaches in a replicate bioequivalence study to evaluate the drug interchangeability. 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. In this study, test formulation was shown to be bio-inequivalent to the reference formulation by average bioequivalence, population bioequivalence, and individual bioequivalence approaches. 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.

Unified approaches to assessing treatment effect of traditional Chinese medicine based on health profiles

ABSTRACTTwo dissimilarity indices are introduced to measure the disharmony of a human body system by mimicking the population bioequivalence and the individual bioequivalence concepts. Hypotheses for the treatment effect of a traditional Chinese medicine are formulated based on the two indices and then tested under the proposed designs by reverting an approximate confidence upper bound. The proposed methods can also be used when a drug product has multiple components or a trial has multiple endpoints.

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

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. 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. 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. 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.

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.

Levothyrox® New and Old Formulations: Are they Switchable for Millions of Patients?

In France, more than 2.5 million patients are currently treated with levothyroxine, mainly as the marketed product Levothyrox®. In March 2017, at the request of French authorities, a new formulation of Levothyrox® was licensed, with the objective of avoiding stability deficiencies of the old formulation. Before launching this new formulation, an average bioequivalence trial, based on European Union recommended guidelines, was performed. The implicit rationale was the assumption that the two products, being bioequivalent, would also be switchable, allowing substitution of the new for the old formulation, thus avoiding the need for individual calibration of the dosage regimen of thyroxine, using the thyroid-stimulating hormone level as the endpoint, as required for a new patient on initiating treatment. Despite the fact that both formulations were shown to be bioequivalent, adverse drug reactions were reported in several thousands of patients after taking the new formulation. In this opinion paper, we report that more than 50% of healthy volunteers enrolled in a successful regulatory average bioequivalence trial were actually outside the a priori bioequivalence range. Therefore, we question the ability of an average bioequivalence trial to guarantee the switchability within patients of the new and old levothyroxine formulations. We further propose an analysis of this problem using the conceptual framework of individual bioequivalence. This involves investigating the bioavailability of the two formulations within a subject, by comparing not only the population means (as established by average bioequivalence) but also by assessing two variance terms, namely the within-subject variance and the variance estimating subject-by-formulation interaction. A higher within individual variability for the new formulation would lead to reconsideration of the appropriateness of the new formulation. Alternatively, a possible subject-by-formulation interaction would allow a judgement on the ability, or not, of doctors to manage patients effectively during transition from the old to the new formulation.Electronic supplementary materialThe online version of this article (10.1007/s40262-019-00747-3) contains supplementary material, which is available to authorized users.

Switchability of Gabapentin Formulations: ARandomized Trial to Assess Bioequivalence Between Neurontin and Gabasandoz on the Individual Subject Level.

Generic substitution of antiepileptic drugs is generally not advised by neurologists. The present study investigated the switchability of gabapentin 800mg tablets (Neurontin and Gabasandoz) using an individual bioequivalence (IBE) study design with two batches of each product and assessed whether between-batch and between-formulation variability in exposure play a significant role in the within-subject variability. The trial was analyzed according to the US Food and Drug Administration (FDA) framework to establish IBE. The IBE was shown between both products with the 95% upper confidence bound of the IBE criterion being -2.01 and -2.31 for area under the concentration-time curve from zero to infinity (AUC0-inf ) and peak plasma concentration (Cmax ), respectively. Subject-by-formulation variability (1.35%) was negligible compared with the within-subject variability of AUC0-inf with Neurontin (19.0%) and Gabasandoz (23.6%). Inclusion of an additional batch did not significantly change this within-subject variability (20.2% and 23.6%, respectively). This study shows that substitution of gabapentin 800mg tablets of Neurontin and Gabasandoz should be possible without affecting clinical outcomes.

Assessment of individual bioequivalence using sufficient bootstrap procedure

This paper proposes a sufficient bootstrap method, which uses only the unique observations in the resamples, to assess the individual bioequivalence under 2 × 4 randomized crossover design. The finite sample performance of the proposed method is illustrated by extensive Monte Carlo simulations as well as a real-experimental data set, and the results are compared with those obtained by the traditional bootstrap technique. Our records reveal that the proposed method is a good competitor or even better than the classical percentile bootstrap confidence limits.

Iterated bootstrap procedure in individual bioequivalence

In this paper, we propose an iterating principle in the bootstrap method to assess the individual bioequivalence under 2×4 randomized crossover design. The finite sample properties of the proposed algorithm are illustrated by an extensive simulation study and a real-world example. Our findings reveal that the proposed idea have better performance than the classical percentile bootstrap confidence limits.

Bioequivalence Between Generic and Branded Lamotrigine in People With Epilepsy

Switching between generic antiepileptic drugs is a highly debated issue that affects both clinical care and overall health care costs. To evaluate the single-dose pharmacokinetic bioequivalence of 3 (1 branded and 2 generic drugs) on-market, immediate-release lamotrigine drug products. The Equivalence Among Antiepileptic Drug Generic and Brand Products in People With Epilepsy (EQUIGEN) single-dose study is a crossover, prospective, sequence-randomized, replicate pharmacokinetic study conducted at 5 US academic epilepsy centers. Fifty adults (≥18 years) with epilepsy who were taking concomitant antiepileptic drugs and not currently receiving lamotrigine were enrolled between July 18, 2013, and January 19, 2015. Every participant was randomly assigned to 1 of 3 equivalent sequences, each comprising 6 study periods, during which they had blood draws before and after medication administration. Forty-nine participants were included in intention-to-treat analyses. Participants received a single 25-mg dose of immediate-release lamotrigine at the start of each period, with the branded and the 2 most disparate generic products each studied twice. Lamotrigine was selected as the antiepileptic drug of interest because of its wide use, publications indicating problems with generic switches, and complaints to the US Food and Drug Administration regarding generic products. Both participants and study personnel were blinded to the specific generic products selected. The primary outcome was bioequivalence between products. Maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC) were compared, and average bioequivalence (ABE) was established if the 90% CIs of the ratios of the 2 products were within equivalence limits (80%-125%). Of the 50 randomized participants, 49 (98%) received all 3 lamotrigine products and completed at least 3 pharmacokinetic assessments and 46 (92%) completed all 6 pharmacokinetic assessments. Among the 49 participants, 28 (57%) were men and 21 (43%) were women, 42 (86%) self-identified as white, and 46 (16) years was the mean (SD) age. The 3 drug products were considered bioequivalent because the 90% CIs were within equivalence limits (lowest and highest CI limits for Cmax, 92.6% and 110.4%; for AUC0-96, 96.9% and 101.9%). Replicate testing demonstrated no significant differences in within-subject variability across the 3 products (likelihood ratios, χ22 for log-transformed variables: AUC0-96, 2.58; Cmax, 0.64; and AUC0-∞, 4.05; P ≥ .13) and that the 3 products were also bioequivalent according to scaled ABE and individual bioequivalence criteria with no subject × formulation interaction (Cmax, 0.00; AUC0-96, 0.54; and AUC0-∞, 0.36; P ≥ .76). This study provides evidence that the disparate lamotrigine products studied are bioequivalent when tested in people with epilepsy taking concomitant antiepileptic drugs. clinicaltrials.gov Identifier: NCT01733394.

Flexible multivariate nonlinear models for bioequivalence problems

Modelling the concentration of a drug in the bloodstream over time is usually done using compartment models. In pharmacokinetic data, they turn into highly nonlinear mixed-effects models (NLMEMs) when we take the heterogeneity between subjects into account. Fitting of NLMEMs can be difficult and may involve complex algorithms, with convergence critically depending on the initial values and maybe requiring data transformations. In this article, we propose a flexible alternative to the usual parametric compartment models, inspired by the Multivariate SuperImposition by Translation and Rotation (MSITAR) model but adapted to be applicable in this new field. A fully parametric one-compartment NLMEM is considered for comparison. We make use of a Bayesian approach and illustrate the method on a real dataset where the interest lies in contrasting the average and individual bioequivalence of a test and reference formulation of an anti-hypertensive drug.

Statistical evaluation of the scaled criterion for drug interchangeability

ABSTRACTAs more and more generic drug products become available in the marketplace, it is a concern whether these generic drug products can be used interchangeably in terms of their quality, safety, and efficacy. The United States Food and Drug Administration (FDA) indicates that an approved generic drug product can serve as a substitute for the innovative drug product. The FDA, however, does not indicate that approved generic drug products can be used interchangeably even if they are bioequivalent to the same innovative drug product. In the past decade, several criteria for assessing interchangeability were proposed in regulatory guidances and/or literature. Chow, Xu, and Endrenyi proposed a scaled criterion for drug interchangeability (SCDI), which takes both intra-subject variability and subject-by-drug variability into consideration. In this paper, the performance of this criterion is statistically evaluated by deriving the upper confidence limit of the test statistic and extrapolating expression of the power to facilitate sample size calculation. The performance of SCDI is also compared with that of the criterion for assessment of individual bioequivalence (IBE) for addressing drug switchability recommended by the FDA, which also takes into account the subject-by-drug variability, under various parameter specifications.

Assessing bioequivalence and drug interchangeability

ABSTRACTAs indicated by the US Food and Drug Administration (FDA), approved generic drug products can be used as substitutes for their respective innovative drug products. The FDA, however, does not indicate that two generic copies of the same innovative drug can be used interchangeably, even though they have been shown to be bioequivalent to the same innovative drug product. As more and more generic drug products become available in the market place, it is a concern whether these approved generic drug products have the same quality and safety/efficacy and hence can be used interchangeably. To address the issue of drug interchangeability, several criteria such as individual bioequivalence criterion, a criterion based on the variability due to subject-by-drug interaction, and a scaled criterion for drug interchangeability (SCDI) have been proposed in the literature. In this article, the performances of these criteria, including a newly proposed reversed average bioequivalence criterion, are studied under a 2x4 replicated crossover design in terms of the percentage of passing at the best and worst possible scenarios of similarity. The goal of this paper is to investigate the interchangeability in terms of switchability between a generic (test) drug product and an originator (reference) drug product.

The interchangeability of gabapentin 800 mg tablets: a randomized, controlled trial to establish individual bioequivalence

The interchangeability of gabapentin 800 mg tablets: a randomized, controlled trial to establish individual bioequivalence

Likelihood approach for evaluating bioequivalence of highly variable drugs.

Bioequivalence (BE) is required for approving a generic drug. The two one-sided tests procedure (TOST, or the 90% confidence interval approach) has been used as the mainstream methodology to test average BE (ABE) on pharmacokinetic parameters such as the area under the blood concentration-time curve and the peak concentration. However, for highly variable drugs (%CV > 30%), it is difficult to demonstrate ABE in a standard cross-over study with the typical number of subjects using the TOST because of lack of power. Recently, the US Food and Drug Administration and the European Medicines Agency recommended similar but not identical reference-scaled average BE (RSABE) approaches to address this issue. Although the power is improved, the new approaches may not guarantee a high level of confidence for the true difference between two drugs at the ABE boundaries. It is also difficult for these approaches to address the issues of population BE (PBE) and individual BE (IBE). We advocate the use of a likelihood approach for representing and interpreting BE data as evidence. Using example data from a full replicate 2 × 4 cross-over study, we demonstrate how to present evidence using the profile likelihoods for the mean difference and standard deviation ratios of the two drugs for the pharmacokinetic parameters. With this approach, we present evidence for PBE and IBE as well as ABE within a unified framework. Our simulations show that the operating characteristics of the proposed likelihood approach are comparable with the RSABE approaches when the same criteria are applied.

Equivalence Tests for Interchangeability Based on Two One-Sided Probabilities

A test treatment is considered to be interchangeable with its reference treatment if they are equivalent and expected to produce the same clinical result in any given patient. To assess interchangeability, FDA Draft Guidance (1999) and Guidance for Industry (2001, 2003) recommend using individual bioequivalence (IBE) and population bioequivalence (PBE) procedures. Chow (1999) and Chow and Liu (1999) gave a discussion on the limitation of the aggregate criteria of the IBE and PBE proposed therein. They mentioned that it is not clear whether IBE or PBE can imply average bioequivalence. Alternative approaches have been proposed to address the weakness of IBE and PBE. Dong et al. (2014) discuss the tolerance interval method and an approximate test for interchangeability defined by a two-sided probability. These tests may not be able to test for the two one-sided tests (TOST) with asymmetric margins around the true mean difference. In addition, the tests of two-sided probability provide no direction when failing the equivalence in interchangeability. Thus, we reexamine the statistical properties of the two one-sided tolerance interval approaches proposed by Tsong and Shen (2007, 2008). In this project, we extend their approach for parallel arms trials and paired/crossover data without the assumption of equal sample sizes and variances. We also develop the exact power function and assess the type I error rate of our proposed approach. In addition, we study the sample size determination based on the interchangeability testing utilizing the tolerance interval method.

Equivalence Assessment for Interchangeability Based on Two-Sided Tests

Interchangeability was originally developed in order to assess drug bioequivalence beyond average bioequivalence. In 2003, the Food and Drug Administration (FDA) published a Guidance documenting the procedures on using in vivo bioequivalence crossover trial to assess interchangeability between test and reference products. In general, this FDA Guidance describes interchangeability in terms of population and individual bioequivalence. The Guidance procedures were criticized for their lack of sampling distribution of the test statistics. As a result, the critical points were generated from simulation studies without adjusting for sample size. Further more, they lack consistency with average bioequivalence required in the 1992 FDA Guidance. Alternative interchangeability or interchangeability procedures were proposed to measure the probability of individual response difference under two treatments within prespecified lower and upper limits. Interchangeability is claimed if this probability is greater than a prespecified threshold. Tse et al. (2006) proposed an approximate distribution of the estimated probability based on the second-order Taylor expansion. For the same interchangeability probability hypothesis, Liu and Chow (1997) and Tsong and Shen (2007) also proposed a tolerance interval-based approach that can be extended to clinical trials with parallel arm design under the normality assumption. In this article, we first generalized the two-sided tolerance interval based interchangeability without equal sample size and variance assumption. We also derived a power function for the proposed method, and performed simulation studies to compare the type I error rate, power, and sample size between the Tse approximated test and the generalized tolerance interval approach for interchangeability assessment.

Sample size determination for individual bioequivalence inference.

Statistical criterion for evaluation of individual bioequivalence (IBE) between generic and innovative products often involves a function of the second moments of normal distributions. Under replicated crossover designs, the aggregate criterion for IBE proposed by the guidance of the U.S. Food and Drug Administration (FDA) contains the squared mean difference, variance of subject-by-formulation interaction, and the difference in within-subject variances between the generic and innovative products. The upper confidence bound for the linearized form of the criterion derived by the modified large sample (MLS) method is proposed in the 2001 U.S. FDA guidance as a testing procedure for evaluation of IBE. Due to the complexity of the power function for the criterion based on the second moments, literature on sample size determination for the inference of IBE is scarce. Under the two-sequence and four-period crossover design, we derive the asymptotic distribution of the upper confidence bound of the linearized criterion. Hence the asymptotic power can be derived for sample size determination for evaluation of IBE. Results of numerical studies are reported. Discussion of sample size determination for evaluation of IBE based on the aggregate criterion of the second moments in practical applications is provided.

Comparison of Scaled-average, Population, and Individual Bioequivalence on 2 Tablets of Pitavastatin Calcium: A 3-Period, Reference-replicated, Crossover Study in Healthy Chinese Volunteers

BackgroundPitavastatin, a fully synthetic β-hydroxy-β-methylglutaryl–coenzyme A reductase inhibitor, is potent for the treatment of primary hyperlipidemia and mixed dyslipidemia. Recently, the original product and some generic products of pitavastatin calcium have become available in China. However, the intrasubject variability and interchangeability of this newly developed generic product and the branded innovator product have rarely been investigated in the Chinese population. PurposeThe aim of this study is to develop and compare the scaled-average, population, and individual bioequivalence (BE) of pitavastatin calcium tablets in healthy Chinese volunteers. This study will be used to allow for the interchangeability (switchability and prescribability) of the 2 products in clinical medication in China. MethodsA single-dose, reference-replicated, 3-period crossover BE study was conducted in 36 healthy male volunteers. Plasma samples were collected before and after oral administration of 2-mg test or reference tablets. A LC-MS/MS method was used to determine the concentration of pitavastatin calcium. A noncompartmental method was used to investigate the pharmacokinetic parameters. The ANOVA and 90% CIs of ln(AUC0–t) and ln(Cmax) were used for statistical analysis of scaled-average BE. A nonparametric test (Wilcoxon signed rank test) was performed to Tmax. The analyses of population BE and individual BE were used to assess the switchability and prescribability of the 2 products. FindingsThirty-six volunteers were enrolled in this clinical research; 33 volunteers completed the 3 treatment periods. The mean (SD) relative bioavailability calculated from the ratios (T/R) of AUC0–t was 101.3% (19.7%). The mean ln(AUC0–t) and ln(Cmax) were 98.64 (90% CI, 93.44–104.13) and 98.68 (90% CI, 91.88–105.99) within previously stipulated ranges recommended by the US Food and Drug Administration and the China Food and Drug Administration (CFDA). The intrasubject %CVs of AUC0–t and Cmax were 12.0% and 18.0% for the reference tablet and 13.0% and 17.0% for the test tablet. No significant differences were found among Tmax (0.742 ± 0.276, 0.674 ± 0.202, and 0.689 ± 0.226, respectively) for reference tablet 1, reference Supplemental Table II in the online version at 10.1016/j.clinthera.2014.06.21, and test tablet by a Wilcoxon test (P > 0.05). For ln(AUC0–t) and ln(Cmax), the statistical test-reference ratios were 99.13% and 98.95%, respectively. After inspecting the results for reference and mixed scaling, all the upper confidence limits were <0; therefore, population and individual BE were given. ImplicationsIn the healthy Chinese males, the generic and branded name tablets of pitavastatin calcium are bioequivalent at the rate and extent of absorption after a comparison of scaled-average, population, and individual BE and thus may be used interchangeably. Both the formulations are generally well tolerated. Chinese Clinical Trial identifier: ChiCTR-TTRCC-13003973.