Decreases in the bioavailability of rifampicin (RFP) can lead to the development of drug resistance and treatment failure. Therefore, we investigated the relative bioavailability of RFP from one four-drug fixed-dose combination (FDC; formulation A) and three two-drug FDCs (formulations B, C, and D) used in China, compared with RFP in free combinations of these drugs (reference), in healthy volunteers.
Methods:
Eighteen and twenty healthy Chinese male volunteers participated in two open-label, randomized two-period crossover (formulations A and C) or one three-period crossover (formulations B and D) study, respectively. The washout period between treatments was 7 days. Bioequivalence was assessed based on 90% confidence intervals, according to two one-sided t-tests. All analyses were done with DAS 3.1.5 (Mathematical Pharmacology Professional Committee of China, Shanghai, China).
Results:
Mean pharmacokinetic parameter values of RFP obtained for formulations A, B, C, and D products were 11.42 ± 3.41 μg/ml, 7.86 ± 5.78 μg/ml, 13.05 ± 6.80 μg/ml, and 16.18 ± 3.87 μg/ml, respectively, for peak plasma concentration (Cmax), 91.43 ± 30.82 μg·h−1 ·ml−1, 55.49 ± 37.58 μg·h−1 ·ml−1, 96.50 ± 47.24 μg·h−1 ·ml−1, 101.47 ± 33.07 μg·h−1 ·ml−1, respectively, for area under the concentration-time curve (AUC0−24 h).
Conclusions:
Although the concentrations of RFP for formulations A, C, and D were within the reported acceptable therapeutic range, only formulation A was bioequivalent to the reference product. The three two-drug FDCs (formulations B, C and D) displayed inferior RFP bioavailability compared with the reference (Chinese Clinical Trials registration number: ChiCTR-TTRCC-12002451). 相似文献
In clinical endpoint bioequivalence (BE) studies, the primary analysis for assessing equivalence between a generic and an innovator product is based on the observed per-protocol (PP) population (usually completers and compliers). However, missing data and noncompliance are post-randomization intercurrent events and may introduce selection bias. Therefore, PP analysis is generally not causal. The FDA Missing Data Working Group recommended using “causal estimands of primary interest.” In this paper, we propose a principal stratification causal framework and co-primary causal estimands to test equivalence, which was also recommended by the recently published ICH E9 (R1) addendum to address intercurrent events. We identify three conditions under which the current PP estimator is unbiased for one of the proposed co-primary causal estimands – the “Survivor Average Causal Effect” (SACE) estimand. Simulation shows that when these three conditions are not met, the PP estimator is biased and may inflate Type 1 error and/or change power. We also propose a tipping point sensitivity analysis to evaluate the robustness of the current PP estimator in testing equivalence when the sensitivity parameters deviate from the three identified conditions, but stay within a clinically meaningful range. Our work is the first causal equivalence assessment in equivalence studies with intercurrent events. 相似文献
Pharmacists need to demonstrate knowledge of and have confidence in Food and Drug Administration (FDA) therapeutic equivalence (TE) standards to improve acceptance of generic medicines amongst patients and other healthcare professionals.
Objective
To evaluate community pharmacists' understanding, interpretation and perceptions of the FDA TE standards to identify if further education is needed on this topic.
Methods
An anonymous, 13-item survey was piloted and then distributed by e-mail to a random sample of 287 Indiana community pharmacists. The 5-min survey included demographic, knowledge-based, and perception-based questions on FDA TE criteria that participants were given one week to complete. Participants completed the survey using a Web-based survey tool (Qualtrics).
Results
192 pharmacists completed the survey achieving a response rate of 66.9%. Only 7.3% of respondents correctly identified FDA bioequivalence criteria for approval of generic drug products. Two questions presented TE codes from the Orange Book and asked respondents to identify if a pair of drug products were therapeutically equivalent: 62.6% and 61.0% of respondents answered correctly. However, 89.4% of respondents correctly indicated that the Orange Book is the location of FDA TE evaluations. 74.9% of responding pharmacists indicated a positive perception of the rigor of FDA approval standards associated with generic medications and 66.0% believed that generic drug products made by different manufacturers are of similar quality.
Conclusions
The results suggest that community pharmacists need additional education on the interpretation of TE codes and FDA bioequivalence criteria for approval of generic drug products. The safety and efficacy of generics are often questioned by patients and physicians. It is important for pharmacists to be knowledgeable of FDA TE standards as they are experts in medicines and need to be confident with the criteria to effectively convey them to patients and healthcare professionals. 相似文献
Introduction: Generic inhalers are often perceived as inferior to their branded counterparts; however, they are safe and effective if they can meet the regulatory requirements. The approach to assess bioequivalence (BE) in oral dosage form products is not sufficient to address the complexities of inhalational products (e.g., patient-device interface); hence, more considerations are needed and caution should be applied in determining BE of inhaled compounds.
Areas covered: This review outlines the evaluation process for generic inhalers, explores the regulatory approaches in BE assessment, and highlights the considerations and challenges in the current in vitro and in vivo approaches (lung deposition, pharmacokinetic, pharmacodynamic/clinical studies, and patient-device interface) for establishing BE of inhaled compounds.
Expert opinion: The ultimate goals in this field are to establish uniformity in the regulatory approaches to speed the drug submission process in different regions, clear physicians’ misconception of generic inhalers, and have meaningful clinical endpoints such as improvement in patient quality of life when compared to placebo and brand name drugs. As inhalational drugs become more common for other indications such as antibiotics, the technologies developed for inhaled compounds in the treatment of chronic pulmonary diseases may be extrapolated to these other agents. 相似文献
SUMMARYObjective: To investigate whether crushed or dissolved tablets of the oral direct thrombin inhibitor ximelagatran are bioequivalent to whole tablet administration. Ximelagatran is currently under development for the prevention and treatment of thromboembolic disorders.Research design and methods: This was an open-label, randomised, three-period, three-treatment crossover study in which 40 healthy volunteers (aged 20–33 years) received a single 36-mg dose of ximelagatran administered in three different ways: I swallowed whole, II crushed, mixed with applesauce and ingested and III dissolved in water and administered via nasogastric tube.Results: The plasma concentrations of ximelagatran, its intermediates and the active form melagatran were determined. Ximelagatran was rapidly absorbed and the bioavailability of melagatran was similar after the three different administrations, fulfilling the criteria for bioequivalence. The mean area under the plasma concentration-versus-time curve (AUC) of melagatran was 1.6μmol-h/l_ (ratio 1.01 for treatment II/I and 0.97 for treatment III/I), the mean peak concentration (Cmax) was 0.3μmol/L (ratio 1.04 for treatment II/I and 1.02 for treatment III/I) and the mean half-life (t1/2) was 2.8?h for all treatments. The time to Cmax (tmax) was 2.2?h for the whole tablet and approximately 0.5?h earlier when the tablet was crushed or dissolved (1.7–1.8?h), due to a more rapid absorption. The study drug was well tolerated as judged from the low incidence and type of adverse events reported.Conclusion: The present study showed that the pharmacokinetics (AUC and Cmax) of melagatran were not significantly altered whether ximelagatran was given orally as a crushed tablet mixed with applesauce or dissolved in water and given via nasogastric tube. 相似文献
This study investigates the robustness of Schuirmann's two one-sided tests procedure under a set of Box-Cox alternatives. A simulation is conducted to study the level of significance and the power of the procedure. Empirical results show that Schuirmann's procedure is robust under Box-Cox alternatives when the mean of the underlying distribution of the reference formulation is known, which suggests that the assumptions of normality or lognormality are sufficient but may not be necessary. It appears that Schuirmann's procedure cannot maintain the proper level of significance when the mean of the reference formulation is unknown, even under the normality or lognormality assumptions. 相似文献
Bioequivalence trials are commonly conducted to assess therapeutic equivalence between a generic and an innovator brand formulations. In such trials, drug concentrations are obtained repeatedly over time and are summarized using a metric such as the area under the concentration vs. time curve (AUC) for each subject. The usual practice is to then conduct two one-sided tests using these areas to evaluate for average bioequivalence. A major disadvantage of this approach is the loss of information encountered when ignoring the correlation structure between repeated measurements in the computation of areas. In this article, we propose a general linear model approach that incorporates the within-subject covariance structure for making inferences on mean areas. The model-based method can be seen to arise naturally from the reparameterization of the AUC as a linear combination of outcome means. We investigate and compare the inferential properties of our proposed method with the traditional two one-sided tests approach using Monte Carlo simulation studies. We also examine the properties of the method in the event of missing data. Simulations show that the proposed approach is a cost-effective, viable alternative to the traditional method with superior inferential properties. Inferential advantages are particularly apparent in the presence of missing data. To illustrate our approach, a real working example from an asthma study is utilized. 相似文献