Determination of bioequivalence for drugs with narrow therapeutic index

The US Food and Drug Administration (FDA) has recently suggested that the bioequivalence (BE) for products of drugs with narrow therapeutic indices (NTI) be assessed by the approach of reference-scaled average BE (SABE). Subsequently, in December, 2012, the FDA issued draft guidances for the comparison of products of warfarin sodium and of tacrolimus. The guidances expect that 4-period studies be performed, that the results be evaluated by SABE, and that the analysis include also unscaled average BE as well as the comparison of the estimated within-subject variations (sW) of the test and reference drug products. This communication discusses the new guidances and suggests considerations to reduce the regulatory burden. It is demonstrated that SABE could be applied when the within-subject variation of the reference product is not higher than 21.42%. Beyond this variation, the BE limits would remain 80% to 125%, as usual. No further testing by unscaled average BE is needed. It is also suggested that a comparison of the within-subject variations of the two drug products although interesting for both NTI and other drugs, is not essential for the determination of BE. In addition, when the within-subject variabilities are low then their ratio depends mainly on the non-product dependent factors. Moreover, introduction of an additional test would affect the probabilities involved in the primary comparison of the two means. Therefore, the test of comparing variances is not needed and replicate measurements of the test formulation need not be performed. Alternative considerations and approaches, including the use of partial AUC's, are suggested for the determination of BE for NTI drugs.This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page

Determinants of biological drug survival in rheumatoid arthritis:Evidence from a Hungarian rheumatology center over 8 years of retrospective data

OBJECTIVE: To compare drug survival of biological therapies in patients with rheumatoid arthritis (RA), and analyze the determinants of discontinuation probabilities and switches to other biological therapies. MATERIALS AND METHODS: Consecutive RA patients initiating first biological treatment in one rheumatology center between 2006 and 2013 were included. Log-rank test was used to analyze the differences between the survival curves of different biological drugs. Cox regression was applied to analyze the discontinuation due to inefficacy, the occurrence of adverse events, or to any reasons. RESULTS: A total of 540 patients were included in the analysis. The most frequently used first-line biological treatments were infliximab (N=176, 33%), adalimumab (N=150, 28%), and etanercept (N=132, 24%). Discontinuation of first tumor necrosis factor-alpha (TNF-α) treatment was observed for 347 (64%) patients, due to inefficacy (n=209, 60%), adverse events (n=103, 30%), and other reasons (n=35, 10%). Drug survival rates for TNF-α and non-TNF-α therapies were significantly different, and were in favor of non-TNF-α therapies. Every additional number of treatment significantly increased the risk of inefficacy by 27% (p<0.001) and of adverse events by 35% (p=0.002). After the discontinuation of the initial TNF-α treatment, switching to rituximab and tocilizumab was associated with significantly longer treatment duration than switching to a second TNF-α. The non-TNF-α therapies resulted in significantly longer treatment duration, due to both less adverse events and longer maintenance of effectiveness. CONCLUSION: Non-TNF-α therapies resulted in significantly longer treatment duration, and lost their effectiveness later. Increase in the number of switches significantly increased the risk of discontinuation of any biological therapy

Acute escitalopram treatment inhibits REM sleep rebound and activation of MCH-expressing neurons in the lateral hypothalamus after long term selective REM sleep deprivation.

RATIONALE: Selective rapid eye movement sleep (REMS) deprivation using the platform-on-water ("flower pot") method causes sleep rebound with increased REMS, decreased REMS latency, and activation of the melanin-concentrating hormone (MCH) expressing neurons in the hypothalamus. MCH is implicated in the pathomechanism of depression regarding its influence on mood, feeding behavior, and REMS. OBJECTIVES: We investigated the effects of the most selective serotonin reuptake inhibitor escitalopram on sleep rebound following REMS deprivation and, in parallel, on the activation of MCH-containing neurons. METHODS: Escitalopram or vehicle (10 mg/kg, intraperitoneally) was administered to REMS-deprived (72 h) or home cage male Wistar rats. During the 3-h-long "rebound sleep", electroencephalography was recorded, followed by an MCH/Fos double immunohistochemistry. RESULTS: During REMS rebound, the time spent in REMS and the number of MCH/Fos double-labeled neurons in the lateral hypothalamus increased markedly, and REMS latency showed a significant decrease. All these effects of REMS deprivation were significantly attenuated by escitalopram treatment. Besides the REMS-suppressing effects, escitalopram caused an increase in amount of and decrease in latency of slow wave sleep during the rebound. CONCLUSIONS: These results show that despite the high REMS pressure caused by REMS deprivation procedure, escitalopram has the ability to suppress REMS rebound, as well as to diminish the activation of MCH-containing neurons, in parallel. Escitalopram caused a shift from REMS to slow wave sleep during the rebound. Furthermore, these data point to the potential connection between the serotonergic system and MCH in sleep regulation, which can be relevant in depression and in other mood disorders

Approvable generic carbamazepine formulations may not be bioequivalent in target patient populations.

OBJECTIVES: To demonstrate that with carbamazepine (CBZ), positive results of bioequivalence trials in healthy volunteers cannot be extrapolated to patients because metabolic enzyme induction fundamentally changes the pharmacokinetics of CBZ. METHODS: Bioequivalence trials were simulated assuming normal and induced metabolic clearance. The relevant pharmacokinetic parameters were drawn from published studies. RESULTS: The Cmax ratio depends on the clearance. A generic product which is fully compliant with the regulatory requirements in healthy volunteers could be non-bioequivalent in patients with enhanced elimination. CONCLUSION: A statement of bioequivalence of CBZ formulations, based on a single-dose study performed in healthy subjects, may not hold for a target patient population in the steady state

Effect of neonatal benzpyrene imprinting on the brain serotonin content and nocistatin level in adult male rats

Single neonatal treatment (imprinting) with 20 μg benzpyrene results in significant increase of the brain serotonin level in the striatum, while in the other four regions (cortex, brainstem, hippocampus, hypothalamus) when measured in adults can be detected. The nocistatin level of cerebrospinal fluid (CSF) significantly decreases, while there is no change in the plasma nocistatin level. The results call attention to the comprehensive imprinting effect of benzpyrene, which in addition to receptorial, hormonal and sexual behavioral disturbances causes lasting differences in the brain serotonin and nocistatin levels, probably influencing mood and pain tolerance

Determinants of biological drug survival in rheumatoid arthritis: evidence from a Hungarian rheumatology center over 8 years of retrospective data

Valentin Brodszky,1 Anik&oacute; B&iacute;r&oacute;,1,2 Zolt&aacute;n Szekanecz,3 Bogl&aacute;rka So&oacute;s,3 Petra Baji,1 Fanni Rencz,1,4 L&aacute;szl&oacute; T&oacute;thfalusi,5 L&aacute;szl&oacute; Gul&aacute;csi,1 M&aacute;rta P&eacute;ntek1,6 1Department of Health Economics, Corvinus University of Budapest, Budapest, , Hungary; 2School of Economics, The University of Edinburgh, Edinburgh, UK; 3Department of Rheumatology, Institute of Medicine, University of Debrecen Faculty of Medicine, Debrecen, Hungary; 4Semmelweis University Doctoral School of Clinical Medicine, Budapest, Hungary; 5Department of Pharmacodynamics, Semmelweis University, Budapest, Hungary; 6Department of Rheumatology, Fl&oacute;r Ferenc County Hospital, Kistarcsa, Hungary Objective: To compare drug survival of biological therapies in patients with rheumatoid arthritis (RA), and analyze the determinants of discontinuation probabilities and switches to other biological therapies.Materials and methods: Consecutive RA patients initiating first biological treatment in one rheumatology center between 2006 and 2013 were included. Log-rank test was used to analyze the differences between the survival curves of different biological drugs. Cox regression was applied to analyze the discontinuation due to inefficacy, the occurrence of adverse events, or to any reasons.Results: A total of 540 patients were included in the analysis. The most frequently used first-line biological treatments were infliximab (N=176, 33%), adalimumab (N=150, 28%), and etanercept (N=132, 24%). Discontinuation of first tumor necrosis factor-alpha (TNF-&alpha;) treatment was observed for 347 (64%) patients, due to inefficacy (n=209, 60%), adverse events (n=103, 30%), and other reasons (n=35, 10%). Drug survival rates for TNF-&alpha; and non-TNF-&alpha; therapies were significantly different, and were in favor of non-TNF-&alpha; therapies. Every additional number of treatment significantly increased the risk of inefficacy by 27% (p&lt;0.001) and of adverse events by 35% (p=0.002). After the discontinuation of the initial TNF-&alpha; treatment, switching to rituximab and tocilizumab was associated with significantly longer treatment duration than switching to a second TNF-&alpha;. The non-TNF-&alpha; therapies resulted in significantly longer treatment duration, due to both less adverse events and longer maintenance of effectiveness.Conclusion: Non-TNF-&alpha; therapies resulted in significantly longer treatment duration, and lost their effectiveness later. Increase in the number of switches significantly increased the risk of discontinuation of any biological therapy. Keywords: rheumatoid arthritis, biologicals, drug survival, switch, registr

Statistical and regulatory considerations in assessments of interchangeability of biological drug products.

When the patent of a brand-name, marketed drug expires, new, generic products are usually offered. Small-molecule generic and originator drug products are expected to be chemically identical. Their pharmaceutical similarity can be typically assessed by simple regulatory criteria such as the expectation that the 90 % confidence interval for the ratio of geometric means of some pharmacokinetic parameters be between 0.80 and 1.25. When such criteria are satisfied, the drug products are generally considered to exhibit therapeutic equivalence. They are then usually interchanged freely within individual patients. Biological drugs are complex proteins, for instance, because of their large size, intricate structure, sensitivity to environmental conditions, difficult manufacturing procedures, and the possibility of immunogenicity. Generic and brand-name biologic products can be expected to show only similarity but not identity in their various features and clinical effects. Consequently, the determination of biosimilarity is also a complicated process which involves assessment of the totality of the evidence for the close similarity of the two products. Moreover, even when biosimilarity has been established, it may not be assumed that the two biosimilar products can be automatically substituted by pharmacists. This generally requires additional, careful considerations. Without declaring interchangeability, a new product could be prescribed, i.e. it is prescribable. However, two products can be automatically substituted only if they are interchangeable. Interchangeability is a statistical term and it means that products can be used in any order in the same patient without considering the treatment history. The concepts of interchangeability and prescribability have been widely discussed in the past but only in relation to small molecule generics. In this paper we apply these concepts to biosimilars and we discuss: definitions of prescribability and interchangeability and their statistical implementation; the relation between bioequivalence and interchangeability for small-molecule drug products; regulatory requirements and expectations of biosimilar products in various jurisdictions; possible statistical approaches to establish the similarity and interchangeability of biologic drug products; definition of other technical terms such as switchability and automatic substitution. The paper will be concluded with a discussion of the anticipated future use of interchangeability of biological drug products