Current Issue : April - June Volume : 2016 Issue Number : 2 Articles : 6 Articles
To develop a biosimilar product, it is necessary to demonstrate\nbiosimilarity between the proposed biosimilar product and the\nreference product in terms of the purity, potency, efficacy, and\nsafety. In this paper, clinical efficacy data required for establishing\nbiosimilarity are considered. Non-inferiority (NI) and equivalence\nmethods are commonly used for analyzing clinical trials to meet\nthis requirement. The equivalence approach often requires large,\ncostly, and lengthy clinical trials. The non-inferiority approach\nwhile requiring somewhat smaller trials are not accepted by all as\nadequately addressing the similarity issue between the proposed\nbiosimilar product and the reference product as they do not rule out\nthe prospect that the biosimilar product has increased activity which\nmight be associated with more adverse effects. To address some\nof the challenges faced by the use of non-inferiority or equivalence\nmethods, a constrained non-inferiority (cNI) approach is proposed\nto address both the clinical efficacy of the biosimilar product and\nthe similarity to the reference product. The performance of the\nproposed constrained non-inferiority approach for analyzing a\nbiosimilar trial is demonstrated through simulation and examples....
Trastuzumab has been widely used among the breast cancer patients with human epidermal growth factor receptor\n2 (HER2) overexpression. The genetically engineered trastuzumab traded as Cipterbin�® was developed in China since\n2003. We have disclosed the phase I clinical trial data of safety, pharmacokinetic profile (PK) in patients with metastasis\nbreast cancer. Subjects identified as HER2 strong positive received single intravenously doses of 100, 250 or 500 mg\nCipterbin�® in dose-escalation manner. The safety evaluations were recorded and plasma concentration profiles for\nthe drug were analyzed. 27 Chinese metastatic breast cancer patients were enrolled in this study. Patients in each\ngroup of different dosage were well-tolerated. The most frequently drug-related adverse events were fever (59.3 %),\ntransaminase increased (22.2 %), chills (18.5 %) and arrhythmia (18.5 %). Only one patient with severe adverse event\nwas observed in 250 mg group revealing brachycardia. PK profile analysis showed that sera steady concentration\ncould be reached in dose-proportional manner, except volume of distribution (Vd) and clearance (CL), which reached\npeak values at 250 mg administration cohort. This genetically engineered HER2-target antibody had demonstrated\nthe accepted safety with well-tolerated....
Capecitabine is an orally administered chemotherapeutic agent used in the treatment of numerous cancers including colon, colorectal, ovarian, breast and pancreatic. Considering the importance of generic drugs in Health Care Systems, it is essential that its quality, safety and efficacy be compared with the corresponding innovator product. The objective of the study was to compare the pharmacokinetics and relative bioequivalence between two tablet (500 mg) formulations of capecitabine in Mexican patients with cancer of colon. The study was designed as open, prospective, randomized, two-way, crossover bioequivalence trial. A single oral dose of 2000 mg capecitabine was administered on two separate days to 24 patients. After each administration, serial blood samples were collected for up 8 hr. The washout between the two administrations was 3 days. Capecitabine was determined in plasma using LC/MS-MS. No statistically significant differences in Cmax, AUC0-t, and AUC0-�± were found between the test and innovator formulations. Both products were well tolerated by the patients, with no serious adverse events. The generic capecitabine was pharmacokinetic bioequivalent with the innovator formulations....
Comparability between a biosimilar and its reference product requires the evaluation of critical quality attributes that may impact\non its pharmacological response. Herein we present a physicochemical characterization of a biosimilar trastuzumab focused on\nthe attributes related to the pharmacokinetic response. Capillary isoelectrofocusing (cIEF) and cation exchange chromatography\n(CEX) were used to evaluate charge heterogeneity; glycosylation profiles were assessed through hydrophilic interaction liquid\nchromatography (HILIC); aggregates content was evaluated through size exclusion chromatography (SEC) while binding affinity to\nFcRn was evaluated using isothermal titration calorimetry (ITC). The biosimilar trastuzumab and its reference product exhibited a\nhigh degree of similarity for the evaluated attributes. In regard to the pharmacokinetic parameters, randomized, double blind, and\ntwo-arm parallel and prospective study was employed after the administration of a single intravenous dose in healthy volunteers.\nNo significant differences were found between the pharmacokinetic profiles of both products. Our results confirm that similarity\nof the critical quality attributes between a biosimilar product, obtained from a different manufacturing process, and the reference\nproduct resulted in comparable pharmacokinetic profiles, diminishing the uncertainty related to the biosimilar�s safety and efficacy....
Background: XM17 is a recombinant human follicle-stimulating hormone (rhFSH) intended mainly for use in\ncontrolled ovarian hyperstimulation and the treatment of anovulation. The purpose of the current study was to\nestablish bioequivalence, safety and tolerability of single 300-IU subcutaneous (sc) doses of XM17 to that of the\nreference follitropin alfa (Gonal-fÃ?®) in healthy young women.\nMethods: This open-label, Phase I, single-dose, single-center, two-way crossover study was conducted from\nFebruary to May 2009. Thirty-six women aged 18ââ?¬â??39 years were included, with a study duration of ~27 days\nper participant. After endogenous FSH downregulation with goserelin (3.6 mg) on study Day 0, XM17 and\nGonal-fÃ?® were administered on Days 11 and 19 in random sequence. Frequent serum samples were drawn for\nstandard pharmacokinetics until 168 h postdosing. Laboratory values, adverse events (AEs) and local tolerability\nwere assessed throughout the study period. Primary endpoints included Cmax and AUC0-t. Secondary endpoints\nincluded additional pharmacokinetic (PK) parameters, safety and tolerability.\nResults: Ratios of XM17 to Gonal-fÃ?® for Cmax and AUC0-t equaled 1.017 (90 % confidence interval [CI]: 0.958, 1.080)\nand 1.028 (90 % CI: 0.931, 1.134), respectively, with the CIs contained within the predefined interval (0.8, 1.25).\nRatios for AUC0-168h, AUC0-âË?ž and t1/2 were also ~1, and no difference in tmax was detected. Both XM17 and\nGonal-fÃ?® were well tolerated, with no detectable anti-FSH antibodies, serious AEs or AEs leading to discontinuation or\ndose reduction.\nConclusions: PK bioequivalence of single 300-IU sc doses of XM17 to the reference product Gonal-fÃ?® was statistically\ndemonstrated. XM17 was well tolerated both systemically and locally....
Drugs with low water solubility are predisposed to poor and variable oral\nbioavailability and, therefore, to variability in clinical response, that might be overcome\nthrough an appropriate formulation of the drug. Polymorphs (anhydrous and solvate/hydrate\nforms) may resolve these bioavailability problems, but they can be a challenge to ensure\nphysicochemical stability for the entire shelf life of the drug product. Since clinical failures\nof polymorph drugs have not been uncommon, and some of them have been entirely\nunexpected, the Food and Drug Administration (FDA) and the International Conference on\nHarmonization (ICH) has required preliminary and exhaustive screening studies to identify\nand characterize all the polymorph crystal forms for each drug. In the past, the polymorphism\nof many drugs was detected fortuitously or through manual time consuming methods;\ntoday, drug crystal engineering, in particular, combinatorial chemistry and high-throughput\nscreening, makes it possible to easily and exhaustively identify stable polymorphic and/or\nhydrate/dehydrate forms of poorly soluble drugs, in order to overcome bioavailability related\nproblems or clinical failures. This review describes the concepts involved, provides examples\nof drugs characterized by poor solubility for which polymorphism has proven important,\noutlines the state-of-the-art technologies and discusses the pertinent regulations....
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