Bioavailability of a New Generic Formulation of Imatinib Mesylate 400mg Tablets Versus Glivec in Healthy Male Adult Volunteers

Abstract

Imatinib is a highly selective inhibitor of tyrosine kinase used in the treatment of CML and GIST. However, the cost of the drug is prohibitive especially in the developing countries. The aim of this study is to compare pharmacokinetics profile of a new Imatinib generic formulation (Imatinib tablets 400mg batch number: 2090602, Hikma Pharmaceuticals PLC) with those of Glivec, (batch number: S0143, Novartis Pharma AG, Basle, Switzerland) in healthy male volunteers /fed state. The study was single center, randomized, single dose, laboratory-blinded, 2-period, 2-sequence, crossover design. The study was performed by CRO Algorithme Pharma Inc, (Quebec, Canada) in accordance with Good Clinical Practices and the applicable regulatory requirements. Male volunteers, non-or ex-smokers, of at least 18 years of age but not older than 55 years with a body mass index (BMI) greater than or equal to 18.5 and below 30 kg/m2 were selected according to the inclusion and exclusion criteria. In each study period, a single 400 mg dose of Imatinib was orally administered with about 240 mL of water in the morning after a 10-hour overnight fast, thirty (30) minutes after the start of a high-fat, high-calorie breakfast. Subjects remained seated for at least the first 4 hours following each drug administration. In each study period, twenty (20) blood samples were collected by venipuncture in pre-cooled Vacutainers containing EDTA. The first blood sample (2 x 4 mL) was collected prior to drug administration while the others (1 x 4 mL each) were collected at 1, 1.5, 2, 2. 33, 2.67, 3, 3.33, 3.67, 4, 4.5, 5, 6, 8, 10, 14, 18, 24, 48 and 72 hours post drug administration. The drug administrations were separated by at least 14 calendar days. Urine drug and ethyl alcohol screening was performed before each period of the study. Hematology and biochemistry tests were repeated after the collection of the last blood sample of the study. Safety was evaluated through the assessment of adverse events, and laboratory tests. Imatinib plasma samples were analyzed employing a validated HPLC method using MS/MS detection. For a 400 mg dose of Imatinib, the analytical range was approximately 10 ng/mL to 4000 ng/mL. Descriptive statistics were used to summarize adverse events, safety results and demographic variables (age, height, weight and BMI). The main pharmacokinetic parameters of interest for this study were C max , AUC 0-T and AUC 0-∞ . Other parameters such as T max , AUC T/∞ , K el and T 1/2el were provided for information purposes only. The natural logarithmic transformation of C max , AUC 0-T and AUC 0-∞ was used for all statistical inference. The mean (C.V. %) of C max , T max , AUC 0-T and AUC 0-∞ ( for Imatinib were 1760.5 ng/ml (26.6%), 3.67 hrs (26.4%), 30946.5 ng.h/ml (28.0%) and 31912.5 ng.h/ml (28.2%) versus 1779.4 ng/ ml (25.8%), 3.67 hrs (39.0%), 31073.6 ng.h/ml (25.7%) and 32270.9 ng.h/ml (26.4%) for Glivec. The 90% confidence intervals of C max , AUC 0-T and AUC 0-∞ for Imatinib 400 mg were (92.00%-105.52%), (95.69%-102.31%) ...

Generic Imatinib Therapy Among Jordanians: An Observational Assessment of Efficacy and Safety in Routine Clinical Practice

“…These favorable outcomes were expected, as generic imatinib is bioequivalent to patented imatinib. 12 In the first-line patients, all patients achieved CHR by 6 months, and 45% of patients achieved MMR by 12 months. By ELN criteria, 61% of the ITT and 87% of the evaluable patients achieved an optimal response by 12 months.…”

“…It was launched after bioequivalence with patented imatinib was demonstrated by investigating pharmacokinetic parameters in a randomized, laboratory-blinded, crossover study. 12 Still, evidence of its safety and efficacy in routine clinical setting is scarce. The current observational study was designed to assess the safety and efficacy of the standard 400 mg/day dose of generic imatinib for an observation period of 12 months in routine clinical practice in Jordan.…”

Clinical efficacy of generic imatinib

“…Unlike the regulatory approval in Canada and the European Union, which establishes clinical bioequivalence in serum imatinib level and AUC after oral ingestion, generic imatinib may be approved in some countries based on only in vitro dissolution tests. 14,15 Imatib (Cipla Ltd), the generic imatinib product used in most of these reports, 6,[9][10][11] was claimed to be bioequivalent to brand name imatinib by its manufacturer Cipla. 16 However, no details of the bioequivalence studies have been provided.…”

Analysis of Pharmacokinetic & Pharmacodynamic Models in Oral and Transdermal Dosage Forms

“…Therefore, acyclovir is replaced with its prodrug valacyclovir, the L-valyl ester of acyclovir has been used orally to increase the systemic bioavailability. Acyclovir is well tolerated whether administrated by ocular, topical, oral or intravenous routes [48].…”