Journal of Bioequivalence & Bioavailability

Abstract

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

Dalia Jawhari, Mahmoud Al Swisi and Mahmoud Ghannam

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 Cmax, AUC0-T and AUC0-?. Other parameters such as Tmax, AUCT/?, Kel and T1/2el were provided for information purposes only. The natural logarithmic transformation of Cmax, AUC0-T and AUC0-? was used for all statistical inference. The mean (C.V. %) of Cmax, Tmax, AUC0-T and AUC0-? (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 Cmax, AUC0-T and AUC0-? for Imatinib 400 mg were (92.00%-105.52%), (95.69%-102.31%) and (95.23%- 101.55%) respectively. The ratio of the geometric LS means for the test to reference Cmax , AUC0-T and AUC0-? for Imatinib 400 mg were 98%, 99% and 99% respectively with low ISCV 12.9 % for Cmax and 6.3 % for AUC0-T and 6.0% for AUC0-?. The results indicated that the products are equivalent and switchable according to FDA rulings.