Bioequivalence of a New Generic Formulation of Erlotinib Hydrochloride 150 mg Tablets versus Tarceva in Healthy Volunteers under Fasting Conditions

Abstract

Erlotinib is a potent and highly selective inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase used in the treatment of patients with locally advanced or metastatic non–small cell lung cancer (NSCLC) and was recently approved for use in combination with gemcitabine. A single center, randomized, single dose, laboratory-blinded, 2-period, 2‑sequence, crossover design bioequivalence study was conducted in 36 fasting, healthy volunteers to compare pharmacokinetics profile of a new Erlotinib generic formulation (Erlotinib tablets 150 mg, Hikma Pharmaceuticals) with those of the reference product(Tarceva, OSI Pharmaceuticals, USA). The study was performed by CRO PHARMA MEDICA RESEARCH INC. (Canada) in accordance with Good Clinical Practices and the applicable regulatory requirements. One tablet of each formulation was administered with water after a 10 hour overnight fast. In each study period, twenty (20) blood samples were collected by venipuncture in pre-cooled Vacutainers containing EDTA. The first blood sample (2×6 mL) was collected prior to drug administration while the others (1×6 mL each) were collected at 0.33, 0.67, 1, 1.33, 1.67, 2, 2.33, 2.67, 3, 3.5, 4, 5, 6, 8, 14, 24, 36, 48 and 72 hours after drug administration. The drug administrations were separated by a washout period of 14 calendar days. Plasma samples were analyzed for Erlotinib by a validated LC/MS/MS method. For a 150 mg dose of erlotinib, the analytical range was approximately 1ng/mL to 3000 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 (CV %) of Cmax, AUC0-T and AUC0- ∞ for Erlotinib were 1108.89 ng/ml (28%), 23764.87 ng.h/ml (31%) and 25489.41 ng.h/ml (36%) versus 1073.06 ng/ml (35%), 24607.87ng.h/ml (33%) and 26565.89ng.h/ml (40%) for Tarceva. The 90% confidence intervals of Cmax, AUC0-T and AUC0-∞ for Erlotinib 150 mg were (96.08%-121.54%), (91.34 %-103.42%) and (89.99 %-103.22%) respectively. The ratio of the geometric LS means for the test to reference Cmax, AUC0-T and AUC0-∞ for Erlotinib 150 mg were 108 %, 97% and 96% respectively. The analysis of variance (ANOVA) did not show any significant difference between the two formulations and 90% confidence intervals (CI) fell within the acceptable range for bioequivalence. Based on these statistical inferences it was concluded that the two formulations of Erlotinib exhibited comparable pharmacokinetics profiles.