Journal of Bioequivalence & Bioavailability

Abstract

Pharmacokinetic Comparison and Bioequivalence of a New Generic Formulation of Lenalidomide 25 mg Capsules versus Revlimid in Healthy Volunteers under Fasting Conditions

Dalia Jawhari, Mahmoud Alswisi and Mahmoud Ghannam

Lenalidomide is an immunomodulatory agent with direct antiproliferative, proapoptotic, and antiangiogenic effects, combined with long-term immunostimulatory effects which improve both cellular and humoral immune function. Lenalidomide is indicated for the treatment of patients with multiple myeloma, who are previously untreated and not eligible for transplant. Lenalidomide has dual effects, involving both direct tumoricidal properties and immunomodulatory activity.

A single centre, open-label, single-dose, randomized, two-period, two-treatment, two sequence, crossover, comparative bioavailability study was conducted in 24 healthy volunteers to compare pharmacokinetics profile of a new lenalidomide generic formulation (lenalidomide capsules 25 mg, Hikma Pharmaceuticals) with those of the reference product (Revlimid, Celgene Gmbh, United Kingdom). The study was conducted at Pharma Medical Research Inc. (Canada) in accordance with Good Clinical Practices and the applicable regulatory requirements.

One capsule of each formulation was administered with 240 mL of water after a 10 hr overnight fast. In each study period, eighteen (18) blood samples were collected by venepuncture in pre-cooled Vacutainers containing EDTA. First blood sample (2 × 6 mL) was collected prior to drug administration while the others (1 × 6 mL each) were collected at 0.167, 0.333, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 10, 12 and 14 h after drug administration. The drug product administrations were separated by a washout period of 7 calendar days.

Plasma samples were analyzed for lenalidomide by a validated LC/MS/MS method. For a 25 mg dose of lenalidomide, the analytical range was approximately 2 ng/mL to 1000 ng/mL. Descriptive statistics were used to summarize adverse events (AE), 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 lenalidomide were 467.1 ng/mL (21%), 1395.4 ng.h/mL (12%) and 1448.7 ng.h/mL (13%) versus 454.3 ng/mL (27%), 1396.3 ng.h/mL (13%) and 1448.1 ng.h/mL (13%) for Revlimid. The 90% confidence intervals of Cmax, AUC0-T and AUC0-∞ for lenalidomide were (93.7%-116.3%), (97.8%-102.3%) and (97.9%-102.4%) respectively. The ratio of the geometric LS means for the test to reference Cmax, AUC0-T and AUC0-∞ were 104.4%, 100.0% and 100.1% 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 outcomes it was concluded that the two formulations of lenalidomide exhibited comparable pharmacokinetic profiles.