Pharmacokinetics and Bioequivalence Evaluation of Lenalidomide in Chinese Patients with Multiple Myeloma
Multiple myeloma (MM) is a systemic neoplasm that remains incurable despite advancements in treatment. The first line of therapy is critical for MM patients, as many do not survive beyond this stage. Lenalidomide, marketed under the trade name Revlimid®, is a first-line drug for MM and is widely used due to its efficacy. However, there is limited pharmacokinetic (PK) data on lenalidomide in Chinese MM patients, as most PK studies have been conducted on young, healthy volunteers. This study aimed to compare the PK and bioequivalence of a generic lenalidomide 10 mg capsule (test formulation) manufactured by Chongqing LUMMY Pharmaceutical Co., Ltd., with the branded Revlimid® 10 mg capsule (reference formulation) in Chinese MM patients. The goal was to provide an economical alternative to the branded drug.
Study Design and Methodology
This was a multicenter, open-label, randomized, two-period, two-sequence crossover study conducted in Chinese MM patients. Patients were recruited nationwide through public announcements and randomly assigned to two groups: Group A (test-reference) and Group B (reference-test). Each participant received either the test or reference formulation first, followed by a 3-day washout period before switching to the other formulation. The study followed International Conference on Harmonization — Good Clinical Practice guidelines and adhered to the Declaration of Helsinki. The protocol was approved by the Ethics Committees of West China Hospital of Sichuan University and the First Affiliated Hospital of the Army Medical University. All participants provided written informed consent before enrollment.
Patients were administered a single dose of the drug with 200 mL of water after fasting for at least 10 hours. Blood samples were collected at specific time points: 0.34, 0.67, 1.00, 1.50, 2.00, 3.00, 4.00, 6.00, 8.00, 12.00, and 24.00 hours post-dosing. Adverse events (AEs) were monitored throughout the study. The study included 50 MM patients who were newly diagnosed or had completed chemotherapy at least seven drug half-lives prior. Of these, 39 patients were enrolled and completed the study without withdrawals.
Patient Characteristics
The enrolled patients were aged 18 to 70 years, with a mean age of 53.40 ± 7.43 years. The mean height, weight, and body mass index (BMI) were 160.00 ± 9.00 cm, 60.86 ± 8.78 kg, and 23.63 ± 1.95 kg/m², respectively. Inclusion criteria required patients to have a creatinine clearance of ≥60 mL/min, alanine aminotransferase and aspartate transaminase levels ≤2.5 times the upper limit of normal (ULN), a serum total bilirubin level ≤1.5 times ULN, a hemoglobin level ≥80 g/L, an absolute neutrophil count ≥1500 cells/mm³, and a platelet count ≥80,000/mm³. Pregnant or lactating females were excluded due to the teratogenicity of lenalidomide. Other exclusion criteria included significant active cardiac diseases, digestive tract diseases affecting drug absorption, a history of deep vein thrombosis or pulmonary embolism in the past 12 months, urinary tract obstruction, insufficient blood volume, drug allergies, peripheral neuropathy ≥2, and a history of malignant tumors other than MM unless cured for >3 years.
Pharmacokinetic Analysis
Plasma concentrations of lenalidomide were measured using ultra-high-performance liquid chromatography-mass spectrometry (UHPLC-MS/MS). The method was validated, and the linear range for lenalidomide was 1.0 to 500 ng/mL. The retention times for lenalidomide and the internal standard (trimethoprim) were 1.1 and 1.3 minutes, respectively. The maximum plasma concentration (Cmax) and time to Cmax (tmax) were determined directly from the observed data. Other PK parameters, including the area under the plasma concentration-time curve (AUC) from time 0 to the last measurable concentration (AUC(0–t)), AUC from time 0 to infinity (AUC(0–∞)), half-life (t1/2), elimination constant (Ke), apparent volume of distribution (V1/F), apparent clearance (CL/F), and mean residence time (MRT(0–t)), were calculated using the statistical moment method. Phoenix WinNonlin software version 6.1 was used for data analysis.
Results and Discussion
The mean plasma concentration-time profiles of lenalidomide for the test and reference formulations were nearly identical, indicating similar PK profiles. Under fasting conditions, the Cmax for the test and reference formulations were 230.44 ± 59.72 ng/mL and 235.70 ± 70.40 ng/mL, respectively, both reached within 1 hour. The half-life of lenalidomide was approximately 3 hours for both formulations. The AUC(0–t) values were 828.62 ± 201.79 ng·h/mL and 856.58 ± 235.51 ng·h/mL, and the AUC(0–∞) values were 845.54 ± 200.08 ng·h/mL and 873.09 ± 235.53 ng·h/mL for the test and reference formulations, respectively. The 90% confidence intervals (CIs) for Cmax, AUC(0–t), and AUC(0–∞) were 92.40% to 106.30%, 94.98% to 100.16%, and 95.20% to 100.17%, respectively, meeting the bioequivalence criteria of 80% to 125%. Thus, the test and reference formulations were deemed bioequivalent.
Comparison with Japanese Patients
Significant differences were observed in the PK data between Chinese and Japanese MM patients. In a study of Japanese patients with relapsed/refractory MM, the Cmax, AUC(0–t), and AUC(0–∞) were 315 ng/mL, 962 ng·h/mL, and 1037 ng·h/mL, respectively, higher than those in Chinese patients. This discrepancy may be attributed to the higher average age of Japanese patients (64 years) compared to Chinese patients (53 years). A linear regression analysis revealed a significant positive correlation between age and AUC(0–∞) in both formulations, indicating that plasma exposure increases with age. This finding suggests that elderly patients may require reduced doses of lenalidomide to avoid excessive plasma exposure.
Safety and Adverse Events
Nine patients (23.07%) experienced 11 AEs during the study. The most common AEs included increased D-dimer levels (four cases), leucopenia (two cases), neutropenia (two cases), and fever (one case). One patient experienced a possibly unrelated blood glucose elevation, and another had a serious AE (fever) unrelated to the study, as determined by a hematologist. The patient, who was in the late stages of MM, died two months after treatment. Both the test and reference formulations were well tolerated, and the observed AEs were consistent with those reported in previous studies.
Conclusion
This study demonstrated that the generic lenalidomide 10 mg capsule (test formulation) and the branded Revlimid® 10 mg capsule (reference formulation) have similar PK profiles and are bioequivalent in Chinese MM patients. The findings support the use of the generic formulation as a cost-effective alternative to the branded drug. Additionally, the study highlighted that plasma exposure to lenalidomide increases with age, suggesting that elderly patients may benefit from reduced doses to minimize toxicity. These results provide valuable insights for clinicians treating MM patients, particularly in the context of aging populations.
doi.org/10.1097/CM9.0000000000001695
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