Relative bioavailability of a newly developed 5-mg levomethadone hydrochloride IR tablet (L-Polamidon (R) 5 mg tablets) in comparison with the 5-mg levomethadone hydrochloride oral solution (L-Polamidon (R) solution for substitution) as reference product

摘要

Objectives: To establish the relative bioavailability (rBA) between two p.o. 5-mg levomethadone hydrochloride formulations, i.e., L-Polamidon (R) 5 mg tablets (test) vs. L-Polamidon (R) solution for substitution (reference). To assess the safety and tolerability of both formulations. Subject and methods: A total of 33 healthy male subjects, aged 29 6 years (BMI: 23.9 +/- 2.5 kg/m(2)) completed this single center, open-label, randomized, 2-period cross-over study with single dose administrations under fasting conditions and coadministration with naltrexone for safety reasons. Administrations of both investigational products were separated by a washout period of at least 2 weeks, i.e., 13 treatment-free days. The total dose for each subject was 2 x 5 mg resulting in 10 mg levomethadone hydrochloride. For pharmacokinetic evaluation, blood samples were withdrawn until 72 hours postdose. A validated non-stereoselective liquid chromatography-tandem mass spectroscopy method (LC-MS/MS) was applied for the determination of levomethadone in plasma. The lower limit of quantitation was 0.100 ng/mL. Adverse events were descriptively analyzed in the study population. Results: The geometric means of the parameters related with the extent of total exposure of levomethadone, i.e., AUC(0-tlast) and AUC(0-infinity), were 244.422 ngxh/mL and 332.999 ngxh/mL for test and 246.837 ngxh/mL and 329.467 ngxh/mL for reference, respectively. The geometric means of the peak exposure for levomethadone, i.e., C-max, were 8.923 ng/mL for test and 8.635 ng/mL for reference. The point estimates (PEs) of the Test/Reference (T/R) adjusted geometric mean ratios of AUC(0-tlast), AUC(0-infinity), and C-max were 99.20%, 101.42%, and 104.11%, respectively, and all of them showed 90%-confidence intervals (CIs) within the range of 80.00 - 125.00% as suggested by regulatory requirements for bioequivalence assessment. In total, 21 subjects experienced 55 AEs during the study, the most frequently reported AE, i.e., headache, accounted for 13 out of the total 55 AEs (23.6%) and no AEs of severe intensity were reported. Conclusions: Bioequivalence could be demonstrated in terms of rate and extent of absorption after administration of test and reference products under naltrexone protection. Concerning the safety evaluation, no negative implications on the possible use of the test formulation could be determined.