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

OBJECTIVES: To establish the relative bioavailability (rBA) between two p.o. 5-mg levomethadone hydrochloride formulations, i.e., L-Polamidon® 5 mg tablets (test) vs. L-Polamidon® 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/m2) 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 treatmentfree 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 For pharmacokinetic evaluation, blood samples were withdrawn until 72 hours postdose.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-∞), were 244.422 ng x h/mL and 332.999 ng x h/mL for test and 246.837 ng x h/mL and 329.467 ng×h/mL for reference, respectively. The geometric means of the peak exposure for levomethadone, i.e., Cmax, 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-last), AUC(0-∞), 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.

Randomized phase III trial of docetaxel plus carboplatin with or without levofloxacin prophylaxis in elderly patients with advanced non-small cell lung cancer: the APRONTA trial.

PURPOSE: To examine the effect of levofloxacin prophylaxis on infection rates during chemotherapy with docetaxel plus carboplatin in elderly patients with advanced non-small cell lung cancer. METHODS: In a randomized, double-blind, phase III study, patients (≥65 years) with untreated, histologically/cytologically proven stage IIIB/IV non-small cell lung cancer received docetaxel (75 mg/m) plus carboplatin (area under the curve 6) on day 1 every 3 weeks, plus once-daily levofloxacin (500 mg orally) or placebo on days 5 to 11. The primary end point was the rate of grade 3/4 infections or grade 1/2 infections treated with additional antibiotics. Secondary end points included overall infection rate, toxicity, overall survival, and progression-free survival. RESULTS: In total, 187 patients were randomized to levofloxacin (n = 95) or placebo (n = 92). The rate of grade 3/4 infections or grade 1/2 infections treated with additional antibiotics (intent-to-treat population) was 27.5% (95% confidence interval, 19.3-39.0%) for levofloxacin versus 36.7% (95% confidence interval, 27.1-48.0%) for placebo. Median time to first infection was 67 days for levofloxacin versus 46 days for placebo. Grade 3/4 infections occurred in 8.8% of patients in the levofloxacin group versus 26.7% for placebo. There was one grade 5 infection in each group. Grade ≥3 toxicities (levofloxacin versus placebo) included leukopenia (63.2 versus 52.2%), neutropenia (62.1 versus 51.1%), dyspnea (12.6 versus 8.7%), and pain (10.5 versus 9.8%). There was no significant difference in overall survival or progression-free survival between groups. CONCLUSIONS: Levofloxacin prophylaxis reduces the rate of infection compared with placebo and is well tolerated in elderly patients receiving docetaxel plus carboplatin.