Tolerability and pharmacokinetics of inhaled bimosiamose disodium in healthy males.

aimsThe aim of these first-in-human studies was to investigate the tolerability and the pharmacokinetics of bimosiamose disodium (TBC1269Z) administered by inhalation.

methodsTwo randomized, double-blind, placebo-controlled Phase I trials were performed in healthy males. In a single-dose escalating study 48 subjects received doses of 2-140 mg bimosiamose disodium by inhalation and in a multiple-dose study 32 subjects received 8-70 mg bimosiamose disodium twice daily. In both studies 4 ml of the drug solution was administered via nebulizer over 15 min. Adverse events, vital signs, ECG, clinical laboratory parameters and forced expiratory volume in 1 s (FEV(1)) data were recorded and nasopharyngeal examinations were performed to address the safety and tolerability. Blood was collected for the determination of plasma concentrations of bimosiamose.

resultsAll subjects completed the study. No deaths or severe adverse events occurred. Eleven mild adverse events occurred in the dose-escalation study and 34 in the multiple-dose study after inhalation of bimosiamose disodium. Adverse events were more frequent at the highest dose (140 mg) of the dose-escalation study. For placebo treatment one moderate adverse event was observed in the dose-escalation study after placebo treatment, eight mild and three moderate adverse events occurred in the multiple-dose study. Bimosiamose was detected in plasma (maximum concentration 64 ng ml(-1)) only at doses > or =50 mg given twice daily and 105 mg once daily. For the highest dose a median value of 5746 h ng ml(-1) was determined for the AUC over the entire period of treatment of the multiple-dose study.

conclusionThe results suggest that single and multiple inhalation of bimosiamose disodium up to 70 mg is well tolerated in healthy males. Systemic bioavailability after inhalation is low.