Single- and multiple-dose pharmacokinetics of the peripheral non-narcotic antitussive moguisteine in healthy Chinese volunteers

Abstract

BackgroundMoguisteine is a non-narcotic peripheral antitussive drug that has been effective and well-tolerated in clinical studies. The aim of the present work was to investigate the pharmacokinetics of moguisteine given as single or multiple doses to healthy Chinese subjects. MethodsIn Stages 1–3 of this study, 12 healthy Chinese subjects (6 males and 6 females) participated in a randomized, open-label, single-dose, 3-period, 3-way crossover study, with a 24-h washout period between each treatment. Eligible subjects were randomized to receive a single dose of 100, 200 or 400 mg moguisteine. Blood was sampled before and up to 10 h after administration. In those receiving 200 mg moguisteine, urine was sampled at intervals of 0–2, 2–4, 4–6, 6–10, and 10–24 h. In Stage 4, subjects received a moguisteine tablet containing 200 mg three times daily for five consecutive days. Blood was sampled for up to 10 h after the last dose. HPLC-tandem mass spectrometry was used to determine concentrations of the moguisteine metabolite M1 in serum, while HPLC-UV was used to determine concentrations of M1 in urine. Safety of the dosing schedules was assessed based on physical examination, recording of adverse events, 12-lead electrocardiography, and laboratory tests. ResultsAll subjects completed all four stages of the study. M1 was detectable at the shortest time points after moguisteine administration; the time to achieve peak concentration was 0.5–1.0 h in single dosing and 1.5 h in multiple dosing. Elimination half-life (t1/2) was 0.91–1.54 h in single dosing and 1.57 h in multiple dosing. AUC increased roughly proportionally with dose, while Cmax increased much more gradually with dose. During 5-day dosing of three tablets per day, a steady state concentration was reached on day 3, and the mean accumulation ratio was 0.87. At 24 h after a single dose of 200 mg moguisteine, approximately 34.0% of the resulting M1 was recovered in urine. Pharmacokinetics of moguisteine did not differ significantly between men and women, except among those receiving a single dose of 100 mg (P < 0.05). Mild adverse events (nausea, loose stool, abdominal distention, or dizziness) occurred in six subjects and resolved without treatment, while no serious adverse events were observed. ConclusionMoguisteine was safe and well-tolerated by our healthy subjects, and it exhibited dose linearity but not proportionality when a single dose of 100–400 mg was given. M1 did not accumulate in subjects after multiple doses of moguisteine.