Pharmacokinetics and safety of 3,4-diaminopyridine base in healthy Japanese volunteers

• Published in: International journal of clinical pharmacology and therapeutics Vol. 53; no. 8; p. 674
• Main Authors: Ishida, Natsuko, Kobayashi, Erina, Kondo, Yuya, Matsushita, Ryo, Komai, Kiyonobu
• Format: Journal Article
• Language: English
• Published: Germany 01.08.2015
• Subjects: 4-Aminopyridine - administration & dosage; 4-Aminopyridine - adverse effects; 4-Aminopyridine - analogs & derivatives; 4-Aminopyridine - blood; 4-Aminopyridine - pharmacokinetics; Administration, Oral; Adult; Area Under Curve; Asian Continental Ancestry Group; Cross-Over Studies; Electrocardiography; Fasting; Half-Life; Healthy Volunteers; Heart Rate - drug effects; Humans; Japan; Metabolic Clearance Rate; Models, Biological; Neural Conduction - drug effects; Neuromuscular Agents - administration & dosage; Neuromuscular Agents - adverse effects; Neuromuscular Agents - blood; Neuromuscular Agents - pharmacokinetics; Nonlinear Dynamics; Postprandial Period; Risk Assessment; Surveys and Questionnaires; Treatment Outcome; Young Adult; Japan
• ISSN: 0946-1965
• DOI: 10.5414/CP202133

3,4-diaminopyridine (3,4-DAP) is commonly used for treating neuromuscular diseases, such as the Lambert-Eaton myasthenic syndrome, but the pharmacokinetics of 3,4-DAP base have not been investigated. We therefore studied 3,4-DAP base pharmacokinetics in healthy Japanese volunteers. In this crossover study, we administered a single oral dose of 10 or 20 mg 3,4-DAP base to healthy Japanese volunteers (n = 5) after food intake, or 10 mg 3,4-DAP to fasting individuals. We measured serum 3,4-DAP concentrations, performed electrocardiography (ECG), and administered questionnaires. After administration of 10 or 20 mg 3,4-DAP following food intake, the maximum serum concentrations (Cmax) were 8.09 ± 4.47 ng/mL and 35.8 ± 15.7 ng/mL, respectively (mean ± standard deviation; SD), and the areas under the serum concentration-time curve (extrapolated to infinity) were 639 ± 213 ng x min/mL and 2,097 ± 936 ng x min/mL (mean ± SD), respectively. Administration to fasted individuals indicated that food intake did not significantly alter 3,4-DAP pharmacokinetics. ECG showed no clinically significant changes, but PR intervals were prolonged in all cases. Two out of 5 subjects showed perioral paresthesia symptoms after administration of 20 mg 3,4-DAP. This study indicated that 3,4-DAP base pharmacokinetics were non-linear. Although no clinically significant changes in ECG were observed, it is advisable to perform ECG periodically during 3,4-DAP administration in order to monitor cardiac function. Moreover, the development of perioral paresthesia may be dependent on the dose of 3,4-DAP used.