Phase I clinical trial with desoxypeganine, a new cholinesterase and selective MAO-A inhibitor: tolerance and pharmacokinetics study of escalating single oral doses.
Desoxypeganine (DOP) is a natural alkaloid that has been characterized as a cholinesterase inhibitor and a selective inhibitor of monoamine oxidase A. DOP has been investigated for its potential utility in the pharmacological treatment of alcohol abuse and as a smoking cessation aid. The aim of this clinical trial was to evaluate the tolerance and single-dose pharmacokinetic profile of DOP in healthy human volunteers. The study was an open-label, dose-escalation, phase I clinical trial involving the administration of increasing single oral doses of DOP (50, 100, 150 and 200 mg). The study was conducted according to the Declaration of Helsinki and Good Clinical Practice. Eighteen healthy adult volunteers (8 males and 10 females, age ranging 20-30 years) were recruited. DOP was administered sequentially, escalating in single doses of 50, 100, 150 and 200 mg in four experimental sessions with a washout period of at least 1 week between them. Progress to the next dose was allowed only if the previous dose was tolerated. Pharmacokinetic parameters were determined using noncompartmental methods. Clinical and analytical safety was assessed throughout the study, and QTc intervals were measured at regular intervals. The main pharmacokinetic parameters and renal excretion are described. No serious adverse events were registered, and none of the subjects discontinued the study because of lack of tolerance. All the adverse events recorded were mild to moderate and increased with the dose. The ECG measurements revealed that even at a higher dose, the QTc interval remained below the safety threshold. In summary, this first phase I study indicates that DOP has linear and dose-proportional pharmacokinetics, satisfactory oral bioavailability and plasma half-life and renal excretion. Also, DOP has shown an adequate safety profile that allows the continuation of clinical development.
Clinical Trials Unit, Hospital Txagorritxu, Vitoria-Gasteiz, Spain. jaime.algorta@ehu.es
J
J
Algorta
M A
MA
Pena
C
C
Maraschiello
A
A
Alvarez-González
D
D
Maruhn
M
M
Windisch
H A M
HA
Mucke
D000284:Administration, Oral; D000328:Adult; D001682:Biological Availability; D002800:Cholinesterase Inhibitors / Q000493:pharmacokinetics*; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D006801:Humans; D008297:Male; D008996:Monoamine Oxidase Inhibitors / Q000493:pharmacokinetics*; D011799:Quinazolines / Q000009:adverse effects / Q000493:pharmacokinetics*
D002800:Cholinesterase Inhibitors; D008996:Monoamine Oxidase Inhibitors; D011799:Quinazolines; C499396:desoxypeganine 1