Evaluation of the effects of AZD3480 on cardiac repolarization: a thorough QT/QTc study using moxifloxacin as a positive control.
In order to evaluate their potential effects on cardiac repolarization, all new drugs must undergo clinical electrocardiographic evaluation in a thorough QT/QTc (TQT) study. AZD3480, a central nervous system-selective, neuronal nicotinic receptor (NNR) agonist, is predominantly metabolized by cytochrome P450 2D6 (CYP2D6). Employing an innovative design, this TQT study assessed the effects of supratherapeutic doses of AZD3480, relative to those of placebo, on cardiac repolarization in healthy male volunteers genotyped as either poor metabolizers (PMs) or extensive metabolizers (EMs) of CYP2D6 substrates. Supratherapeutic doses of AZD3480-resulting in ~10- and ~50-fold higher exposures (PMs and EMs, respectively) than achieved with a 20-mg dose-had no pharmacologic effect on cardiac repolarization relative to placebo. Likewise, no safety/tolerability concerns were observed after either supratherapeutic or 20-mg dosing to either population. No clinically relevant treatment-related changes or trends were observed in laboratory parameters, vital signs, or electrocardiogram (ECG). This study demonstrated that AZD3480 does not prolong QT/QTc interval.
Dalén
P
P
Clinical Pharmacology and DMPK, AstraZeneca R&D Södertälje, Södertälje, Sweden. per.dalen@astrazeneca.com
Vik
T
T
Alverlind
S
S
Jostell
K-G
KG
Hårdemark
H-G
HG
D000328:Adult; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001372:Aza Compounds / Q000494:pharmacology; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography / Q000187:drug effects*; D024841:Fluoroquinolones; D005838:Genotype; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D000077266:Moxifloxacin; D018722:Nicotinic Agonists / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology*; D011725:Pyridines / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D001372:Aza Compounds; D024841:Fluoroquinolones; D018722:Nicotinic Agonists; D011725:Pyridines; D011804:Quinolines; C490152:ispronicline; D019389:Cytochrome P-450 CYP2D6; D000077266:Moxifloxacin