Population pharmacokinetics and safety of AZD1446, a neuronal nicotinic receptor agonist, administered in healthy volunteers

AZD1446 is a highly selective agonist of central α4β2 and α2β2 neuronal nicotinic receptors. The compound has been shown to improve cognition in preclinical studies and thus has potential for treatment of cognitive disorders, including Alzheimer's disease (AD). This report presents the pharmacokinetics of AZD1446 based on a pooled population pharmacokinetic analysis of five studies in Caucasian and Japanese healthy volunteers. The model described the inter-individual and inter-occasion variability as well as identified the impact of covariates such as age and ethnicity on the parameters. Single doses of AZD1446 ranged between 0.5 and 350 mg and the multiple-dose regimens ranged between 10 and 100 mg four times daily. The maximum duration was 4 weeks. AZD1446 exhibited modest variability in CL/F. Compared with Caucasian subjects, Japanese subjects had approximately 25% higher rate of absorption and higher renal clearance as well as volume of distribution, resulting in a similar half-life. Compared with elderly subjects, young subjects had approximately 25% lower rate of absorption. Due to lower creatinine clearance, renal clearance was lower in elderly subjects. AZD1446 was safe and well tolerated, with nausea, headache and dizziness as the most frequently reported adverse events.