Population pharmacokinetic modeling of sertraline treatment in patients with Alzheimer disease: the DIADS-2 study.

Alzheimer’s disease (AD) is a neurodegenerative disease associated with a number of neuropsychiatric symptoms (NPS). One commonly found NPS is depression, affecting as many as 60% of AD patients [1]. The antidepressant sertraline, a selective serotonin reuptake inhibitor (SSRI), has been used for the treatment of depression in AD patients [2]. It is the second most potent inhibitor of serotonin reuptake. [3]. In a study of 117 randomized controlled trials from 1991 to 2007, sertraline was proposed as the best first line treatment for moderate to severe depression in adults based on an overall evaluation of benefits, acceptability and other factors [4]. Sertraline is orally administered with high plasma protein binding affinity [5]. The average elimination half-life of sertraline is approximately 26 hours and the peak plasma concentration (Cmax) is reached at 6–8 hours [6]. Sertraline is mainly eliminated by hepatic metabolism to its major metabolite, N-desmethylsertraline, by multiple cytochrome p450 enzymes including CYP2B6, CYP2D6, CYP2C9, CYP2C19 and CYP3A4 [7]. This metabolite has 5–10% of sertraline’s serotonin reuptake inhibitor potency; thus its clinical effect on sertraline response is negligible [8]. The pharmacokinetic profile of sertraline has been broadly explored in previous clinical studies where patient ages spanned broad ranges [9–11]. In a pharmacokinetic study of 16 elderly (≥65 years of age) patients treated with 100 mg sertraline once daily for 14 days, plasma sertraline clearance was approximately 40% lower compared to similarly studied younger (25–32 years) patients [6,12]. A comparable result was found in a 21 day study (n=44), with the elimination rate constant (0.019/hr) in elderly individuals 16 to 63% lower than that observed in young adults [13]. In the elderly, sertraline’s effectiveness is comparable to the SSRI fluoxetine as well as the tricyclic antidepressants (TCAs) nortriptyline, amitriptyline and imipramine. It has lower rates of adverse side effects than the TCAs [9]. Although many studies have examined the sertraline pharmacokinetic profile in elderly subjects, non-compartmental methods were employed that have limitations in assessing sources of inter-individual variability in sertraline concentration. In fact, this is the first population pharmacokinetic (PPK) study focusing on AD patients with depression. While this analysis was based on data from a null clinical study, it provided an opportunity to capture the pharmacokinetic characteristics in elderly individuals of sertraline. In these analyses, we aim to gain insights relating to inter-individual variability in the pharmacokinetics of sertraline in AD patients. The objective is to identify covariates that contribute to variability in sertraline concentration by performing a PPK analysis of sertraline in elderly patients with AD and generating PPK parameters for this population.