And S-Citalopram and Desmethylcitalopram in Alzheimer's
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J Pharmacokinet Pharmacodyn (2016) 43:99–109 DOI 10.1007/s10928-015-9457-6 ORIGINAL PAPER A population pharmacokinetic model for R- and S-citalopram and desmethylcitalopram in Alzheimer’s disease patients with agitation 1 1,12 2 3 Ayman Akil • Robert R. Bies • Bruce G. Pollock • Dimitrios Avramopoulos • 4 5 6 7 D. P. Devanand • Jacobo E. Mintzer • Anton P. Porsteinsson • Lon S. Schneider • 8 9 10 11 Daniel Weintraub • Jerome Yesavage • David M. Shade • Constantine G. Lyketsos Received: 30 June 2015 / Accepted: 14 November 2015 / Published online: 26 November 2015 Ó The Author(s) 2015. This article is published with open access at Springerlink.com Abstract The citalopram for Alzheimer’s disease trial any patient-specific covariates, the population estimate of evaluated citalopram for the management for agitation in the metabolic clearance of citalopram was 8.6 (R-citalo- Alzheimer’s disease patients. Sparse data was available pram) and 14 L/h (S-citalopram). The population estimate from this elderly patient population. A nonlinear mixed of the clearance of desmethylcitalopram was 23.8 (R-Dcit) effects population pharmacokinetic modeling approach was and 38.5 L/h (S-Dcit). Several patient-specific covariates used to describe the pharmacokinetics of R- and S-citalo- were found to have a significant effect on the pharma- pram and their primary metabolite (desmethylcitalopram). cokinetics of R,S-citalopram and desmethylcitalopram. A A structural model with 4 compartments (one compart- significant difference in the metabolic clearance of R-ci- ment/compound) with linear oral absorption and elimina- talopram between males and females (13 vs 9.05 L/h) was tion described the data adequately. Overall, the model identified in this analysis. Both R- and S-citalopram showed that clearance of the R-enantiomer was slower than metabolic clearance decreased with age. Additionally, the clearance of the S-enantiomer. Without accounting for consistent with literature reports S-citalopram metabolic clearance increased with increasing body weight and was Electronic supplementary material The online version of this significantly influenced by CYPC19 genotype, with a dif- article (doi:10.1007/s10928-015-9457-6) contains supplementary ference of 5.8 L/h between extensive/rapid and material, which is available to authorized users. & Robert R. Bies 8 Perelman School of Medicine at the University of [email protected] Pennsylvania, Philadelphia, PA, USA 9 Stanford University School of Medicine and VA Palo Alto 1 Division of Clinical Pharmacology, Department of Medicine, Health Care System, Stanford, CA, USA School of Medicine, Indiana University, Indianapolis, IN, USA 10 Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA 2 Campbell Institute, CAMH, University of Toronto, Toronto, ON, Canada 11 Johns Hopkins Bayview and Johns Hopkins School of Medicine, Baltimore, MD, USA 3 Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, 12 Department of Pharmaceutical Sciences, School of Pharmacy USA and Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, NY 14214, USA 4 Division of Geriatric Psychiatry, New York State Psychiatric Institute and College of Physicians and Surgeons of Columbia University, New York, NY, USA 5 Clinical Biotechnology Research Institute, Roper St. Francis Healthcare, Charleston, SC, USA 6 University of Rochester School of Medicine and Dentistry, Rochester, NY, USA 7 University of Southern California Keck School of Medicine, Los Angeles, CA, USA 123 100 J Pharmacokinet Pharmacodyn (2016) 43:99–109 intermediate/poor metabolizers. R,S-desmethylcitalopram citalopram and S-citalopram have also shown decreased clearance increased with increasing body weight. This clearance of the drug with increasing age [16, 17]. model may allow for the opportunity to delineate the effect Due to the sparse sampling approach utilized in most of R- and S-citalopram on pharmacodynamics outcomes studies of elderly people it is difficult to perform a classical related to the management of agitation in Alzheimer’s pharmacokinetic analysis, which requires extensive sam- disease. pling. Population mixed effects pharmacokinetic models are widely used as a tool to describe pharmacokinetics and Keywords Citalopram Á Pharmacokinetics Á Agitation Á explore exposure–response relationships in drug develop- Alzheimer’s disease ment [18]. The advantage of a population pharmacokinetic approach is that it can leverage the sparse data available in order to make inferences about population and individual Introduction level pharmacokinetics. As the objective of the CitAD trial was to assess the efficacy and side effects of citalopram for Patients with dementia, including those with Alzheimer’s the management of agitation in AD patients, understanding disease (AD), often suffer from agitation [1]. Symptoms of the pharmacokinetics of citalopram in this elderly patient agitation include restlessness, tumultuous emotions and population is key towards establishing an exposure–response violent/excessive movements [2]. There is no approved FDA relationship. This in turn is critical towards establishing the pharmacological intervention for the management of agita- effectiveness of citalopram as a therapeutic agent for man- tion in patients with AD [3]. Nonetheless, several drug agement of agitation in this patient population. classes are used to manage agitation in AD patients including The objective of this study was to use mixed effects antipsychotics, anticonvulsants and antidepressants [2, 3]. population pharmacokinetic modeling approach to describe A recent multi-center, randomized, placebo-controlled, the pharmacokinetics of R,S-citalopram and their primary double-blind, parallel group trial, The Citalopram in Alz- metabolites (R,S-desmethylcitalopram) and identify heimer’s disease (CitAD) study, evaluated the efficacy of patient-specific covariates that contribute to the variability citalopram for the management of agitation in AD patients in pharmacokinetics parameters. The effect of age, weight, [4]. The dose of citalopram was set to a target of sex and CYP2C19 genotype on the pharmacokinetics 30 mg/daily, with dose adjustment possible based on parameters of the parent and metabolite of both enan- response and tolerability. Overall the study showed that tiomers were assessed using this population pharmacoki- patients who received citalopram improved compared with netic approach. the placebo group on agitation outcomes. However, wors- ening of cognition and QTc prolongation was observed in the citalopram group [4, 5]. Methods Citalopram, a selective serotonin reuptake inhibitor (SSRI), is a racemic mixture composed of 50 % (R)-(-)- Participants data citalopram and 50 % (S)-(?)-citalopram. It has been sug- gested that most of the antidepressant effects are Ninety-four patients from the CitAD study received citalo- attributable to S-citalopram [6, 7]. This is further supported pram. A starting dose of 10 mg was titrated up over 2 weeks by studies showing that S-citalopram (a.k.a., escitalopram) to the target of 30 mg daily, provided as a single dose in the alone exerts better efficacy than racemic citalopram for morning of three capsules each containing 10 mg. Plasma depression [8–11]. Citalopram is readily absorbed after oral samples were collected at weeks 3, 6, and 9. R,S-citalopram administration and has a bioavailability of approximately and R,S-desmethylcitalopram concentrations were deter- 80 %, a volume of distribution of 12–16 L/kg, and an mined using a sensitive high-performance liquid chro- elimination half-life in healthy adults of 30–35 h [12, 13]. matography method (HPLC) with a chiral column with UV It is metabolized by liver cytochrome P450 enzymes (CYP detection [19, 20]. Figure 1 illustrates the sampling design 2C19, 2D6 and 3A4) to its major metabolite desmethylci- by showing the number of plasma samples versus time after talopram, which undergoes further demethylation mediated dose. Scatter plots of concentration versus time after dose by CYP2D6, to form didemethylcitalopram [12, 13]. The stratified per enantiomer (Fig. 2) show the spread of plasma systemic clearance of citalopram decreases with age due to concentrations of each compound after dose. The limit of a decrease in metabolic activity [14], with the elimination quantitation for each enantiomer was 5 ng/mL except for half-life approximately 30 % longer in the healthy elderly S-desmethylcitalopram where the limit was 10 ng/mL. More population compared to a young population [15]. Previ- detailed information about the CitAD trial design can be ously published population pharmacokinetic models for found in previously published reports [4, 5]. 123 J Pharmacokinet Pharmacodyn (2016) 43:99–109 101 addition of its metabolite. Similarly a parent-metabolite model was built for S-citalopram. The two models were then combined into one model describing the pharma- cokinetics of R,S-citalopram and their two primary metabolites. Nonlinear mixed effects modeling was per- formed using NONMEM 7.1 (ICON Software Develop- ment). The model was developed using ordinary differential equations implemented in NONMEM as (ADVAN6 TRANS1). The model equations were as follows: dCðÞ1 Ka  Dose CL ¼ À Rp  C ð1Þ dt V V Fig. 1 Frequency histogram of the sampling distribution for concen- R R tration measurements of the different compounds dCðÞ2 Ka  Dose CL ¼ À Sp  C ð2Þ dt VS VS dCðÞ3 CL CL ¼ Rp  CðÞÀ1 Rm  C ð3Þ dt VR VR dCðÞ4 CL CL ¼ Sp  CðÞÀ2