Courlet Perrine (1), Monia Guidi (1,2), Glatard Anaïs (1,3), Matthias Cavassini (4), Buclin Thierry (1), Marzolini Catia (5), Eap Chin B. (2,3), Decosterd Laurent A. (1), Csajka Chantal (1,2).
(1) Service of Clinical Pharmacology, University Hospital Center, University of Lausanne, Lausanne, Switzerland, (2) School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland, (3) Unit of Pharmacogenetics and Clinical Psychopharmacology, Centre for Psychiatric Neuroscience, Department of Psychiatry, Hospital of Cery, University Hospital Center, Prilly, Switzerland, (4) Division of Infectious Diseases, University Hospital Center, University of Lausanne, (5) Departments of Medicine and Clinical Research, University Hospital of Basel and University of Basel, Switzerland
Objectives:
The rate of depression in patients with HIV is higher than in the general population with up to 40–60 % of HIV-positive subjects reporting depressive symptoms (1-3). Citalopram and escitalopram (S-citalopram), its marketed pharmacologically active enantiomer, are among the most prescribed antidepressants in HIV-infected and uninfected psychiatric patients. Both R- and S-citalopram enantiomers are metabolized equally by the cytochrome P450 isoenzymes (CYP): CYP2C19 (≈37%), CYP3A4 (≈35%), and CYP2D6 (≈28%) (4). The aim of this observational study was to compare the pharmacokinetic profile of escitalopram in HIV-infected individuals with uninfected psychiatric patients, to identify sources of variability that could influence drug exposure, and notably to evaluate drug-drug interactions (DDI) with antiretroviral treatments. Indeed, citalopram and escitalopram are among the antidepressants with the highest risk of QT prolongation, and escitalopram overexposure due to DDI could yield to an increased risk of QT prolongation and arrhythmias (5).
Methods:
Fifty-two plasma samples at unselected time after the last citalopram (n=27) or escitalopram (n=25) intake were collected from 39 HIV-infected patients in the framework of a Swiss HIV Cohort Study (SHCS #815). To estimate escitalopram dose and plasma concentrations from the racemate (citalopram), the total doses were divided by two and plasma concentrations were derived using an S/R ratio of 0.45 (6). Moreover, 115 uninfected psychiatric patients receiving escitalopram provided 212 plasma samples during an ongoing pharmacogenetic study (PsyMetab). Escitalopram pharmacokinetics were analyzed using the non-linear mixed effect modeling (NONMEM®) program. The effect of subject specific continuous (age) and discrete covariates (cohort, citalopram treatment, sex, and co-medications) was explored. Antiretroviral treatments were classified as known CYP2C19 inducers (28% of the HIV-infected patients), CYP3A4 inducers (5%) or inhibitors (44%), as well as p-glycoprotein inducers (10%) or inhibitors (36%).
Results:
A median of one sample (range 1–2 for HIV-infected patients and 1-11 for uninfected psychiatric patients) of citalopram or escitalopram was collected per patient. The pharmacokinetic profile was similar in patients receiving citalopram and escitalopram, supporting the S/R ratio in plasma of 0.45. A one-compartment model with first order absorption and elimination best described escitalopram pharmacokinetics. Due to the paucity of data during the absorption phase, the absorption rate constant was fixed to 0.8 h-1 according to the literature (7, 8). Average escitalopram clearance (CL/F) was 25.7 L/h (RSE 7%), and volume of distribution (V/F) 1410 L (RSE 34%). An inter-subject variability was assigned only on CL/F and was estimated to 54%. None of the tested covariates had an impact on CL/F. Despite the broad range in the participants age (18 – 87 years old), age was not associated with a decrease in CL/F, as opposed to previously published data (9, 10). Of interest, antiretroviral drugs including HIV protease inhibitors did not affect escitalopram concentrations probably due to the contribution of multiple cytochromes in its metabolism and elimination, thus limiting the impact of drug-drug interactions. This observation is consistent with the lack of effect of ketoconazole, another strong CYP3A4 inhibitor, on citalopram pharmacokinetics (11).
Conclusions:
Escitalopram pharmacokinetics did not differ between HIV patients treated with antiretroviral and uninfected psychiatric patients. Although the limited amount of data limits the study power to find out small-sized effects and would require further analysis, this work presents reassuring results concerning the risk of drug-drug interaction between escitalopram and antiretroviral treatments.
References:
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[2] Eller LS, Bunch EH, Wantland DJ, Portillo CJ, Reynolds NR, Nokes KM, et al. Prevalence, correlates, and self-management of HIV-related depressive symptoms. AIDS Care. 2010;22(9):1159-70.
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[5] Citalopram and escitalopram: QT interval prolongation. New maximum daily dose restrictions (including in elderly patients), contraindications, and warnings. Available from: https://www.gov.uk/drug-safety-update/citalopram-and-escitalopram-qt-interval-prolongation, (2011).
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[8] Sogaard B, Mengel H, Rao N, Larsen F. The pharmacokinetics of escitalopram after oral and intravenous administration of single and multiple doses to healthy subjects. Journal of clinical pharmacology. 2005;45(12):1400-6.
[9] Akil A, Bies RR, Pollock BG, Avramopoulos D, Devanand DP, Mintzer JE, et al. A population pharmacokinetic model for R- and S-citalopram and desmethylcitalopram in Alzheimer’s disease patients with agitation. Journal of pharmacokinetics and pharmacodynamics. 2016;43(1):99-109.
[10] Jin Y, Pollock BG, Frank E, Cassano GB, Rucci P, Muller DJ, et al. Effect of age, weight, and CYP2C19 genotype on escitalopram exposure. Journal of clinical pharmacology. 2010;50(1):62-72.
[11] Gutierrez M, Abramowitz W. Lack of effect of a single dose of ketoconazole on the pharmacokinetics of citalopram. Pharmacotherapy. 2001;21(2):163-8.
Reference: PAGE 27 (2018) Abstr 8460 [www.page-meeting.org/?abstract=8460]
Poster: Drug/Disease Modelling - Infection