Influence of Concomitant Medications on the Total Clearance and the Risk for Supra-therapeutic Plasma Concentrations of Citalopram. A Population-Based Cohort Study

Abstract

Introduction: The main objective of this study was to investigate the influence of the use of multiple medications and other risk factors on citalopram plasma concentrations.

Methods: A retrospective cohort study with a naturalistic population of 957 patients for whom routine therapeutic drug monitoring (TDM) of citalopram had been requested between 2006 and 2013 was conducted.

Results: Concomitant drugs inhibiting at least 2 different CYP subtypes involved in the metabolism of citalopram decreased statistically significantly the total clearance (Cl_t). Compared to younger patients over 64-year-old patients had on average a 4.5 times higher risk rate of supra-therapeutic plasma concentrations. However, binary logistic regression showed that age, sex and co-medication accounted only for 26% of the inter-individual variability of citalopram plasma concentrations.

Discussion: Due to pharmacokinetic interactions, citalopram plasma concentrations are often higher than expected with a given dose. Especially in geriatric and often multimorbid patients who are usually prescribed high numbers of concomitant drugs and are at higher risk for adverse drug reactions (ADR), restriction of the maximal dose of citalopram is not sufficient to prevent supra-therapeutic plasma concentrations.

Key words

drug interactions - pharmacokinetics - selective serotonin reuptake inhibitors (SSRIs) - citalopram - therapeutic drug monitoring

• References

• 1 FDA Drug Safety Communication Revised recommendations for Celexa (citalopram hydrobromide) related to a potential risk of abnormal heart rhythms with high doses. 28.03.2012. Available: http://www.fda.gov/Drugs/DrugSafety/ucm297391.htm (accessed: 29.08.2014)
• 2 Wenzel-Seifert K, Wittmann M, Haen E. QTc prolongation by psychotropic drugs and the risk of Torsade de Pointes. Dtsch Arztebl Int 2011; 108: 687-693
• 3 Wenzel-Seifert K, Wittmann M, Haen E. Torsades de pointes episodes under treatment with selective serotonin reuptake inhibitors. Pharmacopsychiatry 2010; 43: 279-281
• 4 Vieweg WV, Hasnain M, Howland RH et al. Citalopram, QTc interval prolongation, and torsade de pointes. How should we apply the recent FDA ruling?. Am J Med 2012; 125: 859-868
• 5 Castro VM, Clements CC, Murphy SN et al. QT interval and antidepressant use: a cross sectional study of electronic health records. BMJ 2013; 346: f288
• 6 Hiemke C. Therapeutic drug monitoring in neuropsychopharmacology: does it hold its promises?. Eur Arch Psychiatry Clin Neurosci 2008; 258: 21-27
• 7 Fredericson Overo K, Toft B, Christophersen L et al. Kinetics of citalopram in elderly patients. Psychopharmacology 1985; 86: 253-257
• 8 Reis M, Lundmark J, Bengtsson F. Therapeutic drug monitoring of racemic citalopram: a 5-year experience in Sweden, 1992–1997. Ther Drug Monit 2003; 25: 183-191
• 9 Barak Y, Swartz M, Levy D et al. Age-related differences in the side effect profile of citalopram. Prog Neuropsychopharmacol Biol Psychiatry 2003; 27: 545-548
• 10 Rochat B, Amey M, Gillet M et al. Identification of three cytochrome P450 isozymes involved in N-demethylation of citalopram enantiomers in human liver microsomes. Pharmacogenetics 1997; 7: 1-10
• 11 Brosen K, Naranjo CA. Review of pharmacokinetic and pharmacodynamic interaction studies with citalopram. Eur Neuropsychopharmacol 2001; 11: 275-283
• 12 Sangkuhl K, Klein TE, Altman RB. PharmGKB summary: citalopram pharmacokinetics pathway. Pharmacogenet Genomics 2011; 21: 769-772
• 13 Haen E. Therapeutic drug monitoring in pharmacovigilance and pharmacotherapy safety. Pharmacopsychiatry 2011; 44: 254-258
• 14 Greiner C, Hiemke C, Bader W et al. Determination of citalopram and escitalopram together with their active main metabolites desmethyl(es-)citalopram in human serum by column-switching high performance liquid chromatography (HPLC) and spectrophotometric detection. J Chromatogr B Analyt Technol Biomed Life Sci 2007; 848: 391-394
• 15 Gutierrez M, Abramowitz W. Steady-state pharmacokinetics of citalopram in young and elderly subjects. Pharmacotherapy 2000; 20: 1441-1447
• 16 Fredricson Overo K. Kinetics of citalopram in man; plasma levels in patients. Prog Neuropsychopharmacol Biol Psychiatry 1982; 6: 311-318
• 17 Spigset O, Hagg S, Stegmayr B et al. Citalopram pharmacokinetics in patients with chronic renal failure and the effect of haemodialysis. Eur J Clin Pharmacol 2000; 56: 699-703
• 18 Hiemke C, Baumann P, Bergemann N et al. AGNP Consensus guidelines for therapeutic drug monitoring in psychiatry: update 2011. Pharmacopsychiatry. 2011 44. 195-235
• 19 Fudio S, Borobia AM, Pinana E et al. Evaluation of the influence of sex and CYP2C19 and CYP2D6 polymorphisms in the disposition of citalopram. Eur J Pharmacol 2010; 626: 200-204
• 20 Mrazek DA, Biernacka JM, O’Kane DJ et al. CYP2C19 variation and citalopram response. Pharmacogenet Genomics 2011; 21: 1-9
• 21 Herrlin K, Yasui-Furukori N, Tybring G et al. Metabolism of citalopram enantiomers in CYP2C19/CYP2D6 phenotyped panels of healthy Swedes. Br J Clin Pharmacol 2003; 56: 415-421
• 22 Yin OQ, Wing YK, Cheung Y et al. Phenotype-genotype relationship and clinical effects of citalopram in Chinese patients. J Clin Psychopharmacol 2006; 26: 367-372
• 23 Yu BN, Chen GL, He N et al. Pharmacokinetics of citalopram in relation to genetic polymorphism of CYP2C19. Drug Metab Dispos 2003; 31: 1255-1259