The Population Pharmacokinetics of Citalopram After Deliberate Self-Poisoning: A Bayesian Approach

  • Lena E. Friberg
  • Geoffrey K. Isbister
  • L. Peter Hackett
  • Stephen B. Duffull


Defining the pharmacokinetics of drugs in overdose is complicated. Deliberate self-poisoning is generally impulsive and associated with poor accuracy in dose history. In addition, early blood samples are rarely collected to characterize the whole plasma-concentration time profile and the effect of decontamination on the pharmacokinetics is uncertain. The aim of this study was to explore a fully Bayesian methodology for population pharmacokinetic analysis of data that arose from deliberate self-poisoning with citalopram. Prior information on the pharmacokinetic parameters was elicited from 14 published studies on citalopram when taken in therapeutic doses. The data set included concentration–time data from 53 patients studied after 63 citalopram overdose events (dose range: 20–1700 mg). Activated charcoal was administered between 0.5 and 4 h after 17 overdose events. The clinical investigator graded the veracity of the patients’ dosing history on a 5-point ordinal scale. Inclusion of informative priors stabilised the pharmacokinetic model and the population mean values could be estimated well. There were no indications of non-linear clearance after excessive doses. The final model included an estimated uncertainty of the dose amount which in a simulation study was shown to not affect the model’s ability to characterise the effects of activated charcoal. The effect of activated charcoal on clearance and bioavailability was pronounced and resulted in a 72% increase and 22% decrease, respectively. These findings suggest charcoal administration is potentially beneficial after citalopram overdose. The methodology explored seems promising for exploring the dose–exposure relationship in the toxicological settings.


Informative priors Bayesian analysis MCMC drug overdose activated charcoal dosing history citalopram toxicity poisoning 


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  1. Isbister, GK., Dawson, AH., Whyte, IM. 2003Feasibility of prehospital treatment with activated charcoal: Who could we treat, who should we treat?Emerg. Med. J.20375378CrossRefPubMedGoogle Scholar
  2. Prescott, LF., Roscoe, P., Wright, N., Brown, SS. 1971Plasma-paracetamol half-life and hepatic necrosis in patients with paracetamol overdosageLancet.1519522PubMedGoogle Scholar
  3. Prescott, LF., Illingworth, RN., Critchley, JA., Stewart, MJ., Adam, RD., Proudfoot, AT. 1979Intravenous N-acetylcystine: The treatment of choice for paracetamol poisoningBr. Med. J.210971100PubMedCrossRefGoogle Scholar
  4. Bailey, B., Buckley, NA., Amre, DK. 2004A meta-analysis of prognostic indicators to predict seizures, arrhythmias or death after tricyclic antidepressant overdose. J. ToxicolClin. Toxicol.42877888CrossRefGoogle Scholar
  5. Dawson AH., Whyte IM. (2001). Therapeutic drug monitoring in drug overdose. Br. J. Clin. Pharmacol. 1:97S–102SGoogle Scholar
  6. Lunn, DJ., Best, N., Thomas, A., Wakefield, J., Spiegelhalter, D. 2002Bayesian analysis of population PK/PD models: General concepts and softwareJ. Pharmacokinet.Pharmacodyn.29271307CrossRefPubMedGoogle Scholar
  7. Mu, S., Ludden, TM. 2003Estimation of population pharmacokinetic parameters in the presence of non-complianceJ. Pharmacokinet. Pharmacodyn.305381CrossRefPubMedGoogle Scholar
  8. Gurrin, LC., Moss, TJ., Sloboda, DM., Hazelton, ML., Challis, JR., Newnham, JP. 2003Using WinBUGS to fit nonlinear mixed models with an application to pharmacokinetic modelling of insulin response to glucose challenge in sheep exposed antenatally to glucocorticoidsJ. Biopharm Stat.13117139CrossRefPubMedGoogle Scholar
  9. Stickland, MD., Kirkpatrick, CM., Begg, EJ., Duffull, SB., Oddie, SJ., Darlow, BA.. 2001An extended interval dosing method for gentamicin in neonatesJ. Antimicrob Chemother.48887893CrossRefPubMedGoogle Scholar
  10. Meineke, I., Turck, D. 2003Population pharmacokinetic analysis of meloxicam in rheumatoid arthritis patientsBr. J. Clin. Pharmacol.553238CrossRefPubMedGoogle Scholar
  11. Duffull, SB., Kirkpatrick, CM., Green, B., Holford, NH. 2005Analysis of population pharmacokinetic data using NONMEM and WinBUGSJ. Biopharm. Stat.155373PubMedGoogle Scholar
  12. Keller, MB. 2000Citalopram therapy for depression: A review of 10 years of European experience and data from U.S. clinical trialsJ. Clin. Psychiatry.61896908PubMedGoogle Scholar
  13. Isbister, GK., Bowe, SJ., Dawson, A., Whyte, IM. 2004Relative toxicity of selective serotonin reuptake inhibitors (SSRIs) in overdoseJ. Toxicol. Clin. Toxicol.42277285PubMedGoogle Scholar
  14. Meuleman, C., Jourdain, P., Bellorini, M., Sadeg, N., Loiret, J., Guillard, N., Thebault, B., Funck, F. 2001Citalopram and Torsades de PointesA case report. Arch. Mal. Coeur. Vaiss.9410211024Google Scholar
  15. Ostrom, M., Eriksson, A., Thorson, J., Spigset, O. 1996Fatal overdose with citalopramLancet.348339340CrossRefPubMedGoogle Scholar
  16. Baumann, P., Larsen, F. 1995The pharmacokinetics of citalopramRev. Contemp. Pharmacother.6287295Google Scholar
  17. Reis, M., Lundmark, J., Bengtsson, F. 2003Therapeutic drug monitoring of racemic citalopram: A 5-year experience in Sweden, 1992–1997Ther. Drug. Monit.25183191CrossRefPubMedGoogle Scholar
  18. Le Bloc’h, Y., Woggon, B., Weissenrieder, H., Brawand-Amey, M., Spagnoli, J., Eap, CB., Baumann, P. 2003Routine therapeutic drug monitoring in patients treated with 10–360 mg/day citalopramTher. Drug. Monit.25600608PubMedGoogle Scholar
  19. Brosen, K., Naranjo, CA. 2001Review of pharmacokinetic and pharmacodynamic interaction studies with citalopramEur. Neuropsychopharmacol.11275283PubMedGoogle Scholar
  20. Cooper, GM., Le Couteur, DG., Richardson, D., Buckley, NA. 2005A randomised clinical trial of activated charcoal for the routine management of drug overdoseQJM.98655660CrossRefPubMedGoogle Scholar
  21. Lapatto-Reiniluoto, O., Kivisto, KT., Neuvonen, PJ. 1999Effect of activated charcoal alone or given after gastric lavage in reducing the absorption of diazepam, ibuprofen and citalopramBr. J. Clin. Pharmacol.48148153CrossRefPubMedGoogle Scholar
  22. Milne, RJ., Goa, KL. 1991Citalopram A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in depressive illnessDrugs.41450477PubMedGoogle Scholar
  23. Rampono, J., Kristensen, JH., Hackett, LP., Paech, M., Kohan, R., Ilett, KF. 2000Citalopram and demethylcitalopram in humaR. milk; distribution, excretion and effects in breast fed infantsBr. J. Clin. Pharmacol.50263268CrossRefPubMedGoogle Scholar
  24. Kragh-Sorensen, P., Overo, KF., Petersen, OL., Jensen, K., Parnas, W. 1981The kinetics of citalopram: Single and multiple dose studies in man. Acta PharmacolToxicol. (Copenh).485360Google Scholar
  25. Fredricson Overo, K. 1982Kinetics of citalopram in man; plasma levels in patientsProg. Neuropsychopharmacol. Biol. Psychiatry.6311318PubMedGoogle Scholar
  26. Fredricson Overo, K., Toft, B., Christophersen, L., Gylding-Sabroe, JP. 1985Kinetics of citalopram in elderly patientsPsychopharmacology (Berl.)86253257Google Scholar
  27. Sindrup, SH., Brosen, K., Hansen, MG., Aaes-Jorgensen, T., Overo, KF., Gram, LF. 1993Pharmacokinetics of citalopram in relation to the sparteine and the mephenytoin oxidation polymorphismsTher. Drug. Monit.151117PubMedGoogle Scholar
  28. Laine, K., Anttila, M., Heinonen, E., Helminen, A., Huupponen, R., Maki-Ikola, O., Reinikainen, K., Scheinin, M. 1997Lack of adverse interactions between concomitantly administered selegiline and citalopramClin. Neuropharmacol.20419433PubMedGoogle Scholar
  29. Priskorn, M., Larsen, F., Segonzac, A., Moulin, M. 1997Pharmacokinetic interaction study of citalopram and cimetidine in healthy subjectsEur. J. Clin. Pharmacol.52241242CrossRefPubMedGoogle Scholar
  30. Sidhu, J., Priskorn, M., Poulsen, M., Segonzac, A., Grollier, G., Larsen, F. 1997Steady-state pharmacokinetics of the enantiomers of citalopram and its metabolites in humansChirality.9686692CrossRefPubMedGoogle Scholar
  31. Joffe, P., Larsen, FS., Pedersen, V., Ring-Larsen, H., Aaes-Jorgensen, T., Sidhu, J. 1998Single-dose pharmacokinetics of citalopram in patients with moderate renal insufficiency or hepatic cirrhosis compared with healthy subjectsEur. J.Clin. Pharmacol.54237242CrossRefPubMedGoogle Scholar
  32. Spigset, O., Hagg, S., Stegmayr, B., Dahlqvist, R. 2000Citalopram pharmacokinetics in patients with chronic renal failure and the effect of haemodialysisEur. J. Clin. Pharmacol.56699703CrossRefPubMedGoogle Scholar
  33. Gutierrez, M., Abramowitz, W. 2000Steady-state pharmacokinetics of citalopram in young and elderly subjectsPharmacotherapy.2014411447PubMedGoogle Scholar
  34. Gutierrez, MM., Abramowitz, W. 2000Pharmacokinetic comparison of oral solution and tablet formulations of citalopram: A single-dose, randomized, crossover studyClin. Ther.2215251532CrossRefPubMedGoogle Scholar
  35. Gutierrez, M., Abramowitz, W. 2001Lack of effect of a single dose of ketoconazole on the pharmacokinetics of citalopramPharmacotherapy.21163168PubMedGoogle Scholar
  36. Yu, BN., Chen, GL., He, N., Ouyang, DS., Chen, XP., Liu, ZQ., Zhou, HH. 2003Pharmacokinetics of citalopram in relation to genetic polymorphism of CYP2C19Drug. Metab. Dispos.3112551259CrossRefPubMedGoogle Scholar
  37. Spiegelhalter, DJ., Thomas, A., Best, NG. 2003WinBUGS Version 1.4 User ManualMedical Research Council Biostatics UnitCambridgeGoogle Scholar
  38. Soy, D., Beal, SL., Sheiner, LB. 2004Population one-compartment pharmacokinetic analysis with missing dosage dataClin.Pharmacol.Ther.76441451CrossRefPubMedGoogle Scholar
  39. Gelman, A., Rubin, C. 1992Inference from iterative simlation using multiple sequencesStat. Sci.7457511Google Scholar
  40. Spiegelhalter, DJ., Best, NG., Carlin, BR., Linde, A. 2002Bayesian measures of model complexity and fitJ. Roy.Stat. Soc. Ser. B-Stat. Meth.64583616Google Scholar
  41. Friberg, LE., Dansirikul, C., Duffull, SB. 2004Simultaneous fit of competing models as a model discrimination tool in a fully Bayesian approachIn Population Approach Group Europe (PAGE)UppsalaGoogle Scholar
  42. Gelman A., Carlin JB., Stern HS., Rubin DB. Bayesian Data Analysis.(ed). Chapman Hall CRC, Boca Raton.Google Scholar
  43. Wade, JR., Kelman, AW., Howie, CA., Whiting, B. 1993Effect of misspecification of the absorption process on subsequent parameter estimation in population analysisJ. Pharmacokinet.Biopharm.21209222CrossRefPubMedGoogle Scholar
  44. Karlsson, MO., Jonsson, EN., Wiltse, CG., Wade, JR. 1998Assumption testing in population pharmacokinetic models: Illustrated with an analysis of moxonidine data from congestive heart failure patientsJ. Pharmacokinet. Biopharm.26207246CrossRefPubMedGoogle Scholar
  45. Lu, J., Gries, JM., Verotta, D., Sheiner, LB. 2001Selecting reliable pharmacokinetic data for explanatory analyses of clinical trials in the presence of possible noncomplianceJ.Pharmacokinet. Pharmacodyn.28343362CrossRefPubMedGoogle Scholar
  46. Chyka, PA., Seger, D. 1997Position Statement: Single-dose activated charcoal American Academy of Clinical Toxicology; European Association of Poisons Centres and Clinical ToxicologistsJ. Toxicol. Clin. Toxicol.35721741PubMedGoogle Scholar
  47. Neuvonen, PJ., Olkkola, KT. 1988Oral activated charcoal in the treatment of intoxications. Role of single and repeated dosesMed. Toxicol. Adverse. Drug. Exp.33358PubMedGoogle Scholar
  48. Chyka, PA. 1995Multiple-dose activated charcoal and enhancement of systemic drug clearance: summary of studies in animals and human volunteersJ. Toxicol. Clin. Toxicol.33399405PubMedCrossRefGoogle Scholar
  49. Overo, KF. 1978Preliminary studies of the kinetics of citalopram in manEur. J. Clin. Pharmacol.146973PubMedGoogle Scholar
  50. Bies, RR., Feng, Y., Lotrich FE., , Kirshner, MA., Roose, S., Kupfer, DJ., Pollock, BG. 2004Utility of sparse concentration sampling for citalopram in elderly clinical trial subjectsJ. Clin. Pharmacol.4413521359PubMedGoogle Scholar
  51. Deeks JJ., Altman DG., Bradburn MJ. (2001).Statistical methods for examining heterogeneity and combining results from several studies in meta-analysis. In Systematic Reviews in Health Care: Meta-analysis in context, Altman DG., Smith GD., Egger M. (eds.). BMJ Books, Manchester, UK, pp. 285–303,Google Scholar
  52. Bland, J.M., Kerry, S.M. 1997Statistics notes. Trials randomised in clustersBmj.315600PubMedGoogle Scholar
  53. Dansirikul, C., Choi, M., Duffull, S.B. 2005Estimation of pharmacokinetic parameters from non-compartmental variables using Microsoft Excel(R)Comput Biol Med.35389403CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2005

Authors and Affiliations

  • Lena E. Friberg
    • 1
  • Geoffrey K. Isbister
    • 2
  • L. Peter Hackett
    • 3
  • Stephen B. Duffull
    • 1
  1. 1.School of PharmacyUniversity of QueenslandBrishaneAustralia
  2. 2.Department of Clinical Toxicology and Pharmacology, Newcastle Mater Hospital and Tropical Toxinology Unit, Menzies School of Health ResearchCharles Darwin UniversityDarwinAustralia
  3. 3.Clinical Pharmacology and ToxicologyWestern Australian Centre for Pathology and Medical ResearchWestern AustraliaAustralia

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