Skip to main content
SpringerLink
Log in

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

  • Published:
Journal of Pharmacokinetics and Pharmacodynamics Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • GK. Isbister AH. Dawson IM. Whyte (2003) ArticleTitleFeasibility of prehospital treatment with activated charcoal: Who could we treat, who should we treat? Emerg. Med. J. 20 375–378 Occurrence Handle10.1136/emj.20.4.375 Occurrence Handle12835364 Occurrence Handle1:STN:280:DC%2BD3szgslWktw%3D%3D

    Article  PubMed  CAS  Google Scholar 

  • LF. Prescott P. Roscoe N. Wright SS. Brown (1971) ArticleTitlePlasma-paracetamol half-life and hepatic necrosis in patients with paracetamol overdosage Lancet. 1 519–522 Occurrence Handle4100436 Occurrence Handle1:CAS:528:DyaE3MXhtlykur0%3D

    PubMed  CAS  Google Scholar 

  • LF. Prescott RN. Illingworth JA. Critchley MJ. Stewart RD. Adam AT. Proudfoot (1979) ArticleTitleIntravenous N-acetylcystine: The treatment of choice for paracetamol poisoning Br. Med. J. 2 1097–1100 Occurrence Handle519312 Occurrence Handle1:CAS:528:DyaL3cXht1ejs7k%3D Occurrence Handle10.1136/bmj.2.6198.1097

    Article  PubMed  CAS  Google Scholar 

  • B. Bailey NA. Buckley DK. Amre (2004) ArticleTitleA meta-analysis of prognostic indicators to predict seizures, arrhythmias or death after tricyclic antidepressant overdose. J. Toxicol Clin. Toxicol. 42 877–888 Occurrence Handle10.1081/CLT-200035286 Occurrence Handle1:CAS:528:DC%2BD2cXot1ahs7c%3D

    Article  CAS  Google Scholar 

  • Dawson AH., Whyte IM. (2001). Therapeutic drug monitoring in drug overdose. Br. J. Clin. Pharmacol. 1:97S–102S

    Google Scholar 

  • DJ. Lunn N. Best A. Thomas J. Wakefield D. Spiegelhalter (2002) ArticleTitleBayesian analysis of population PK/PD models: General concepts and software J. Pharmacokinet.Pharmacodyn. 29 271–307 Occurrence Handle10.1023/A:1020206907668 Occurrence Handle12449499 Occurrence Handle1:CAS:528:DC%2BD38XntFGrt7w%3D

    Article  PubMed  CAS  Google Scholar 

  • S. Mu TM. Ludden (2003) ArticleTitleEstimation of population pharmacokinetic parameters in the presence of non-compliance J. Pharmacokinet. Pharmacodyn. 30 53–81 Occurrence Handle10.1023/A:1023297426153 Occurrence Handle12800807

    Article  PubMed  Google Scholar 

  • LC. Gurrin TJ. Moss DM. Sloboda ML. Hazelton JR. Challis JP. Newnham (2003) ArticleTitleUsing WinBUGS to fit nonlinear mixed models with an application to pharmacokinetic modelling of insulin response to glucose challenge in sheep exposed antenatally to glucocorticoids J. Biopharm Stat. 13 117–139 Occurrence Handle10.1081/BIP-120017730 Occurrence Handle12635907

    Article  PubMed  Google Scholar 

  • MD. Stickland CM. Kirkpatrick EJ. Begg SB. Duffull SJ. Oddie BA.. Darlow (2001) ArticleTitleAn extended interval dosing method for gentamicin in neonates J. Antimicrob Chemother. 48 887–893 Occurrence Handle10.1093/jac/48.6.887 Occurrence Handle11733474 Occurrence Handle1:CAS:528:DC%2BD38Xjt1eiug%3D%3D

    Article  PubMed  CAS  Google Scholar 

  • I. Meineke D. Turck (2003) ArticleTitlePopulation pharmacokinetic analysis of meloxicam in rheumatoid arthritis patients Br. J. Clin. Pharmacol. 55 32–38 Occurrence Handle10.1046/j.1365-2125.2003.01753.x Occurrence Handle12534638 Occurrence Handle1:CAS:528:DC%2BD3sXhsFOktb0%3D

    Article  PubMed  CAS  Google Scholar 

  • SB. Duffull CM. Kirkpatrick B. Green NH. Holford (2005) ArticleTitleAnalysis of population pharmacokinetic data using NONMEM and WinBUGS J. Biopharm. Stat. 15 53–73 Occurrence Handle15702605

    PubMed  Google Scholar 

  • MB. Keller (2000) ArticleTitleCitalopram therapy for depression: A review of 10 years of European experience and data from U.S. clinical trials J. Clin. Psychiatry. 61 896–908 Occurrence Handle11206593 Occurrence Handle1:CAS:528:DC%2BD3MXhtVChtrw%3D

    PubMed  CAS  Google Scholar 

  • GK. Isbister SJ. Bowe A. Dawson IM. Whyte (2004) ArticleTitleRelative toxicity of selective serotonin reuptake inhibitors (SSRIs) in overdose J. Toxicol. Clin. Toxicol. 42 277–285 Occurrence Handle15362595 Occurrence Handle1:CAS:528:DC%2BD2cXmvVClsbw%3D

    PubMed  CAS  Google Scholar 

  • C. Meuleman P. Jourdain M. Bellorini N. Sadeg J. Loiret N. Guillard B. Thebault F. Funck (2001) ArticleTitleCitalopram and Torsades de Pointes A case report. Arch. Mal. Coeur. Vaiss. 94 1021–1024 Occurrence Handle1:STN:280:DC%2BD3MrlslelsA%3D%3D

    CAS  Google Scholar 

  • M. Ostrom A. Eriksson J. Thorson O. Spigset (1996) ArticleTitleFatal overdose with citalopram Lancet. 348 339–340 Occurrence Handle10.1016/S0140-6736(05)64513-8 Occurrence Handle8709713 Occurrence Handle1:STN:280:DyaK28zht1artA%3D%3D

    Article  PubMed  CAS  Google Scholar 

  • P. Baumann F. Larsen (1995) ArticleTitleThe pharmacokinetics of citalopram Rev. Contemp. Pharmacother. 6 287–295 Occurrence Handle1:CAS:528:DyaK2sXnvFylsg%3D%3D

    CAS  Google Scholar 

  • M. Reis J. Lundmark F. Bengtsson (2003) ArticleTitleTherapeutic drug monitoring of racemic citalopram: A 5-year experience in Sweden, 1992–1997 Ther. Drug. Monit. 25 183–191 Occurrence Handle10.1097/00007691-200304000-00007 Occurrence Handle12657912 Occurrence Handle1:CAS:528:DC%2BD3sXitlKitL8%3D

    Article  PubMed  CAS  Google Scholar 

  • Y. Le Bloc’h B. Woggon H. Weissenrieder M. Brawand-Amey J. Spagnoli CB. Eap P. Baumann (2003) ArticleTitleRoutine therapeutic drug monitoring in patients treated with 10–360 mg/day citalopram Ther. Drug. Monit. 25 600–608 Occurrence Handle14508384 Occurrence Handle1:CAS:528:DC%2BD3sXnsFanurs%3D

    PubMed  CAS  Google Scholar 

  • K. Brosen CA. Naranjo (2001) ArticleTitleReview of pharmacokinetic and pharmacodynamic interaction studies with citalopram Eur. Neuropsychopharmacol. 11 275–283 Occurrence Handle11532381 Occurrence Handle1:CAS:528:DC%2BD3MXmt1ygsb0%3D

    PubMed  CAS  Google Scholar 

  • GM. Cooper DG. Le Couteur D. Richardson NA. Buckley (2005) ArticleTitleA randomised clinical trial of activated charcoal for the routine management of drug overdose QJM. 98 655–660 Occurrence Handle10.1093/qjmed/hci102 Occurrence Handle16040667 Occurrence Handle1:STN:280:DC%2BD2MvlsVSrsg%3D%3D

    Article  PubMed  CAS  Google Scholar 

  • O. Lapatto-Reiniluoto KT. Kivisto PJ. Neuvonen (1999) ArticleTitleEffect of activated charcoal alone or given after gastric lavage in reducing the absorption of diazepam, ibuprofen and citalopram Br. J. Clin. Pharmacol. 48 148–153 Occurrence Handle10.1046/j.1365-2125.1999.00995.x Occurrence Handle10417490 Occurrence Handle1:CAS:528:DyaK1MXlslyjtbg%3D

    Article  PubMed  CAS  Google Scholar 

  • RJ. Milne KL. Goa (1991) ArticleTitleCitalopram A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in depressive illness Drugs. 41 450–477 Occurrence Handle1711447 Occurrence Handle1:CAS:528:DyaK3MXktVSjtLs%3D

    PubMed  CAS  Google Scholar 

  • J. Rampono JH. Kristensen LP. Hackett M. Paech R. Kohan KF. Ilett (2000) ArticleTitleCitalopram and demethylcitalopram in humaR. milk; distribution, excretion and effects in breast fed infants Br. J. Clin. Pharmacol. 50 263–268 Occurrence Handle10.1046/j.1365-2125.2000.00253.x Occurrence Handle10971311 Occurrence Handle1:CAS:528:DC%2BD3cXnt1Kgur8%3D

    Article  PubMed  CAS  Google Scholar 

  • P. Kragh-Sorensen KF. Overo OL. Petersen K. Jensen W. Parnas (1981) ArticleTitleThe kinetics of citalopram: Single and multiple dose studies in man. Acta Pharmacol Toxicol. (Copenh). 48 53–60 Occurrence Handle1:STN:280:DyaL3M7otVCmtQ%3D%3D

    CAS  Google Scholar 

  • K. Fredricson Overo (1982) ArticleTitleKinetics of citalopram in man; plasma levels in patients Prog. Neuropsychopharmacol. Biol. Psychiatry. 6 311–318 Occurrence Handle6959195 Occurrence Handle1:STN:280:DyaL3s%2Fms1ahsw%3D%3D

    PubMed  CAS  Google Scholar 

  • K. Fredricson Overo B. Toft L. Christophersen JP. Gylding-Sabroe (1985) ArticleTitleKinetics of citalopram in elderly patients Psychopharmacology (Berl.) 86 253–257

    Google Scholar 

  • SH. Sindrup K. Brosen MG. Hansen T. Aaes-Jorgensen KF. Overo LF. Gram (1993) ArticleTitlePharmacokinetics of citalopram in relation to the sparteine and the mephenytoin oxidation polymorphisms Ther. Drug. Monit. 15 11–17 Occurrence Handle8451774 Occurrence Handle1:CAS:528:DyaK3sXhvVaksLc%3D

    PubMed  CAS  Google Scholar 

  • K. Laine M. Anttila E. Heinonen A. Helminen R. Huupponen O. Maki-Ikola K. Reinikainen M. Scheinin (1997) ArticleTitleLack of adverse interactions between concomitantly administered selegiline and citalopram Clin. Neuropharmacol. 20 419–433 Occurrence Handle9331518 Occurrence Handle1:CAS:528:DyaK2sXmslWqtbs%3D

    PubMed  CAS  Google Scholar 

  • M. Priskorn F. Larsen A. Segonzac M. Moulin (1997) ArticleTitlePharmacokinetic interaction study of citalopram and cimetidine in healthy subjects Eur. J. Clin. Pharmacol. 52 241–242 Occurrence Handle10.1007/s002280050282 Occurrence Handle9218934 Occurrence Handle1:CAS:528:DyaK2sXktF2itL0%3D

    Article  PubMed  CAS  Google Scholar 

  • J. Sidhu M. Priskorn M. Poulsen A. Segonzac G. Grollier F. Larsen (1997) ArticleTitleSteady-state pharmacokinetics of the enantiomers of citalopram and its metabolites in humans Chirality. 9 686–692 Occurrence Handle10.1002/(SICI)1520-636X(1997)9:7<686::AID-CHIR9>3.0.CO;2-5 Occurrence Handle9366029 Occurrence Handle1:CAS:528:DyaK2sXnt1Ggsrs%3D

    Article  PubMed  CAS  Google Scholar 

  • P. Joffe FS. Larsen V. Pedersen H. Ring-Larsen T. Aaes-Jorgensen J. Sidhu (1998) ArticleTitleSingle-dose pharmacokinetics of citalopram in patients with moderate renal insufficiency or hepatic cirrhosis compared with healthy subjects Eur. J.Clin. Pharmacol. 54 237–242 Occurrence Handle10.1007/s002280050452 Occurrence Handle9681666 Occurrence Handle1:CAS:528:DyaK1cXjt1Olurg%3D

    Article  PubMed  CAS  Google Scholar 

  • O. Spigset S. Hagg B. Stegmayr R. Dahlqvist (2000) ArticleTitleCitalopram pharmacokinetics in patients with chronic renal failure and the effect of haemodialysis Eur. J. Clin. Pharmacol. 56 699–703 Occurrence Handle10.1007/s002280000205 Occurrence Handle11214779 Occurrence Handle1:CAS:528:DC%2BD3MXlt1Kmtg%3D%3D

    Article  PubMed  CAS  Google Scholar 

  • M. Gutierrez W. Abramowitz (2000) ArticleTitleSteady-state pharmacokinetics of citalopram in young and elderly subjects Pharmacotherapy. 20 1441–1447 Occurrence Handle11130216 Occurrence Handle1:CAS:528:DC%2BD3cXptVegtLg%3D

    PubMed  CAS  Google Scholar 

  • MM. Gutierrez W. Abramowitz (2000) ArticleTitlePharmacokinetic comparison of oral solution and tablet formulations of citalopram: A single-dose, randomized, crossover study Clin. Ther. 22 1525–1532 Occurrence Handle10.1016/S0149-2918(00)83050-7 Occurrence Handle11192143 Occurrence Handle1:CAS:528:DC%2BD3MXlt1Cruw%3D%3D

    Article  PubMed  CAS  Google Scholar 

  • M. Gutierrez W. Abramowitz (2001) ArticleTitleLack of effect of a single dose of ketoconazole on the pharmacokinetics of citalopram Pharmacotherapy. 21 163–168 Occurrence Handle11213852 Occurrence Handle1:CAS:528:DC%2BD3MXktVGqtrc%3D

    PubMed  CAS  Google Scholar 

  • BN. Yu GL. Chen N. He DS. Ouyang XP. Chen ZQ. Liu HH. Zhou (2003) ArticleTitlePharmacokinetics of citalopram in relation to genetic polymorphism of CYP2C19 Drug. Metab. Dispos. 31 1255–1259 Occurrence Handle10.1124/dmd.31.10.1255 Occurrence Handle12975335 Occurrence Handle1:CAS:528:DC%2BD3sXnslKitrg%3D

    Article  PubMed  CAS  Google Scholar 

  • DJ. Spiegelhalter A. Thomas NG. Best (2003) WinBUGS Version 1.4 User Manual Medical Research Council Biostatics Unit Cambridge

    Google Scholar 

  • D. Soy SL. Beal LB. Sheiner (2004) ArticleTitlePopulation one-compartment pharmacokinetic analysis with missing dosage data Clin.Pharmacol.Ther. 76 441–451 Occurrence Handle10.1016/j.clpt.2004.07.010 Occurrence Handle15536459 Occurrence Handle1:CAS:528:DC%2BD2cXpslWnt7c%3D

    Article  PubMed  CAS  Google Scholar 

  • A. Gelman C. Rubin (1992) ArticleTitleInference from iterative simlation using multiple sequences Stat. Sci. 7 457–511

    Google Scholar 

  • DJ. Spiegelhalter NG. Best BR. Carlin A. Linde ParticleVan der (2002) ArticleTitleBayesian measures of model complexity and fit J. Roy.Stat. Soc. Ser. B-Stat. Meth. 64 583–616

    Google Scholar 

  • LE. Friberg C. Dansirikul SB. Duffull (2004) Simultaneous fit of competing models as a model discrimination tool in a fully Bayesian approach In Population Approach Group Europe (PAGE) Uppsala

    Google Scholar 

  • Gelman A., Carlin JB., Stern HS., Rubin DB. Bayesian Data Analysis.(ed). Chapman Hall CRC, Boca Raton.

  • JR. Wade AW. Kelman CA. Howie B. Whiting (1993) ArticleTitleEffect of misspecification of the absorption process on subsequent parameter estimation in population analysis J. Pharmacokinet.Biopharm. 21 209–222 Occurrence Handle10.1007/BF01059771 Occurrence Handle8229681 Occurrence Handle1:CAS:528:DyaK2cXhsFaqtLw%3D

    Article  PubMed  CAS  Google Scholar 

  • MO. Karlsson EN. Jonsson CG. Wiltse JR. Wade (1998) ArticleTitleAssumption testing in population pharmacokinetic models: Illustrated with an analysis of moxonidine data from congestive heart failure patients J. Pharmacokinet. Biopharm. 26 207–246 Occurrence Handle10.1023/A:1020561807903 Occurrence Handle9795882 Occurrence Handle1:CAS:528:DyaK1cXntVKqurY%3D

    Article  PubMed  CAS  Google Scholar 

  • J. Lu JM. Gries D. Verotta LB. Sheiner (2001) ArticleTitleSelecting reliable pharmacokinetic data for explanatory analyses of clinical trials in the presence of possible noncompliance J.Pharmacokinet. Pharmacodyn. 28 343–362 Occurrence Handle10.1023/A:1011582713692 Occurrence Handle11677931 Occurrence Handle1:CAS:528:DC%2BD3MXot1GjsLw%3D

    Article  PubMed  CAS  Google Scholar 

  • PA. Chyka D. Seger (1997) ArticleTitlePosition Statement: Single-dose activated charcoal American Academy of Clinical Toxicology; European Association of Poisons Centres and Clinical Toxicologists J. Toxicol. Clin. Toxicol. 35 721–741 Occurrence Handle9482427 Occurrence Handle1:STN:280:DyaK1c7ktFGgsw%3D%3D

    PubMed  CAS  Google Scholar 

  • PJ. Neuvonen KT. Olkkola (1988) ArticleTitleOral activated charcoal in the treatment of intoxications. Role of single and repeated doses Med. Toxicol. Adverse. Drug. Exp. 3 33–58 Occurrence Handle3285126 Occurrence Handle1:CAS:528:DyaL1cXhvVWnu7Y%3D

    PubMed  CAS  Google Scholar 

  • PA. Chyka (1995) ArticleTitleMultiple-dose activated charcoal and enhancement of systemic drug clearance: summary of studies in animals and human volunteers J. Toxicol. Clin. Toxicol. 33 399–405 Occurrence Handle7650764 Occurrence Handle1:CAS:528:DyaK2MXoslSltb8%3D Occurrence Handle10.3109/15563659509013748

    Article  PubMed  CAS  Google Scholar 

  • KF. Overo (1978) ArticleTitlePreliminary studies of the kinetics of citalopram in man Eur. J. Clin. Pharmacol. 14 69–73 Occurrence Handle729609 Occurrence Handle1:STN:280:DyaE1M%2FosFOqsQ%3D%3D

    PubMed  CAS  Google Scholar 

  • RR. Bies Y. Feng Lotrich FE. MA. Kirshner S. Roose DJ. Kupfer BG. Pollock (2004) ArticleTitleUtility of sparse concentration sampling for citalopram in elderly clinical trial subjects J. Clin. Pharmacol. 44 1352–1359 Occurrence Handle15545305 Occurrence Handle1:CAS:528:DC%2BD2cXhtFCht7rE

    PubMed  CAS  Google Scholar 

  • 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,

  • J.M. Bland S.M. Kerry (1997) ArticleTitleStatistics notes. Trials randomised in clusters Bmj. 315 600 Occurrence Handle9302962 Occurrence Handle1:STN:280:DyaK2svkvVKgtA%3D%3D

    PubMed  CAS  Google Scholar 

  • C. Dansirikul M. Choi S.B. Duffull (2005) ArticleTitleEstimation of pharmacokinetic parameters from non-compartmental variables using Microsoft Excel(R) Comput Biol Med. 35 389–403 Occurrence Handle10.1016/j.compbiomed.2004.02.008 Occurrence Handle15767115 Occurrence Handle1:CAS:528:DC%2BD2MXit1eqsrY%3D

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. School of Pharmacy, University of Queensland, Brishane, Australia

    Lena E. Friberg & Stephen B. Duffull

  2. Department of Clinical Toxicology and Pharmacology, Newcastle Mater Hospital and Tropical Toxinology Unit, Menzies School of Health Research, Charles Darwin University, Darwin, Australia

    Geoffrey K. Isbister

  3. Clinical Pharmacology and Toxicology, Western Australian Centre for Pathology and Medical Research, Western Australia, Australia

    L. Peter Hackett

Authors
  1. Lena E. Friberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Geoffrey K. Isbister
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. L. Peter Hackett
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Stephen B. Duffull
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Friberg, L.E., Isbister, G.K., Hackett, L.P. et al. The Population Pharmacokinetics of Citalopram After Deliberate Self-Poisoning: A Bayesian Approach. J Pharmacokinet Pharmacodyn 32, 571–605 (2005). https://doi.org/10.1007/s10928-005-0022-6

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10928-005-0022-6

Keywords

Search

Navigation