In silico characterization of clozapine pharmacokinetics in different patient populations.
Abstract Clozapine is an atypical antipsychotic drug with a narrow therapeutic margin (0.35 mg/L – 0.60 mg/L) and with a risk of rare but high-risk side effects, which is why it is necessary its monitoration. With the advance of the design of applicatoins and computer programs, pharmacokinetic simulations of different molecules can be performed to estimate their behavior in the human body. The aim of this study is to perform varios simulations in silico, modifying clearance parameters according to age, sex or smoking habit, comparing the results obtained with population-based trials. SymCYP® v16.1 is a software that has libraries of physicochemical data on varios substrates and population data that, together with the pharmacokinetic data obtained from the literatura review, allow the simulation of pharmacokinetic curves and pharmacokinetic parameters of clozapine in a given population. The results obtained show significant differences in the serum concentrations of clozapine according to sex and age, with dose adjustments being necessary to maintain concentrations within safe levels. In conclusión, this work offers a new visión to the development of new molecules thanks to the use of massive in silico simulations.
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Agencia Española del Medicamento y Productos Sanitarios. Ficha técnica de Clozaril®. [Internet] Consultado 20 abril 2018. Disponible en: https://www.aemps.gob.es/home.htm
Castberg I, Westin AA, Skogvol E, Spigset O. Effects of age and gender on the serum levels of clozapine, olanzapine, risperidone, and quetiapine. Acta Psychiatr Scand. 2017;1:1-10. - https://doi.org/10.1111/acps.12794
Drugbank.ca. (2018). Clozapine - DrugBank. [Internet] Consultado 18 abril 2018. Disponible en: https://www.drugbank.ca/drugs/DB00363
Haring C, Meise U, Humpei C, Saria A, Fleischhacker WW, Hinterhuber H. Dose-related plasma levels of clozapine: influence of smoking behaviour, sex and age. J Psychopharmacol. 1989;99:S38-S40. - https://doi.org/10.1007/BF00442557
Ismail Z, Wessels AM et al. Age and sex impact clozapine plasma concentrations in inpatients and outpatients with schizophrenia. Am J Geriatr Psychiatry. 2012;20(1):53-60. - https://doi.org/10.1097/JGP.0b013e3182118318
Jamei M, Marciniak S et al. The simcyp population based simulator: architecture, implementation, and quality assurance. In Silico Pharmacology. 2013;1(9):1-14. - https://doi.org/10.1186/2193-9616-1-9
Jann MW, Grisley SR, Gray EC, Chan WH. Pharmacokinetics and pharmacodynamics of clozapine. Clin Pharmacokinetic. 1993;24(2):161-176. - https://doi.org/10.2165/00003088-199324020-00005
Jerling M, Merlé Y, Mentré F, Mallet A. Population pharmacokinetics of clozapine evaluated with the nonparametric maximum likelihood method. Br J Clin Pharmacol. 1997;44:447-453. - https://doi.org/10.1046/j.1365-2125.1997.t01-1-00606.x
Ng W, Uchida H et al. Clozapine exposure and the impact of smoking and gender: a population pharmacokinetic study. The Drug Monit. 2009;31(3):360-366. - https://doi.org/10.1097/FTD.0b013e31819c7037
Rostami-Hodjegan A, Amin AM, Spencer EP, Lennard MS, Tucker GT, Flanagan RJ. Influence of dose, cigarette smoking, age, sex, and metabolic activity on plasma clozapine concentrations: a predictive model and nomograms to aid clozapine dose adjustment and to asses compliance in individual patients. J Psychopharmacol. 2004;24(1):70-78. - https://doi.org/10.1097/01.jcp.0000106221.36344.4d
Scandlyn MJ , Stuart EC, Rosengren RJ. Sex-specific differences in CYP450 isoforms in humans. Drug Metab Toxicol. 2008;4(4):413-424. - https://doi.org/10.1517/17425255.4.4.413
Simcyp simulator (v.16) [software] 2011-2017. Princeton: Certara USA, Inc. Obtenido de: https://support.certara.com
Tsuda Y, Saruwatari J, Yasui-Furukori N. Meta-analysis: the effects of smoking on the disposition of two commonly used antipsychotic agents, olanzapine and clozapine. BMJ Open. 2014;4:1-9. - https://doi.org/10.1136/bmjopen-2013-004216
XLSTAT-Base [software] 2017. Barcelona: Addinsoft España. Obtenido de: https://www.xlstat.com/es/
Zanger UM, Schwab M. Cytochrome P450 enzymes in drug metabolism: Regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Therapeut. 2013;138:103-141. - https://doi.org/10.1016/j.pharmthera.2012.12.007
Castberg I, Westin AA, Skogvol E, Spigset O. Effects of age and gender on the serum levels of clozapine, olanzapine, risperidone, and quetiapine. Acta Psychiatr Scand. 2017;1:1-10. - https://doi.org/10.1111/acps.12794
Drugbank.ca. (2018). Clozapine - DrugBank. [Internet] Consultado 18 abril 2018. Disponible en: https://www.drugbank.ca/drugs/DB00363
Haring C, Meise U, Humpei C, Saria A, Fleischhacker WW, Hinterhuber H. Dose-related plasma levels of clozapine: influence of smoking behaviour, sex and age. J Psychopharmacol. 1989;99:S38-S40. - https://doi.org/10.1007/BF00442557
Ismail Z, Wessels AM et al. Age and sex impact clozapine plasma concentrations in inpatients and outpatients with schizophrenia. Am J Geriatr Psychiatry. 2012;20(1):53-60. - https://doi.org/10.1097/JGP.0b013e3182118318
Jamei M, Marciniak S et al. The simcyp population based simulator: architecture, implementation, and quality assurance. In Silico Pharmacology. 2013;1(9):1-14. - https://doi.org/10.1186/2193-9616-1-9
Jann MW, Grisley SR, Gray EC, Chan WH. Pharmacokinetics and pharmacodynamics of clozapine. Clin Pharmacokinetic. 1993;24(2):161-176. - https://doi.org/10.2165/00003088-199324020-00005
Jerling M, Merlé Y, Mentré F, Mallet A. Population pharmacokinetics of clozapine evaluated with the nonparametric maximum likelihood method. Br J Clin Pharmacol. 1997;44:447-453. - https://doi.org/10.1046/j.1365-2125.1997.t01-1-00606.x
Ng W, Uchida H et al. Clozapine exposure and the impact of smoking and gender: a population pharmacokinetic study. The Drug Monit. 2009;31(3):360-366. - https://doi.org/10.1097/FTD.0b013e31819c7037
Rostami-Hodjegan A, Amin AM, Spencer EP, Lennard MS, Tucker GT, Flanagan RJ. Influence of dose, cigarette smoking, age, sex, and metabolic activity on plasma clozapine concentrations: a predictive model and nomograms to aid clozapine dose adjustment and to asses compliance in individual patients. J Psychopharmacol. 2004;24(1):70-78. - https://doi.org/10.1097/01.jcp.0000106221.36344.4d
Scandlyn MJ , Stuart EC, Rosengren RJ. Sex-specific differences in CYP450 isoforms in humans. Drug Metab Toxicol. 2008;4(4):413-424. - https://doi.org/10.1517/17425255.4.4.413
Simcyp simulator (v.16) [software] 2011-2017. Princeton: Certara USA, Inc. Obtenido de: https://support.certara.com
Tsuda Y, Saruwatari J, Yasui-Furukori N. Meta-analysis: the effects of smoking on the disposition of two commonly used antipsychotic agents, olanzapine and clozapine. BMJ Open. 2014;4:1-9. - https://doi.org/10.1136/bmjopen-2013-004216
XLSTAT-Base [software] 2017. Barcelona: Addinsoft España. Obtenido de: https://www.xlstat.com/es/
Zanger UM, Schwab M. Cytochrome P450 enzymes in drug metabolism: Regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Therapeut. 2013;138:103-141. - https://doi.org/10.1016/j.pharmthera.2012.12.007
García, A., & Santos, M. D. (2019). In silico characterization of clozapine pharmacokinetics in different patient populations. FarmaJournal, 4(2), 7–18. https://doi.org/10.14201/fj201942718
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