Abstract
The clinical outcomes of three pivotal clinical trials with paliperidone ER, an atypical antipsychotic were prospectively predicted with a model using a limited amount of paliperidone ER pharmacokinetic data, human in vivo D2-receptor occupancy data and the generally accepted D2-receptor derived therapeutic window hypothesis. The latter was further substantiated using historical risperidone safety data. Model predictions guided the selection of the dose range for clinical trials, particularly with regards to the extremes of the dose range studied.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsReferences
Chue P, Eerdekens M, Augustyns I, Lachaux B, Molcan P, Eriksson L, Pretorius H, David AS (2005) Comparative efficacy and safety of long-acting risperidone and risperidone oral tablets. Eur Neuropsychopharmacol 15:111–117
Cirincione BB, Redman ML, Fiedler-Kelly J, Ludwig EA, Vermeulen A (2007) Population pharmacokinetics of paliperidone ER in healthy subjects and schizophrenia patients. Clin Pharmacol Ther 81(1 suppl):S19
Cox EH, Veyrat-Follet C, Beal SL, Fuseau E, Kenkare S, Sheiner LB (1999) A population pharmacokinetic-pharmacodynamic analysis of repeated measures time-to-event pharmacodynamic responses: the antiemetic effect of ondansetron. J Pharmacokinet Biopharm 27:625–644
Friberg LE, de Greef R, Kerbusch T, Karlsson M (2009) Modeling and simulation of the time course of asenapine exposure response and dropout patterns in acute schizophrenia. Clin Pharmacol Ther 86(1):84–91
Gefvert O, Eriksson B, Persson P, Helldin L, Bjorner A, Mannaert E, Remmerie B, Eerdekens M, Nyberg S (2005) Pharmacokinetics and D2 receptor occupancy of long-acting injectable risperidone (Risperdal Consta™) in patients with schizophrenia. Int J Neuropsychopharmacol 8:27–36
Hosmer DW, Lemeshow S, May S (2008) Applied survival analysis: regression modeling of time to event data, Wiley series in probability and statistics. Wiley, New York
Ito K, Hutmacher MM, Liu J, Qiu R, Frame B, Miller R (2008) Exposure-response analysis for spontaneously reported dizziness in pregabalin-treated patients with generalized anxiety disorder. Clin Pharmacol Ther 84(1):127–135
Kalbfleish JD, Prentice RL (2002) The statistical analysis of failure time data, Wiley series in probability and statistics. Wiley, New York
Kane JM, Eerdekens M, Lindenmayer J-P, Keith SJ, Lesem M, Karcher K (2003) Long-acting risperidone: efficacy and safety of the first long-acting atypical antipsychotic. Am J Psychiatry 160:1125–1132
Karlsson P, Dencker E, Nyberg S, Mannaert E, Boom S, Talluri K, Rossenu S, Eriksson B, Eerdekens M, Farde L (2005) Pharmacokinetics and dopamine D2 and serotonin 5-HT2A receptor occupancy of paliperidone in healthy subjects. Eur Neuropsychopharmacol 15(suppl 3):S386
Kimko HC, Reele SSB, Holford NHG, Peck CC (2000) Prediction of the outcome of a phase 3 clinical trial of an antischizophrenic agent (quetiapine fumarate) by simulation with a population pharmacokinetic and pharmacodynamic model. Clin Pharmacol Ther 68(5):568–577
Lindsey JK (2000) Dropouts in longitudinal studies: definitions and models. J Biopharm Stat 10:503–526
Mauri MC, Volonteri LS, Colasanti A, Fiorentini A, De Caspari IF, Bareggi SR (2007) Clinical pharmacokinetics of atypical antipsychotics. Clin Pharmacokinet 45(5):359–388
Medori R, Mannaert E, Gruender G (2006) Plasma antipsychotic concentration and receptor occupancy, with special focus on risperidone long-acting injectable. Eur Neuropsychopharmacol 16:233–240
Meltzer HY, Bobo WV, Nuamah IF, Lane R, Hough D, Kramer M, Eerdekens M (2008) Efficacy and tolerability of oral paliperidone extended release tablets in the treatment of acute schizophrenia: pooled data from three 6-week, placebo-controlled studies. J Clin Psychiatry 69(5):817–829
Nucci G, Gomeni R, Poggesi I (2009) Model-based approaches to increase efficiency of drug development in schizophrenia: a can’t miss opportunity. Expert Opin Drug Discov 4(8):837–856
Nyberg S, Farde L, Halldin C (1996) Test-retest reliability of central [11C]raclopride binding at high D2 receptor occupancy. Psychiatry Res 67:163–171
Nyberg S, Eriksson B, Oxenstierna G, Halldin C, Farde L (1999) Suggested minimal effective dose of risperidone based on PET-measured D2 and 5-HT2A receptor occupancy in schizophrenic patients. Am J Psychiatry 156(6):869–875
Ortega I, Perez-Ruixo JJ, Stuyckens K, Piotrovsky V, Vermeulen A (2010) Modeling the effectiveness of paliperidone ER and olanzapine in schizophrenia: meta-analysis of 3 randomized, controlled clinical trials. J Clin Pharmacol 50:293–310
Pani L, Pira L, Marchese G (2007) Antipsychotic efficacy: relationship to optimal D2-receptor occupancy. Eur Psychiatry 22:267–275
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2011 Springer Science+Business Media, LLC
About this chapter
Cite this chapter
De Ridder, F., Vermeulen, A. (2011). Balancing Efficacy and Safety in the Clinical Development of an Atypical Antipsychotic, Paliperidone Extended-Release. In: Kimko, H., Peck, C. (eds) Clinical Trial Simulations. AAPS Advances in the Pharmaceutical Sciences Series, vol 1. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-7415-0_16
Download citation
DOI: https://doi.org/10.1007/978-1-4419-7415-0_16
Published:
Publisher Name: Springer, New York, NY
Print ISBN: 978-1-4419-7414-3
Online ISBN: 978-1-4419-7415-0
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)
