Pharmacokinetic Correlates of Once-Monthly Paliperidone Palmitate-Related Adverse Drug Reactions

Abstract

Objective

The objective of this study was to investigate associations between pharmacokinetic correlates and once-monthly paliperidone palmitate (PP1M)-related adverse drug reactions (ADRs).

Methods

Plasma concentrations and dose-adjusted plasma concentrations (‘concentration-by-dose’ [C/D]) of paliperidone from a naturalistic therapeutic drug monitoring database of PP1M-treated patients were compared between patients with ADRs, classified according to the Udvalg for Kliniske Undersogelser side-effect rating scales categories, and patients without ADRs. Analyses included non-parametric tests and a logistic regression model with a significance level set at 0.05.

Results

In 172 patients, we found no differences in sex, age, smoking, body mass index, PP1M dose, paliperidone plasma concentrations, and C/D values (p > 0.05) between 44 patients with and 128 patients without PP1M-related ADRs. We did not detect differences when specifying for different types of ADRs (p > 0.05). Injection intervals were shorter in patients with vs patients without ADRs (p = 0.03). The logistic regression did not report effects for sex, plasma concentrations, or C/D values (p > 0.05). Post hoc analyses in male patients receiving PP1M every 28 weeks reported higher paliperidone concentrations and C/D values in patients with vs without ADRs (p = 0.049 and p = 0.022). Within the group of male patients, we found an odds ratio of 3.07 for PP1M-associated ADRs in patients with C/D values above 7.7 (ng/mL)/(mg/day).

Conclusions

Our findings did not reveal distinct patterns of paliperidone concentrations in patients with PP1M-related ADRs. However, male patients receiving PP1M every 28 days with C/D values higher than 7.7 (ng/mL)/(mg/day) showed a higher risk for ADRs, implying that therapeutic drug monitoring may be useful in assessing the risk of PP1M-related ADRs.

This is a preview of subscription content, access via your institution.

References

  1. 1.

    Schoretsanitis G, Spina E, Hiemke C, de Leon J. A systematic review and combined analysis of therapeutic drug monitoring studies for long-acting risperidone. Expert Rev Clin Pharmacol. 2017;10(9):965–81.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  2. 2.

    Schoretsanitis G, Spina E, Hiemke C, de Leon J. A systematic review and combined analysis of therapeutic drug monitoring studies for oral paliperidone. Expert Rev Clin Pharmacol. 2018;11(6):625–39.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  3. 3.

    Corena-McLeod M. Comparative pharmacology of risperidone and paliperidone. Drugs R D. 2015;15(2):163–74.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  4. 4.

    Netley J, Gaul J, Ferguson C. Evaluation of prescribing patterns of long-acting injectable antipsychotics within a community health system. J Clin Psychopharmacol. 2019;39(5):494–8.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  5. 5.

    Barbui C, Bertolini F, Bartoli F, Calandra C, Callegari C, Carra G, et al. Reasons for initiating long-acting antipsychotics in psychiatric practice: findings from the STAR Network Depot Study. Ther Adv Psychopharmacol. 2020. https://doi.org/10.1177/2045125320978102.

    Article  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Gaviria AM, Franco J, Rico G, Muntane G, Saez C, Sanchez-Gistau V, et al. Noninterventional, naturalistic, retrospective study to describe prescription patterns of long-acting injectable antipsychotics and the impact of introducing a new atypical antipsychotic in the Spanish province of Tarragona catchment area. Prim Care Companion CNS Disord. 2017. https://doi.org/10.4088/PCC.16m02044.

    Article  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Magnusson MO, Samtani MN, Plan EL, Jonsson EN, Rossenu S, Vermeulen A, et al. Population pharmacokinetics of a novel once-every 3 months intramuscular formulation of paliperidone palmitate in patients with schizophrenia. Clin Pharmacokinet. 2017;56(4):421–33.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  8. 8.

    Samtani MN, Vermeulen A, Stuyckens K. Population pharmacokinetics of intramuscular paliperidone palmitate in patients with schizophrenia: a novel once-monthly, long-acting formulation of an atypical antipsychotic. Clin Pharmacokinet. 2009;48(9):585–600.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  9. 9.

    Ravenstijn P, Remmerie B, Savitz A, Samtani MN, Nuamah I, Chang CT, et al. Pharmacokinetics, safety, and tolerability of paliperidone palmitate 3-month formulation in patients with schizophrenia: a phase-1, single-dose, randomized, open-label study. J Clin Pharmacol. 2016;56(3):330–9.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  10. 10.

    Schoretsanitis G, Spina E, Hiemke C, de Leon J. A systematic review and combined analysis of therapeutic drug monitoring studies for long-acting paliperidone. Expert Rev Clin Pharmacol. 2018;11(12):1237–53.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  11. 11.

    Coppola D, Liu Y, Gopal S, Remmerie B, Samtani MN, Hough DW, et al. A one-year prospective study of the safety, tolerability and pharmacokinetics of the highest available dose of paliperidone palmitate in patients with schizophrenia. BMC Psychiatry. 2012;12:26.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  12. 12.

    Hiemke C, Bergemann N, Clement HW, Conca A, Deckert J, Domschke K, et al. Consensus guidelines for therapeutic drug monitoring in neuropsychopharmacology: update 2017. Pharmacopsychiatry. 2018;51(1–02):9–62.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Schoretsanitis G, Kane JM, Correll CU, Marder SR, Citrome L, Newcomer JW, et al. Blood levels to optimize antipsychotic treatment in clinical practice: a joint consensus statement of the American Society of Clinical Psychopharmacology and the Therapeutic Drug Monitoring Task Force of the Arbeitsgemeinschaft fur Neuropsychopharmakologie und Pharmakopsychiatrie. J Clin Psychiatry. 2020. https://doi.org/10.4088/JCP.19cs13169.

    Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Korell J, Green B, Remmerie B, Vermeulen A. Determination of plasma concentration reference ranges for risperidone and paliperidone. CPT Pharmacometrics Syst Pharmacol. 2017;6(9):589–95.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  15. 15.

    Schoretsanitis G, Baumann P, Conca A, Dietmaier O, Giupponi G, Grunder G, et al. Therapeutic drug monitoring of long-acting injectable antipsychotic drugs. Ther Drug Monit. 2021;43(1):79–102.

    PubMed  Article  PubMed Central  Google Scholar 

  16. 16.

    Schoretsanitis G, de Leon J, Haen E, Stegmann B, Hiemke C, Grunder G, et al. Pharmacokinetics of risperidone in different application forms: comparing long-acting injectable and oral formulations. Eur Neuropsychopharmacol. 2018;28(1):130–7.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  17. 17.

    Tveito M, Smith RL, Molden E, Haslemo T, Refsum H, Hartberg C, et al. Age impacts olanzapine exposure differently during use of oral versus long-acting injectable formulations: an observational study including 8,288 patients. J Clin Psychopharmacol. 2018;38(6):570–6.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  18. 18.

    Gefvert O, Eriksson B, Persson P, Helldin L, Bjorner A, Mannaert E, et al. Pharmacokinetics and D2 receptor occupancy of long-acting injectable risperidone (Risperdal Consta) in patients with schizophrenia. Int J Neuropsychopharmacol. 2005;8(1):27–36.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  19. 19.

    Remington G, Mamo D, Labelle A, Reiss J, Shammi C, Mannaert E, et al. A PET study evaluating dopamine D2 receptor occupancy for long-acting injectable risperidone. Am J Psychiatry. 2006;163(3):396–401.

    PubMed  Article  PubMed Central  Google Scholar 

  20. 20.

    Arakawa R, Ito H, Takano A, Takahashi H, Morimoto T, Sassa T, et al. Dose-finding study of paliperidone ER based on striatal and extrastriatal dopamine D2 receptor occupancy in patients with schizophrenia. Psychopharmacology. 2008;197(2):229–35.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  21. 21.

    Pani L, Pira L, Marchese G. Antipsychotic efficacy: relationship to optimal D2-receptor occupancy. Eur Psychiatry. 2007;22(5):267–75.

    PubMed  Article  PubMed Central  Google Scholar 

  22. 22.

    Uchida H, Takeuchi H, Graff-Guerrero A, Suzuki T, Watanabe K, Mamo DC. Dopamine D2 receptor occupancy and clinical effects: a systematic review and pooled analysis. J Clin Psychopharmacol. 2011;31(4):497–502.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  23. 23.

    Uchida H, Takeuchi H, Graff-Guerrero A, Suzuki T, Watanabe K, Mamo DC. Predicting dopamine D(2) receptor occupancy from plasma levels of antipsychotic drugs: a systematic review and pooled analysis. J Clin Psychopharmacol. 2011;31(3):318–25.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  24. 24.

    Kramer M, Litman R, Hough D, Lane R, Lim P, Liu Y, et al. Paliperidone palmitate, a potential long-acting treatment for patients with schizophrenia. Results of a randomized, double-blind, placebo-controlled efficacy and safety study. Int J Neuropsychopharmacol. 2010;13(5):635–47.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  25. 25.

    Si T, Su Y, Liu Y, Zhang H, Li H, Rui Q, et al. Pharmacokinetics and tolerability of paliperidone palmitate injection in Chinese subjects. Hum Psychopharmacol. 2014;29(2):203–10.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  26. 26.

    Mauri MC, Paletta S, Di Pace C, Reggiori A, Rovera C, Fiorentini A, et al. Paliperidone long-acting plasma level monitoring and a new method of evaluation of clinical stability. Pharmacopsychiatry. 2017;50(4):145–51.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  27. 27.

    Mauri MC, Reggiori A, Minutillo A, Franco G, Pace CD, Paletta S, et al. Paliperidone LAI and aripiprazole LAI plasma level monitoring in the prophylaxis of bipolar disorder type I with manic predominance. Pharmacopsychiatry. 2020;53(5):209–19.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  28. 28.

    Rossenu S, Cleton A, Hough D, Crauwels H, Vandebosch A, Berwaerts J, et al. Pharmacokinetic profile after multiple deltoid or gluteal intramuscular injections of paliperidone palmitate in patients with schizophrenia. Clin Pharmacol Drug Dev. 2015;4(4):270–8.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  29. 29.

    Santoro V, Bruno A, Muscatello MR, D’Amico G, Nucifora D, Zoccali R, et al. Pharmacokinetics of paliperidone palmitate in schizophrenic patients: data from a routine therapeutic drug monitoring service. Clin Ther. 2017;39(8S):e50.

    Article  Google Scholar 

  30. 30.

    Zipursky Z, Huynh H, Agid O, Kiang M, Remington G. Can long-acting injectable paliperidone dosing be optimized with plasma levels measurements? Schizophr Bull. 2019;44:S415.

    Article  Google Scholar 

  31. 31.

    Verdoux H, Pambrun E, Tournier M, Bezin J, Pariente A. Antipsychotic long-acting injections: a community-based study from 2007 to 2014 of prescribing trends and characteristics associated with initiation. Schizophr Res. 2016;178(1–3):58–63.

    PubMed  Article  PubMed Central  Google Scholar 

  32. 32.

    Fischer-Barnicol D, Lanquillon S, Haen E, Zofel P, Koch HJ, Dose M, et al. Typical and atypical antipsychotics: the misleading dichotomy. Results from the Working Group “Drugs in Psychiatry” (AGATE). Neuropsychobiology. 2008;57(12):80–7.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  33. 33.

    US Food and Drug Administration. Drug development and drug interactions: table of substrates, inhibitors and inducers. 2014. http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm. Accessed 2 Oct 2020.

  34. 34.

    Hoy SM, Scott LJ, Keating GM. Intramuscular paliperidone palmitate. CNS Drugs. 2010;24(3):227–44.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  35. 35.

    Lingjaerde O, Ahlfors UG, Bech P, Dencker SJ, Elgen K. The UKU side effect rating scale: a new comprehensive rating scale for psychotropic drugs and a cross-sectional study of side effects in neuroleptic-treated patients. Acta Psychiatr Scand Suppl. 1987;334:1–100.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  36. 36.

    Schoretsanitis G, Stegmann B, Hiemke C, Gründer G, Schruers KR, Walther S, et al. Pharmacokinetic patterns of risperidone-associated adverse drug reactions. Eur J Clin Pharmacol. 2016;72(9):1091–8.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  37. 37.

    Bader W, Melchner D, Nonenmacher T, Haen E. Determination of five commonly used antipsychotics in human serum by high performance-liquid chromatography (HPLC) and electrochemical detection. Pharmacopsychiatry. 2005;38(01):4.

    Article  Google Scholar 

  38. 38.

    Paul L, Musshoff F, Aebi B, Auwärter V, Krämer T, Peters F, et al. Richtlinie der GTFCh zur Qualitätssicherung bei forensisch-toxikologischen Untersuchungen. Toxichem Krimtech. 2009;76(3):142–76.

    Google Scholar 

  39. 39.

    US Food and Drug Administration. Guidance for industry on biomedical method validation. 2001. http://www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugs-gen/documents/document/ucm070107.pdf. Accessed 2 Oct 2020.

  40. 40.

    Hiemke C. Concentration-Effect Relationships of psychoactive drugs and the problem to calculate therapeutic reference ranges. Ther Drug Monit. 2019;41(2):174–9.

    PubMed  Article  PubMed Central  Google Scholar 

  41. 41.

    Pharmaceuticals J. Invega Sustenna® (paliperidone palmitate) extended-release injectable suspension, for intramuscular use. Titusville: Janssen Pharmaceuticals, Inc.; 2009.

    Google Scholar 

  42. 42.

    Cohen JY, Dumoulin-Charette A, Meraabi N, Poirier R. Serum concentration of paliperidone palmitate administered every 3 weeks. Psychopharmacol Bull. 2019;49(2):57–62.

    PubMed  PubMed Central  Google Scholar 

  43. 43.

    Russu A, Savitz A, Mathews M, Gopal S, Feng Y, Samtani MN. Pharmacokinetic-pharmacodynamic characterization of relapse risk for paliperidone palmitate 1-month and 3-month formulations. J Clin Psychopharmacol. 2019;39(6):567–74.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  44. 44.

    Samtani MN, Gopal S, Gassmann-Mayer C, Alphs L, Palumbo JM. Dosing and switching strategies for paliperidone palmitate: based on population pharmacokinetic modelling and clinical trial data. CNS Drugs. 2011;25(10):829–45.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Gopal S, Gassmann-Mayer C, Palumbo J, Samtani MN, Shiwach R, Alphs L. Practical guidance for dosing and switching paliperidone palmitate treatment in patients with schizophrenia. Curr Med Res Opin. 2010;26(2):377–87.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  46. 46.

    Su YA, Bousman C, Li Q, Li JT, Lin JY, Si TM. Genetic variations in the ADCK1 gene predict paliperidone palmitate efficacy in Han Chinese patients with schizophrenia. J Neural Transm (Vienna). 2019;126(1):19–25.

    CAS  Article  Google Scholar 

Download references

Acknowledgements

The authors express their gratitude to the number of people who contributed with excellent professional, technical, as well as pharmacological competence to build up the KONBEST database.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Georgios Schoretsanitis.

Ethics declarations

Funding

This research did not receive any funding.

Conflicts of interest/Competing interest

Ekkehard Haen received speaker’s or consultancy fees from the following pharmaceutical companies: Servier, Novartis, and Janssen-Cilag. He is the managing director of AGATE. He reports no conflict of interest with this publication. Christoph Hiemke has received speaker’s or consultancy fees from Otsuka. He reports no conflict of interest with this publication. Andreas Conca has served as a consultant for Lilly, Bristol-Myers Squibb, and Pfizer. He has served on the speakers’ bureau of Lilly, BMS, Astra Zeneca, Lundbeck, Italfarma, and Janssen. Gerhard Gründer has served as a consultant for Allergan, Boehringer Ingelheim, Institute for Quality and Efficiency in Health Care, JanssenCilag, Lundbeck, Otsuka, Recordati, Sage, and Takeda. He has served on the speakers’ bureau of Gedeon Richter, Janssen Cilag, Lundbeck, Otsuka, and Recordati. He has received grant support from Boehringer Ingelheim, Lundbeck, and Saladax. He is a co-founder and/or shareholder of Mind and Brain Institute GmbH, Brainfoods GmbH, InMediCon GmbH, OVID Health Systems GmbH, and MIND Foundation gGmbH. Michael Paulzen has received speaker’s fees from Neuraxpharm, Lundbeck, and Otsuka. He has served as a consultant for Novartis. He reports no conflict of interest with this publication. Georgios Schoretsanitis, Daria Piacentino, Katharina Endres, and Fabio Carpi have no conflicts of interest that are directly relevant to the content of this article.

Ethics approval

This study was approved by the local regulatory authorities of RWTH Aachen University Hospital, Aachen, Germany.

Consent to participate

No informed consent was required for this type of research.

Consent for publication

Not applicable.

Availability of data and material

The data are available from the corresponding author upon reasonable request.

Code availability

Not applicable.

Author contributions

Participated in research design: GS, EH, AC, DP, MP, GG, CH, KE, FC. Performed data analysis: GS, MP. Wrote or contributed to the writing of the manuscript: GS, EH, AC, DP, MP, GG, CH, KE, FC.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 155 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Schoretsanitis, G., Haen, E., Piacentino, D. et al. Pharmacokinetic Correlates of Once-Monthly Paliperidone Palmitate-Related Adverse Drug Reactions. Clin Pharmacokinet (2021). https://doi.org/10.1007/s40262-021-01044-8

Download citation