Paliperidone palmitate is an antipsychotic medication available as long-acting injectable (LAI) formulations. The aim of this study was to investigate the effect of age and gender on paliperidone exposure after administration of LAI formulations.
Data on serum concentrations of paliperidone from patients using LAI during were included retrospectively from a therapeutic drug monitoring (TDM) service. Information about dose was obtained from the requisition forms. As a measure of exposure, daily dose-adjusted serum concentration (C/D ratio) was used. Based on initial analysis of C/D ratios versus age, a breaking point close to 50 years was observed, thus deciding the grouping of patients as older (≥50 years) or younger (15–49 years). Linear mixed model analyses, allowing multiple measurements per patients, were used.
In total, 1223 patients were included, whereof 1158 patients used paliperidone LAI in once-monthly intervals. In these patients (27.9% older), older patients had significantly higher paliperidone C/D ratio than younger patients (+20%, p<0.001). Compared to males, females had higher C/D ratio (+14%; p<0.001). Subsequently, older female users of once-monthly LAI intervals had 41% higher paliperidone C/D ratios compared to younger males (15.0 vs. 21.2 nM/mg; p<0.001). Compared to females aged 21–30 years, females with high age (≥70 years) had at least 105% higher paliperidone C/D ratio (p<0.001).
The present study shows that older age and female gender are associated with higher paliperidone exposure than younger age and males, respectively. Particularly, older female patients (>50 years) are likely exposed to high concentration and cautious dosing in this subgroup is required.
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The data that supports the findings of this study are available upon reasonable request from the corresponding author. The data are not publicly available due to privacy and ethical restrictions.
Hendrie HC, Tu W, Tabbey R, Purnell CE, Ambuehl RJ, Callahan CM (2014) Health outcomes and cost of care among older adults with schizophrenia: a 10-year study using medical records across the continuum of care. Am J Geriatr Psychiatry 22:427–436. https://doi.org/10.1016/j.jagp.2012.10.025
Leucht S, Leucht C, Huhn M, Chaimani A, Mavridis D, Helfer B, Samara M, Rabaioli M, Bacher S, Cipriani A, Geddes JR, Salanti G, Davis JM (2017) Sixty years of placebo-controlled antipsychotic drug trials in acute schizophrenia: systematic review, Bayesian meta-analysis, and meta-regression of efficacy predictors. Am J Psychiatry 174:927–942. https://doi.org/10.1176/appi.ajp.2017.16121358
Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, Keefe RS, Davis SM, Davis CE, Lebowitz BD, Severe J, Hsiao JK, Clinical Antipsychotic Trials of Intervention Effectiveness I (2005) Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 353:1209–1223. https://doi.org/10.1056/NEJMoa051688
Smith RL, Tveito M, Kylleso L, Jukic MM, Ingelman-Sundberg M, Andreassen OA, Molden E (2020) Impact of antipsychotic polypharmacy on nonadherence of oral antipsychotic drugs - a study based on blood sample analyses from 24,239 patients. Eur Neuropsychopharmacol 37:64–69. https://doi.org/10.1016/j.euroneuro.2020.06.007
Haddad PM, Brain C, Scott J (2014) Nonadherence with antipsychotic medication in schizophrenia: challenges and management strategies. Patient Relat Outcome Meas 5:43–62. https://doi.org/10.2147/PROM.S42735
Verdoux H, Pambrun E, Tournier M, Bezin J, Pariente A (2016) Antipsychotic long-acting injections: a community-based study from 2007 to 2014 of prescribing trends and characteristics associated with initiation. Schizophr Res 178:58–63. https://doi.org/10.1016/j.schres.2016.09.014
Janzen D, Bolton J, Kuo IF, Leong C, Alessi-Severini S (2020) Trends in the use of long-acting injectable antipsychotics in the province of Manitoba, Canada. J Clin Psychopharmacol 40:6–13. https://doi.org/10.1097/JCP.0000000000001148
Tiihonen J, Mittendorfer-Rutz E, Majak M, Mehtala J, Hoti F, Jedenius E, Enkusson D, Leval A, Sermon J, Tanskanen A, Taipale H (2017) Real-world effectiveness of antipsychotic treatments in a nationwide cohort of 29823 patients with schizophrenia. JAMA Psychiatry 74:686–693. https://doi.org/10.1001/jamapsychiatry.2017.1322
Taipale H, Mehtala J, Tanskanen A, Tiihonen J (2017) Comparative effectiveness of antipsychotic drugs for rehospitalization in schizophrenia-a nationwide study with 20-year follow-up. Schizophr Bull 44:1381–1387. https://doi.org/10.1093/schbul/sbx176
Kane JM, Schooler NR, Marcy P, Correll CU, Achtyes ED, Gibbons RD, Robinson DG (2020) Effect of long-acting injectable antipsychotics vs usual care on time to first hospitalization in early-phase schizophrenia: a randomized clinical trial. JAMA Psychiatry 77:1217. https://doi.org/10.1001/jamapsychiatry.2020.2076
Xeplion (2011) Summary of product characteristics, European Medicines Agency (EMA). https://www.ema.europa.eu/en/medicines/human/EPAR/xeplion. Accessed 09 Dec 2020
Trevicta (2014) Summary of product characteristics, European Medicines Agency (EMA). https://www.ema.europa.eu/en/medicines/human/EPAR/trevicta. Accessed 09 Dec 2020
Emsley R, Kilian S (2018) Efficacy and safety profile of paliperidone palmitate injections in the management of patients with schizophrenia: an evidence-based review. Neuropsychiatr Dis Treat 14:205–223. https://doi.org/10.2147/NDT.S139633
Corena-McLeod M (2015) Comparative pharmacology of risperidone and paliperidone. Drugs R D 15:163–174. https://doi.org/10.1007/s40268-015-0092-x
Kleinberg DL, Davis JM, de Coster R, Van Baelen B, Brecher M (1999) Prolactin levels and adverse events in patients treated with risperidone. J Clin Psychopharmacol 19:57–61. https://doi.org/10.1097/00004714-199902000-00011
Olfson M, Gerhard T, Huang C, Crystal S, Stroup TS (2015) Premature mortality among adults with schizophrenia in the United States. JAMA Psychiatry 72:1172–1181. https://doi.org/10.1001/jamapsychiatry.2015.1737
Laursen TM (2011) Life expectancy among persons with schizophrenia or bipolar affective disorder. Schizophr Res 131:101–104. https://doi.org/10.1016/j.schres.2011.06.008
Cohen CI, Meesters PD, Zhao J (2015) New perspectives on schizophrenia in later life: implications for treatment, policy, and research. Lancet Psychiatry 2:340–350. https://doi.org/10.1016/S2215-0366(15)00003-6
Masand PS (2000) Side effects of antipsychotics in the elderly. J Clin Psychiatry 61(Suppl 8):43–49 discussion 50-41
Helland A, Spigset O (2017) Serum concentrations of paliperidone after administration of the long-acting injectable formulation. Ther Drug Monit 39:659–662. https://doi.org/10.1097/FTD.0000000000000457
Hiemke C, Bergemann N, Clement HW, Conca A, Deckert J, Domschke K, Eckermann G, Egberts K, Gerlach M, Greiner C, Grunder G, Haen E, Havemann-Reinecke U, Hefner G, Helmer R, Janssen G, Jaquenoud E, Laux G, Messer T, Mossner R, Muller MJ, Paulzen M, Pfuhlmann B, Riederer P, Saria A, Schoppek B, Schoretsanitis G, Schwarz M, Gracia MS, Stegmann B, Steimer W, Stingl JC, Uhr M, Ulrich S, Unterecker S, Waschgler R, Zernig G, Zurek G, Baumann P (2017) Consensus guidelines for therapeutic drug monitoring in neuropsychopharmacology: update 2017. Pharmacopsychiatry 51:9–62. https://doi.org/10.1055/s-0043-116492
Tveito M, Smith RL, Molden E, Haslemo T, Refsum H, Hartberg C, Correll CU, Hoiseth G (2018) Age impacts olanzapine exposure differently during use of oral versus long-acting injectable formulations: an observational study including 8,288 patients. J Clin Psychopharmacol 38:570–576. https://doi.org/10.1097/JCP.0000000000000961
Castberg I, Westin AA, Skogvoll E, Spigset O (2017) Effects of age and gender on the serum levels of clozapine, olanzapine, risperidone, and quetiapine. Acta Psychiatr Scand 136:455–464. https://doi.org/10.1111/acps.12794
Molden E, Waade RB, Hoff M, Haslemo T (2016) Impact of ageing on serum concentrations of risperidone and its active metabolite in patients with known CYP2D6 genotype. Basic Clin Pharmacol Toxicol 119:470–475. https://doi.org/10.1111/bcpt.12614
Tveito M, Molden E, Hoiseth G, Correll CU, Smith RL (2020) Impact of age and CYP2D6 genetics on exposure of aripiprazole and dehydroaripiprazole in patients using long-acting injectable versus oral formulation: relevance of poor and intermediate metabolizer status. Eur J Clin Pharmacol 76:41–49. https://doi.org/10.1007/s00228-019-02768-0
Tveito M, Smith RL, Molden E, Hoiseth G (2020) Impact of age and CYP2D6 genotype on exposure of zuclopenthixol in patients using long-acting injectable versus oral formulation-an observational study including 2044 patients. Eur J Clin Pharmacol 77:215–221. https://doi.org/10.1007/s00228-020-03002-y
Waade RB, Solhaug V, Hoiseth G (2020) Impact of CYP2D6 on serum concentrations of flupentixol, haloperidol, perphenazine and zuclopenthixol. Br J Clin Pharmacol. https://doi.org/10.1111/bcp.14626
Wang JS, Ruan Y, Taylor RM, Donovan JL, Markowitz JS, DeVane CL (2004) The brain entry of risperidone and 9-hydroxyrisperidone is greatly limited by P-glycoprotein. Int J Neuropsychopharmacol 7:415–419. https://doi.org/10.1017/S1461145704004390
Toornvliet R, van Berckel BN, Luurtsema G, Lubberink M, Geldof AA, Bosch TM, Oerlemans R, Lammertsma AA, Franssen EJ (2006) Effect of age on functional P-glycoprotein in the blood-brain barrier measured by use of (R)-[(11)C]verapamil and positron emission tomography. Clin Pharmacol Ther 79:540–548. https://doi.org/10.1016/j.clpt.2006.02.004
Denic A, Glassock RJ, Rule AD (2016) Structural and functional changes with the aging kidney. Adv Chronic Kidney Dis 23:19–28. https://doi.org/10.1053/j.ackd.2015.08.004
Fenton A, Montgomery E, Nightingale P, Peters AM, Sheerin N, Wroe AC, Lipkin GW (2018) Glomerular filtration rate: new age- and gender- specific reference ranges and thresholds for living kidney donation. BMC Nephrol 19:336. https://doi.org/10.1186/s12882-018-1126-8
Invega (2006) Drug Approval Package, U.S. Food & Drug administration (FDA). https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021999s000_TOC.cfm. Accessed 05 Feb 2021
Schoretsanitis G, Spina E, Hiemke C, de Leon J (2017) A systematic review and combined analysis of therapeutic drug monitoring studies for long-acting risperidone. Expert Rev Clin Pharmacol 10:965–981. https://doi.org/10.1080/17512433.2017.1345623
This work was funded by the South-Eastern Norway Regional Health Authority (grant number 2017085).
The study was approved by the Regional Committee for Medical and Health Research Ethics (2017/9121) and Health Research Ethics and the Hospital Investigational Review Board.
Consent to participate
The use of historical patient data for the purpose of this study was approved by the Regional Committee for Medical and Health Research Ethics and the Hospital Investigational Review Board without consent from the patients, as the study was based on retrospective data only.
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Prof. Molden has received speaker´s honoraria from Lundbeck and Lilly. The other authors have no conflicts of interest to declare.
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Tveito, M., Høiseth, G., Haslemo, T. et al. Impact of age and gender on paliperidone exposure in patients after administration of long-acting injectable formulations—an observational study using blood samples from 1223 patients. Eur J Clin Pharmacol (2021). https://doi.org/10.1007/s00228-021-03114-z
- Long-acting injectable