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A comparison of continuous subcutaneous paliperidone infusion and repeated subcutaneous injection of risperidone free-base in rats

Published online by Cambridge University Press:  16 April 2020

G. Marchese ,
B. Pittau ,
G. Casu ,
G. Peddio ,
G.P. Spada ,
M. Pira ,
A. Deriu ,
F. Portesani ,
C. Pisu  and
P. Lazzari
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G. Marchese
Affiliation:
National Research Council (C.N.R), Institute of Biomedical Technology, Sect. Cagliari, Technological Park of Sardinia Sardegna Ricerche, Building 5, Loc. Piscinamanna, 09010Pula, Cagliari, Italy
B. Pittau
Affiliation:
PharmaNess S.c.a.r.l., Technological Park of Sardinia Sardegna Ricerche, Building 5, Loc. Piscinamanna, 09010Pula, Cagliari, Italy
G. Casu
Affiliation:
PharmaNess S.c.a.r.l., Technological Park of Sardinia Sardegna Ricerche, Building 5, Loc. Piscinamanna, 09010Pula, Cagliari, Italy
G. Peddio
Affiliation:
PharmaNess S.c.a.r.l., Technological Park of Sardinia Sardegna Ricerche, Building 5, Loc. Piscinamanna, 09010Pula, Cagliari, Italy
G.P. Spada
Affiliation:
National Research Council (C.N.R), Institute of Biomedical Technology, Sect. Cagliari, Technological Park of Sardinia Sardegna Ricerche, Building 5, Loc. Piscinamanna, 09010Pula, Cagliari, Italy
M. Pira
Affiliation:
PharmaNess S.c.a.r.l., Technological Park of Sardinia Sardegna Ricerche, Building 5, Loc. Piscinamanna, 09010Pula, Cagliari, Italy
A. Deriu
Affiliation:
National Research Council (C.N.R), Institute of Biomedical Technology, Sect. Cagliari, Technological Park of Sardinia Sardegna Ricerche, Building 5, Loc. Piscinamanna, 09010Pula, Cagliari, Italy
F. Portesani
Affiliation:
PharmaNess S.c.a.r.l., Technological Park of Sardinia Sardegna Ricerche, Building 5, Loc. Piscinamanna, 09010Pula, Cagliari, Italy
C. Pisu
Affiliation:
PharmaNess S.c.a.r.l., Technological Park of Sardinia Sardegna Ricerche, Building 5, Loc. Piscinamanna, 09010Pula, Cagliari, Italy
P. Lazzari
Affiliation:
PharmaNess S.c.a.r.l., Technological Park of Sardinia Sardegna Ricerche, Building 5, Loc. Piscinamanna, 09010Pula, Cagliari, Italy
L. Pani*
Affiliation:
National Research Council (C.N.R), Institute of Biomedical Technology, Sect. Cagliari, Technological Park of Sardinia Sardegna Ricerche, Building 5, Loc. Piscinamanna, 09010Pula, Cagliari, Italy
*
*Corresponding author. Tel.: +39 070 924 2025; fax: +39 070 924 2206. E-mail address: luca.pani@itb.cnr.it (L. Pani).
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Abstract

It is proposed that to achieve a therapeutic effect in schizophrenia patients, dopamine D2-receptor occupancy by antipsychotics within the striatum must exceed 60−65%. However, at high levels of D2-receptor occupancy, the risk of extrapyramidal symptoms (EPS) is increased. Following oral dosing of antipsychotics, peaks and troughs in plasma drug concentrations may be mirrored by fluctuations in D2-receptor occupancy. Paliperidone, a novel antipsychotic available as extended-release tablets (paliperidone ER), is the major active metabolite of risperidone and exhibits a plasma pharmacokinetic profile with reduced peak−trough fluctuations and consistent D2-receptor occupancy compared with conventional oral antipsychotic formulations. Using formulations that resemble those in clinical practice, this study provides a preclinical evaluation of the pharmacological properties of paliperidone ER and risperidone immediate-release formulation in terms of consistent antipsychotic efficacy over time and extrapyramidal symptom liability. Significant fluctuations in inhibition of d-amphetamine-induced hyperlocomotion were observed for repeated subcutaneous (SC) risperidone injections, whereas stable inhibitory efficacy was demonstrated during continuous SC paliperidone infusion. Similarly, significant fluctuations in latency on-bar were observed with repeated SC risperidone injections, whereas significantly lower latency on-bar was demonstrated following continuous SC paliperidone infusion. These results in an animal model suggest that although risperidone and paliperidone demonstrate similar pharmacologic effects, continuous administration of paliperidone achieves more stable antipsychotic efficacy with reduced motor impairment, akin to the effects observed with paliperidone ER in clinical studies.

Keywords

AntipsychoticHyperlocomotionMotor impairmentPaliperidonePlasma concentrationRisperidone
Type
Original articles
Information
European Psychiatry , Volume 25 , Issue 2 , March 2010 , pp. 92 - 100
Copyright
Copyright © Elsevier Masson SAS 2010

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References

Agid, O., Mamo, D., Ginovart, N., Vitcu, I., Wilson, A.A., Zipursky, R.B.et al. Striatal vs extrastriatal dopamine D2 receptors in antipsychotic response--a double-blind PET study in schizophrenia. Neuropsychopharmacology 2007; 32(6): 1209–1215.CrossRefGoogle Scholar
Altamura, A.C., Tacchini, G.L., Maes, M.Haloperidol plasma ‘threshold’ levels for relapse prevention in schizophrenia: a study with haloperidol decanoate. Eur Neuropsychopharmacol 5 (Suppl.): 55–58.CrossRefGoogle Scholar
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 (Berl). 2008; 197(2): 229–235.CrossRefGoogle ScholarPubMed
Arnt, J.Differential effects of classical and newer antipsychotics on the hypermotility induced by two dose levels of D-amphetamine. Eur J Pharmacol 1995; 283(1–3):55–62.CrossRefGoogle ScholarPubMed
Arnt, J., Skarsfeldt, T., Hyttel, J.Differentiation of classical and novel antipsychotics using animal models. International clinical psychopharmacology 1997;12(Suppl. 1): S9–17.CrossRefGoogle ScholarPubMed
Catafau, A.M., Penengo, M.M., Nucci, G., Bullich, S., Corripio, I., Parellada, E.et al. Pharmacokinetics and time-course of D(2) receptor occupancy induced by atypical antipsychotics in stabilized schizophrenic patients. J Psychopharmacol (Oxford, England). 2008; 22(8): 882–894.CrossRefGoogle ScholarPubMed
Chue, P, Devos, E, Duchesne, I, Leal, A, Mehnert, A.Hospitalization rates in patients during long-term treatment with long-acting risperidone injection. J Appl Res 2005; 5(2): 266–74.Google Scholar
Corripio, I., Catafau, A.M., Perez, V., Puigdemont, D., Mena, E., Aguilar, Y.et al. Striatal dopaminergic D2 receptor occupancy and clinical efficacy in psychosis exacerbation: a 123I-IBZM study with ziprasidone and haloperidol. Prog Neuropsychopharmacol Biol Psychiatry. 2005; 29(1): 91–96.CrossRefGoogle ScholarPubMed
Davidson, M., Emsley, R., Kramer, M., Ford, L., Pan, G., Lim, P.et al. Efficacy, safety and early response of paliperidone extended-release tablets (paliperidone ER): results of a 6-week, randomized, placebo-controlled study. Schizophr Res. 2007; 93(1–3): 117–130.CrossRefGoogle ScholarPubMed
Fleischhacker, W., Eerdekens, M., Karcher, K., Remington, G., Llorca, P., Chrzanowski, W.et al. Treatment of schizophrenia with long-acting injectable risperidone: a 12 month evaluation of the first long-acting 2nd generation antipsychotic. J Clin Psychiatry 2003; 64: 1250–1257.CrossRefGoogle Scholar
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 ConstaTM) in patients with schizophrenia. Int J Neuropsychopharmacol. 2005; 8(1): 27–36.CrossRefGoogle Scholar
Kane, J., Canas, F., Kramer, M., Ford, L., Gassmann-Mayer, C., Lim, P.et al. Treatment of schizophrenia with paliperidone extended-release tablets: a 6-week placebo-controlled trial. Schizophr Res. 2007; 90(1–3): 147–161.CrossRefGoogle ScholarPubMed
Kane, J.M., Davis, J.M., Schooler, N., Marder, S., Casey, D., Brauzer, B.et al. A multidose study of haloperidol decanoate in the maintenance treatment of schizophrenia. Am J Psychiatry. 2002; 159(4): 554–560.CrossRefGoogle ScholarPubMed
Kapur, S., VanderSpek, S.C., Brownlee, B.A., Nobrega, J.N.Antipsychotic dosing in preclinical models is often unrepresentative of the clinical condition: a suggested solution based on in vivo occupancy. J Pharmacol Exp Ther. 2003; 305(2): 625–631.CrossRefGoogle ScholarPubMed
Kapur, S., Zipursky, R., Jones, C., Remington, G., Houle, S.Relationship between dopamine D(2) occupancy, clinical response, and side effects: a double-blind PET study of first-episode schizophrenia. Am J Psychiatry. 2000; 157(4): 514–520.CrossRefGoogle ScholarPubMed
Kapur, S., Zipursky, R., Jones, C., Shammi, C.S., Remington, G., Seeman, P.A positron emission tomography study of quetiapine in schizophrenia: a preliminary finding of an antipsychotic effect with only transiently high dopamine D2 receptor occupancy. Arch Gen Psychiatry. 2000; 57(6): 553–559.CrossRefGoogle ScholarPubMed
Karlsson, P, Dencker, E, Nyberg, S, Mannaert, E, Boom, S K T, et al. Pharmacokinetics and dopamine D2 and serotonin 5-HT2A receptor occupancy of paliperidone in healthy subjects: Two open-label, single-dose studies. Clin Pharmacol Ther 2006; 79(2): 74.CrossRefGoogle Scholar
Kessler, R.M., Ansari, M.S., Riccardi, P., Li, R., Jayathilake, K., Dawant, B.et al. Occupancy of striatal and extrastriatal dopamine D2 receptors by clozapine and quetiapine. Neuropsychopharmacology. 2006; 31(9): 1991–2001.CrossRefGoogle ScholarPubMed
Kramer, M., Simpson, G., Maciulis, V., Kushner, S., Vijapurkar, U., Lim, P.et al. Paliperidone extended-release tablets for prevention of symptom recurrence in patients with schizophrenia: a randomized, double-blind, placebo-controlled study. J Clin Psychopharmacol. 2007; 27(1): 6–14.CrossRefGoogle ScholarPubMed
La Fougere, C., Meisenzahl, E., Schmitt, G., Stauss, J., Frodl, T., Tatsch, K.et al. D2 receptor occupancy during high- and low-dose therapy with the atypical antipsychotic amisulpride: a 123I-iodobenzamide SPECT study. J Nucl Med. 2005; 46(6): 1028–1033.Google ScholarPubMed
Lipska, B.K., Weinberger, D.R.To model a psychiatric disorder in animals: schizophrenia as a reality test. Neuropsychopharmacology. 2000; 23(3): 223–239.CrossRefGoogle Scholar
Mannens, G., Huang, M.L., Meuldermans, W., Hendrickx, J., Woestenborghs, R., Heykants, J.Absorption, metabolism, and excretion of risperidone in humans. Drug Metab Dispos. 1993; 21(6): 1134–1141.Google ScholarPubMed
Marder, S.R., Kramer, M., Ford, L., Eerdekens, E., Lim, P., Eerdekens, M.et al. Efficacy and safety of paliperidone extended-release tablets: results of a 6-week, randomized, placebo-controlled study. Biol Psychiatry. 2007; 62(12): 1363–1370.CrossRefGoogle ScholarPubMed
Natesan, S., Reckless, G.E., Nobrega, J.N., Fletcher, P.J., Kapur, S.Dissociation between in vivo occupancy and functional antagonism of dopamine D2 receptors: comparing aripiprazole to other antipsychotics in animal models. Neuropsychopharmacology. 2006; 31(9): 1854–1863.CrossRefGoogle ScholarPubMed
Pani, L., Marchese, G.Expected clinical benefits of paliperidone extended-release formulation when compared with risperidone immediate-release. Expert Opin Drug Deliv. 2009; 6(3): 319–331.CrossRefGoogle ScholarPubMed
Regenthal, R., Kunstler, U., Hesse, S., Sabri, O., Preiss, R.D2 dopamine receptor occupancy, risperidone plasma level and extrapyramidal motor symptoms in previously drug-free schizophrenic patients. Int J Clin Pharmacol Ther. 2005; 43(8): 370–378.CrossRefGoogle ScholarPubMed
Schotte, A., Bonaventure, P., Janssen, P.F., Leysen, J.E.In vitro receptor binding and in vivo receptor occupancy in rat and guinea pig brain: risperidone compared with antipsychotics hitherto used. Jpn J Pharmacol. 1995; 69(4): 399–412.CrossRefGoogle Scholar
Schotte, A., Janssen, P.F., Gommeren, W., Luyten, W.H., Van Gompel, P., Lesage, A.S.et al. Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding. Psychopharmacology (Berl). 1996; 124(1–2): 57–73.CrossRefGoogle ScholarPubMed
Seeman, P., Tallerico, T.Antipsychotic drugs which elicit little or no parkinsonism bind more loosely than dopamine to brain D2 receptors, yet occupy high levels of these receptors. Mol Psychiatry. 1998; 3(2): 123–134.CrossRefGoogle ScholarPubMed
Takano, A., Suhara, T., Kusumi, I., Takahashi, Y., Asai, Y., Yasuno, F.et al. Time course of dopamine D2 receptor occupancy by clozapine with medium and high plasma concentrations. Prog Neuropsychopharmacol Biol Psychiatry. 2006; 30(1): 75–81.CrossRefGoogle ScholarPubMed
Tauscher, J., Jones, C., Remington, G., Zipursky, R.B., Kapur, S.Significant dissociation of brain and plasma kinetics with antipsychotics. Mol Psychiatry. 2002; 7(3): 317–321.CrossRefGoogle ScholarPubMed
Tauscher-Wisniewski, S., Kapur, S., Tauscher, J., Jones, C., Daskalakis, Z.J., Papatheodorou, G.et al. Quetiapine: an effective antipsychotic in first-episode schizophrenia despite only transiently high dopamine-2 receptor blockade. J Clin Psychiatry. 2002; 63(11): 992–997.CrossRefGoogle ScholarPubMed
Tort, A.B., Souza, D.O., Lara, D.R.Theoretical insights into the mechanism of action of atypical antipsychotics. Prog Neuropsychopharmacol Biol Psychiatry. 2006; 30(4): 541–548.CrossRefGoogle ScholarPubMed
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