A systematic review and combined analysis of therapeutic drug monitoring studies for long-acting risperidone

ABSTRACT

Introduction: This systematic review of therapeutic drug monitoring (TDM) identifies three long-acting injectable (LAI) risperidone formulations.

Areas covered: Limited data is available on two formulations (RBP-7000 and in Situ Microparticle), but 20 TDM articles on the microsphere formulation were found. Risperidone TDM includes the serum concentrations of risperidone and its active metabolite, 9-hydroxyrisperidone, used for calculating: 1) the risperidone/9-hydroxyrisperidone (R/9-OH-R) ratio (a measure of CYP2D6; values >1 are indicative of a CYP2D6 poor metabolizer) and 2) the total risperidone concentration-to-dose (C/D) ratio (a measure of risperidone clearance with a normal value around 7 in oral risperidone). The weighted mean R/9-OH-R ratio was 0.48 (approximately twice that of oral risperidone TDM) in a combined analysis from 329 patients in 6 risperidone LAI studies without major confounders. The total C/D ratios from 297 patients in 6 risperidone LAI studies ranged from 7.4 to 9.7 ng/ml/mg/day with a weighted mean of 8.8 ng/ml/mg/day.

Expert commentary: Clinicians using TDM for risperidone LAI microsphere formulation need to: 1) consider steady state to be reached ≥ 6 weeks after the first injection, 2) pay attention to a) co-medications with inducers/inhibitors, b) severe inflammations/infections, and c) hepatic/renal impairment, and 3) use Castberg’s recommendation to calculate risperidone dosing.

KEYWORDS:

• Antipsychotic agents/administration & dosage
• delayed-action preparations
• drug monitoring
• injections
• risperidone/administration & dosage
• risperidone/blood
• risperidone/metabolism
• risperidone/pharmacokinetics
• risperidone/pharmacology
• risperidone/therapeutic use
• schizophrenia/drug therapy

Acknowledgments

The authors acknowledge Lorraine Maw, M.A., from the University of Kentucky Mental Health Research Center at Eastern State Hospital, who helped in editing the article. The authors are grateful to Ragnar Nesvåg, M.D., Ph.D. (Department of Mental Health and Addiction, Oslo University Hospital, Norway), who provided orientation in how to handle two of his studies having overlapping patients.

Declaration of interest

No commercial organizations had any role in the writing of this paper for publication. G. Schoretsanitis received a grant from the bequest ‘in memory of Maria Zaoussi’, State Scholarships Foundation, Greece, for clinical research in psychiatry for the academic year 2015–2016. In the past few years, E. Spina has participated in speakers/advisory boards and lectured, supported by AstraZeneca, Bristol-Myers, Eli Lilly and Company, Janssen Pharmaceuticals, Lundbeck and Pfizer. C. Hiemke has received speaker´s or consultancy fees from the following pharmaceutical companies: Pfizer, Lilly and Servier. C. Hiemke is managing director of the PSIAC GmbH, which provides an internet-based drug-drug interaction program. He declares no conflict of interest related to this article. J. de Leon personally develops his presentations for lecturing, has never lectured using any pharmaceutical or pharmacogenetic company presentations, and has never been a consultant for pharmacogenetic or pharmaceutical companies. In the past, J. de Leon received researcher-initiated grants from Eli Lilly (one ended in 2003 and the other, as co-investigator, ended in 2007); from Roche Molecular Systems, Inc. (ended in 2007); and, in a collaboration with Genomas, Inc., from the NIH Small Business Innovation Research program (ended in 2010). J. de Leon has been on the advisory boards of Bristol-Myers Squibb (2003/04) and AstraZeneca (2003). Roche Molecular Systems supported one of his educational presentations, which was published in a peer-reviewed journal (2005). His lectures were supported once by Sandoz (1997), twice by Lundbeck (1999 and 1999), twice by Pfizer (2001 and 2001), three times by Eli Lilly (2003, 2006, and 2006), twice by Janssen (2000 and 2006), once by Bristol-Myers Squibb (2006), and seven times by Roche Molecular Systems, Inc. (once in 2005 and six times in 2006). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

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Funding

This manuscript was not funded.