A systematic review and combined analysis of therapeutic drug monitoring studies for oral paliperidone

ABSTRACT

Introduction: This article includes a combined analysis of therapeutic drug monitoring (TDM) studies and a review of the marketer’s data on pharmacological mechanisms.

Areas covered: An article search led to the inclusion of 21 paliperidone studies in the systematic review plus 2 case reports. Paliperidone clearance was calculated from: 1) steady-state studies using concentration/dose (C/D) ratios, and 2) single-dose studies describing 24-h area under the curve calculations. The marketed extended-release formulation has 28% bioavailability. Calculated mean C/D ratios (ng/ml/mg/d) were: 1) 4.09 in 6 studies of 221 non-Korean and non-geriatric adult patients, 2) 2.59 in 2 studies of 100 Korean adult patients, and 3) 6.89 in 1 study with 15 elderly Japanese patients. The limited drug–drug interaction studies indicated that carbamazepine is a clinically relevant inducer requiring three times the dosage, and that valproate, probably an inhibitor, requires half the dosage. Renal impairment markedly decreased paliperidone elimination, and other antipsychotics should be considered.

Expert Commentary: We recommend more use of: 1) paliperidone TDM in clinical practice, 2) TDM when moving from oral to long-acting paliperidone, 3) better designs for paliperidone TDM studies, 4) laboratory studies on paliperidone pharmacokinetic mechanisms, and 5) TDM studies comparing paliperidone and risperidone dosing.

KEYWORDS:

• Antipsychotic agents/administration & dosage
• antipsychotic agents/pharmacology
• drug monitoring
• paliperidone palmitate
• risperidone/pharmacokinetics
• schizophrenia/drug therapy
• schizoaffective disorder/drug therapy

Box 1. Pharmacodynamics of paliperidone and risperidone at the neurotransmitter receptors.

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Box 2. Pharmacokinetics of oral paliperidone.

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Box 3. Delivery system for oral paliperidone ER.

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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 Yumiko Akamine, PhD (Department of Pharmacy, Akita University Hospital, Akita, Japan) and Kristof Maudens, PhD (Toxicological Centre, University of Antwerp, Belgium), who provided orientation on how to handle the data from their studies.

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 Arcapharma, Janssen Pharmaceuticals, Lundbeck, Otsuka and Recordati. C. Hiemke has received speaker´s or consultancy fees from the following pharmaceutical companies: Janssen and Servier. 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. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

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Funding

This paper was not funded.