A comprehensive review of the clinical utility of and a combined analysis of the clozapine/norclozapine ratio in therapeutic drug monitoring for adult patients

ABSTRACT

Introduction: This article comprehensively reviews the clinical utility of the serum clozapine/norclozapine (CLO/NCLO) ratio.

Areas covered: Fifty-four published studies used this ratio (21 from a PubMed search from onset to 10/21/18 and 33 identified by the authors). To estimate a combined mean of the CLO/NCLO ratio in published studies, a PubMed search on 10/21/18 identified 422 articles leading to 19 included. The systematic review focused on 1) the combined analysis, 2) CYP1A2 activity, 3) clinical response, 4) cognition, and 5) renal function.

Expert opinion: Our combined analysis provided a weighted mean CLO/NCLO ratio of 1.73 in 2,317 adult patients from 19 studies, but the range in the studies varied widely from 1.19 to 3.37. No study provided data on variability of the CLO/NCLO ratios within individual patients. The CLO/NCLO ratio is not a measure of CYP1A2 activity and is not associated with clinical response. The association of the CLO/NCLO ratio with cognitive measures is unclear (4 cross-sectional studies were positive and post-hoc analysis of a randomized clinical trial was negative). Future studies must replicate the finding of a case report that gemfibrozil may invert the CLO/NCLO ratio (making it <1), indicating that gemfibrozil inhibits the renal transporter that excretes NCLO.

KEYWORDS:

• Antipsychotic agents/pharmacology
• clozapine
• drug monitoring
• norclozapine
• schizophrenia

Article highlights

• The most important metabolic pathway for clozapine (CLO) is demethylation leading to norclozapine (NCLO).

• NCLO is further metabolized by conjugation. It is estimated that serum free NCLO is mainly eliminated by tubular secretion by a transporter. In summary, NCLO is mainly eliminated by the kidneys.

• NCLO has no efficacy as an antipsychotic. The serum NCLO concentration in CLO patients may contribute to adverse drug reactions (ADRs), but this has not been well studied. NCLO possibly contributes to sedation, hypersalivation, constipation, metabolic complications, myoclonus, and seizures.

• In 19 studies with a total of 2,317 adult patients, we computed a weighted mean CLO/NCLO ratio of 1.73, but its range was from 1.19 to 3.37, indicating a 2-fold variability. No published study provided data concerning the variability of the CLO/NCLO ratio in the same individual.

• The published studies using pharmacological indexes of CYP1A2 activity or CYP1A2 gene variants do not support the idea that the CLO/NCLO ratio is a measure of CYP1A2 activity.

• In the eight studies included in Table 3, we did not find that the CLO/NCLO ratios of smokers were significantly higher in rank order than those of non-smokers.

• In the 13 studies included in Table 4, we did not find that the CLO/NCLO ratios of males were significantly higher in rank order than those of females.

• In the 11 studies included in Table 6, we did not find that the CLO/NCLO ratios of responders were significantly different in rank order than those of non-responders.

• Four cross-sectional studies reported a correlation between higher CLO/NCLO ratio and lower cognitive performance, whereas one post-hoc analysis of a randomized clinical trial yielded no significant correlation between the ratio and cognition.

• As NCLO is mainly eliminated by the kidneys, it is likely that the CLO/NCLO ratio is influenced by aging and by renal impairment, but there are almost no published studies in this area.

• Future studies are needed to replicate the finding that gemfibrozil inverted the CLO/NCLO ratio, providing values around 0.50, under trough and steady-state conditions in a CLO patient. In this patient, gemfibrozil possibly inhibited the unknown renal transporter that eliminates NCLO.

Acknowledgments

The authors are grateful to Irina Piatkov and Micheline S.Z. Coelho, Molecular Research Laboratory, Blacktown Clinical School and Research Centre, Blacktown Hospital, WSU/WSLHD, Blacktown, Australia, who provided valuable information about their study. 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.

Declaration of interest

J.M Kane has been a consultant for or received honoraria from Alkermes, Dainippon Sumitomo, Eli Lilly, Forum, Allergan, Genentech, H. Lundbeck, Intracellular Therapies, Janssen Pharmaceuticals, Johnson and Johnson, LB Pharmaceuticals, Merck, Minerva, Neurocrine, Otsuka, Pierre Fabre, Reviva, Roche, Sunovion, Takeda and Teva. He has received grant support from Otsuka, Lundbeck and Janssen. He has participated in advisory boards for Alkermes, Dainippon Sumitomo, Intracellular Therapies, Lundbeck, Neurocrine, Otsuka, Pierre Fabre, Takeda, and Teva. He is a Shareholder in Vanguard Research Group and LB Pharmaceuticals, Inc. 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.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

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Funding

This paper was not funded.