Clozapine metabolism rate as a possible index of drug-induced granulocytopenia

Mauri, Massimo C.; Rudelli, Renata; Bravin, Silvia; Gianetti, S.; Giuliani, E.; Guerrini, Alessandro; Orlandi, Rosaria; Invernizzi, G

doi:10.1007/s002130050628

Cited by 16 publications

(8 citation statements)

References 12 publications

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“…It is unclear whether clozapine plasma levels are associated with development of neutropenia. 32–34 One of the best-supported hypotheses to explain clozapine’s association with agranulocytosis relates to the bioactivation of clozapine, or a stable metabolite, to a chemically reactive nitrenium ion. 35 The propensity for nitrenium ions to cause apoptosis to neutrophils, or be toxic to neutrophil precursors, is dose dependent, lending support to the hypothesis that clozapine pharmacokinetics and bioavailability are related to its potential to cause neutropenia.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide common and rare variant analysis provides novel insights into clozapine-associated neutropenia

et al. 2016

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The antipsychotic clozapine is uniquely effective in the management of schizophrenia, but its use is limited by its potential to induce agranulocytosis. The causes of this, and of its precursor neutropenia, are largely unknown although genetic factors play an important role. We sought risk alleles for clozapine-associated neutropenia in a sample of 66 cases and 5583 clozapine-treated controls, through a genome-wide association study (GWAS), imputed HLA alleles, exome array, and copy number variation analyses. We then combined associated variants in a meta-analysis with data from the Clozapine-Induced Agranulocytosis Consortium (up to 163 cases and 7970 controls). In the largest combined sample to date, we identified a novel association with rs149104283 (OR=4.32, P=1.79×10-8), intronic to transcripts of SLCO1B3 and SLCO1B7, members of a family of hepatic transporter genes previously implicated in adverse drug reactions including simvastatin-induced myopathy and docetaxel-induced neutropenia. Exome array analysis identified gene-wide associations of uncommon non-synonymous variants within UBAP2 and STARD9. We additionally provide independent replication of a previously identified variant in HLA-DQB1 (OR=15.6, P = 0.015, positive predictive value = 35.1%). These results implicate biological pathways through which clozapine may act to cause this serious adverse effect.

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Section: Discussionmentioning

confidence: 99%

Genome-wide common and rare variant analysis provides novel insights into clozapine-associated neutropenia

et al. 2016

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“…The pathophysiological mechanism of agranulocyotosis is uncertain, but hypotheses include a direct toxic effect on neutrophils or haemopoietic precursors (Veys et al, 1992;Gerson et al, 1994;Deliliers et al, 1998), and an immunological basis (Pisciottta et al, 1992), the latter with a possible genetic predisposition (Lieberman et al, 1990;Corzo et al, 1995). Desmethylclozapine at high concentrations has been seen to have a toxic effect on the precursors of both myeloid and erythroid lineages (Gerson et al, 1994), and the desmethylclozapine/clozapine ratio has been seen to be inversely correlated with neutrophil count in patients treated with clozapine (Mauri et al, 1998). If the formation of Motor impairment in the mice was rated using the criteria given in Table 1.…”

Section: Discussionmentioning

confidence: 99%

Clozapine pharmacokinetics and pharmacodynamics studied with CYP1A2-null mice

Aitchison

Jann

Zhao³

et al. 2000

J Psychopharmacol

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The aim of this study was to use the CYP1A2-null mouse to investigate the in-vivo contribution of CYP1A2 to clozapine pharmacokinetics and pharmacodynamics. An intraperitoneal injection of 10 mg/kg clozapine was administered to four male CYP1A2 -/- mice and four male wild-type mice. Clozapine, desmethylclozapine, and clozapine N-oxide concentrations in sequential tail blood samples were measured by HPLC with UV detection. Behavioural parameters were recorded at each time point. The area under the curve (AUC) of clozapine was 2.6 times greater, the clearance of clozapine was 2.6 times slower, and the half-life was 1.2 times longer in the CYP1A2 -/- mice (p = 0.0143) as compared to the wild-type mice. Sixty-one percent of the clozapine clearance in wild-type mice was calculated to be mediated by CYP1A2. The AUC of desmethylclozapine was 1.6 times lower in the CYP1A2 -/- mice compared to the wild-type mice (p = 0.0286), while there was a trend for the AUC of clozapine N-oxide to be greater in the CYP1A2 -/- mice (p = 0.0571). The CYP1A2 -/- mice were significantly more drowsy and showed more motor impairment (p = 0.0145) and myoclonus than the wild-type mice. Our results indicate that, in vivo, CYP1A2 is the major determinant of clozapine clearance, contributes significantly to the demethylation of clozapine, and has a negligible contribution to the N-oxidation. Our data also indicate that CYP1A2 poor metabolizers might be more susceptible than extensive metabolizers to dose-related adverse effects of clozapine, such as sedation, myoclonus and seizures.

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“…Many studies were performed in a small or small to medium size sample, ranging from 6 to 190 patients receiving clozapine. Correlation of clozapine or metabolite levels with dose was calculated in thirteen studies [ 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 ]; nine reported a positive correlation between dose and plasma clozapine levels alone or with metabolite levels as well [ 34 , 35 , 36 , 37 , 39 , 41 , 42 , 43 , 44 ] and two reported no correlation with clozapine and norclozapine levels [ 45 , 46 ]. Sporn et al [ 40 ] found a positive correlation of clozapine dose with norclozapine but not clozapine plasma levels, and Mauri et al [ 38 ] reported that clozapine dosage correlated with clozapine but not norclozapine plasma levels.…”

Section: Resultsmentioning

confidence: 99%

“…Correlation of clozapine or metabolite levels with dose was calculated in thirteen studies [ 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 ]; nine reported a positive correlation between dose and plasma clozapine levels alone or with metabolite levels as well [ 34 , 35 , 36 , 37 , 39 , 41 , 42 , 43 , 44 ] and two reported no correlation with clozapine and norclozapine levels [ 45 , 46 ]. Sporn et al [ 40 ] found a positive correlation of clozapine dose with norclozapine but not clozapine plasma levels, and Mauri et al [ 38 ] reported that clozapine dosage correlated with clozapine but not norclozapine plasma levels. Furthermore, 27 studies examined the correlation of clozapine dose with adverse effects; of them, 19 found no correlation between dose and side effects studied [ 22 , 35 , 36 , 37 , 38 , 41 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 ,…”

Section: Resultsmentioning

confidence: 99%

Adverse Drug Reactions in Relation to Clozapine Plasma Levels: A Systematic Review

et al. 2022

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Clozapine is the gold standard for treatment-resistant schizophrenia. Serious and even life-threatening adverse effects, mostly granulocytopenia, myocarditis, and constipation, are of great clinical concern and constitute a barrier to prescribing clozapine, thus depriving many eligible patients of a lifesaving treatment option. Interestingly, clozapine presents variable pharmacokinetics affected by numerous parameters, leading to significant inter- and intra-individual variation. Therefore, therapeutic drug monitoring of plasma clozapine levels confers a significant benefit in everyday clinical practice by increasing the confidence of the prescribing doctor to the drug and the adherence of the patient to the treatment, mainly by ensuring effective treatment and limited dose-related side effects. In the present systematic review, we aimed at identifying how a full range of adverse effects relates to plasma clozapine levels, using the Jadad grading system for assessing the quality of the available clinical evidence. Our findings indicate that EEG slowing, obsessive-compulsive symptoms, heart rate variability, hyperinsulinemia, metabolic syndrome, and constipation correlate to plasma clozapine levels, whereas QTc, myocarditis, sudden death, leucopenia, neutropenia, sialorrhea, are rather unrelated. Rapid dose escalation at the initiation of treatment might contribute to the emergence of myocarditis, or leucopenia. Strategies for managing adverse effects are different in these conditions and are discussed accordingly.

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Clozapine metabolism rate as a possible index of drug-induced granulocytopenia

Cited by 16 publications

References 12 publications

Genome-wide common and rare variant analysis provides novel insights into clozapine-associated neutropenia

Genome-wide common and rare variant analysis provides novel insights into clozapine-associated neutropenia

Clozapine pharmacokinetics and pharmacodynamics studied with CYP1A2-null mice

Adverse Drug Reactions in Relation to Clozapine Plasma Levels: A Systematic Review

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