Dose-Dependent Pharmacokinetic Interaction of Clozapine and Paroxetine in an Extensive Metabolizer

Joos, Andreas; König, Frank; Frank, Udo; Kaschka, Wolfgang P.; Mörike, Klaus; Ewald, R. W.

doi:10.1055/s-2007-979505

Cited by 19 publications

(10 citation statements)

References 5 publications

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“…Our findings in patients from the paroxetine group are in agreement with those of Centorrino et al, who found higher concentrations of clozapine and norclozapine in patients also taking paroxetine than the control patient group on clozapine monotherapy [9], but contradict the results of Anghelescu et al, who reported no elevation of clozapine plasma concentrations following coadministration with paroxetine [2]. Differences in paroxetine dosage may partially explain such discrepancies, as the magnitude of the interaction appears to be dose-dependent [24]. In the study by Anghelescu et al, all patients were receiving 20 mg of paroxetine [2], while in the study of Centorrino et al [9] and in our investigation, the mean paroxetine dose was higher.…”

Section: Discussionsupporting

confidence: 90%

Plasma Concentrations of Clozapine and its Major Metabolites During Combined Treatment with Paroxetine or Sertraline

Spina¹,

Avenoso²,

Salemi³

et al. 2000

Pharmacopsychiatry

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The effect of paroxetine or sertraline on steady-state plasma concentrations of clozapine and its major metabolites was studied in 17 patients with schizophrenia or schizoaffective disorder stabilized on clozapine therapy (200-400 mg/day). In order to treat negative symptomatology or concomitant depression, 9 patients received additional paroxetine (20-40mg/day) and 8 patients sertraline (50-100 mg/day). After 3 weeks of paroxetine administration, mean plasma concentrations of clozapine and norclozapine increased significantly by 31% (p<0.01) and by 20% (p<0.05), respectively, while levels of clozapine N-oxide remained almost unchanged. The mean plasma norclozapine/clozapine and clozapine N-oxide/clozapine ratios were not modified during paroxetine treatment. No significant changes in plasma concentrations of clozapine and its major metabolites were observed after 3 weeks of combined therapy with sertraline. Clozapine coadministration with either paroxetine or sertraline was well tolerated. Our findings suggest that the metabolism of clozapine is not affected by sertraline treatment at typical therapeutic doses, while paroxetine, a potent inhibitor of CYP2D6, appears to inhibit the metabolism of clozapine, possibly by affecting pathways other than N-demethylation and N-oxidation. While sertraline may be added safely to patients on maintenance treatment with clozapine, careful clinical observation and monitoring of plasma clozapine levels may be useful whenever paroxetine is coadministered with clozapine.

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Section: Discussionsupporting

confidence: 90%

Plasma Concentrations of Clozapine and its Major Metabolites During Combined Treatment with Paroxetine or Sertraline

Spina¹,

Avenoso²,

Salemi³

et al. 2000

Pharmacopsychiatry

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“…Using their equation, the estimated clozapine level without the bupropion interaction is 262 ng/mL. While CYP 2D6 is a minor phase 1 metabolic pathway for clozapine, strong 2D6 inhibitors increase plasma clozapine levels 40%–70% [13], with one case report of paroxetine increasing clozapine levels 100% in a patient whose baseline clozapine level was in the range of 666 ng/mL–684 ng/mL [33]. When that patient's clozapine dose was halved, paroxetine increased clozapine levels approximately 30% [33].…”

Section: Discussionmentioning

confidence: 99%

“…While CYP 2D6 is a minor phase 1 metabolic pathway for clozapine, strong 2D6 inhibitors increase plasma clozapine levels 40%–70% [13], with one case report of paroxetine increasing clozapine levels 100% in a patient whose baseline clozapine level was in the range of 666 ng/mL–684 ng/mL [33]. When that patient's clozapine dose was halved, paroxetine increased clozapine levels approximately 30% [33]. As this patient's estimated plasma clozapine level is <300 ng/mL, a 100% increase from bupropion is unlikely, but if we use the high value of 70% obtained from case reports with strong 2D6 inhibitors, the estimated baseline clozapine level for this patient prior to ciprofloxacin exposure was 445 ng/mL.…”

Section: Discussionmentioning

confidence: 99%

Ciprofloxacin and Clozapine: A Potentially Fatal but Underappreciated Interaction

Meyer

Proctor²,

Cummings³

et al. 2016

Case Reports in Psychiatry

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Objective. Clozapine provides a 50%–60% response rate in refractory schizophrenia but has a narrow therapeutic index and is susceptible to pharmacokinetic interactions, particularly with strong inhibitors or inducers of cytochrome P450 (CYP) 1A2. Case Report. We report the case of a 28-year-old nonsmoking female with intellectual disability who was maintained for 3 years on clozapine 100 mg orally twice daily. The patient was treated for presumptive urinary tract infection with ciprofloxacin 500 mg orally twice daily and two days later collapsed and died despite resuscitation efforts. The postmortem femoral clozapine plasma level was dramatically elevated at 2900 ng/mL, and the cause of death was listed as acute clozapine toxicity. Conclusion. Given the potentially fatal pharmacokinetic interaction between clozapine and ciprofloxacin, clinicians are advised to monitor baseline clozapine levels prior to adding strong CYP450 1A2 inhibitors, reduce the clozapine dose by at least two-thirds if adding a 1A2 inhibitor such as ciprofloxacin, check subsequent steady state clozapine levels, and adjust the clozapine dose to maintain levels close to those obtained at baseline.

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“…Thus, serum levels of clozapine were increased in patients who also received the SSRIs paroxetine, fluoxetine and sertraline (Wetzel et al 1998). Such effects have not been observed uniformly in clinical studies so that their general applicability remains unclear (Arranz et al 1995;Joos et al 1997).…”

Section: Clozapine Biotransformation By Other Cypsmentioning

confidence: 99%

Role of CYP pharmacogenetics and drug-drug interactions in the efficacy and safety of atypical and other antipsychotic agents

Murray

2006

Journal of Pharmacy and Pharmacology

104

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Cytochrome P450 (CYP) drug oxidases play a pivotal role in the elimination of antipsychotic agents, and therefore influence the toxicity and efficacy of these drugs. Factors that affect CYP function and expression have a major impact on treatment outcomes with antipsychotic agents. In particular, aspects of CYP pharmacogenetics, and the processes of CYP induction and inhibition all influence invivo rates of drug elimination. Certain CYPs that mediate the oxidation of antipsychotic drugs exhibit genetic variants that may influence in-vivo activity. Thus, single nucleotide polymorphisms (SNPs) in CYP genes have been shown to encode enzymes that have decreased drug oxidation capacity. Additionally, psychopharmacotherapy has the potential for drug-drug inhibitory interactions involving CYPs, as well as drug-mediated CYP induction. Literature evidence supports a role for CYP1A2 in the clearance of the atypical antipsychotics clozapine and olanzapine; CYP1A2 is inducible by certain drugs and environmental chemicals. Recent studies have suggested that specific CYP1A2 variants possessing individual SNPs, and possibly also SNP combinations (haplotypes), in the 5 0 -regulatory regions may respond differently to inducing chemicals. CYP2D6 is an important catalyst of the oxidation of chlorpromazine, thioridazine, risperidone and haloperidol. Certain CYP2D6 allelic variants that encode enzymes with decreased drug oxidation capacity are more common in particular ethnic groups, which may lead to adverse effects with standard doses of psychoactive drugs. Thus, genotyping may be useful for dose optimization with certain psychoactive drugs that are substrates for CYP2D6. However, genotyping for inducible CYPs is unlikely to be sufficient to direct therapy with all antipsychotic agents. In-vivo CYP phenotyping with cocktails of drug substrates may assist at the commencement of therapy, but this approach could be complicated by pharmacokinetic interactions if applied when an antipsychotic drug regimen is ongoing.

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Dose-Dependent Pharmacokinetic Interaction of Clozapine and Paroxetine in an Extensive Metabolizer

Cited by 19 publications

References 5 publications

Plasma Concentrations of Clozapine and its Major Metabolites During Combined Treatment with Paroxetine or Sertraline

Plasma Concentrations of Clozapine and its Major Metabolites During Combined Treatment with Paroxetine or Sertraline

Ciprofloxacin and Clozapine: A Potentially Fatal but Underappreciated Interaction

Role of CYP pharmacogenetics and drug-drug interactions in the efficacy and safety of atypical and other antipsychotic agents

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