Pharmacokinetics clozapine

Frazier JA, Cohen LG, Jacobsen L, Grothe D, Flood J, Baldessarini RJ, Piscitelli S, Kim GS, Rapoport JL. Clozapine pharmacokinetics in children and adolescents with childhood-onset schizophrenia. J Clin Psychopharmacol 2003 23 87-91. 

Hagg S, Spigset O, Mjorndal T, Dahlqvist R. Effect of caffeine on clozapine pharmacokinetics in healthy volunteers. Br J Chn Pharmacol 2000 49(l) 59-63. 

Fluvoxamine Pharmacokinetic—CYP1A2 inhibition TCAs Clozapine Theophylline... 

Caccia, S. (2000). Biotransformation of post-clozapine antipsychotics pharmacological implications. Clin. Pharmacokinet., 38, 393-414. 

Byerly M, DeVane L. Pharmacokinetics of Clozapine and Risperidone A Review of Recent Literature. J Clin Psychophar-macol 1996 16(2) 177-187. 

An Example of Major Mental Illness 370 Pharmacodynamics of Clozapine Response 371 Pharmacokinetics of Clozapine Response 372 Tardive Dyskinesia 373 Weight Gain 374... 

Another practical example of a pharmacokinetic drug interaction concerns the incidence of seizures in patients given a standard (300 mg/ day) dose of clozapine. Should the patient be given an SSRI antidepressant (such as fluoxetine, fluvoxamine, sertraline or paroxetine) concurrently then the clearance of clozapine could be reduced by up to 50%, an effect which would be comparable with a doubling of the dose. This could lead to a threefold increase in the risk of the patient suffering a seizure. 

Clozapine is metabolized by hepatic CYP 1A2 and, to a lesser degree, CYP 3A3/4 therefore, the drug is subject to changes in serum concentration when combined with medications that inhibit or induce these enzymes. Serum clozapine levels increase with coadministration of fluvoxamine or erythromycin and decrease with coadministration of phenobarbital or phenytoin and with cigarette smoking (Byerly and DeVane 1996). These pharmacokinetic interactions are particularly important because of the dose-dependent risk of seizures. 

Byerly MJ, DeVane CL Pharmacokinetics of clozapine and risperidone a review of recent literature. J Clin Psychopharmacol 16 177-187, 1996... 

Wetzel H, Anghelescu 1, Szegedi A, et al Pharmacokinetic interactions of clozapine with selective serotonin reuptake inhibitors differential effects of fluvoxamine and paroxetine in a prospective study. J Clin Psy-chopharmacol 18 2-9, 1998... 

Among the reports on overlapping or combining clozapine and risperidone, some pharmacokinetic interactions have been reported ( 100, 103,104 and 105). 

Risch SC, Jackson C, Ware M, et al. Case reports of combined clozapine and risperidone pharmacotherapy pharmacokinetic and pharmacodynamic interactions. Poster presentation at the 33rd Annual Meeting of the American College of Neuropsychopharmacology, San Juan, Puerto Rico, December 1994. 

Tyson SC, Devane CL, Risch SC. Pharmacokinetic interaction between risperidone and clozapine [Letter]. Am J Psychiatry 1995 152 1401-1402. 

GFJ has been shown to increase the exposure of carbamazepine (175), cisapride (176-179), fluvoxamine (184), losartan (188), methadone (189), scopolamine (191), and sertraline (192). However, only the interaction of GFJ with carbamazepine and cisapride seems to be clinically relevant. No alteration in exposure was observed for clozapine (180,181), heophylline (195), halo-peridol (196), and omeprazole (190). Reports of increased pharmacokinetic parameters of clozapine, theophylline, and haloperidol suggest that an interaction is unlikely to be clinically relevant. Contradicting results were reported for itraconazole (185-187), digoxin (75,183), and sildenafil (193,194). An increased effect on concomitant use of diclofenac and GFJ was observed in rats (182). Overall, the clinical relevance for this drug class appears to be low. 

Fluvoxamine increases clozapine plasma concentrations (34,35). In 16 patients taking clozapine monotherapy, fluvoxamine 50 mg was added in the hope of ameliorating the negative symptoms of schizophrenia (36). At steady state the serum concentrations of clozapine and its metabolites increased up to five-fold (average two- to three-fold). However, adverse effects were almost unchanged in frequency and severity, in spite of the pharmacokinetic interaction. 

In a brief review, emphasis has been placed on pharmacokinetic interactions between neuroleptic drugs and benzodiazepines, as much information on their metabolic pathways is emerging (629). Thus, CYP3A4, which plays a dominant role in the metabolism of benzodiazepines, also contributes to the metabolism of clozapine, haloper-idol, and quetiapine, and plasma neuroleptic drug concentrations can rise. 

Since the adverse effects of clozapine may be more common in children than adults, perhaps reflecting developmental pharmacokinetic differences, clozapine and its metabolites, norclozapine and clozapine-N-oxide, have been studied in six youths aged 9-16 years, with childhood onset schizophrenia (222). Dose-normalized concentrations of clozapine did not vary with age and were similar to reported adult values. Clinical improvement in five patients correlated with serum clozapine concentrations, and clinical response and total number of common adverse effects (sialorrhea, n = 5 tachycardia, n = 4 sedation, n = 1 enuresis, n = 1) correlated with norclozapine concentrations. One child had a reduced neutrophil count (1.1 x 109/1) and another child had increased hepatic transaminases. 

A possible pharmacokinetic interaction between ciprofloxacin, which inhibits CYP1A2, and clozapine, with moderately increased serum concentrations of clozapine, has been reported (249). 

Fluvoxamine increases clozapine plasma concentrations (SEDA-27, 58). and the differential effects of steady-state fluvoxamine on the pharmacokinetics of olanzapine and clozapine have been studied in healthy volunteers (256). Fluvoxamine significantly reduced the N-des-methylclozapine to clozapine ratio, implying reduced metabolism of clozapine. 

Schulte PFJ. What is an adequate trial with clozapine Clin Pharmacokinet 2003 42 607-18. 

Olesen OV. Therapeutic drug monitoring of clozapine treatment. Therapeutic threshold value for serum clozapine concentrations. Clin Pharmacokinet 1998 34(6) 497-502. 

Taylor D. Pharmacokinetic interactions involving clozapine. Br J Psychiatry 1997 171 109-12. 

Conca A, Beraus W, Konig P, Waschgler R. A case of pharmacokinetic interference in comedication of clozapine and valproic acid. Pharmacopsychiatry 2000 33(6) 234—5. 

Joos AA, Frank UG, Kaschka WP. Pharmacokinetic interaction of clozapine and rifampicin in a forensic patient with an atypical mycobacterial infection. J Clin Psychopharmacol 1998 18(l) 83-5. 

Because of the frequency of co-administration of benzodiazepines with neuroleptic drugs, it is important to consider possible adverse effects that can result from such combinations. In a brief review, emphasis has been placed on pharmacokinetic interactions between neuroleptic drugs and benzodiazepines, as much information on their metabolic pathways is emerging (166). Thus, the enzyme CYP3A4, which plays a dominant role in the metabolism of benzodiazepines, also contributes to the metabolism of clozapine, haloperidol, and quetiapine, and neuroleptic drug plasma concentrations can rise. Intramuscular levomepromazine in combination with an intravenous benzodiazepine has been said to increase the risk of airways obstruction, on the basis of five cases of respiratory impairment the doses of levomepromazine were higher in the five cases that had accompanying airways obstruction than in another 95 patients who did not (167). 

Via CYP4501A2 inhibition, duloxetine could theoretically reduce clearance of theophylline and clozapine however, studies of co-administration with theophylline did not demonstrate significant effects of duloxetine on theophylline pharmacokinetics... 

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