Staffan Hägg

Association of venous thromboembolism and clozapine

Data from the Swedish Adverse Reactions Advisory Committee suggest that use of clozapine is associated with venous thromboembolic complications. We summarise 12 cases of thromboembolism during clozapine treatment. In five cases the outcome was fatal.

Relationship between fluvoxamine pharmacokinetics and CYP2D6/CYP2C19 phenotype polymorphisms

Objective: The purpose of this study was to investigate whether the disposition of fluvoxamine is associated with the CYP2D6 and CYP2C19 phenotype polymorphisms. Methods: The serum concentration of fluvoxamine was followed for 48u2009h after oral administration of a single dose of 50u2009mg fluvoxamine to five poor metabolizers of the CYP2D6 test drug dextromethorphan, five poor metabolizers of the CYP2C19 test drug mephenytoin, and five extensive metabolizers of both test drugs. Results: Poor metabolizers of dextromethorphan had significantly higher areas under the serum concentration-time curve than extensive metabolizers of dextromethorphan (mean 1.31 vs 1.00u2009μmolu200a·u200ahu200a·u200al−1). There were no differences between poor and extensive metabolizers of mephenytoin (mean, 1.00 vs 1.15u2009μmolu200a· hu200a·u200al−1). Conclusion: The results are consistent with a possible minor to moderate role of CYP2D6, but not CYP2C19, in fluvoxamine metabolism.

Olanzapine disposition in humans is unrelated to CYP1A2 and CYP2D6 phenotypes.

Abstract.Objective: Limited data suggest that CYP1A2 and CYP2D6 are involved in the metabolism of olanzapine. The purpose of this study was to further elucidate the role of these enzymes in the disposition of olanzapine in vivo. Methods: Seventeen healthy non-smoking male volunteers were included in the study. Five subjects were CYP2D6 poor metabolisers (PMs), and 12 were CYP2D6 extensive metabolisers (EMs). All subjects received a single oral dose of 7.5xa0mg olanzapine, and serum concentrations were measured for 96xa0h using gas chromatography. A cross-over study was undertaken in the 12 CYP2D6 EMs who at least 2xa0weeks before or after the olanzapine dose received a single oral dose of 200xa0mg caffeine. The concentrations of caffeine and paraxanthine were measured in saliva 10xa0h after caffeine intake, and the paraxanthine/caffeine ratio was calculated as a measure of CYP1A2 activity. Results: A threefold inter-individual variability in oral clearance (CLoral) and maximum serum concentration (Cmax) of olanzapine was observed and a 2.3-fold inter-individual variability in CYP1A2 activity. There was no significant correlation between CYP1A2 activity and oral clearance of olanzapine (r=–0.19, P=0.56). Moreover, there were no significant differences in any of the olanzapine pharmacokinetic parameters between the CYP2D6 PMs and EMs (CLoral=0.246xa0l h–1 kg–1 and 0.203xa0l h–1 kg–1, respectively, P=0.30). Conclusion: Neither CYP1A2 nor CYP2D6 seem to have a dominating role in olanzapine biotransformation after intake of a single dose.

The major fluvoxamine metabolite in urine is formed by CYP2D6.

Objective: Previous studies have shown that fluvoxamine is metabolized by CYP1A2 and CYP2D6, but there is no information on the impact the various CYP enzymes have on the different metabolic pathways of fluvoxamine biotransformation. The present study was designed to investigate this issue. Methods: The major fluvoxamine metabolite, the 5-demethoxylated carboxylic acid metabolite, was analyzed in urine from 50 healthy volunteers after intake of a single oral dose of 50xa0mg fluvoxamine, and the formation clearance for the metabolite (CLm) was calculated. Of the subjects, 28 were non-smoking CYP2D6 and CYP2C19 extensive metabolizers (EMs), 12 were smokers and were thus considered to have an induced CYP1A2 activity, 5 were CYP2D6 poor metabolizers (PMs), and 5 were CYP2C19 PMs. In 11 of the non-smoking EMs, 200xa0mg caffeine was given at another occasion in order to calculate oral caffeine clearance as a measure of CYP1A2 activity. In addition, CLm was calculated in ten other subjects given increasing doses of fluvoxamine for 4xa0weeks. Results: Oral clearance of fluvoxamine was significantly higher in smokers, and significantly lower in CYP2D6 PMs than in non-smoking EMs. CLm was 78% lower in CYP2D6 PMs than in the EMs. Smoking and being a CYP2C19 PM did not influence CLm. There was no significant correlation between oral caffeine clearance and CLm. CLm decreased with increasing fluvoxamine dosage, but the decrease in oral clearance was even higher. Conclusion: These results indicate that CYP2D6 catalyzes the major metabolic pathway of fluvoxamine, whereas CYP1A2 seems to catalyze other less important pathways. Both the CYP2D6 and the CYP1A2 pathways seem to be saturated in parallel with increasing fluvoxamine dosage.

Absence of interaction between erythromycin and a single dose of clozapine.

AbstractObjective: To study the suggested pharmacokinetic interaction between erythromycin, a strong inhibitor of CYP3A4, and clozapine.nn Methods: Twelve healthy male volunteers received a single dose of 12.5u2009mg of clozapine alone or in combination with a daily dose of 1500u2009mg erythromycin in a randomised crossover study. Clozapine and its metabolites clozapine-N-oxide and desmethyl-clozapine were measured in serum samples which were collected during a 48u2009h period and in a sample of the urine secreted over the interval 0–12u2009h.nn Results: There were no significant differences in mean area under the serum concentration time curves (1348 (633) nmolu2009hu200a·u200a1−1 in the control phase and 1180 (659) nmol hu200a·u200a1−1 in the erythromycin phase), terminal half-lives (19 (13)u2009h and 15 (6)u2009h, respectively), peak serum concentrations (92 (53)u2009nmolu200a·u200a1−1 and 77 (40)u2009nmolu200a·u200a1−1, respectively), time to peak serum concentrations (1.4 (0.7)u2009h and 1.5 (1.0)u2009h, respectively) or apparent oral clearances of clozapine (34 (15)u2009lu200a·u200ah−1 and 46 (37)u2009lu200a·u200ah−1, respectively). There were no significant differences in partial metabolic clearances to clozapine-N-oxide (5.1 (3.6)u2009lu200a·u200ah−1 and 7.8 (9.4)u2009lu200a·u200ah−1, respectively) or to desmethyl-clozapine (1.5 (1.3)u2009lu200a·u200ah−1 and 1.8 (1.7)u2009lu200a·u200ah−1, respectively) or in renal clearances of clozapine (0.8 (0.5)u2009lu200a·u200ah−1 and 1.0 (0.7)u2009lu200a·u200ah−1, respectively) between the two phases. nn Conclusion: These results demonstrate that erythromycin at a clinically relevant dosage does not inhibit the metabolism of clozapine. Hence, CYP3A4 seems to be of minor importance in the disposition of clozapine in humans at least when clozapine is taken at a low single dose.

Citalopram pharmacokinetics in patients with chronic renal failure and the effect of haemodialysis.

Abstract. Objective: To study the effects of severe renal failure and haemodialysis on the pharmacokinetics of citalopram. Methods: Four patients with renal failure undergoing haemodialysis and eight healthy controls were given a single dose of citalopram. The concentrations of citalopram and its metabolites desmethylcitalopram and didesmethylcitalopram were measured in serum and urine. On a different day, the four patients undergoing haemodialysis were given another single dose of citalopram, and the drug concentrations were measured in serum from the artery leading to the dialyser and in the dialysate. In addition, one anuric patient treated with citalopram on a regular basis was included in the study. Results: There were no significant differences between the two groups in any of the pharmacokinetic parameters with the exception of the renal clearance of citalopram, which was significantly lower in the renal failure group than in the control group (1.70xa0ml/min versus 66.2xa0ml/min, P<0.001). Oral clearance of citalopram was almost identical in the two groups (452xa0ml/min versus 456xa0ml/min). The process of haemodialysis cleared about 1% of the dose as citalopram and 1% as desmethylcitalopram only. Conclusion: Severe renal failure does not affect the pharmacokinetics of citalopram and modification of the usual citalopram dose does thus not seem to be necessary. The contribution of haemodialysis to the total elimination of citalopram is negligible.

Enhanced platelet serotonin 5-HT2A receptor binding in anorexia nervosa and bulimia nervosa

Some evidence exists to suggest that serotonin 5-HT2A receptor function is altered in anorexia nervosa and bulimia nervosa. In order to further investigate the 5-HT2A receptor in eating disorders, platelet [3H]lysergic acid diethylamide ([3H]LSD) binding was studied in ten patients with anorexia nervosa, 23 patients with bulimia nervosa and 33 healthy controls. At admission, Bmax for platelet [3H]LSD binding was significantly higher both in the anorexia nervosa group (30.6+/-4.2 fmol/mg protein; mean+/-S.D.) and in the bulimia nervosa group (30.8+/-7.6 fmol/mg protein) than in the control group (23.5+/-6.3 fmol/mg protein; p=0.01 and p=0.003, respectively). Kd was borderline significantly higher among anorexics (median 1.45 nM) and significantly higher among bulimics (median 1.66 nM) than among controls (median 0.95 nM; p=0.05 and 0.003, respectively). The Global Assessment of Functioning score and the body mass index were both significantly negatively correlated to Kd (r=-0.40; p=0.03 and r=-0.41 p=0.03, respectively), but not to Bmax. The present study indicates that patients with anorexia nervosa as well as patients with bulimia nervosa have an enhanced 5-HT2A receptor binding and provides further evidence for a serotonergic dysfunction in eating disorders.

Lack of correlation between fluvoxamine clearance and CYP1A2 activity as measured by systemic caffeine clearance.

AbstractObjective: Evidence exists to suggest that fluvoxamine is metabolized by CYP1A2. The present study was undertaken in order to further elucidate the role of CYP1A2 in fluvoxamine disposition.nn Methods: Twelve healthy non-smoking male volunteers participated in this cross-over study. Six subjects received first fluvoxamine 50u2009mg as a single oral dose and, some weeks later, caffeine 200u2009mg as a single oral dose. The other six subjects received the drugs in reverse order. Serum concentrations of fluvoxamine, caffeine and paraxanthine were measured and standard pharmacokinetic parameters were calculated.nn Results: There were no significant correlations between caffeine clearance and fluvoxamine oral clearance (rsu2009=u2009−0.30; Pu2009=u20090.43) or between the paraxanthine/caffeine ratio in serum 6u2009h after caffeine intake and fluvoxamine oral clearance (rsu2009=u2009−0.18; Pu2009=u20090.58).nn Conclusion: CYP1A2 does not appear to be of major importance in the metabolism of fluvoxamine.

Clozapine and pulmonary embolism [2] (multiple letters)

The use of clozapine, a tricyclic dibenzodiazepine that is effective in the treatment of resistant schizophrenia (1), has been limited by its adverse drug profile, which includes agranulocytosis, sedation, weight gain, diabetes mellitus, and cardial complications (2–4). Recently clozapine has also been associated with venous thromboembolism (5, 6). In this letter, we describe a patient with a previous history of pulmonary embolism who developed a new episode of pulmonary embolism shortly after clozapine treatment was initiated. Mr A, a 58-year-old white deaf male diagnosed with schizoaffective disorder for 5 years prior to admission. He was treated with Risperdal for 3 years and then received olanzapine for the next 2 years. He had no previous history of trauma, immobilization, surgery, or malignant disorders. However, he had one episode of pulmonary embolism 2 years prior to this admission for which he was anticoagulated with daily coumadin for 1 year. He also revealed a family history of two first-degree relatives with history of stroke and myocardial infarction and one first degree relative had died of sudden death . Despite good symptom relief with olanzapine, his antipsychotic treatment was switched to clozapine as a result of prominent Tardive Dyskinesia. The dose was gradually increased and after 5 days, a daily dose of 250 mg had been reached. In the evening of the fifth day of treatment he complained of lower extremity muscle weakness and mild shortness of breath. On physical examination, he was afebrile, tachycardic, and mildly orthostatic. He was hyperventilating with a respiratory rate of 28 with a pulse oximetry reading of 92% oxygen saturation. An electrocardiogram showed sinus tachycardia with no abnormal waveforms or ST segment changes. A spiral CT scan of the chest confirmed a diagnosis of multiple pulmonary emboli. The clozapine treatment was promptly discontinued and the patient was restarted on olanzapine. Supplemental oxygen and anticoagulation with heparin and coumadin followed. In addition, a hypercoagulability workup was pursued. Studies such as factor V Leiden, Protein C, Protein S, and tissue thromboplastin inhibition were within normal limits. During the change from clozapine to olanzapine the patient did not exhibit a relapse of psychotic symptoms. He was stabilized on olanzapine and discharged on daily coumadin.