Effects of age and gender on the serum levels of clozapine, olanzapine, risperidone, and quetiapine.

OBJECTIVE: To investigate serum concentrations of second-generation antipsychotics in relation to age and gender in a population ranging from 18 to 100 years. METHOD: Results from a routine therapeutic drug monitoring database were retrieved, and 43 079 samples from 11 968 patients were included (17 249 samples for clozapine, 16 171 samples for olanzapine, 5343 samples for risperidone, and 4316 samples for quetiapine). The dose-adjusted concentration was used as the primary target variable. A linear mixed model was used to allow the inclusion of multiple samples from each patient. RESULTS: Age had a significant impact on the concentrations of all four drugs. At the age of 80, the dose-adjusted concentrations were up to twice those of the age of 40. At the age of 90, dose-adjusted concentrations were two- to three-fold higher. Age-related increases were largest for clozapine (+108% at 80 years; +197% at 90 years) and smallest for olanzapine (+28% at 80 years; +106% at 90 years). Females generally had dose-adjusted concentrations 20-30% higher than males. CONCLUSION: The effect of age on the serum concentrations of the antipsychotics studied becomes pronounced with advanced age. The patient population aged above 70 should be subdivided according to exact age, and considerable dose reductions are recommended.

Characterisation of zuclopenthixol metabolism by in vitro and therapeutic drug monitoring studies.

OBJECTIVE: Zuclopenthixol pharmacokinetics is incompletely characterised. We investigated potential interactions mediated through cytochrome P450 enzymes. METHOD: In vitro, we examined the impact of CYP2D6 and CYP3A4 inhibitors on zuclopenthixol metabolism in microsomes from six human livers. Subsequently, we compared dose-corrected serum zuclopenthixol concentrations in 923 samples from a therapeutic drug monitoring database from patients prescribed oral (n = 490) or injected (n = 423) zuclopenthixol alone or with fluoxetine, paroxetine, levomepromazine or carbamazepine. RESULTS: In vitro fluoxetine, paroxetine, ketoconazole and quinidine all significantly inhibited zuclopenthixol metabolism. Ketoconazole and quinidine together abolished zuclopenthixol disappearance. Clinically, dose-corrected oral zuclopenthixol serum concentrations increased significantly, after adjustment, by 93%, 78% and 46% during co-treatment with fluoxetine, paroxetine and levomepromazine and decreased 67% with carbamazepine. Carbamazepine caused dose-dependent reductions in the oral zuclopenthixol concentration-dose ratio (P < 0.001), fluoxetine (P < 0.001) and paroxetine (P = 0.011) dose-dependent increases and levomepromazine an increase related to its serum concentration (P < 0.001). Results for injected zuclopenthixol were similar but not all reached statistical significance. CONCLUSION: The In vitro study suggests zuclopenthixol is metabolised primarily by CYP2D6 and CYP3A4. The clinical study supports this, demonstrating the impact of co-prescribed inhibitors or inducers. Guidelines should incorporate these interactions noting the potential for zuclopenthixol-related toxicity or treatment failure.

Effects of comedication on the serum levels of aripiprazole: evidence from a routine therapeutic drug monitoring service.

INTRODUCTION: The objective of the study was to compare the serum concentrations of the atypical antipsychotic aripiprazole in monotherapy with the concentrations found during concomitant therapy with other drugs. METHODS: Samples analyzed for aripiprazole by a liquid chromatography-mass spectrometry method in a routine therapeutic drug monitoring setting were collected consecutively. RESULTS: Samples from 81 patients were included in the study. Comedication with the CYP3A4 inducer carbamazepine lowered the dose-adjusted aripiprazole concentration by 88%. Comedication with CYP2D6 inhibitors gave a mean concentration 44% higher than in the monotherapy group. Subjects comedicated with valproate had lower aripiprazole concentrations, while subjects comedicated with lamotrigine, citalopram/escitalopram and lithium had higher concentrations than the subjects in the monotherapy group. CONCLUSION: Although the study is small and the results should be interpreted very cautiously, it indicates that comedication with drugs inhibiting or inducing CYP2D6 or CYP3A4 affects the serum concentrations of aripiprazole. The other findings should be considered as preliminary and have to be replicated in a larger setting before firm conclusions can be drawn.