CYP1A2 inHibition Examples including Clozapine-Fluvoxamine

Excerpt from Cafer's Mood Stabilizers and Antiepileptics



CYP1A2 inHibition Examples

Ciprofloxacin, a moderate 1A2 inHibitor,  increases clozapine levels about 2-fold.

Fluvoxamine, a strong 1A2 inHibitor, increases clozapine levels 3-fold on average, but up to 10-fold in some cases.           

Kinetic interactions can be more complicated than simply increasing/decreasing concentrations of victim substrates. 

Combining clozapine and fluvoxamine is hazardous, but can potentially be used for therapeutic advantage. Close monitoring of serum clozapine levels would be required.

Norclozapine is the main metabolite of clozapine, formed by 1A2. When clozapine blood levels are reported, clozapine and metabolite (norclozapine) levels are provided separately. Through 1A2 inHibition, Luvox increases the clozapine:norclozapine ratio. A Higher serum clozapine:norclozapine ratio is generally considered desirable*. Norclozapine provides little antipsychotic benefit and causes weight gain, diabetes, seizures, and neutropenia. 

Patients given clozapine 100 mg + Luvox 50 mg daily (compared to clozapine 300 mg monotherapy) demonstrated more improvement with less weight gain. Clozapine levels were similar for both groups with, as expected,  lower norclozapine levels for those taking Luvox. 
(Lu ML et al, 2018; randomized controlled trial, N=85).

*The negative aspect of a Higher clozapine:norclozapine is greater anticholinergic burden (pages 161-162). Clozapine is anticholinergic, whereas norclozapine is cholinergic. Consequently, clozapine causes constipation, while norclozapine does not. The anticholinergic properties of clozapine may impair cognition, whereas norclozapine provides cognitive benefits such as enhanced working memory (page 177).
           

Certain physiologic states may increase levels of olanzapine and clozapine up to 2-fold. 


For a patient with efficacy or tolerability issues, consider monitoring serum levels of the antipsychotic. The author checks clozapine levels routinely, and olanzapine levels in some cases.


Fluvoxamine and ramelteon should not be prescribed concomitantly because ramelteon levels will be increased up to 100-fold!
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