Quetiapine Blood Level Variability

Dear Editor:

Quetiapine, a dibenzothiazepine derivative, is one of the newer atypical antipsychotics. It undergoes extensive hepatic metabolism by cytochrome P450 3A4 (CYP3A4) (1). Many drugs, including some serotonin reuptake inhibitors, macrolide antibiotics, antifungals, and older anticonvulsants, affect the activity of this isoenzyme. They may alter the plasma concentration and efficacy of quetiapine. A recent study has shown that co-administration of phenytoin, a known inducer of several CYP isoenzymes, including CYP3A4, increased the hepatic clearance of quetiapine fivefold (2). Increased dosages of quetiapine may be necessary to treat patients also receiving phenytoin, and other hepatic-enzyme inducers (2). We present 2 cases in which co-administration of quetiapine with anticonvulsant drugs significantly reduced quetiapine availability.

Ms A is a 67-year-old woman diagnosed with psychosis due to simple partial epilepsy and dementia. We started her on quetiapine in July 2000 and titrated the quetiapine to a maximum dosage of 500 mg daily over the subsequent weeks. In February 2001, we started her on phenytoin, titrating the dosage up to 200 mg daily. This was in the therapeutic range for epilepsy. Her quetiapine blood level on April 2, 2001, was only 26 nmol/L. While a therapeutic range is not yet established for quetiapine, we felt this level would not be efficacious, and we discontinued the phenytoin. Subsequently, her quetiapine blood level increased to 622 nmol/L while on 500 mg daily. Her psychosis improved considerably.

Ms B is a 46-year-old woman diagnosed with paranoid schizophrenia. We started her on quetiapine in May 1999 and titrated the quetiapine to a maximum of 800 mg daily over the following months. In November 2000, we added carbamazepine to try to augment the effect of quetiapine. Carbamazepine, like phenytoin, is a powerful inducer of CYP3A4 (3). While receiving quetiapine 800 mg and carbamazepine 1400 mg daily, her quetiapine level was 18 nmol/L. On June 26, 2001, we restarted Ms B on quetiapine therapy alone. Quetiapine blood level taken July 17, 2001, was 249 nmol/L on quetiapine 800 mg daily.

The drug–drug interactions are much more significant than anticipated from the literature. In contrast to previous reports, we found a 24-fold and a 14-fold reduction of quetiapine blood levels on therapeutic doses of phenytoin and carbamazepine, respectively. This may be explained by the difference in time allowed for CYP3A4 induction, because previous reports measured quetiapine plasma concentrations after only 10 days of phenytoin administration (2). If we had not been aware of this effect, we would have abandoned quetiapine prematurely. Clinicians need to be vigilant about the marked impact drugs affecting the CYP3A4 isoenzyme can have on quetiapine blood levels.

References

Ingrid Savasi, Msc
Richard C Millson, MD
James A Owen, PhD
Kingston, Ontario