Open-label steady-state pharmacokinetic drug interaction study on co-administered quetiapine fumarate and divalproex sodium in patients with schizophrenia, schizoaffective disorder, or bipolar disorder.
OBJECTIVE
To determine whether there is a pharmacokinetic drug interaction between quetiapine fumarate and divalproex sodium.


METHODS
The pharmacokinetics and short-term tolerability and safety of coadministered quetiapine and divalproex were examined in adults with schizophrenia/schizoaffective disorder (Cohort A) or bipolar disorder (Cohort B) in an open-label, parallel, 2-cohort drug-interaction study conducted at three centers in the United States. Cohort A was administered quetiapine (150 mg bid) prospectively for 13 days, with divalproex (500 mg bid) added on days 6-13. Cohort B was administered divalproex (500 mg bid) for 16 days, with quetiapine (150 mg bid) added on days 9-16. Quetiapine and valproic acid plasma concentration-time data over a 12-h steady-state dosing interval were used to determine C(max), T(max), C(min), area under the plasma concentration-time curve (AUC(tau)), and oral clearance (CL/F).


RESULTS
In Cohort A (n = 18), addition of divalproex did increase the C(max) of quetiapine by 17% but did not change AUC(tau). In Cohort B (n = 15), addition of quetiapine decreased both total valproic acid C(max) and AUC(tau) by 11%. No differences were observed in adverse events (AEs) with either quetiapine or divalproex monotherapy or their combination.


CONCLUSIONS
Combination therapy with quetiapine (150 mg bid) and divalproex (500 mg bid) resulted in small and statistically non-significant pharmacokinetic changes.
Winter
Helen R
HR
AstraZeneca Pharmaceuticals LP, Wilmington, DE, USA. helen.winter@astrazeneca.com
DeVane
C Lindsay
CL
Figueroa
Carlos
C
Ennis
Debra J
DJ
Hamer-Maansson
Jennifer E
JE
Davis
Patty C
PC
Smith
Mark A
MA
D000328:Adult; D018692:Antimanic Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D014150:Antipsychotic Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D019540:Area Under Curve; D001714:Bipolar Disorder / Q000188:drug therapy*; D015331:Cohort Studies; D003987:Dibenzothiazepines / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D000069348:Quetiapine Fumarate; D012559:Schizophrenia / Q000188:drug therapy*; D012565:Schizophrenic Psychology; D014481:United States; D014635:Valproic Acid / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology
D018692:Antimanic Agents; D014150:Antipsychotic Agents; D003987:Dibenzothiazepines; D000069348:Quetiapine Fumarate; D014635:Valproic Acid