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Pharmacokinetic Drug-Drug Interactions Between Olanzapine and Valproate Need to Be Better Studied

To the Editor: We read with interest the study by Houston et al1 of olanzapine versus placebo in bipolar patients taking divalproex for at least 2 weeks. The authors did not mention the lack of published pharmacokinetic drug-drug interaction (DDI) studies of these drugs. According to olanzapine prescribing information,2 10 mg/d of olanzapine for 2 weeks did not influence valproate concentrations. Divalproex prescribing information3 does not mention olanzapine.

Olanzapine is mainly metabolized by the cytochrome P450 (CYP) 1A2 and uridine diphosphate glucuronosyltransferases (UGTs), possibly UGT1A4,4 with minor roles played by CYP2D6 and the flavin monooxygenase system.4 Valproate is mainly metabolized by several UGTs and β-oxidation and less so by some CYPs (probably CYP2C9).5 Olanzapine is probably not a clinically relevant inducer or inhibitor.4,6 However, valproate is definitely a clinically relevant inhibitor of some metabolic enzymes including some UGTs (valproate increases lamotrigine levels) and CYP2C9.5 Valproate may potentially induce some metabolic enzymes, its own β-oxidation,7 and, according to an in vitro study, CYP3A and the P-glycoprotein.8

Psychiatrists skeptical of the clinical relevance of mood stabilizer DDIs should remember Yatham and colleagues’ study,9 which failed to demonstrate that risperidone was better than placebo for mania in patients taking carbamazepine. When considering the study design, the risperidone marketer forgot that carbamazepine is a powerful inducer of risperidone metabolism, which had previously been hypothesized10 and demonstrated.11 Pharmaceutical companies are apparently not particularly interested in mood stabilizer DDIs. The frequent clinical use of valproate-olanzapine combinations should have prompted their marketers to use their abundant resources to conduct pharmacokinetic DDI studies.

In the absence of such studies, Bergemann et al12 found a halving of olanzapine concentrations in 4 patients who received valproate, and we13 completed a preliminary study in which a valproate dose ranging from 600 to 2000 mg/d was administered for 4 weeks to 18 patients stabilized on treatment with olanzapine (5–20 mg/d). During valproate coadministration, mean plasma olanzapine concentrations in our sample decreased significantly from 32.9 ± 9.7 ng/mL at baseline to 27.4 ± 9.8 ng/mL at week 2 (P = .02) and 26.9 ± 9.2 ng/mL at week 4 (P = .001). Thus, valproate was associated with minimal average decreases in olanzapine concentration, possibly due to induction of olanzapine metabolism.13 A small increase in olanzapine concentration between weeks 2 and 4 in patients with high valproate levels suggested competitive inhibition. A statistical model of a hypothetical smoker aged 40 years and taking 10 mg/d of olanzapine was used to provide some idea of the clinical relevance of valproate-olanzapine interactions. If this patient had a valproate level of 30 μg/mL, respective olanzapine concentrations of 24 and 21 ng/mL would be obtained at weeks 2 and 4. If the patient’s valproate level were 80 μg/mL, the respective predicted concentrations would be 6 and 10 ng/mL,13 which may be lower than the therapeutic range.14

New valproate-olanzapine DDI studies with longer duration and more repeated measures are needed to establish our preliminary finding13 that valproate induces olanzapine metabolism in a mild way, because, in extreme situations (high valproate concentrations or low olanzapine doses), the effect could be clinically relevant. These DDI studies should provide practical dosing recommendations for clinicians.15

References

1. Houston JP, Tohen M, Degenhardt EK, et al. Olanzapine-divalproex combination versus divalproex monotherapy in the treatment of bipolar mixed episodes: a double-blind, placebo-controlled study. J Clin Psychiatry. 2009;70(11):1540–1547. PubMed doi:10.4088/JCP.08m04895yel

2. Zyprexa Tablets for Oral Use, Zyprexa Zydis Tablet Orally Disintegrating for Oral Use, Zyprexa IntraMuscular, Powder, for Solution for Intramuscular Injection [highlights of prescribing information]. Indianapolis, IN: Eli Lilly and Company; 2009.

3. Depakote Capsules for Oral Use [package insert]. North Chicago, IL: Abbott Laboratories; 2009.

4. Spina EA, de Leon J. Metabolic drug interactions with newer antipsychotics: a comparative review. Basic Clin Pharmacol Toxicol. 2007;100(1):4–22. PubMed doi:10.111/j.1742-7843.2007.00017.x

5. Anderson GD. A mechanistic approach to antiepileptic drug interactions. Ann Pharmacother. 1998;32(5):554–563. PubMed doi:10.1345/aph.17332

6. de Leon J, Armstrong SC, Cozza KL. The dosing of atypical antipsychotics. Psychosomatics. 2005;46(3):262–273. PubMed doi:10.1176/appi.psy.46.3.262

7. McLaughlin DB, Andrews JA, Hooper WD, et al. Apparent autoinduction of valproate β-oxidation in humans. Br J Clin Pharmacol. 2000;49(5):409–415. PubMed doi:10.1046/j.1365-2125.2000.00191.x

8. Cerveny L, Svecova L, Anzenbacherova E, et al. Valproic acid induces CYP3A4 and MDR1 gene expression by activation of constitutive androstane receptor and pregnane X receptor pathways. Drug Metab Dispos. 2007;35(7):1032–1041. PubMed doi:10.1124/dmd.106.014456

9. Yatham LN, Grossman F, Augustyns I, et al. Mood stabilisers plus risperidone or placebo in the treatment of acute mania: international, double-blind, randomised controlled trial. Br J Psychiatry. 2003;182(2):141–147. PubMed doi:10.1192/bjp.182.2.141

10. de Leon J, Bork JA. Risperidone and cytochrome P450 3A [letter]. J Clin Psychiatry. 1997;58(10):450. PubMed

11. Spina E, Avenoso A, Facciolà G, et al. Plasma concentrations of risperidone and 9-hydroxyrisperidone: effect of comedication with carbamazepine or valproate. Ther Drug Monit. 2000;22(4):481–485. PubMed doi:10.1097/00007691-200008000-00019

12. Bergemann N, Kress KR, Abu-Tair F, et al. Valproate lowers plasma concentration of olanzapine. J Clin Psychopharmacol. 2006;26(4):432–434. PubMed doi:10.1097/01.jcp.0000227353.46450.52

13. Spina E, D’Arrigo C, Santoro V, et al. Effect of valproate on olanzapine plasma concentrations in patients with bipolar or schizoaffective disorder. Ther Drug Monit. 2009;31(6):758–763. PubMed

14. Baumann P, Hiemke C, Ulrich S, et al. The AGNP-TDM expert group consensus guidelines: therapeutic drug monitoring in psychiatry. Pharmacopsychiatry. 2004;37(6):243–265. PubMed doi:10.1055/s-2004-832687

15. de Leon J, Spina E, Diaz FJ. Pharmacokinetic drug interaction studies must consider pharmacological heterogeneity, use of repeated dosing, and translation into a message understandable to practicing clinicians. J Clin Psychopharmacol. 2009;29(3):201–205. PubMed doi:10.1097/JCP.0b013e3181a497f1

Jose de Leon, MD

jdeleon@uky.edu

Francisco J. Diaz, PhD

Edoardo Spina, MD, PhD

Author affiliations: Mental Health Research Center, Eastern State Hospital, Lexington, Kentucky (Dr de Leon); Psychiatry and Neurosciences Research Group (CTS-549), Institute of Neurosciences, University of Granada, Granada, Spain (Dr de Leon); Department of Biostatistics, University of Kansas Medical Center, Kansas City (Dr Diaz); and Section of Pharmacology, Department of Clinical and Experimental Medicine and Pharmacology, University of Messina, and IRCCS Centro Neurolesi “Bonino-Pulejo,” Messina, Italy (Dr Spina). Potential conflicts of interest: Dr de Leon is currently a coinvestigator for a National Institutes of Health Small Business Innovation Research Grant awarded to Genomas, Inc. Since December 1, 2008, Dr de Leon had no conflict of interest with any pharmaceutical company. He personally develops his presentations for lecturing, has never lectured using any pharmaceutical company presentation, and has never been a consultant for pharmacogenetic or pharmaceutical companies. Since December 1, 2008, Drs Diaz and Spina report no conflict of interest with any pharmaceutical company. Funding/support: None reported. Acknowledgment: The authors thank Lorraine Maw, MA, and Margaret T. Susce, RN, MLT, from the Mental Health Research Center at Eastern State Hospital, Lexington, Kentucky, for their editorial assistance. Mss Maw and Susce report no potential conflict of interest.