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<p class="ltrs-br-ltr-br-title">Pharmacokinetic Drug-Drug Interactions Between Olanzapine and Valproate Need to Be Better Studied</p>
<p class="ltrs-br-ltr-br-body-text"><span class="bold">To the Editor:</span> We read with interest the study by Houston et al<span class="htm-cite"><a href="#ref1">1</a> </span>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,<span class="htm-cite"><a href="#ref2">2</a></span> 10 mg/d of olanzapine for 2 weeks did not influence valproate concentrations. Divalproex prescribing information<span class="htm-cite"><a href="#ref3">3</a></span> does not mention olanzapine.</p>
<p class="ltrs-br-ltr-br-body-text">Olanzapine is mainly metabolized by the cytochrome P450 (CYP) 1A2 and uridine diphosphate glucuronosyltransferases (UGTs), possibly UGT1A4,<span class="htm-cite"><a href="#ref4">4</a></span> with minor roles played by CYP2D6 and the flavin monooxygenase system.<span class="htm-cite"><a href="#ref4">4</a></span> Valproate is mainly metabolized by several UGTs and β-oxidation and less so by some CYPs (probably CYP2C9).<span class="htm-cite"><a href="#ref5">5</a></span> Olanzapine is probably not a clinically relevant inducer or inhibitor.<span class="htm-cite"><a href="#ref4">4</a>,<a href="#ref6">6</a></span> However, valproate is definitely a clinically relevant inhibitor of some metabolic enzymes including some UGTs (valproate increases lamotrigine levels) and CYP2C9.<span class="htm-cite"><a href="#ref5">5</a></span> Valproate may potentially induce some metabolic enzymes, its own β-oxidation,<span class="htm-cite"><a href="#ref7">7</a></span> and, according to an in vitro study, CYP3A and the P-glycoprotein.<span class="htm-cite"><a href="#ref8">8</a></span></p>
<p class="ltrs-br-ltr-br-body-text">Psychiatrists skeptical of the clinical relevance of mood stabilizer DDIs should remember Yatham and colleagues’ study,<span class="htm-cite"><a href="#ref9">9</a></span> 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 hypothesized<span class="htm-cite"><a href="#ref10">10</a></span> and demonstrated.<span class="htm-cite"><a href="#ref11">11</a></span> 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. </p>
<p class="ltrs-br-ltr-br-body-text">In the absence of such studies, Bergemann et al<span class="htm-cite"><a href="#ref12">12</a></span> found a halving of olanzapine concentrations in 4 patients who received valproate, and we<span class="htm-cite"><a href="#ref13">13</a></span> 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<span class="thinspace"> </span>±<span class="thinspace"> </span>9.7 ng/mL at baseline to 27.4<span class="thinspace"> </span>±<span class="thinspace"> </span>9.8 ng/mL at week 2 (<span class="italic">P</span><span class="thinspace"> </span>=<span class="thinspace"> </span>.02) and 26.9<span class="thinspace"> </span>±<span class="thinspace"> </span>9.2 ng/mL at week 4 (<span class="italic">P</span><span class="thinspace"> </span>=<span class="thinspace"> </span>.001). Thus, valproate was associated with minimal average decreases in olanzapine concentration, possibly due to induction of olanzapine metabolism.<span class="htm-cite"><a href="#ref13">13</a></span> 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,<span class="htm-cite"><a href="#ref13">13</a></span> which may be lower than the therapeutic range.<span class="htm-cite"><a href="#ref14">14</a></span> </p>
<p class="ltrs-br-ltr-br-body-text">New valproate-olanzapine DDI studies with longer duration and more repeated measures are needed to establish our preliminary finding<span class="htm-cite"><a href="#ref13">13</a></span> 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.<span class="htm-cite"><a href="#ref15">15</a></span></p>
<p class="ltrs-br-ltr-br-references-head"><span class="smallcaps">References</span></p>
<p class="references-references-text-1-9"><a name="ref1"></a>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. <span class="italic">J Clin Psychiatry</span>. 2009;70(11):1540–1547. <span class="pubmed-crossref"><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=19778495&dopt=Abstract">PubMed</a> <a href="http://dx.doi.org/10.4088/JCP.08m04895yel">doi:10.4088/JCP.08m04895yel</a></span></p>
<p class="references-references-text-1-9"><a name="ref2"></a>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. </p>
<p class="references-references-text-1-9"><a name="ref3"></a>3. Depakote Capsules for Oral Use [package insert]. North Chicago, IL: Abbott Laboratories; 2009. </p>
<p class="references-references-text-1-9"><a name="ref4"></a>4. Spina EA, de Leon J. Metabolic drug interactions with newer antipsychotics: a comparative review. <span class="italic">Basic Clin Pharmacol Toxicol</span>. 2007;100(1):4–22. <span class="pubmed-crossref"><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=17214606&dopt=Abstract">PubMed</a> <a href="http://dx.doi.org/10.1111/j.1742-7843.2007.00017.x">doi:10.111/j.1742-7843.2007.00017.x</a></span></p>
<p class="references-references-text-1-9"><a name="ref5"></a>5. Anderson GD. A mechanistic approach to antiepileptic drug interactions. <span class="italic">Ann Pharmacother</span>. 1998;32(5):554–563. <span class="pubmed-crossref"><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9606477&dopt=Abstract">PubMed</a> <a href="http://dx.doi.org/10.1345/aph.17332">doi:10.1345/aph.17332</a></span></p>
<p class="references-references-text-1-9"><a name="ref6"></a>6. de Leon J, Armstrong SC, Cozza KL. The dosing of atypical antipsychotics. <span class="italic">Psychosomatics</span>. 2005;46(3):262–273. <span class="pubmed-crossref"><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15883149&dopt=Abstract">PubMed</a> <a href="http://dx.doi.org/10.1176/appi.psy.46.3.262">doi:10.1176/appi.psy.46.3.262</a></span></p>
<p class="references-references-text-1-9"><a name="ref7"></a>7. McLaughlin DB, Andrews JA, Hooper WD, et al. Apparent autoinduction of valproate β-oxidation in humans. <span class="italic">Br J Clin Pharmacol</span>. 2000;49(5):409–415. <span class="pubmed-crossref"><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10792197&dopt=Abstract">PubMed</a> <a href="http://dx.doi.org/10.1046/j.1365-2125.2000.00191.x">doi:10.1046/j.1365-2125.2000.00191.x</a></span></p>
<p class="references-references-text-1-9"><a name="ref8"></a>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. <span class="italic">Drug Metab Dispos</span>. 2007;35(7):1032–1041. <span class="pubmed-crossref"><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=17392393&dopt=Abstract">PubMed</a> <a href="http://dx.doi.org/10.1124/dmd.106.014456">doi:10.1124/dmd.106.014456</a></span></p>
<p class="references-references-text-1-9"><a name="ref9"></a>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. <span class="italic">Br J Psychiatry</span>. 2003;182(2):141–147. <span class="pubmed-crossref"><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12562742&dopt=Abstract">PubMed</a> <a href="http://dx.doi.org/10.1192/bjp.182.2.141">doi:10.1192/bjp.182.2.141</a></span></p>
<p class="references-references-text-10-99"><a name="ref10"></a>10. de Leon J, Bork JA. Risperidone and cytochrome P450 3A [letter]. <span class="italic">J Clin Psychiatry</span>. 1997;58(10):450. <span class="pubmed-crossref"><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9375597&dopt=Abstract">PubMed</a></span></p>
<p class="references-references-text-10-99"><a name="ref11"></a>11. Spina E, Avenoso A, Facciolà G, et al. Plasma concentrations of risperidone and 9-hydroxyrisperidone: effect of comedication with carbamazepine or valproate. <span class="italic">Ther Drug Monit</span>. 2000;22(4):481–485. <span class="pubmed-crossref"><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10942191&dopt=Abstract">PubMed</a> <a href="http://dx.doi.org/10.1097/00007691-200008000-00019">doi:10.1097/00007691-200008000-00019</a></span></p>
<p class="references-references-text-10-99"><a name="ref12"></a>12. Bergemann N, Kress KR, Abu-Tair F, et al. Valproate lowers plasma concentration of olanzapine. <span class="italic">J Clin Psychopharmacol</span>. 2006;26(4):432–434. <span class="pubmed-crossref"><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=16855466&dopt=Abstract">PubMed</a> <a href="http://dx.doi.org/10.1097/01.jcp.0000227353.46450.52">doi:10.1097/01.jcp.0000227353.46450.52</a></span></p>
<p class="references-references-text-10-99"><a name="ref13"></a>13. Spina E, D’Arrigo C, Santoro V, et al. Effect of valproate on olanzapine plasma concentrations in patients with bipolar or schizoaffective disorder. <span class="italic">Ther Drug Monit</span>. 2009;31(6):758–763. <span class="pubmed-crossref"><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=19865002&dopt=Abstract">PubMed</a></span></p>
<p class="references-references-text-10-99"><a name="ref14"></a>14. Baumann P, Hiemke C, Ulrich S, et al. The AGNP-TDM expert group consensus guidelines: therapeutic drug monitoring in psychiatry. <span class="italic">Pharmacopsychiatry</span>. 2004;37(6):243–265. <span class="pubmed-crossref"><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15551191&dopt=Abstract">PubMed</a> <a href="http://dx.doi.org/10.1055/s-2004-832687">doi:10.1055/s-2004-832687</a></span></p>
<p class="references-references-text-10-99"><a name="ref15"></a>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. <span class="italic">J Clin Psychopharmacol</span>. 2009;29(3):201–205. <span class="pubmed-crossref"><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=19440070&dopt=Abstract">PubMed</a> <a href="http://dx.doi.org/10.1097/JCP.0b013e3181a497f1">doi:10.1097/JCP.0b013e3181a497f1</a></span></p>
<p class="ltrs-br-ltr-br-author"><span class="bold">Jose de Leon, MD</span></p>
<p class="ltrs-br-ltr-br-author"><a href="mailto:jdeleon@uky.edu">jdeleon@uky.edu</a></p>
  <p class="ltrs-br-ltr-br-author"><span class="bold">Francisco J. Diaz, PhD</span></p>
<p class="ltrs-br-ltr-br-author"><span class="bold">Edoardo Spina, MD, PhD</span></p>
<p class="ltrs-br-ltr-br-endmatter-fieldnotes"><span class="bold-italic">Author affiliations:</span> 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). <span class="bold-italic">Potential conflicts of interest:</span> <span class="bold">Dr de Leon</span> is currently a coinvestigator for a National Institutes of Health Small Business Innovation Research Grant awarded to Genomas, Inc. Since December 1, 2008, <span class="bold">Dr de Leon</span> 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, <span class="bold">Drs Diaz </span>and<span class="bold"> Spina</span> report no conflict of interest with any pharmaceutical company. <span class="bold-italic">Funding/support: </span>None reported. <span class="bold-italic">Acknowledgment:</span> 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.</p>
<p class="ltrs-br-ltr-br-copyright-doi"><span class="doi">doi:10.4088/JCP.09lr05902yel</span></p>
<p class="ltrs-br-ltr-br-copyright-doi"><span class="italic">© Copyright 2010 Physicians Postgraduate Press, Inc.</span></p>
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