Pneumonia Can Cause Clozapine Intoxication: A Case Report

Author’s Accepted Manuscript Pneumonia can Cause Clozapine Intoxications: A Case ReportPneumonia clozapine Can-Jun Ruan, Xue-Yang Zhen, Xin-Liang Ge, Chuan-Yue Wang, Wei Guo, Yi-Lang Tang, WenBiao Li, Jose de Leon www.elsevier.com/locate/psym

PII: DOI: Reference:

S0033-3182(17)30127-5 http://dx.doi.org/10.1016/j.psym.2017.05.003 PSYM785

To appear in: Psychosomatics Cite this article as: Can-Jun Ruan, Xue-Yang Zhen, Xin-Liang Ge, Chuan-Yue Wang, Wei Guo, Yi-Lang Tang, Wen-Biao Li and Jose de Leon, Pneumonia can Cause Clozapine Intoxications: A Case ReportPneumonia clozapine, Psychosomatics, http://dx.doi.org/10.1016/j.psym.2017.05.003 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

1 Pneumonia can cause clozapine intoxications: a case report RUNNING TITLE: Pneumonia clozapine Can-Jun Ruan1,a, Xue-Yang Zhen2,a, Xin-Liang Ge2, Chuan-Yue Wang2,Wei Guo3,Yi-Lang Tang2,4, Wen-Biao Li1,*, Jose de Leon5,6* 1

Laboratory of Clinical Psychopharmacology, Beijing Key Laboratory of Mental Disorders, Beijing

Anding Hospital, Capital Medical University, Beijing, China 2

Department of Psychiatry, Beijing Key Laboratory of Mental Disorders, Beijing Institute for Brain

Disorders, Center of Schizophrenia, Beijing Anding Hospital, Capital Medical University, Beijing, China 3

Department of Pharmacy, Beijing Anding Hospital, Capital Medical University, Beijing, China

4

Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA,

USA 5

Mental Health Research Center, Eastern State Hospital, Lexington, KY, USA

6

Psychiatry and Neurosciences Research Group (CTS-549), Institute of Neurosciences, University of

Granada, Granada, Spain, and Biomedical Research Centre in Mental Health Net (CIBERSAM), Santiago Apóstol Hospital, University of the Basque Country, Vitoria, Spain a

The first two authors contributed equally to this paper.

*Corresponding author for managing article until publication: Jose de Leon, M.D., Mental Health Research Center at Eastern State Hospital, 1350 Bull Lea Road, Lexington, KY

40511.

E-mail:

[email protected] Phone: 1-859-246-8440 Fax: 1-859-246-8446 Address for reprints after publication: Wen-Biao Li, Beijing Anding Hospital, Capital Medical University, Capital Medical University, No.5 Ankang Lane, Dewai Avenue, Xicheng District, 100088 Beijing, China

2

Disclosure: No commercial organizations had any role in writing this paper for publication. All authors declare no competing interest during the last 36 months. All authors meet criteria for authorship and approved the final manuscript. The study was financed by three grants to the Beijing Anding Hospital. The principal investigators were Dr. Ruan (Beijing Science and Technology Plan Project Z171100001017074), Dr. Guo (Beijing Science and Technology Plan Project Z151100004015180) and Dr. Wang (Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding ZY201403). Acknowledgments: The authors are grateful to the reviewer who helped them to improve the text and table of this article. The authors acknowledge Lorraine Maw, M.A., at the Mental Health Research Center at Eastern State Hospital, Lexington, KY, who helped in editing this article. KEY WORDS: clozapine/blood; clozapine/metabolism; clozapine/pharmacokinetics; drug interaction; infection; inflammation; pneumonia.

3 INTRODUCTION Since the 1970s it was thought that respiratory infections, including pneumonia, may inhibit cytochrome P450 1A2 (CYP1A2) because they decrease theophylline clearance and theophylline metabolism is mediated by CYP1A2 inhibition.1 The mechanism was not completely understood, but it was thought that the release of cytokines during the infection decrease the activity and synthesis of CYP1A2.2 Therefore, Shilalukey et al.3 suggested that when a child taking theophylline develops an upper respiratory infection, the theophylline dose should be decreased almost by half. Using a 10-mg single oral dose in healthy volunteers, Bertilsson et al.4 proposed that CYP1A2 explains 70% of clozapine metabolism. Therefore, in 20025 when the last author observed symptoms of clozapine intoxication in a patient with an infection, he immediately decreased the clozapine dose since it takes several days to reach the ordered serum clozapine level. In that patient, after repeated levels, or what pharmacologists call therapeutic drug monitoring (TDM) and long-term follow-up, it was clear that the Streptococcal upper respiratory infection was associated with a 50% decrease in clozapine metabolism. Other similar cases were published during other severe infections or inflammations.6,7 After reviewing the limited available literature, it was proposed that during severe inflammations or severe infections, including pneumonia, it may be reasonable to cut the dose in half until TDM results are available to better personalize clozapine dosing in each patient.7 Currently, there is general agreement that severe inflammations can inhibit CYP1A2 and other CYPs by releasing cytokines.8 In an in vitro study, Olesen et al.9 found that CYP metabolism depends on clozapine dosages. At low concentrations, CYP1A2 is the most important pathway, but in higher concentrations, CYP2C19 is important, too. Other CYPs, such as CYP2C9, CYP2D6, and CYP3A4, had more minor roles. Therefore, during inflammation cytokines may inhibit clozapine metabolism by inhibiting both CYP1A2 and CYP2C19. A TDM guideline recommends steady-state early-morning serum concentrations for clozapine of 350-600 ng/mL;10 this indicates that clozapine has a relatively narrow therapeutic window or index. Some

4 clozapine adverse drug reactions (ADRs) such hypersalivation, seizures, constipation or sedation appear to be definitively dose-related, or more precisely, serum concentration-related. Therefore, many patients may have signs of clozapine intoxication with high TDMs but others appear to be very resistant to them and show no obvious signs of intoxication. In a dose-response double-blind clozapine study 5 patients out of 50 had serum clozapine concentrations >1000 ng/ml without obvious manifestations of clozapine intoxication.11 Patients are probably characterized by variability in personal, environmental and genetic influences on the receptors associated with pharmacodynamic actions, which may explain the presence or absence of clozapine ADRs in the context of high serum clozapine concentrations. The concentration-to-dose (C/D) ratio is a measure of the ability to eliminate the drug and is influenced by genetic, personal and environmental factors.12 Inhibitors increase the C/D ratio.12 The C/D ratio can be calculated by using only clozapine concentrations, which helps relate dosages to efficacy and can be used to personalize clozapine dosing. The total clozapine C/D ratio (calculated by adding clozapine and norclozapine concentrations) reflects clozapine clearance better than the clozapine C/D ratio5,12 and is better for estimating drug-drug interaction (DDI) effects on clozapine metabolism. Male tobacco smokers tend to have greater clozapine metabolism since smoking is a CYP1A2 inducer, while female non-smokers tend to have lower metabolic capacity since the estrogens may inhibit clozapine metabolism.13 Therefore, in the US, clozapine C/D ratios typically range from 0.6 to 1.2, with 0.6 as a typical value for male smokers and 1.2 as a typical value for female non-smokers.12 The C/D ratios in Chinese patients tend to be approximately double, with ranges from 1.2 to 2.4,12 reflecting that, compared with Caucasian patients, Chinese patients get approximately the same concentrations with half the dosage.14,15 Jaquenoud Sirot et al.16 reported that CYP2C19 poor metabolizers (PMs), who do not have any CYP2C19 activity, have 2.3-fold higher plasma clozapine concentrations than other patients which may contribute to explaining the lower metabolic capacity of Chinese patients, since approximately 25% of Chinese individuals are CYP2C19 PMs.12

5 This case in a Chinese patient using repeated clozapine TDM and statistical testing illustrates that pneumonia can increase clozapine C/D ratios and allows further comment on the clinical relevance of this issue. Pfuhlmann et al.17 recommended using serum C-reactive protein (CRP) elevations to establish the severity of inflammations in patients taking clozapine. Thus, serum CRP levels were measured, too. METHOD Clozapine Serum Concentrations and C/D ratios Trough serum clozapine and norclozapine concentrations were analyzed by using high performance liquid chromatography-ultraviolet (HPLC-UV) with a method validated by the Food and Drug Administration guidelines for biological methods. Concentrations were considered to be in steady state after 5 days, approximately 5 clozapine half-lives. Clozapine C/D ratios were calculated by dividing serum clozapine concentrations by daily dose. Total clozapine C/D ratios were calculated by dividing serum total clozapine concentrations (clozapine plus norclozapine) by the dose. Statistics The Statistical Package for the Social Sciences (SPSS 22) was used to analyze the repeated clozapine and total C/D ratios. Median C/D ratios are less sensitive to outliers, which is a major problem in small samples such as the one from this case. The Supplemental Table provides mean and standard deviations and a statistical test for significance for those readers who are interested. CASE REPORT A 35-year-old Han Chinese male with schizoaffective disorder had taken olanzapine, clozapine, valproic acid and lithium carbonate in the past. He was hospitalized due to a psychotic exacerbation. He smoked 5 cigarettes/day and refused to stop smoking, even while he had pneumonia. On day 14, the patient complained of cough and red sputum, but the physical examination showed no throat irritation or swelling of tonsils; wet rale was not heard in either lung, but the body temperature of the patient was 39.9° C. On day 16, his chest X-ray indicated pneumonia in the right lung and he was transferred to a general hospital.

6 The pneumonia started on day 14 and lasted until day 24, with its highest levels of severity between days 14 and 18 (see white blood cell count and CRP in the Table) and was aggressively treated with different antibiotics including cefoperazone sodium and azithromycin. None of the antibiotics were inhibitors of clozapine metabolism.11All co-medications are described in the Supplemental Table footnotes. Clozapine TDM The maximum serum clozapine and norclozapine concentrations were 2032.7 ng/ml and 748.7 ng/ml on day 14 (Supplemental Table) but there were no obvious symptoms or signs of clozapine intoxication. The Table describes 10 steady-state TDMs (3 other TDMs that were not during steady state are also available in the Supplemental Table). Before the pneumonia there was only one TDM that provided a clozapine C/D ratio and a total clozapine C/D ratio of 1.1 and 1.6, respectively. During the peak of pneumonia, there were two TDMs (days 14 and 15) that provided respective ratios of 6.8 and 6.2 for clozapine C/D and 9.3 and 9.0 for total clozapine C/D. On day 19, when the patient still had elevated CRP levels, the clozapine and total clozapine C/D ratios appeared to have returned to normal with respective values of 0.9 and 1.5. After the pneumonia was over, there were 6 TDMs during steady state, providing a median clozapine C/D ratio and a total C/D ratio of 1.3 and 1.9, respectively. They are slightly elevated when compared with baseline, which is probably explained by the addition of two possible mild clozapine inhibitors (valproate and sertraline in low doses).18 The median clozapine C/D ratios measured before pneumonia, at the peak of pneumonia, and after pneumonia were 1.1, 6.5 and 1.4. When comparing the baseline with the median during the peak of pneumonia, a correction factor of 0.17 (1.1/6.5=0.17) was obtained, indicating that, to compensate for the peak, the dose should have been multiplied by 0.17 or reduced by approximately 4/5.The median total

7 clozapine C/D ratios measured before pneumonia, at the peak of pneumonia, and after pneumonia were 1.6, 9.1 and 2.0. The median clozapine C/D ratio was 6.5 during the peak of pneumonia versus 1.3 during the times without pneumonia. The median total clozapine C/D ratio was 9.1 during the peak of pneumonia versus 1.9 during the times without pneumonia. Discussion This case describes a patient with a major elevation in clozapine TDM (>2000 ng/ml) during the peak of pneumonia. This high level was not associated with obvious signs of clozapine intoxication, but it cannot be ruled out that the fever and prostration during the peak of pneumonia may have obscured the signs of intoxication. Moreover, antibiotics were starting to control the infection when the high TDM values were obtained. We cannot rule out the possibility that if the pneumonia had not been aggressively treated the patient would have developed signs of clozapine intoxication. Obviously, the treating clinicians focused on helping the patient, rather than getting the best TDM data for publication. In that sense, several TDM values were far from ideal: 1) only one was available before the pneumonia, and 2) the six obtained after the pneumonia were contaminated by co-medication prescribed to augment clozapine. Similarly, the number of serum CRP levels was limited. On the other hand, this patient had multiple steady-state TDMs, allowing us to calculate that, at the peak of pneumonia, clozapine and total clozapine C/D ratios were remarkably higher than the 7 TDMs without pneumonia. The median clozapine C/D ratio without pneumonia was 1.3, within the range of what one should expect for a male Chinese smoker, but it increased substantially to a median 6.5 during the two TDMs at the peak of pneumonia. Clozapine, as with other antipsychotics, can interfere with swallowing and is particularly associated with high risk for sedation and hypersalivation, so it is not surprising that it may be associated with greater risks for pneumonia than other antipsychotics.19,20 It is likely that once pneumonia develops and cytokines are released, the possibility of a secondary clozapine intoxication may further contribute to the morbidity of the pneumonia,20 possibly increasing the mortality risk.

8 Conclusion This male Chinese smoker displayed a major elevation in clozapine levels (>2000 ng/ml) during the peak of pneumonia, with the median clozapine C/D ratio increasing from 1.3 to 6.9. Clozapine may be associated with greater risk of pneumonia than other antipsychotics. Clinicians need to be aware that pneumonia and other severe infections/inflammations can be associated with potential for major elevations in clozapine serum concentrations and potential for clozapine intoxication. It is important to collect a trough clozapine TDM and consider adjusting the clozapine dosage whenever a clozapine patient develops 1) a severe infection or inflammation, or 2) a CRP elevation which suggests an undiagnosed infection/inflammation.17 In this patient, the highest peak TDM was not available on the same day it was ordered, but it indicated that the clozapine dose should be cut by 4/5, which is much higher than in other published cases.5,7 Based on the limited literature and our personal experience,7 we are conservative and in favor of a simple recommendation, as was made for theophylline many years ago;3 if clozapine TDM is not available or it takes several days for results to arrive, clinicians should consider cutting the clozapine dosage in half during the infection/inflammation. If this patient’s psychiatrist had used that recommendation of cutting the dose in half as soon as the highest level of 2032.7 ng/ml was known, this would have substantially reduced the risks. In summary, in an ideal world, clinicians should receive clozapine TDM results on the same day that TDM levels were collected in the early morning and use that to personalize dosing in that specific patient. If that is not possible, they could start by cutting the dose in half until TDM data arrives. Finally, all clinicians using clozapine need to warn their patients and families to contact them when severe infections, such as pneumonia, develop and make them aware of the potential for clozapine intoxication.

9 References 1. Chang KC, Bell TD, Lauer BA, Chai H: Altered theophylline pharmacokinetics during acute respiratory viral illness. Lancet 1978; 1(8074):1132-1133 2. Abdel-Razzak Z, Loyer P, Fautrel A, et al: Cytokines down-regulate expression of major cytochrome P-450 enzymes in adult human hepatocytes in primary culture. Mol Pharmacol 1993;44(4):707-715 3. Shilalukey K, Robieu I, Spino M, Greenwald M, Shear N, Koren G: Are current pediatric dose recommendations for intravenous theophylline appropriate? J Asthma 1993; 30(2):109-112 4. Bertilsson L, Carrillo JA, Dahl ML, Llerena A, Alm C, Bondesson U, Sjöqvist F, IngelmanSundberg M: Clozapine disposition covaries with CYP1A2 activity determined by a caffeine test. Br J Clin Pharmacol 1994; 38(5):471-473 5. de Leon J, Diaz FJ: Serious respiratory infections can increase clozapine levels and contribute to side effects: a case report. Prog Neuropsychopharmacol Biol Psychiatry 2003;27(6):1059-1063 6. Haack MJ, Bak ML, Beurskens R, Maes M, Stolk LM, Delespaul PA: Toxic rise of clozapine plasma concentrations in relation to inflammation. Eur Neuropsychopharmacol 2003;13(5):381385 7. de Leon J: Respiratory infections rather than antibiotics may increase clozapine levels: a critical review of the literature. J Clin Psychiatry 2004;65(8):1144-1145 8. Shah RR, Smith RL: Inflammation-induced phenoconversion of polymorphic drug metabolizing enzymes: hypothesis with implications for personalized medicine. Drug Metab Dispos 2015;43(3):400-410 9. Olesen OV, Linnet K: Contributions of five human cytochrome P450 isoforms to the Ndemethylation of clozapine in vitro at low and high concentrations. J Clin Pharmacol 2001; 41(8):823-832

10 10. Hiemke C, Baumann P, Bergemann N, et al: AGNP consensus guidelines for therapeutic drug monitoring in psychiatry: update 2011. Pharmacopsychiatry 2011; 44(6):195-235 11. de Leon J, Henighan V, Stanilla JK, Simpson GM: Clozapine levels after clozapine discontinuation. J Clin Psychopharmacol 1996; 16(2):193-194 12. Spina E, de Leon J: Clinical applications of CYP genotyping in psychiatry. J Neural Transm (Vienna) 2015;122(1):5-28 13. Sandson NB, Cozza KL, Armstrong SC, Eckermann G, Fischer BA, Phillips B: Clozapine case series. Psychosomatics 2007; 48(2):170-175 14. Chang WH, Lin SK, Lane HY, Hu WH, Jann MW, Lin HN: Clozapine dosages and plasma drug concentrations. J Formos Med Assoc 1997; 96(8):599-605 15. Chong SA, Tan CH, Khoo YM, Lee HS, Wong KE, Ngui F, Winslow M: Clinical evaluation and plasma clozapine concentrations in Chinese patients with schizophrenia. Ther Drug Monit 1997; 19(2):219-223 16. JaquenoudSirot E, Knezevic B, Morena GP, et al: ABCB1 and cytochrome P450 polymorphisms: clinical pharmacogenetics of clozapine. J Clin Psychopharmacol 2009; 29(4):319-326 17. Pfuhlmann B, Hiemke C, Unterecker S, et al: Toxic clozapine serum levels during inflammatory reactions. J Clin Psychopharmacol 2009;29(4):392-394 18. Spina E, Hiemke C, de Leon J. Assessing drug-drug interactions through therapeutic drug monitoring when administering oral second-generation antipsychotics. Expert Opin Drug Metab Toxicol. 2016; 12(4):407-422 19. Stoecker ZR, George WT, O'Brien JB, Jancik J, Colon E, Rasimas JJ: Clozapine usage increases the incidence of pneumonia compared with risperidone and the general population: a retrospective comparison of clozapine, risperidone, and the general population in a single hospital over 25 months. Int Clin Psychopharmacol2017; 32(3):155-160

11 rd

20. Leung JG, Hasassri ME, Barreto JN, Nelson S, Morgan RJ 3 : Characterization of admission types in medically hospitalized patients prescribed clozapine. Psychosomatics 2017; 58(2):164172

12 TABLE. Changes in clozapine steady-state TDM, clozapine dosages and CRP before, during and after pneumoniaa Da y

Pneumon ia

Clozapi ne dose (mg/day )

Clozapine concentrati on (ng/mL)

Norclozapi ne concentrati on (ng/mL)

Clozapi ne C/D ratio

Tot al C/D rati o

CRP (mg/d l)

WBC count (x 109 cell/ L)

3 Before 150 164.0 80.6 1.1 1.6 14 During 300 2032.7 748.7 6.8 9.3 15 During 300 1867.2 832.9 6.2 9.0 20.9 19 During 350 322.1 216.0 0.9 1.5 5.59 8.1 22 During 400 32 After 425 771.8 402.8 1.8 2.8 9.6 34 After 400 37 After 400 39 After 400 583.8 210.5 1.5 2.0 41 After 400 46 After 400 467.5 205.9 1.2 1.7 49 After 350 53 After 350 361.6 206.6 1.0 1.6 55 After 400 56 After 400 60 After 400 557.4 336.2 1.4 2.2 64 After 400 451.0 272.7 1.1 1.8 C/D = concentration-to-dose; CRP = C-reactive protein; TDM = therapeutic drug monitoring; WBC = white blood cell count. a The Supplemental Table includes: 1) additional TDM results that were not obtained during steady state, allowing one to see how many days the dose was stable before TDM was collected, 2) all co-medications and dosage changes, and 3) statistical testing.