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Predictive Model of Bosentan-Induced Liver Toxicity in Japanese Patients with Pulmonary Arterial Hypertension

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Predictive Model of Bosentan-Induced Liver Toxicity in Japanese Patients with Pulmonary Arterial Hypertension Canadian Journal of Physiology and Pharmacology Predictive model of bosentan-induced liver toxicity in Japanese patients with pulmonary arterial hypertension Journal: Canadian Journal of Physiology and Pharmacology Manuscript ID cjpp-2019-0656.R1 Manuscript Type: Article Date Submitted by the 24-Mar-2020 Author: Complete List of Authors: Yorifuji, Kennosuke; Shinko Hospital Uemura, Yuko; Shinko Hospital Horibata, Shinji; Shinko Hospital Tsuji, Goh; Shinko Hospital Suzuki, Yoko;Draft Kobe Pharmaceutical University, Clinical Pharmaceutical Science Nakayama, Kazuhiko; Shinko Hospital Hatae, Takashi; Kobe Pharmaceutical University Kumagai, Shunichi; Shinko Hospital EMOTO, Noriaki; Kobe Pharmaceutical University, Clinical Pharmaceutical Science; Kobe University Graduate School of Medicine School of Medicine, Division of Cardiovascular Medicine Is the invited manuscript for consideration in a Special ET-16 Kobe 2019 Issue: bosentan, pulmonary arterial hypertension, pharmacogenetics, CHST3, Keyword: CHST13 https://mc06.manuscriptcentral.com/cjpp-pubs Page 1 of 13 Canadian Journal of Physiology and Pharmacology Predictive model of bosentan-induced liver toxicity in Japanese patients with pulmonary arterial hypertension Kennosuke Yorifuji, M.Pharm.1, 2, 3; Yuko Uemura2; Shinji Horibata, M.Pharm.2, 3; Goh Tsuji, M.D., PhD.2, 4; Yoko Suzuki, M.Pharm.1, 5; Kazuhiko Nakayama, M.D., PhD.6; Takashi Hatae, PhD.7; Shunichi Kumagai, M.D., PhD.2, 4; Noriaki Emoto, M.D., PhD.1, 5 1Laboratory of Clinical Pharmaceutical Science, 7 Education and Research Center for Clinical Pharmacy, Kobe Pharmaceutical University, 4-19-1 Motoyama-kitamachi, Higashinada, Kobe 658-8558, Japan 2The Shinko Institute for Medical Research, 3Department of Pharmacy, and 4Center for Rheumatic Diseases, 6Depertment ofDraft Cardiovascular Medicine Shinko Hospital, 1-4-47, Wakinohama, Chuo, Kobe 651-0072, Japan 5Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe Graduate School of Medicine, 7-5-1 Kusunoki, Chuo, Kobe 650-0017, Japan *To whom correspondence should be addressed: Noriaki Emoto, MD, PhD. Laboratory of Clinical Pharmaceutical Science, Kobe Pharmaceutical University 4-19-1, Motoyama-kitamachi, Higashinada, 658-8558 Kobe, Japan Tel. and Fax: +81-78-441-7536 E-mail: [email protected] Keywords: Bosentan, Pulmonary arterial hypertension, Pharmacogenomics, CHST3, https://mc06.manuscriptcentral.com/cjpp-pubs Canadian Journal of Physiology and Pharmacology Page 2 of 13 CHST13 Abstract Bosentan, an endothelin receptor antagonist, has been widely used as a first-line medication for the treatment of pulmonary arterial hypertension (PAH). It has been shown to improve symptoms of hypertension, exercise capacity, and hemodynamics and prolong time to clinical worsening. However, liver dysfunction is a major side effect of bosentan treatment that could hamper the optimal management of patients with PAH. Previously, we demonstrated, using drug metabolism enzymes and transporters (DMET) analysis, that the carbohydrate sulfotransferase 3 (CHST3) and CHST13 alleles are significantly more frequent in patients with elevated amino-transferases during therapy with bosentan than they are in patients without liver toxicity. In addition, we constructed a pharmacogenomics model to predict bosentan-induced liver injury in patients with PAH using two single nucleotide polymorphisms (SNPs) and two non-genetic factors. The purpose of the present study was to Draftexternally validate the predictive model of bosentan- induced liver toxicity in Japanese patients. We evaluated five cases of patients treated with bosentan, and one presented with liver dysfunction. We applied mutation alleles of CHST3 and CHST13, serum creatinine, and age to our model to predict liver dysfunction. The sensitivity and specificity were calculated as 100% and 50%, respectively. Considering that PAH is a rare disease, multicenter collaboration would be necessary to validate our model. Keywords: Bosentan, Pulmonary arterial hypertension, Pharmacogenomics, CHST3, CHST13 https://mc06.manuscriptcentral.com/cjpp-pubs Page 3 of 13 Canadian Journal of Physiology and Pharmacology Introduction Pulmonary arterial hypertension (PAH) is a rare disease with a high mortality rate (Galie N et al. 2016). Treatment options have improved in the last two decades including prostanoids, phosphodiesterase-5 (PDE-5) inhibitors, a soluble guanylate cyclase stimulator, and endothelin receptor antagonists (ERAs). Accordingly, the prognosis of PAH has improved dramatically. However, patients still die prematurely of right heart failure if left untreated or are inappropriately treated (Lau EMT et al. 2017). Currently, there are three ERAs available on the market for the treatment of PAH, bosentan, ambrisentan, and macitentan. Bosentan and macitentan are dual ERAs with similar affinity for the endothelin A (ETA) and ETB receptors whereas ambrisentan has a higher selectivity for the ETA receptor than for the ETB receptor (Vignon-Zellweger N et al. 2012). Bosentan is the first ERA approved for the clinical treatment of PAH, and it has been shown to improve clinical symptoms, exercise tolerance, and hemodynamic parameters and delay clinical progressionDraft of PAH (Miyagawa K and Emoto N. 2014). Furthermore, bosentan is approved for secondary prevention in patients with digital skin ulcers related to systemic sclerosis. Liver toxicity is the main adverse effect of bosentan, which is also associated with reversible, dose-dependent, and in most cases asymptomatic increase in aminotransferases. The reported annual rate of liver toxicity induced by bosentan was approximately 10% (Humbert M et al. 2007). The liver enzymes are elevated in the first six months of bosentan treatment but could also occur later on. Therefore, liver function monitoring is recommended monthly in patients receiving bosentan. Previously, we demonstrated that the carbohydrate sulfotransferase 3 (CHST3) and CHST13 alleles are significantly more frequent in patients with elevated amino- transferases during therapy with bosentan than they are in patients without liver toxicity using drug metabolism enzymes and transporters (DMET) analysis(Yorifuji K et al. 2018). Furthermore, we constructed a pharmacogenomics model to predict bosentan- induced liver injury in patients with PAH using two single nucleotide polymorphisms (SNPs) and two non-genetic factors (Yorifuji K et al. 2018). However, we cannot rule out the possibility that the results may be derived from random associations that occur to show the statistical significance. Thus, the implication of our model needs to be validated in an independent sample set. The primary aim of this study was to externally validate the predictive model of liver toxicity induced by bosentan treatment of Japanese patients. https://mc06.manuscriptcentral.com/cjpp-pubs Canadian Journal of Physiology and Pharmacology Page 4 of 13 Methods 1. Patients We evaluated four patients with PAH and one with digital ulcer treated with bosentan in August 2016 at Shinko Hospital. The study protocols were approved by the Institutional Review Board of Shinko Hospital (number 1615). All patients provided written informed consent prior to participating in the study. 2. Blood sampling and processing for genotype analysis For the five enrolled patients, stored whole blood samples were archived and subjected to DNA extraction. Genomic DNA was isolated using the QuickGene DNA whole blood kit S (Kurabo Industries, Osaka, Japan) according to the manufacturer’s recommendations. The primer designDraft was based on published sequences of CHST3 and CHST13 to avoid the amplification of sequences from homologous genes. Genotyping was performed using the StepOnePlus real-time polymerase chain reaction (PCR) system (Applied Biosystems, USA, Ltd.). PCR was carried out in a total reaction volume of 10 µL with 20 ng DNA, 5 µL TaqMan® GTXpress™ master mix (Applied Biosystems Ltd.), a TaqMan genotyping assay mix customized for studying SNP (rs4148953) and (rs6783962), and 25 µL water. The default thermal cycling conditions (20 s at 95°C followed by 40 cycles for 3 s at 95°C plus 20 s at 60°C) were used. 3. Risk evaluation of bosentan-induced liver injury We evaluated the risk of bosentan-induced liver injury using our predictive model as previously described. The SNP information of patients was evaluated using genotype analysis. The probability was calculated by substituting w/w = 0, w/m = 1, and m/m = 2. A total P > 0.4942 was considered a high-risk group. 4. Statistical analysis For test power analysis, we used the free software G*power (G*Power 3.1.9.2) (Faul F et al. 2007). Results https://mc06.manuscriptcentral.com/cjpp-pubs Page 5 of 13 Canadian Journal of Physiology and Pharmacology 1. Patient characteristics Table 1 shows the baseline characteristics of the five patients and the dosage of bosentan was 250 mg twice daily after a 4-week titration period (62.5 mg twice daily) in all cases. The underlining cause of PAH included systemic sclerosis (patients 1, 3, and 5), mixed connective tissue disease (patient 2), and congenital heart disease (patient 4). Patient 5 showed elevated transaminase levels 3 weeks after bosentan initiation. The aspartate transaminase (AST) and alanine transaminase (ALT) value were 2.74 × upper limit normal (ULN) and 1.94 × ULN, respectively. Treatment with ursodeoxycholic acid normalized the transaminase levels in 2 weeks without changing the bosentan dosage. Other patients did not show elevated aminotransferases for up to
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