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Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 51 – No. 10/2013 (807-815)

Difference between the frequencies of antisecretory drug prescriptions in users of buffered vs. enteric-coated low-dose aspirin therapies

Hiroko Hachiken¹, Ai Murai¹, Kyoichi Wada², Takeshi Kuwahara², Kouichi Hosomi¹ and Mitsutaka Takada¹

¹Division of Clinical Drug Informatics, School of Pharmacy, Kinki University, and ²Department of Pharmacy, National Cerebral and Cardiovascular Center, Osaka, Japan
Objective: To provide further insights on the risks of gastrointestinal (GI) complications in individuals using low-dose aspirin (LDA), we investigated the concomitant use of LDA and antisecretory drugs. Additionally, we examined the frequency distributions of prescribing sequences for LDA and antisecretory drugs. Methods: Data from a computerized prescription order entry system was analyzed at the National Cerebral and Cardiovascular Center of Japan. LDA use in combination with H2-receptor antagonists (H2RAs) and proton pomp inhibitors (PPIs) was examined over the period from January 2001 to December 2010. Prescription sequence symmetry analyses were used to identify LDA-induced H2RAs or PPIs users. Results: In December 2010, PPIs accounted for 9.9% of the prescriptions for buffered LDA users and 16.1% of those for enteric-coated LDA users. Incident use of PPIs occurred more frequently among enteric-coated LDA users than buffered LDA users (17.6% vs. 11.0%, respectively). Prescription sequence symmetry analyses of PPI use revealed significant associations with enteric-coated LDA use, resulting in adjusted sequence ratios of 1.82 (95%CI, 1.11 – 3.03) and 1.87 (95% CI, 1.26 – 2.83) at intervals of 182 and 365 days, respectively. Enteric-coated LDA users tended to initiate PPI therapy on the same date more frequently than buffered LDA users (35.1% vs. 10.8%, respectively). Conclusions: Our findings do not support the notion that entericcoated LDA products confer a lower risk for GI complications than buffered formulations, but may conversely imply that the risk of GI complications associated with buffered LDA is lower than that of enteric-coated LDA.Correspondence to:
Mitsutaka Takada, PhD
Division of Clinical Drug Informatics
School of Pharmacy, Kinki University
577-8502, 3-4-1, Kowakae,
Higashi-osaka, Osaka, 577-8502, Japan
Email: [email protected]

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 52 – No. 3/2014 (181-191)

Difference in risk of gastrointestinal complications between users of enteric-coated and buffered low-dose aspirin

Mitsutaka Takada, Mai Fujimoto, and Kouichi Hosomi

Division of Clinical Drug Informatics, School of Pharmacy, Kinki University, Osaka, Japan
Objective: Difference in the risk of gastrointestinal (GI) complications between users of enteric-coated and buffered low-dose aspirin (LDA) is unclear. The purpose of the study is to examine the difference in risk of GI damage between enteric-coated and buffered LDA products. Methods: A large and chronologically organized receipt database constructed by a database vendor was utilized. Prescription and event sequence symmetry analysis was used to identify the risk of LDA-induced GI complications over the period from January 2005 to July 2011. LDA use in combination with H2-receptor antagonists (H2RAs) and proton pump inhibitors (PPIs) was examined by prescription sequence symmetry analysis. Likewise, symmetry analysis was undertaken to evaluate the association between the diagnosis of GI disease and the prescription of LDA products. Results: In July 2011, enteric-coated LDA users were more frequently co-administered PPIs than buffered LDA users (25.4% vs. 14.4%). Prescription sequence symmetry analysis of acid inhibitor use found no significant associations with enteric-coated LDA use and buffered LDA use. The event sequence symmetry analysis of ulcer, gastritis and duodenitis, and melena found significant associations with entericcoated LDA use, with adjusted sequence ratios (ASRs) of 1.58 (1.23 – 2.06), 1.30 (1.03 – 1.65), and 14.38 (2.19 – 607.95), respectively, at the 6-month interval. At the 12-month interval, analysis of ulcers and melena found significant associations for enteric-coated LDA users, with ASRs of 1.39 (1.13 – 1.73) and 20.83 (3.33 – 863.25), respectively. Conclusions: Our findings do not support that there is no difference in the risk of GI complications between enteric-coated LDA and buffered LDA, but rather may imply that the risk of GI complications associated with enteric-coated LDA is higher than that with buffered LDA.Correspondence to:
Mitsutaka Takada, PhD
Division of Clinical Drug Informatics
School of Pharmacy, Kinki University
577-8502, 3-4-1, Kowakae,
Higashi-osaka, Osaka 577-8502, Japan
Email: [email protected]

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 52 – No. 4/2014 (259-266)

Statin-associated lower urinary tract symptoms: data mining of the public version of the FDA adverse event reporting system, FAERS

Mai Fujimoto, Kouichi Hosomi, and Mitsutaka Takada

Division of Clinical Drug Informatics, School of Pharmacy, Kinki University, Osaka, Japan
Objective: To examine the association between statin use and the risk of lower urinary tract symptoms (LUTS) in reports submitted to the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) between 2004 and 2011. Methods: Relevant reports in the FAERS were identified and analyzed. The reporting odds ratio (ROR) was used to detect spontaneous report signals, calculated using the case/non-case method. Cases were identified by the presence of reports of an adverse drug reaction (ADR) in which statins were the suspected drug. Non-cases were all the reports of the same reactions induced by drugs other than statins. The reporting odds ratio (ROR) and 95% confidential interval (CI) was calculated as a measure of disproportionality. Results: A total of 44,959,104 drug-reaction pairs was found in 2,681,739 reports. Significant RORs were found for both voiding (ROR; 1.16, 95% CI; 1.10 – 1.23) and storage symptoms (ROR; 1.25, 95% CI; 1.20 – 1.30). Analysis of individual statins showed that rosuvastatin, atorvastatin, and lovastatin had significant disproportionality for voiding symptoms, while simvastatin, rosuvastatin, pravastatin, atorvastatin, pitavastatin, and lovastatin had significant disproportionality for storage symptoms. Of the four voiding symptoms, significant RORs were found for urine flow decrease and dysuria. Of the four storage symptoms, significant RORs were found for pollakiuria and nocturia. No fundamental differences in disproportionality were observed between genders. Conclusions: Analysis of the FAERS database showed small but reliable signals for LUTS in statin users. The mechanism responsible for these reactions is unknown. However, these adverse events should be monitored closely.Correspondence to:
Mitsutaka Takada, PhD
Division of Clinical Drug Informatics
School of Pharmacy, Kinki University
3-4-1, Kowakae, Higashi-osaka, Osaka, 577-8502, Japan
Email: [email protected]

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 52 – No. 9/2014 (762-769)

Association of statin use with storage lower urinary tract symptoms (LUTS): data mining of prescription database

Mai Fujimoto, Tomoya Higuchi, Kouichi Hosomi, and Mitsutaka Takada

Division of Clinical Drug Informatics, School of Pharmacy, Kinki University, Osaka, Japan
Objective: The efficacy and safety of statins have been studied in a number of clinical trials and epidemiological studies. In recent years, the Medicine and Healthcare Products Regulatory Agency (MHRA) has assessed the evidence available on the following adverse reactions associated with the use of statins: sleep disturbances, memory loss, micturition disorders (problems with urination), sexual disturbances, depression, and interstitial pneumopathy. However, the association between statin use and the risk of these adverse reactions remains unclear. To examine the association between statin use and the risk of lower urinary tract symptoms (LUTS) or the disorder causing LUTS, we carried out data mining using a prescription database. Methods: A large organized database of prescriptions constructed by a database vendor was used in the study. Symmetry analysis was used to identify the risk of LUTS after using statins over the period January 2006 to August 2013. Statin use in combination with drugs administered for storage LUTS was examined by prescription sequence symmetry analysis (PSSA). Results: A significant association between statins and drugs for storage LUTS was found, with adjusted sequence ratios (ASRs) of 1.21 (95% CI, 1.00 – 1.46), 1.19 (95% CI, 1.04 – 1.38), and 1.17 (95% CI, 1.05 – 1.30) for intervals of 91, 182, and 365 days, respectively. In the analyses of individual statins, significant associations were found only for pravastatin. Significant associations with individual drugs for storage LUTS were found for solifenacin succinate with ASRs of 1.36 (95% CI, 1.02 – 1.81), 1.48 (95% CI, 1.19 – 1.84), and 1.47 (95% CI, 1.25 – 1.73) for intervals of 91, 182, and 365 days, for flavoxate hydrochloride with an ASR of 1.56 (95% CI, 1.13 – 2.17) at an interval of 182 days, and for oxybutynin hydrochloride with ASRs of 2.06 (95% CI, 1.11 – 3.94) and 1.71 (95% CI, 1.09 – 2.72) at intervals of 182 and 365 days. Significant associations with gender were found only in females with ASRs of 1.25 (95% CI, 1.04 – 1.51) and 1.23 (95% CI, 1.07 – 1.41) at intervals of 182 and 365 days, respectively. Conclusions: Analysis of the prescription database showed significant association for storage LUTS in statin users.Correspondence to:
Mitsutaka Takada, PhD
Division of Clinical Drug Informatics
School of Pharmacy, Kink University
577-8502, 3-4-1, Kowakae, Higashi-osaka, Osaka, 577-8502, Japan
Email: [email protected]

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 54 – No. 10/2016 (795-803)

Long-term impact of therapeutic drug monitoring on the risk of hypoglycemia in HOCM patients on cibenzoline therapy 

Yutaro Mukai¹,², Kyoichi Wada¹,², Mai Fujimoto³, Kouichi Hosomi³, Takeshi Kuwahara¹,², Mitsutaka Takada²,³

¹Department of Pharmacy, National Cerebral and Cardiovascular Center, Suita, Osaka, ²Division of Cardiovascular Drugs and Therapy, Kindai University Graduate School of Pharmacy, Higashi-osaka, and ³Division of Clinical Drug Informatics, Kindai University School of Pharmacy, Higashi-osaka, Japan
Objective: The purpose of this study was to evaluate the long-term impact of therapeutic drug monitoring (TDM) services on the risk of hypoglycemia in cibenzoline therapy. In addition, we evaluated the impact of changes in clinical setting or patient background on the risk of hypoglycemia in patients receiving cibenzoline. Methods: TDM services for cibenzoline have been performed at the Japan National Cerebral and Cardiovascular Center since March 1998. A case-control study was performed from September 2012 to February 2013, and the calculated risk of hypoglycemia associated with cibenzoline use was compared with data from our previous studies, which were performed ~ 15 years ago. Results: A significantly increased risk for hypoglycemia was observed for users of cibenzoline (adjusted OR: 2.6; 95% CI: 1.5 – 4.7). In an additional analysis, the calculated risk was slightly reduced (adjusted OR; 2.1, 95% CI; 1.1 – 3.8) and hypertrophic obstructive cardiomyopathy (HOCM) was identified as a possible risk factor for hypoglycemia (adjusted OR: 4.7, 95% CI: 1.8 – 12.3). There was a significant difference in the mean level of cibenzoline between outpatients with and without HOCM (360.5 ± 166.9 ng/mL vs. 276.4 ± 136.3 ng/mL). An inverse relationship was observed between the percentage of outpatients whose cibenzoline serum level had been measured and their risk of hypoglycemia. Conclusions: Consistent TDM services for cibenzoline have contributed to a reduced risk of hypoglycemia associated with cibenzoline therapy. Patients with HOCM have a higher risk of developing hypoglycemia. Clinicians should therefore carefully monitor serum glucose levels in patients with HOCM taking cibenzoline. Correspondence to:
Mitsutaka Takada, PhD
Division of Clinical Drug Informatics
Kindai University School of Pharmacy
577-8502, 3-4-1, Kowakae, Higashi-osaka,
Osaka, 577-8502, Japan
Email: takada@ phar.kindai.ac.jp

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 55 – No. 4/2017 (295-303)

Angiotensin receptor blockers and the risk of cancer: data mining of a spontaneous reporting database and a claims database 

Mai Fujimoto, Migiwa Kanou, Kouichi Hosomi, Mitsutaka Takada 

Division of Clinical Drug Informatics, School of Pharmacy, Kindai University, Osaka, Japan
Objective: The aim of this study was to examine the associations between angiotensin receptor blockers (ARBs) and the risk of 10 major cancers by employing different pharmacoepidemiological assessments. Materials & methods: Data from the first quarter of 2004 through 2012 were downloaded from the US Food and Drug Administration Adverse Event Reporting System (FAERS). The reporting odds ratio (ROR) and information component (IC) were used to detect the signals. Furthermore, symmetry analysis was applied to the claims database to identify the risk of cancer after using ARBs from January 2005 to July 2013. Results: Significant inverse associations were found for all cancer types assessed as a whole (ROR: 0.78, 95% confidence interval (CI): 0.75 – 0.80; IC: –0.36, 95% CI: –0.40 to –0.31) in the analyses of FAERS database. Likewise, significant inverse association was found for all cancer types assessed as a whole (adjusted sequence ratio: 0.89, 95% CI: 0.82 – 0.96) in claims database. In addition, a significantly decreased risk for breast cancer and increased risks for pancreatic and prostate cancer were found in patients treated with ARBs in the analyses of individual cancers. Conclusions: Significant inverse association was found between ARB use and all cancer types assessed as a whole. However, in the analyses of individual cancers, the risks of ARB-induced cancer may differ according to cancer site. It may be reasonable to assume that the risks of ARB-induced cancer may differ according to cancer site. Correspondence to:
Mitsutaka Takada, PhD
Division of Clinical Drug Informatics
School of Pharmacy, Kindai University
577-8502, 3-4-1, Kowakae, Higashi-osaka,
Osaka, 577-8502, Japan 
Email: takada@ phar.kindai.ac.jp

Abstract

Risk of malignant lymphoma in patients with rheumatoid arthritis treated with biological disease-modifying antirheumatic drugs and methotrexate 

Ryo Inose¹, Kouichi Hosomi², Katsuyuki Takahashi¹, Satoshi Yokoyama², and Mitsutaka Takada²

¹Department of Pharmacy, Osaka City University Hospital, and ²Division of Clinical Drug Informatics, School of Pharmacy, Kindai University, Osaka, Japan
Objective: This study investigated whether using biological disease-modifying antirheumatic drugs (bDMARDs) further increases the risk of malignant lymphoma in patients with rheumatoid arthritis undergoing methotrexate therapy using spontaneous adverse reaction databases in different countries. Materials and methods: Patient data were acquired from the US Food and Drug Administration’s Adverse Event Reporting System (FAERS), the Japanese Adverse Drug Event Report (JADER), and the Canada Vigilance Adverse Reaction Online Database (CVARD) from the first quarter of 2004 to the end of 2015. Data subset analysis was performed to investigate whether the use of bDMARDs further increased the risk of malignant lymphoma in patients receiving methotrexate therapy. Results: The FAERS subset data indicated a significant association between Hodgkin lymphoma and methotrexate with infliximab (reporting odds ratio (ROR): 8.28. 95% CI: 5.70 – 12.02; information component (IC): 2.04, 95% CI: 1.59 – 2.49). In addition, signal scores suggested that methotrexate with infliximab (ROR: 3.26. 95% CI: 2.68 – 3.98; IC: 1.31, 95% CI: 1.04 – 1.58) was significantly associated with non-Hodgkin lymphoma (NHL). The CVARD subset data also indicated a significant association between NHL and methotrexate with infliximab (ROR: 22.82. 95% CI: 5.02 – 103.78; IC: 1.77, 95% CI: 0.13 – 3.41). However, the JADER subset data revealed no significant associations. Conclusion: The present study shows that using infliximab further increases the risk of malignant lymphoma in patients receiving methotrexate therapy. Correspondence to:
Mitsutaka Takada, PhD
Division of Clinical Drug Informatics
Kindai University School of Pharmacy
3-4-1, Kowakae, Higashi-osaka, Osaka, 577-8502, Japan 
Email: takada@ phar.kindai.ac.jp

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 57 – No. 4/2019 (197-206)

Adherence to guidelines for antiulcer drug prescription in patients receiving low-dose aspirin therapy in Japan

Makiko Iwasawa¹, Keiko Sagami², Satoshi Yokoyama², Kouichi Hosomi², and Mitsutaka Takada²

¹Division of Drug Information, School of Pharmacy, Kitasato University, Sagamihara, Kanagawa, and ²Division of Clinical Drug Informatics, School of Pharmacy,  Kindai University, Higashi-osaka-city, Osaka, Japan
Objective: Prevalence of guideline adherence for antiulcer drug prescription in patients receiving low-dose aspirin (LDA) therapy was examined and the association of risk factors with the adherence was assessed. Materials and methods: A retrospective cohort study using a population-based longitudinal healthcare database was conducted. Claims data between January 2005 and April 2016 were analyzed. A total of 3,079 patients were included in the study. The selected patients taking LDA were divided into two categories: those taking and those not taking antiulcer drugs in an inpatient setting. Additionally, they were classified into four groups according to the time antiulcer therapy was initiated. The risk factors for ulcer, such as history of gastrointestinal injuries; age ≥ 65 years; and concomitant use of anticoagulants, antiplatelets, oral corticosteroids, and nonsteroidal anti-inflammatory drugs except aspirin, were assessed. Results: A total of 3,079 patients were included in the study. The rate of LDA patients using antiulcer drugs was 65.2%, with the strongest single factor associated with the use of antiulcer drugs being the concomitant use of corticosteroids. Among the LDA patients not taking antiulcer drugs, 66.8% had more than one risk factor. Irrespective of the use of concomitant treatment with antiulcer drug prior to hospital admission, 78.3% of the LDA patients continued their home regimen after hospital admission. Conclusion: Our results showed that the requirement of antiulcer therapy is not routinely evaluated at hospital admission, and antiulcer drugs for patients with ulcer risks are under-prescribed. Developing strategies to screen gastrointestinal risk factors at hospital admission is required to improve the guideline adherence for LDA-induced ulcer.Correspondence to:
Mitsutaka Takada, PhD 
Division of Clinical Drug Informatics
School of Pharmacy, Kindai University
577-8502, 3-4-1, Kowakae, Higashi-osaka,
Osaka, 577-8502, Japan
Email: takada@ phar.kindai.ac.jp

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 57 – No. 3/2019 (135-143)

Voriconazole trough concentration and hepatotoxicity in patients with low serum albumin 

Atsushi Hirata¹, Keisuke Noto¹, Ryosuke Ota¹, Satoshi Yokoyama², Kouichi Hosomi², Mitsutaka Takada², and Hiroshi Matsuoka¹

¹Department of Pharmacy, Kindai University Nara Hospital, and  ²Division of Clinical Drug Informatics, School of Pharmacy, Kindai University, Japan
Objective: We aimed to investigate the relationship between voriconazole (VRCZ) trough concentrations and hepatotoxicity and to evaluate whether the recommended trough concentration is adequate in our clinical setting. Materials and methods: A retrospective study was performed to investigate the relationship between serum VRCZ concentrations and the development of hepatotoxicity at the Kindai University Nara Hospital. Patients treated with VRCZ from March 2010 to January 2018 were identified from the medical records. A total of 42 patients (mean age of 61.9 ± 16.9 years; 33 males and 9 females) were enrolled in this study. Results: Hepatotoxicity developed in 28.6% (12/42) of patients treated with VRCZ, and 91.7% (11/12) of these patients developed hepatotoxicity within 3 weeks after initiating the treatment. Significantly increased aspartate aminotransferase (AST; p < 0.001), alkaline phosphatase (ALP; p < 0.001), and alanine aminotransferase (p = 0.001) levels were observed after the initiation of VRCZ therapy. In addition, significant positive correlations between AST and VRCZ trough concentrations (p = 0.017) and between ALP and VRCZ trough concentrations (p = 0.012) were observed. VRCZ trough concentration was identified as a significant independent risk factor for hepatotoxicity (adjusted odds ratio: 1.611, 95% confidence interval: 1.131 – 2.579, p = 0.006), and the cutoff serum trough concentration was calculated to be 4.2 μg/mL. Conclusion: VRCZ-induced hepatotoxicity should be noted in the early stages of therapy. A sustained VRCZ trough concentration of ~ < 4.2 μg/mL is recommended to prevent hepatotoxicity in patients with low serum albumin levels. 

This study was conducted in the Department of Pharmacy, Nara Hospital, Japan.Correspondence to:
Mitsutaka Takada, PhD 
Division of Clinical Drug Informatics
School of Pharmacy, Kindai University
3-4-1, Kowakae, Higashi-osaka, Osaka, 577-8502, Japan
Email:  takada@ phar.kindai.ac.jp

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 57 – No. 11/2019 (561-566)

Relationship between the blood concentrations of tacrolimus and voriconazole in hematopoietic stem cell transplant recipients 

Ryosuke Ota¹, Atsushi Hirata¹, Keisuke Noto¹, Satoshi Yokoyama², Kouichi Hosomi², Mitsutaka Takada², and Hiroshi Matsuoka¹

¹Department of Pharmacy, Kindai University Nara Hospital, Ikoma, Nara, and  ²Division of Clinical Drug Informatics, School of Pharmacy, Kindai University, Higashi-osaka, Osaka, Japan
Objective: We aimed to clarify the drug interaction between tacrolimus and voriconazole and investigate the relationship between blood concentrations of tacrolimus and voriconazole in hematopoietic stem cell transplantation (HSCT) patients.

Materials and methods: A retrospective study was conducted to investigate the relationship between blood concentration of tacrolimus and that of voriconazole at the Kindai University Nara Hospital. Patients who received HSCT and tacrolimus and were prescribed voriconazole for the prevention or treatment of aspergillosis from April 2010 to July 2018 were identified from the medical records. A total of 13 patients (administration route of tacrolimus: intravenously in 6 patients, orally in 7 patients) were enrolled in the present study.

Results: No significant correlation was observed between the blood concentration/dose (C/D) ratio of tacrolimus and the blood concentration of voriconazole (r = 0.38; p = 0.402; y = 102.8x + 928.1). However, a significant correlation was observed between the C/D ratio of tacrolimus and the blood concentration of voriconazole in the intravenous-administration group (r = 0.94; p = 0.0048; y = 421.9x + 810.5). Meanwhile, no significant correlation was observed in the oral-administration group (r = 0.43; p = 0.34; y = 7.9x + 719).

Conclusion: The C/D ratio of tacrolimus was significantly correlated with the blood concentration of voriconazole when tacrolimus was intravenously administered. There was a difference in the mechanism of drug interaction between tacrolimus and voriconazole depending on the administration routes.Correspondence to:
 Mitsutaka Takada, PhD
Division of Clinical Drug Informatics
School of Pharmacy, Kindai University
3-4-1, Kowakae, Higashi-osaka, Osaka, 577-8502, Japan
Email:  [email protected]

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 58 – No. 3/2020 (131-138)

Association between malignancy and methotrexate and biological disease-modifying antirheumatic drugs in patients with rheumatoid arthritis 

Ryo Inose¹, Natsue Hashimoto², Kouichi Hosomi², Satoshi Yokoyama², and Mitsutaka Takada²

¹Department of Pharmacy, Osaka City University Hospital, and ²Division of Clinical Drug Informatics, School of Pharmacy, Kindai University, Osaka, Japan
Objective: This study was aimed at investigating the risk of malignancies in rheumatoid arthritis patients treated with methotrexate (MTX), and whether the addition of biological disease-modifying antirheumatic drugs (bDMARDs) further increases the risk of malignancies in patients receiving MTX therapy, by using data from a spontaneous adverse reaction database.
Materials: Patient data from the U.S. Food and Drug Administration’s Adverse Event Reporting System (FAERS) from the first quarter of 2004 to the end of 2015 were analyzed.
Methods: A data subset analysis was performed to investigate whether the use of bDMARDs further increased the risk of malignancies in patients receiving MTX therapy.
Results: MTX showed significant associations with all malignancies except liver cancer. bDMARDs showed significant associations with stomach cancer, colorectal cancer, prostate cancer, ovarian cancer, malignant melanoma, and lung cancer. In addition, bDMARD use increased the risk of breast, ovarian, and lung cancers in rheumatoid arthritis patients receiving MTX therapy.
Conclusion: MTX use was significantly associated with various malignancies. Moreover, concomitant use of bDMARDs further increased the risk of breast, ovarian, and lung cancers in MTX-treated patients with rheumatoid arthritis.Correspondence to:
 Mitsutaka Takada, PhD
Division of Clinical Drug Informatics
Kindai University School of Pharmacy
3-4-1, Kowakae, Higashi-osaka, Osaka, 577-8502, Japan
Email: takada@ phar.kindai.ac.jp

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 58 – No. 4/2020 (214-222)

Influence of co-initiation of antiulcer drugs on persistence and adherence to low-dose aspirin: A retrospective cohort study using a Japanese claims database 

Makiko Iwasawa¹, Keiko Sagami², Satoshi Yokoyama², Kouichi Hosomi², and Mitsutaka Takada²

¹Division of Clinical Pharmacy (Laboratory of Drug Information) and Research and Education Center for Clinical Pharmacy, School of Pharmacy, Kitasato University, Kanagawa, and ²Division of Clinical Drug Informatics, School of Pharmacy, Kindai University, Osaka, Japan
Objective: The purpose of this study was to examine whether co-initiation of antiulcer drugs (AUDs) and low-dose aspirin (LDA) therapy is beneficial for good adherence to LDA therapy.
Materials and methods: A retrospective cohort study was conducted using the JMDC claims database. Patients for whom LDA therapy was newly initiated between January 2005 and April 2016 were selected from the JMDC database. The selected patients were divided into LDA and LDA+AUD groups and were followed up from the first prescription of LDA or LDA+AUD until the earliest of the following events: discontinuation or the end of the observation period. Unadjusted and multivariable Cox proportional hazards models controlling for all demographic and clinical characteristics were applied to examine whether the addition of an AUD to LDA improved adherence. A 1 : 1 propensity score matching analysis was conducted to balance confounders between the two groups.
Results: After the propensity score matching analysis, 4,089 patients were matched in each therapy group. The Kaplan-Meier curves for the rate of LDA continuation showed a sharp decline just after the initiation of LDA therapy. A significant difference was observed in the incidence of LDA therapy discontinuation between the LDA+AUD and LDA groups (HR: 0.87, 95% CI: 0.82 – 0.92), and the median duration of LDA therapy in the LDA+AUD and LDA groups were 18 and 11 months (log-rank test: p < 0.0001), respectively.
Conclusion: The therapy persistence rate in the LDA+AUD group was significantly higher than that in the LDA group.Correspondence to:
 Mitsutaka Takada, PhD 
Division of Clinical Drug Informatics
School of Pharmacy, Kindai University
577-8502, 3-4-1, Kowakae, Higashi-osaka,
Osaka, 577-8502, Japan
Email: takada@ phar.kindai.ac.jp

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 58 – No. 5/2020 (274-281)

Relationship between serum calcium and creatinine in hematopoietic stem cell transplantation patients treated with foscarnet 

Ryosuke Ota¹, Atsushi Hirata¹, Keisuke Noto¹, Satoshi Yokoyama², Kouichi Hosomi², Mitsutaka Takada², and Hiroshi Matsuoka¹

¹Department of Pharmacy and ²Division of Clinical Drug Informatics, School of Pharmacy, Kindai University, Higashiosaka, Osaka, Japan
Objective: The relationship between serum creatinine and calcium (Ca) was investigated in hematopoietic stem cell transplantation (HSCT) patients treated with foscarnet.
Materials and methods: A retrospective study was performed to investigate the development of foscarnet-induced renal dysfunction in patients who received HSCT from April 2010 to November 2018 at the Kindai University Nara Hospital. A total of 80 patients were identified from the medical records, and 42 patients who met the inclusion criteria were enrolled in this study. Renal dysfunction was classified according to the Kidney Disease: Improving Global Outcomes (KDIGO) criteria.
Results: A significant inverse relationship was observed between serum creatinine and Ca levels (r = –0.372; p < 0.0001; y = –0.537x + 9.268). A separate analysis divided into renal dysfunction and non-renal dysfunction groups showed that there was a signiﬁcant relationship between serum creatinine and Ca levels in the renal dysfunction group (r = –0.531; p < 0.0001; y = –0.617x + 9.239) but not in the non-renal dysfunction group (r = –0.011; p = 0.561; y = –0.023x + 8.934). The optimal cutoff for the minimum Ca level was calculated to be 8.1 mg/mL.
Conclusion: A significant inverse relationship was observed between serum creatinine and Ca levels in HSCT patients with foscarnet-induced renal dysfunction. Foscarnet-induced renal dysfunction should be noted if Ca levels fall below 8.1 mg/dL. Monitoring Ca levels may be useful for detecting renal dysfunction at early stages in patients treated with foscarnet.Correspondence to:
 Mitsutaka Takada, PhD
Division of Clinical Drug Informatics
School of Pharmacy, Kindai University
3-4-1, Kowakae Higashi-osaka, Osaka 577-5802, Japan
Email:  [email protected]

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 58 – No. 11/2020 (601-607)

Polypharmacy in three different spontaneous adverse drug event databases 

Takayuki Mabuchi¹#³, Kouichi Hosomi¹#², Satoshi Yokoyama¹#², and Mitsutaka Takada¹#²

¹Division of Clinical Drug Informatics, Kindai University Graduate School of Pharmacy, ²Division of Clinical Drug Informatics, School of Pharmacy, Kindai University, and ³Maruzen Pharmacy, Osaka, Japan
Objective: Polypharmacy has become a major problem in medical care worldwide, including in Japan. The purpose of this study was to investigate the current situation of polypharmacy using different spontaneous adverse drug event report databases.
Materials and methods: A retrospective data analysis was performed using reports from 2007 to 2015 from three different spontaneous adverse drug event report databases: the Japanese Adverse Drug Event Report (JADER) constructed by the Pharmaceuticals and Medical Devices Agency in Japan, the US Food and Drug Administration (FDA) Adverse Drug Event Reporting System (FAERS) constructed by the FDA in the United States, and the Canada Vigilance Adverse Reaction Online Database (CVARD) constructed by the government of Canada. Polypharmacy trends during the study period were investigated.
Results: The mean numbers of drugs per report in the JADER, FAERS, and CVARD databases during the study period were 6.62, 3.76, and 3.44, respectively. The mean number of drugs per report increased with age in all three databases, with a peak at ages 70 – 79 years in all three databases (7.0 drugs for JADER, 4.7 drugs for FAERS, and 4.2 drugs for CVARD).
Conclusion: Adverse event reports were more likely to develop in the patients treated through polypharmacy. Polypharmacy in Japan should be improved to prevent adverse events. Additionally, the patients aged ≥ 80 years tended to develop adverse events even if the number of prescribed drugs was relatively small. Therefore, polypharmacy should be noted in these patients to prevent adverse events.Correspondence to:
 Mitsutaka Takada, PhD
 Division of Clinical Drug Informatics
School of Pharmacy, Kindai University
3-4-1, Kowakae, Higashi-osaka, Osaka,  577-8502, Japan
Email: takada@ phar.kindai.ac.jp

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 59 – No. 1/2021 (63-70)

Relationship between serum bepridil concentration and corrected QT interval 

Kazuki Matsui¹#²#³, Yutaro Mukai³, Kota Sakakura³, Kyoichi Wada⁴, Tsutomu Nakamura⁴, Atsufumi Kawabata², Nobue Terakawa³, Naoki Hayakawa³, Kengo Kusano⁵, Kouichi Hosomi⁶#⁷, Satoshi Yokoyama⁶#⁷, and Mitsutaka Takada¹#⁶#⁷

¹Division of Cardiovascular Drugs, Therapy, Kindai University Graduate School of Pharmacy, ²Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University, Higashi-Osaka, ³Department of Pharmacy, National Cerebral and Cardiovascular Center, Suita, ⁴Education and Research Center for Clinical Pharmacy, Osaka University of Pharmaceutical Sciences, Takatsuki, ⁵Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Suita, ⁶Division of Clinical Drug Informatics, Kindai University Graduate School of Pharmacy, and ⁷Division of Clinical Drug Informatics, School of Pharmacy, Kindai University, Higashi-Osaka, Japan
Objective: Bepridil prolongs the QT interval and can induce torsade de pointes. Although increased bepridil concentration may be a primary cause of prolonged QT, the relationship between serum bepridil concentration and prolonged QT remains unclear. We investigated the relationship between serum bepridil concentration and the corrected QT (QTc) interval in patients treated with bepridil.
Materials and methods: A retrospective study was performed at the National Cerebral and Cardiovascular Center in Japan. Patients with atrial fibrillation who were treated with bepridil from January 2014 to December 2015 were enrolled in the study. Serum bepridil concentrations and electrocardiogram data collected more than 21 days after the initiation of bepridil were used for analysis.
Results: A total of 60 patients were included in this study. There was a significant difference in mean QTc interval before and after initiation of bepridil (p < 0.0001). A significant relationship was observed between bepridil dose (p = 0.014) or serum bepridil concentration (p < 0.001) and QTc interval. Additionally, a significant relationship was observed between serum bepridil concentration and ΔQTc (p = 0.034). In the study, 4 patients developed QTc prolongation ≥ 500 ms after the initiation of bepridil. Serum bepridil concentration in this group was significantly higher compared with the group that did not display prolonged QTc (973 ± 651 vs. 526 ± 310 ng/mL, p = 0.01).
Conclusion: This study revealed that the QTc interval was significantly associated with serum bepridil concentration. Serum bepridil concentration beyond a therapeutic range may be a critical risk factor for developing QTc prolongation.Correspondence to:
Mitsutaka Takada, PhD
Division of Clinical Drug Informatics
Kindai University Graduate School of Pharmacy
Higashi-Osaka, Osaka, 577-8502, Japan
Email:  takada@ phar.kindai.ac.jp

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 59 – No. 5/2021 (353-357)

Relationship between polypharmacy and adverse events 

Takayuki Mabuchi¹#³, Kouichi Hosomi¹#², Satoshi Yokoyama¹#², and Mitsutaka Takada¹#²

¹Division of Clinical Drug Informatics, Kindai University Graduate School of Pharmacy, ²Division of Clinical Drug Informatics, School of Pharmacy, Kindai University, and ³Maruzen Pharmacy, Osaka, Japan
A retrospective data analysis was performed to investigate the association between polypharmacy and adverse events using three different spontaneous adverse event reporting system databases. Multivariate logistic regression analyses were performed to investigate the association between the number of drugs and adverse events, including hepatic disorders, renal disorders, hypersensitivity, and extrapyramidal syndrome. The results showed that the risk of hepatic and renal disorders increased with the number of drugs. Thus, decreasing the number of drugs may reduce the risk of hepatic and renal disorders. Furthermore, attention should be given to specific drugs that may cause hypersensitivity and extrapyramidal syndrome.Correspondence to:
Mitsutaka Takada, PhD
Division of Clinical  Drug Informatics
School of Pharmacy, Kindai University
3-4-1, Kowakae, Higashi-osaka
Osaka, 577-8502, Japan
Email: takada@ phar.kindai.ac.jp

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 60 – No. 11/2022 (477-485)

Effect of mammalian-target-ofrapamycin inhibitors on the cancer risk in patients receiving calcineurin inhibitors: Data mining of a spontaneous reporting database

Takaya Uno¹#², Mitsutaka Takada², Satoshi Yokoyama², Kazuyoshi Kawabata¹, and Kouichi Hosomi²

¹Department of Pharmacy, National Cerebral and Cardiovascular Center, Suita, and ²Division of Clinical Drug Informatics, Faculty of Pharmacy, Kindai University, Higashi-Osaka, Japan
Objective: Calcineurin inhibitors (CNIs), including cyclosporine and tacrolimus, are associated with an increased cancer risk. However, whether mammalian target of rapamycin inhibitors (mTORis), including sirolimus and everolimus, decrease the cancer risk in patients receiving CNIs remains uncertain. We aimed to determine whether mTORis are associated with a decreased cancer risk in patients receiving CNIs using data mining of a spontaneous adverse reaction database.
Materials and methods: Disproportionality analysis was conducted using the U.S. Food and Drug Administration Adverse Event Reporting System database (2004 – 2019) with reporting odds ratio and information component being used to indicate a signal.
Results: Data subset analyses indicated that sirolimus and everolimus were not associated with a decreased cancer risk in patients receiving cyclosporine or tacrolimus but were associated with an increased risk of nonmelanoma skin cancer (NMSC) and Kaposi’s sarcoma.
Conclusion: mTORis are not associated with a decreased cancer risk but are associated with a further increase in the risk of NMSC and Kaposi’s sarcoma in patients receiving CNIs. Further studies are necessary to clarify the mechanism underlying the association between mTORis and NMSC or Kaposi’s sarcoma.Correspondence to:
Takaya Uno, PhD
Department of Pharmacy
National Cerebral and Cardiovascular Center
564-8565, Suita, Osaka, Japan
Email: [email protected]

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 61 – No. 1/2023 (33-36)

Trends in tolvaptan prescription and the association between hypernatremia and aging in tolvaptan-treated patients in Japan: Real-world data mining using Japanese databases 

Takaya Uno¹#², Kouichi Hosomi², Satoshi Yokoyama², and Kazuyoshi Kawabata¹

¹Department of Pharmacy, National Cerebral and Cardiovascular Center, Suita, and ²Division of Clinical Drug Informatics, Faculty of Pharmacy, Kindai University, Higashi-Osaka, Japan
Objective: To identify the trends in tolvaptan prescription and the association between aging and tolvaptan-induced hypernatremia.

Materials and methods: A health insurance claims database and a spontaneous adverse drug reaction database were used.

Results: Of all patients who had been prescribed tolvaptan, the proportion of patients aged 60 – 79 years and ≥ 80 years was consistent at ~ 40%. Moreover, the prescription frequency of tolvaptan increased over time for patients in the same age groups. The adjusted reporting odds ratio of tolvaptan-induced hypernatremia was 5.54 (95% confidence interval, 3.31 – 9.25) in patients aged ≥ 60 years from among all patients and 2.09 (95% confidence interval, 1.59 – 2.75) in those aged ≥ 80 years from among those aged ≥ 60 years.

Conclusion: It may be necessary to be aware of hypernatremia in elderly patients who are expected to have increased prescriptions of tolvaptan.Correspondence to:
Takaya Uno, PhD

Department of Pharmacy

National Cerebral and Cardiovascular Center

564-8565, Suita, Osaka, Japan
Email: [email protected]

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 61 – No. 4/2023 (148-158)

Association between hemorrhage and direct oral anticoagulants in combination with verapamil: Analysis of Japanese Adverse Drug Event Report database and electronic medical record data 

Yuika Komatsu¹#², Masahiro Yodoshi², Manabu Takegami², Satoshi Yokoyama¹, and Kouichi Hosomi¹

¹Division of Drug Informatics, School of Pharmacy, Kindai University, Higashi-osaka, and ²Division of Pharmacy, Kindai University Hospital, Osakasayama, Osaka, Japan
Objective: The aim of this study was to investigate the risk of hemorrhage in concomitant therapy with direct oral anticoagulants (DOACs) and class IV antiarrhythmic drugs.
Materials and methods: First, disproportionality analysis (DPA) was performed using the Japanese Adverse Drug Event Report (JADER) database to investigate the risk of hemorrhage with DOACs. Second, a cohort study was performed using electronic medical record data to confirm the results of the JADER analysis.
Results: In the JADER analysis, hemorrhage was significantly associated with treatment with edoxaban and verapamil (reporting odds ratio = 1.66; 95% confidence interval (CI) = 1.04 – 2.67). The cohort study revealed that hemorrhage incidence significantly differed between the verapamil-treated group and the bepridil-treated group, with a higher risk for hemorrhage in the verapamil group (log-rank test: p < 0.001). The multivariate Cox proportional hazards model also showed that the verapamil and DOAC combination was significantly associated with hemorrhage events compared with the bepridil and DOAC combination (hazard ratio (HR): 2.87, 95% CI: 1.17 – 7.07, p = 0.022). Furthermore, creatinine clearance (Ccr) ≥ 50 mL/min was significantly associated with hemorrhage events (HR: 2.72, 95% CI: 1.03 – 7.18, p = 0.043), and verapamil was significantly associated with hemorrhage in patients with Ccr ≥ 50 mL/min (HR: 3.58, 95% CI: 1.36 – 9.39, p = 0.010) but not in patients with Ccr < 50 mL/min.
Conclusion: Verapamil increases the risk of hemorrhage in patients on DOACs. Dose adjustment of DOACs based on renal function may prevent hemorrhage when verapamil is concomitantly administered.Correspondence to:
Kouichi Hosomi, PhD
Division of Drug Informatics, School of Pharmacy
Kindai University
3-4-1 Kowakae, Higashi-osaka
Osaka, 577-8502, Japan
Email: [email protected]

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 61 – No. 9/2023 (386-393)

Platelet count and dose, but not comorbidities, predict severe neutropenia in cabazitaxel-treated prostate cancer patients: A retrospective observational study 

Noriaki Kataoka¹, Takeo Hata¹#², Kouichi Hosomi³, Atsushi Hirata⁴, Emi Goto¹, Masami Nishihara¹#², Teruo Inamoto⁵, Haruhito Azuma⁵, and Masashi Neo¹#⁶

¹Department of Pharmacy, ²Department of Hospital Quality and Safety Management, Osaka Medical and Pharmaceutical University Hospital, ³Faculty of Pharmacy, Kindai University, Osaka, ⁴Department of Pharmacy, Kindai University Nara Hospital, Nara, ⁵Department of Urology, and ⁶Department of Orthopedic Surgery, Faculty of Medicine, Osaka Medical and Pharmaceutical University, Osaka, Japan
Objective: To determine the safety of cabazitaxel and predictors of severe neutropenia caused by cabazitaxel in a patient population that includes those with comorbidities.
Materials and methods: Of 42 prostate cancer patients treated with cabazitaxel at Osaka Medical and Pharmaceutical University Hospital between September 2014 and June 2022, 33 were included in this study, whereas 6 patients who were outpatients and 3 who were discharged early within 7 days upon patient request were excluded. Logistic regression analysis was used to examine predictors of severe neutropenia.
Results: Of the 33 eligible patients, 24 had comorbidities, with hypertension being the most common (n = 19), followed by dyslipidemia (n = 14) and diabetes (n = 11). There was no statistically significant difference in the rate of severe neutropenia due to any of the comorbidities, depending on the presence or absence of the comorbidity. However, the rate of severe neutropenia was significantly higher in patients with baseline platelet levels < 22.4×10⁴/μL and those receiving cabazitaxel doses > 34 mg/body. In the final model adjusted for age, body mass index, C-reactive protein, and monocyte count, lower baseline platelet levels and higher doses of cabazitaxel were also predictors of the development of severe neutropenia.
Conclusion: Comorbidities such as hypertension, dyslipidemia, diabetes mellitus, cerebrovascular disease, chronic kidney disease, liver dysfunction, and cardiac disease did not affect the incidence of severe neutropenia in patients receiving cabazitaxel. The baseline platelet count and the dose of cabazitaxel were also suggested to be markers for the development of severe neutropenia.Correspondence to:
Noriaki Kataoka, MSc
Department of Pharmacy
Osaka Medical and Pharmaceutical University Hospital
2-7, Daigaku-machi, Takatsuki,
Osaka 569-8686, Japan
Email: [email protected]

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