Int J Clin Oncol (2013) 18:735–742 DOI 10.1007/s10147-012-0425-5
ORIGINAL ARTICLE
Concomitant polypharmacy is associated with irinotecan-related adverse drug reactions in patients with cancer Tetsuya Sasaki • Ken-ichi Fujita • Yu Sunakawa • Hiroo Ishida • Keishi Yamashita • Keisuke Miwa • Shigehira Saji • Yasuhisa Kato • Yasutsuna Sasaki
Received: 27 December 2011 / Accepted: 27 April 2012 / Published online: 26 May 2012 Ó Japan Society of Clinical Oncology 2012
Abstract Background Patients with cancer often receive chemotherapeutic agents concurrently with other medications to treat comorbidity. The practical effects of concomitant medications, especially polypharmacy, on adverse drug reactions related to irinotecan-based chemotherapy are not well documented. Methods Associations of adverse drug reactions related to irinotecan monotherapy or a combination of irinotecan, 5-fluorouracil, and L-leucovorin (FOLFIRI) with concomitant medicines used to treat comorbidity were retrospectively investigated in Japanese patients with cancer. Results Of the 172 patients, 118 received concomitant medications. Twenty-one patients had grade 4 neutropenia and/or grade 3 or 4 diarrhea. Univariate and multivariate analyses revealed that concomitant medications were significantly associated with irinotecan-related severe neutropenia and/or diarrhea (P = 0.023 and 0.044). Multiple concomitant medications were significantly related to
severe irinotecan-related toxicity in patients given monotherapy or FOLFIRI (P = 0.01). The incidence of severe irinotecan-related toxicities increased in parallel with the number of concomitant medications. Conclusion We found that multiple concomitant medicines were significantly associated with severe irinotecanrelated toxicity, indicating that polypharmacy must be effectively managed to decrease the risk of adverse drug reactions in patients with cancer who received irinotecanbased chemotherapy.
T. Sasaki Department of Clinical Research Support Center, International Medical Center, Saitama Medical University, 1397-1 Yamane, Hidaka, Saitama 350-1298, Japan
K. Fujita Y. Sasaki Project Research Laboratory, Research Center for Genomic Medicine, Saitama Medical University, 1397-1 Yamane, Hidaka, Saitama 350-1241, Japan
T. Sasaki Y. Kato Department of Drug Information, Showa University School of Pharmaceutical Sciences, 1-5-8 Hatanodai, Shinagawa, Tokyo 142-8555, Japan
Present Address: H. Ishida Division of Respiratory Medicine and Allergology, Department of Internal Medicine, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa, Tokyo 142-8666, Japan
K. Fujita (&) Y. Sunakawa H. Ishida K. Yamashita K. Miwa S. Saji Y. Sasaki Department of Medical Oncology, International Medical Center-Comprehensive Cancer Center, Saitama Medical University, 1397-1 Yamane, Hidaka, Saitama 350-1298, Japan e-mail:
[email protected]
Keywords Adverse drug reactions Cancer Clinical practice Concomitant medications Irinotecan
Introduction Twenty to thirty percent of all adverse drug reactions are caused by interactions between therapeutic drugs, and such
Present Address: S. Saji Department of Target Therapy Oncology, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo, Kyoto 606-8507, Japan
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reactions are clinically relevant in up to 80 % of elderly patients [1]. Anticancer drugs are no exception. Clearly, anticancer drugs are some of the most potent cytotoxic drugs available. These drugs are characterized by narrow therapeutic windows, with very small differences between effective and toxic dose levels. Patients with cancer often receive anticancer drugs concurrently with other medications to treat comorbidity [2]. They are particularly therefore susceptible to drug–drug interactions, because concurrent medications can alter the pharmacokinetics or pharmacodynamics of the anticancer drugs, which sometimes induces the toxicities related to the anticancer drugs. To date, several studies have assessed potential drug–drug interactions between anticancer drugs and various other drugs used to manage comorbidity. In these studies, the potential drug–drug interactions were estimated by using software, database or literature [3–6]. Riechelmann et al. [6] used a questionnaire to obtain information on patient demographics and medications. Potential drug–drug interactions were evaluated with the use of Drug Interaction Facts software, and the severity of such interactions were classified. In other studies, electronic database or literature searches were used to examine potential drug–drug interactions [3–5]. However, in these studies, no practical data with regard to the effects of concomitant medications, especially polypharmacy, on adverse drug reactions related to anticancer drugs were obtained. Irinotecan is a camptothecin derivative that acts cytotoxically by inhibiting topoisomerase I. This drug has been approved for the treatment of a wide variety of solid tumors, including colorectal cancer. Patients and oncologists are deeply concerned about the dose-limiting toxic effects of irinotecan, such as myelosuppression and delayed-type diarrhea [7–9]. UDP-glucuronosyltransferase (UGT) 1A1 is predominantly responsible for the detoxification of the active metabolite SN-38, which is produced from irinotecan by carboxylesterases and then undergoes glucuronidation to form inactive SN-38 glucuronide (SN38G) [10]. Several studies have linked UGT1A1*28 and *6 alleles to irinotecan-related neutropenia [10–15]. Besides these factors, concomitant medications, especially polypharmacy, might alter the expression or activity of factors affecting the pharmacokinetics (http://www.pharmgkb.org/ do/serve?objCls=Pathway&objId=PA2001) and pharmacodynamics (http://www.pharmgkb.org/do/serve?objCls= Pathway&objId=PA2029) of irinotecan, potentially causing the irinotecan-related toxicities. We retrospectively studied the association of adverse drug reactions related to irinotecan-based chemotherapy with concomitant medications, especially polypharmacy, used to treat comorbidity in Japanese patients with cancer.
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Patients and methods Study design This retrospective study was performed at Saitama Medical University International Medical Center. All the Japanese patients with cancer who received the first cycle of irinotecan-based regimens between April 2007, when this center was newly established, and December 2010 were studied. The primary objective was to evaluate the effects of concomitant medication used to treat comorbidity on irinotecan-related adverse drug reactions. This study was approved by the Institutional Review Board of Saitama Medical University International Medical Center. Patients All patients, who were managed by medical oncologists of our department, were 20 years or older, had histologically confirmed solid tumors, and were given irinotecan monotherapy or a combination of irinotecan, 5-fluorouracil, and L-leucovorin (FOLFIRI). All patients provided written informed consent for their peripheral blood samples to be used for UGT1A1 genotyping. The protocol for UGT1A1 genotyping was separately approved by the Ethical Committee of Saitama Medical University. Treatments Irinotecan monotherapy regimens comprised a 1.5-h intravenous infusion of irinotecan (150 mg/m2) every 2 weeks, or weekly irinotecan (100 mg/m2) for the first 3 weeks, repeated every 4 weeks. FOLFIRI regimens comprised a 1.5-h intravenous infusion of irinotecan (150 or 180 mg/m2) and L-leucovorin (200 mg/m2) on day 1, followed by an intravenous bolus injection of 5-fluorouracil (400 mg/m2) and a 46-h intravenous infusion of 5-fluorouracil (2400 mg/m2), repeated twice every 2 weeks. These treatments were defined as 1 cycle. Doses of irinotecan in both monotherapy and FOLFIRI regimens could be reduced for patients with UGT1A1*6/*6, *28/*28 or *6/*28 by the physician in charge. Evaluation of baseline patient characteristics, concomitant medications, and toxicity Baseline patient characteristics were collected from electronic medical records on the last visit before day 1 of irinotecan-based chemotherapy or on day 1 of such therapy.
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Concomitant medications were defined as therapeutic drugs used to manage comorbid conditions besides cancer. Concomitant medications continuously administered at least from the last visit before the start of irinotecan-based chemotherapy until after day 1 of chemotherapy were recorded on the basis of the patients’ electronic charts. Topically applied medications were excluded. Therapeutic drugs used to treat chemotherapy-related adverse drug reactions such as neutropenia and diarrhea were also excluded. Premedication for irinotecan treatment such as steroids and antiemetics was also excluded. The categories of concomitant drugs were classified according to Goodman & Gilman’s The Pharmacological Basis of Therapeutics [16]. In this study, we could not completely monitor the intake of complementary and alternative medicine(s) by patients. Toxicities induced by irinotecan-based chemotherapy were monitored during the first cycle according to the National Cancer Institute Common Terminology Criteria for adverse events, version 3.0 (http://ctep.cancer.gov/ reporting/ctc_v30.html). The highest grade toxicity(ies) during the first cycle was recorded. Statistical analyses All statistical analyses were performed with SPSS statistical software, version 16.0 (SPSS Japan, Tokyo, Japan). Correlations or associations between irinotecan-related severe toxicity and categorical variables were assessed with the use of the chi-squared test or Fisher’s exact test. Variables that were significantly associated with severe toxicity on univariate analysis were considered for inclusion in multiple logistic regression analysis. Variables included in the final model were chosen by backward elimination. Correlations or associations were considered statistically significant when the two-tailed P value was \0.05.
737 Table 1 Baseline characteristics of patients (N = 172) n (%) Age (years) Median (range)
64 (31–78)
Gender Male Female
107 (62) 65 (38)
ECOG performance status 0
91 (53)
1
74 (43)
2
7 (4)
Primary disease Colorectal
111 (65)
Gastric
44 (25)
Other
17 (10)
Previous chemotherapy 0
60 (35)
1
87 (50)
C2
25 (15)
Regimens Irinotecan monotherapy
98 (57)
FOLFIRI
74 (43)
Irinotecan dose (mg/m2) \100 100–150 C150
9 (5) 120 (70) 43 (25)
UGT1A1 genotype *1/*1, *1/*6, and *1/*28 *6/*6, *28/*28, and *6/*28
158 (92) 14 (8)
Total bilirubin (mg/dL) Median (range)
0.5 (0.1–1.5)
Serum creatinine (mg/dL) Median (range)
0.8 (0.4–3.6)
Creatinine clearance (mL/min)a Median (range)
76.5 (14–148)
C60
130 (75)
\60
42 (25)
Concomitant medication Yes
Results Baseline patient characteristics The study group comprised 172 patients who received irinotecan monotherapy or FOLFIRI. The baseline characteristics of the patients are shown in Table 1. The median age was 61 years (range 31–78). Most patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Fourteen patients had the UGT1A1*6/*6, *28/*28, or *6/*28 genotype, associated with an increased risk of irinotecan-related neutropenia [14, 15]. Although few patients had severely elevated total
118 (69)
Cardiovascular disordersb
50 (29)
Pain
39 (23)
Hyperlipidemia
10 (6)
Diabetes
7 (4)
Hyperuricemia
5 (3)
Renal disorders
2 (1)
Liver disorder
1 (1)
No
54 (31)
ECOG Eastern Cooperative Oncology Group, UGT1A1 UDP-glucuronosyltransferase 1A1 a Creatinine clearance was calculated with the Cockcroft–Gault equation b
Main comorbid conditions which necessitated concomitant medication
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Table 2 Concomitant medications (N = 351) given with irinotecan-based chemotherapy n
Renal and cardiovascular disorders
118
n
Gastrointestinal disorders
50
Concomitant medications (patients)
Calcium channel blockers
34
Amlodipine (17), benidipine (5), azelnidipine (3), diltiazem (3), nifedipine (3), nitrendipine (2), bepridil (1)
Proton pump inhibitors
27
Lansoprazole (14), rabeprazole (11), omeprazole (2)
Non-peptide angiotensin II receptor antagonists
23
Candesartan (7), valsartan (7), olmesartan (4), losartan (3), telmisartan (2)
H2-receptor antagonists
18
Famotidine (10), lafutidine (5), ranitidine (3)
Diuretics
14
Furosemide (7), spironolactone (4), trichlormethiazide (2), tripamide (1)
Bile acids
4
Ursodeoxycholic acid (4)
Statins
11
Pravastatin (5), rosuvastatin (3), atorvastatin (2), simvastatin (1)
Improvement of liver function drug
1
Glycyrrhizic acid (1)
b-Adrenergic receptor antagonists
10
Carvedilol (5), atenolol (2), metoprolol (2), bisoprolol (1)
Blood and blood-forming organs disorders
35
Angiotensin converting enzyme inhibitors
10
Enalapril (7), benazepril (1), imidapril (1), temocapril (1)
Anti-platelet drugs
17
Aspirin (11), ticlopidine (4), clopidogrel (2)
Organic nitrates
5
Isosorbide mononitrate (3), isosorbide dinitrate (2)
Hematopoietic agents
15
Ferrous citrate (10), ferrous fumarate (3), ferrous sulfate (2)
3
Warfarin (3)
Cardiotonic glycosides
3
Digoxin (2), metildigoxin (1)
Anti-plasmins
2
Tranexamic acid (2)
Capillary stabilizers
2
Adrenochrome monoaminoguanidine (2)
Oral hypoglycemic agents
10
Glimepiride (5), glibenclamide (2), metformin (1), nateglinide (1), pioglitazone (1)
a1-Adrenergic receptor antagonist
1
Doxazosin (1)
Thyroid hormones
2
Levothyroxine (2)
Anion exchange resin
1
Colestimide (1)
Adrenocortical steroid
1
Prednisolone (1)
Metabolic activator
1
Adenosine triphosphate (1)
Anti-thyroid drug
1
Thiamazole (1)
Potassium channel activator
1
Nicorandil (1)
Estrogen
1
Conjugated estrogen (1)
Central nervous system disorders
61
Oral anti-coagulants Hormones
Microbial diseases
15
3
Opioid analgesics
24
Oxycodone (17), morphine (6), fentanyl (1)
Antibiotics
2
Cefcapene pivoxil (2)
Sedative-hypnotic drugs
18
Brotizolam (8), zolpidem (4), flunitrazepam (3), rilmazafone (2), estazolam (1)
Antiviral agent
1
Entecavir (1)
Anti-anxiety drugs
11
Etizolam (5), alprazolam (4), bromazepam (1), tofisopam (1)
Immune disease
1
Anti-seizure drugs
4
Gabapentin (2), clonazepam (1), zonisamide (1)
Anti-depressants
2
Amoxapine (1), mianserin (1)
Anti-psychotic drugs
2
Sulpiride (1), olanzapine (1)
Inflammations
a
Concomitant medications (patients)
57
Immunosuppressant Othersa
1
Mizoribine (1)
11
a1A-Adrenergic receptor antagonists
4
Tamsulosin (2), naftopidil (1), silodosin (1)
Expectorants
4
Ambroxol (2), carbocisteine (2)
Non-steroidal antiinflammatory drugs
41
Loxoprofen (29), diclofenac (6), meloxicam (3), acetaminophen (2), etodolac (1)
Anti-tussive agent
1
Benproperine (1)
H1-receptor antagonists
7
Cetirizine (2), chlorpheniramine (2), fexofenadine (2), loratadine (1)
Ergot alkaloid
1
Nicergoline (1)
Xanthine oxidase inhibitors
5
Allopurinol (5)
Muscarinic receptor antagonist
1
Propiverine (1)
Bronchodilator
1
Tulobuterol (1)
Prostaglandin E1 analogue
1
Limaprost (1)
Protease inhibitor
1
Camostat mesilate (1)
Uricosuric agent
1
Benzbromarone (1)
These medicines do not appear in Goodman & Gilman’s The Pharmacological Basis of Therapeutics
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bilirubin levels, the creatinine clearance was \60 mL/min in about 25 % of the study group. Concomitant medications were administered to 118 patients. Table 3 Associations of baseline patient characteristics with irinotecan-related severe toxicities Grade 4 neutropenia and/or grade 3 or 4 diarrhea Yes (N = 21)
No (N = 151) 0.358a
Age (years) C65
12 (57)
\65
9 (43)
b
69 (46)
Female
14 (67)
93 (62)
7 (33)
58 (38)
ECOG performance status 0
7 (33)
84 (56)
1
12 (57)
62 (41)
2 (10)
5 (3)
2 Primary disease Colorectal
15 (71)
96 (64)
6 (29)
38 (25)
Others
0 (0)
17 (11)
0
5 (24)
1
14 (67)
73 (48)
2 (9)
23 (15)
100–150 C150 UGT1A1 genotype *1/*1, *1/*6, and *1/*28 *6/*6, *28/*28, and *6/*28
14 (67)
84 (56)
7 (33)
67 (44) 0.495c
0 (0)
9 (6)
16 (76)
104 (69)
5 (24)
38 (25)
18 (86)
140 (93)
3 (14)
11 (7) 0.014a
C60
11 (52)
119 (79)
\60
10 (48)
32 (21)
No
Number of concomitant medications and irinotecan-related severe toxicities 0.384a
Creatinine clearance (mL/min)
Concomitant medication Yes
In this study, grade 4 neutropenia and/or grade 3 or 4 diarrhea were defined as irinotecan-related severe toxicities. Of the 172 patients, 21 had grade 4 neutropenia (15 patients), or grade 3 or 4 diarrhea (6 patients). Univariate analyses were performed to evaluate the association between baseline patient characteristics and irinotecanrelated severe toxicities. As shown in Table 3, concomitant medications and creatinine clearance were significantly associated with irinotecan-related severe neutropenia and/ or diarrhea. No association was observed between concomitant medications and creatinine clearance (Table 4), indicating that these were not confounding factors. On multiple logistic regression analysis, the use of concomitant medication and a creatinine clearance of \60 mL/min remained important risk factors for the occurrence of irinotecan-related severe toxicities (Table 5).
0.481a
Irinotecan dose (mg/m2) \100
0.101c
55 (37)
Regimens FOLFIRI
Associations of patient characteristics with irinotecan-related severe toxicities
0.290c
Previous chemotherapy
Irinotecan monotherapy
0.811a
0.269c
Gastric
C2
A total of 351 concomitant medications were used in 118 patients (Table 2). Almost all concomitant medications were continuously administered from the last visit before starting irinotecan-containing chemotherapy until the end of 1 cycle. Drugs used to treat renal and cardiovascular disorders were most commonly prescribed, followed by drugs for the management of central nervous system disorders, gastrointestinal disorders, inflammation, blood and blood-forming organ disorders, hormones, microbial diseases, and immune disease. The number of concomitant medicines per patient ranged from 1 to 10.
82 (54)
Gender Male
P value
Concomitant medications
The number of concomitant medications was significantly associated with irinotecan-related severe toxicities (Table 6). The number of patients with toxicities increased in parallel with the number of concomitant medications, Table 4 Associations of creatinine clearance with concomitant medication
0.023a 19 (90)
98 (65)
2 (10)
53 (35)
ECOG Eastern Cooperative Oncology Group, UGT1A1 UDP-glucuronosyltransferase 1A1
Concomitant medication Yes (N = 117)
No (N = 55)
C60 mL/min
85 (73)a
45 (82)
\60 mL/min
32 (27)
10 (18)
Creatinine clearance
a
Fisher’s exact test
b
Number (%)
a
c
Number (%)
Chi-squared test
b
Fisher’s exact test
P valueb
0.254
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Table 5 Multiple logistic regression analysis b coefficient
Variable
Standard error
v2
P value
Odds ratio (95 % confidence interval)
Presence of concomitant medication
1.55
0.77
4.06
0.044
4.71 (1.04–21.3)
Creatinine clearance \60 mL/min
1.13
0.49
5.37
0.021
3.11 (1.19–8.10)
Table 6 Association between the number of concomitant medications and irinotecan-related severe toxicities Number of concomitant medications
Grade 4 neutropenia and/ or grade 3 or 4 diarrhea Yes (N = 21)
No (N = 151)
0–1
5 (24)b
80 (53)
2–3
7 (33)
45 (30)
C4 a
Chi-squared test
b
Number (%)
9 (43)
P valuea
Table 8 Concomitant medications given to patients who had severe irinotecan-related toxicities Number of medicines (patients)
Concomitant medications
1 (3)
Famotidinea,b Ferrous sulfate
0.01
26 (17)
2 (5)
Loxoprofen Adrenochrome monoaminoguanidine/ tranexamic acid
3 (2)
Cetirizine/glibenclamide/loxoprofen
Loxoprofen/oxycodone (given to 4 patients) Rabeprazole/sodium ferrous citrate/warfarin 4 (4)
Table 7 Associations of creatinine clearance with number of concomitant medications Number of concomitant medications 0–1 (N = 5)
2–3 (N = 7)
3 (60)b
4 (57)
4 (44)
\60 mL/min
2 (40)
3 (43)
5 (56)
Chi-squared test
b
Number (%)
Amlodipine/diclofenac/glimepiride/morphine Brotizolam/diclofenac/flunitrazepam/ morphine 0.816
C60 mL/min a
whereas the number of patients with no toxicity increased as the number of concurrent medicines decreased. Creatinine clearance was not significantly related to the number of multiple medications in patients with severe irinotecanrelated toxicities (Table 7). The details of the concomitant drugs given to the patients who had severe toxicities are shown in Table 8. In total, 13 concomitant medications were given to patients; nevertheless in each case comorbidity had been improved. The concomitant medications which were predominantly excreted via the kidney are represented with underlines. There was no significant association between the number of concomitant medications excreted by the kidney and creatinine clearance (C and \60 mL/min) (P = 0.298).
Discussion The present study demonstrated that concomitant medications were significantly associated with severe irinotecan-
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Allopurinol/mizoribine/prednisolone/ zolpidem
P valuea
C4 (N = 9)
Creatinine clearance
Adrenochrome monoaminoguanidine/ alprazolam/diclofenac/tranexamic acid
5 (1)
Amlodipine/atenolol/benzbromarone/ ferrous fumarate/ranitidine
6 (1)
Aspirin/carvedilol/glimepiride/isosorbide mononitrate/losartan/rosuvastatin
8 (2)
Allopurinol/carvedilol/enalapril/furosemide/ loxoprofen/olanzapine/spironolactone/ zolpidem Aspirin/clopidogrel/diltiazem/enalapril/ glimepiride/isosorbide mononitrate/ lansoprazole/metformin
10 (1)
Amlodipine/alprazolam/bromazepam/ etizolam/ferrous sulfate/lansoprazole/ loxoprofen/morphine/olmesartan/sulpiride
a
Bold type shows concomitant medications which were continuously given to patients; nevertheless in each case the comorbidity had been improved as shown by the electronic medical record
b
Text in italics represents concomitant medications which were predominantly excreted via the kidney (information from interview form of each medicine)
related toxicity in patients given irinotecan monotherapy or FOLFIRI (Tables 3, 5). The greater the number of concomitant drugs administered, the higher was the incidence of severe irinotecan-related toxicities (Table 6). In the 1990s, Corcoran [17] reported that the number of potential drug-related problems in cancer chemotherapy is related to the total number of prescriptions. Our study revealed that multiple concomitant medication remains an unresolved
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Table 9 Associations of age or performance status with number of concomitant medications P valuea
Number of concomitant medications 0–1 (N = 5)
2–3 (N = 7)
C4 (N = 9)
\65 years
2 (40)b
2 (29)
6 (67)
C65 years
3 (60)
5 (71)
3 (33)
Age
0.295
ECOG performance status
0.918
0
2 (40)
2 (29)
3 (33)
1–2
3 (60)
5 (71)
6 (67)
ECOG Eastern Cooperative Oncology Group a
Chi-squared test
b
Number (%)
problem in patients who receive cancer chemotherapy. An important message of our study is that patients with polypharmacy must be carefully managed to prevent adverse drug reactions caused by irinotecan-related chemotherapy. In total, 13 concomitant medications were continuously given to patients who had severe irinotecan-related toxicity; nevertheless in each case comorbidity had been improved (Table 8). Another essential message is that unnecessary and excessive medications should be avoided, even though it was unclear whether these medications were directly associated with the irinotecan-induced toxicity. It is well documented that elderly patients (65 years or older) receive more medications than their younger counterparts because the number of comorbid conditions per patient increases in an age-related fashion [2, 18]. In general, polypharmacy used to manage multiple comorbidity is often associated with poor performance status. Such patients might be prone to experience irinotecan-related severe toxicities. We thus investigated the relation between multiple concurrent medications and age as well as performance status in patients who had irinotecan-related severe toxicities. In the present study, however, age and performance status were not significantly related to multiple medications in patients with severe irinotecan-related toxicities (Table 9). The medicines that were administered to patients who had severe irinotecan-related toxicities are listed in Table 8. One patient with irinotecan-related adverse drug reactions was receiving 10 concomitant medicines, including four drugs (amlodipine, alprazolam (http://medicine.iupui.edu/ clinpharm/ddis/table.aspx), bromazepam [19], and etizolam [20]) that are substrates for CYP3A4, which is responsible for the irinotecan metabolism generating the inactive APC and NPC [21]. These drugs might have cooperatively interacted to inhibit CYP3A4, thereby inducing toxicity.
However, it is generally difficult to elucidate scientifically the true mechanism of polypharmacy-induced severe adverse reactions. First, the intake of various combinations of therapeutic drugs necessitates complex analyses of pharmacokinetic and pharmacodynamic drug interactions. Second, patients usually take multiple medications to manage comorbid conditions, and comorbidity can affect the pharmacokinetics of drugs by altering organ functions. Such conditions make scientific elucidation of the causes of polypharmacy-related toxicities difficult. Creatinine clearance was significantly associated with irinotecan-related severe toxicities (Tables 3, 5). Patients who had a creatinine clearance of \60 mL/min were likely to have severe toxicity. The incidence of grade 4 neutropenia was associated with a creatinine clearance of \60 mL/min, but the association was of borderline significance (P = 0.055). The incidence of grade 3 or 4 irinotecan-induced neutropenia has been reported to increase in patients with impaired renal function [22]. Patients with slower creatinine clearance (35–66 mL/min) had a fourfold higher risk of grade 3 or 4 neutropenia, although the underlying mechanism remains unclear. Our present results partly support these findings. UGT1A1*6/*6, *28/*28, and *6/*28 genotypes, which are related to an elevated risk of irinotecan-related neutropenia [14, 15], were not associated with irinotecanrelated severe toxicities (Table 3). This might be caused by the appropriate dose reduction by the physician in charge. In conclusion, we found that concomitant medications were significantly related to irinotecan-related severe toxicity in patients given irinotecan monotherapy or FOLFIRI. The incidence of severe irinotecan-related toxicities increased in parallel with the number of concomitant medications. Our results indicate that polypharmacy must be effectively managed to decrease the risk of adverse drug reactions caused by irinotecan-based chemotherapy. Acknowledgments This work was supported in part by a Grant-inAid for Cancer Research from the Ministry of Health, Labour and Welfare of Japan (21S-8-1 to Y.S.), in part by a Grant-in-Aid for Scientific Research (C) (23590198 to K.F.) from the Japan Society for the Promotion of Science (JSPS), and in part by a Grant-in-Aid for ‘‘Support Project of Strategic Research Center in Private Universities’’ from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) to Saitama Medical University Research Center for Genomic Medicine. Conflict of interest
All authors have no conflict of interests.
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