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Introduction

In recent years, it has become increasingly common for cancer chemotherapy to be administered even to patients with underlying diseases. However, there is limited clinical data for drug-drug interactions between anticancer agents and other disease therapeutics.

Paclitaxel has been widely used as a key drug for a number of cancers including ovarian cancer and lung cancer. The major metabolic pathway of paclitaxel is via cytochrome P5402C8 (CYP2C8), which deactivates it to 6α-hydroxide (1). Clopidogrel is a common antiplatelet agent used to inhibit blood clots. Clopidogrel is metabolized in the liver to acyl-β-D-glucuronide, which has been recently shown to inhibit CYP2C8 (2). Therefore, the potential exists for paclitaxel and clopidogrel to cause drug interactions, but the combination has rarely been examined clinically (3).

In the present study, patients who had been administered the combination of paclitaxel and clopidogrel were investigated. To the best of our knowledge, this is the first retrospective study investigating the potential interaction between these two drugs.

Materials and methods

Background

Patients who were administered a combination of paclitaxel and clopidogrel (75 mg/day) at Ogaki Municipal Hospital (Ogaki, Gifu, Japan) between January 2009 and October 2015 were identified. The gender, age, cancer type, regimen, paclitaxel dose, kidney function, liver function and any adverse events were extracted from the electronic medical record. The severity of adverse events was evaluated using the Common Terminology Criteria for Adverse Events (version 4.0; http://evs.nci.nih.gov/ftp1/CTCAE/About.html). The present study was conducted with the approval of the Ogaki Municipal Hospital ethics committee.

Adverse events and discontinuation rate

The incidence of adverse events was analyzed, including the discontinuation rate due to adverse events. These rates were compared with typical clinical trials (4,5).

Comparison of average neutrophil count prior and subsequent to administration of clopidogrel and paclitaxel

Neutrophil counts and neutrophil reduction rate were recorded and compared in patients prior and subsequent to the combined administration of clopidogrel and paclitaxel. Neutrophil reduction rate was calculated by this formula: [1 - (day 8 neutrophil counts/day 1 neutrophil counts)] × 100 (%).

Statistical analysis

Average neutrophil counts prior and subsequent to co-administration of clopidogrel and paclitaxel were compared using an unpaired t-test, and the neutrophil reduction rate was compared using Mann-Whitney U-test with P<0.05 considered to indicate a statistically significant difference. The statistical analysis software used was EZR version 1.26 (6).

Results

Background

Patient characteristics and background are shown in Table I. A total of 5 patients received paclitaxel and clopidogrel concomitantly. The therapeutic regimen for the patients included was carboplatin (nedaplatin) + paclitaxel (4 cases), paclitaxel alone (1 case), carboplatin + paclitaxel + radiation therapy (2 cases), or carboplatin + paclitaxel (1 case). A total of 8 cases were analyzed. The only drug used that influences CYP2C8 was clopidogrel. None of the 8 cases had any notable problems regarding blood cell counts prior to chemotherapy.

Table I. Background information for the patients administered a combination of paclitaxel and clopidogrel.

Table I.

Background information for the patients administered a combination of paclitaxel and clopidogrel.

Patient	Case no.	Gender	Age, years	Reason for clopidogrel use	PS	Liver functiona	Creatinin clearance, ml/minb	Cancer	Regimen	Paclitaxel, dose mg/week	Total times of paclitaxel administration
A	1	Female	62	Myocardial infarction	0	Normal	44	Ovarian cancer (following surgery)	Carboplatin+paclitaxel every (AUC=5, 175mg/m2, 3 weeks, 3 courses)	86.3	3
B	2	Female	77	Cerebral infarction	1	Normal	68	Ovarian cancer (following surgery)	Carboplatin+paclitaxel every (AUC=5, 175mg/m2, 3 weeks, 3 courses)	70.0	1
C	3	Female	78	Myocardial infarction	0	Normal	45	Lung squamous cell carcinoma (stage IIa)	Carboplatin+paclitaxel+radiation therapy (AUC=2, 40 mg/m2, weekly, 6 courses)	60.0	3
D	4	Male	74	Myocardial infarction	1	Normal	97	Lung adenocarcinoma (stage IIIa)	Carboplatin+paclitaxel+radiation therapy (AUC=2, 40 mg/m2, weekly, 6 courses)	70.0	4
	5		74		1	Normal	95	Recurrent lung adenocarcinoma	Carboplatin+paclitaxel (AUC=6, 200 mg/m2, 21 daily)	94.9	1
E	6	Female	62	Angina pectoris (following PCI4)	0	Normal	62	Second recurrent ovarian cancer	Nedaplatin+paclitaxel (75 and 180 mg/m2, respectively, every 3 weeks)	96.0	6
	7		65		0	Normal	69	Third recurrent ovarian cancer	Paclitaxel (80 mg/m2, weekly)	132.8	15
	8		65		0	Normal	69	Third recurrent ovarian cancer	Nedaplatin+paclitaxel (75 and 180 mg/m2, respectively, every 3 weeks)	96.0	5

a Alanine aminotransferase level <30 IU/l, aspartate aminotransferase level <30 IU/l, and total bilirubin level <1.0 mg/dl indicate normal liver function.

b Creatinine clearance calculated using the Cockcroft-Gault formula. PS, performance status; PCI, percutaneous coronary intervention; AUC, area under the curve.

Adverse events and discontinuation rate

A summary of the adverse events for each case is shown in Table II. Grade 3 (<1,000 to 500 counts/mm3) or higher neutropenia presented in all cases, occurring from the first course of treatment in 5 cases. Grade 4 neutropenia (<500 counts/mm3) was observed in 5 cases (88%) and 4 cases showed febrile neutropenia (50%). Treatment was discontinued due to adverse events in 4 cases (50%). Reduction of paclitaxel dose or skipping a course of treatment was required in 6 cases (75%).

Table II. Summary of the adverse events (AE).

Table II.

Summary of the adverse events (AE).

			Average cell count after 8 days of paclitaxel, administration counts/mm3		Minimum cell count in all courses, counts/mm3
Case no.	Received courses, n	Dose reduction or skip	Leucocyte	Neutrophil	Leucocyte	Neutrophil	Febrile neutropenia	Administration end reason
1	3	Yes	1,243	140	960	100	Yes	Protocol finished
2	1	No	–	–	860	340	Yes	Discontinued for AE
3	1	Yes	2,097	1,047	1,350	710	No	Discontinued for AE
4	1	Yes	1,655	1,040	620	300	Yes	Protocol finished
5	1	Yes	–	–	640	190	Yes	Discontinued for AE
6	6	No	1,148	370	840	230	No	Completely response
7	7	Yes	1,781	875	850	250	No	Progressive disease
8	9	Yes	818	200	410	50	No	Discontinued for AE

Comparison of average neutrophil counts prior and subsequent to combination of clopidogrel and paclitaxel

The data include the findings for 1 patient who underwent 6 courses of paclitaxel + nedaplatin therapy for a second recurrent ovarian cancer and 3 years later had 6 courses of paclitaxel + nedaplatin therapy for a third recurrence. Data were not available on potential bone marrow suppressive therapy between courses of chemotherapy.

On the initial day of paclitaxel administration (day 1), average neutrophil counts showed no significant difference with or without clopidogrel administration (without clopidogrel, 2,312±712 counts/mm3; with clopidogrel, 1,815±438 counts/mm3, mean ± standard deviation; P=0.18). At day 8 of paclitaxel administration, the average neutrophil counts with clopidogrel co-administration were significantly reduced (without clopidogrel, 1,240±395 counts/mm3; with clopidogrel, 370±148 counts/mm3, mean ± standard deviation; P<0.01) (Fig. 1).

Figure 1. Comparison of neutrophil counts prior and subsequent to administration of clopidogrel (mean ± SD). SD, standard deviation; n.s., not significant.

The neutrophil reduction rate was significantly higher in combination with clopidogrel compared to without clopidogrel [without clopidogrel: 54.1% (39.5–59.9%); with clopidogrel: 82.6% (60.5–89.4%), median (range); P<0.01].

Discussion

Paclitaxel is believed to be mainly inactivated to 6α-hydroxide by CYP2C8 (1). Poor metabolism by CYP2C8 reduces the clearance of paclitaxel by 11%. An increased neuropathy risk by 2–3 times has been reported (7–9). In addition, this has been shown to increase the risk of leucopenia (10,11). Therefore, drug interaction with CYP2C8 inhibitors is assumed to increase the incidence and severity of adverse events of paclitaxel.

Clopidogrel is metabolized in the liver and the active metabolite has been shown to inhibit CYP2C8 (2). It has been reported that the activity of CYP2C8 is inhibited 60–85% by continuous administration of 75 mg clopidogrel/day; thus, its inhibitory effect is shown to be strong. When clopidogrel is used in combination with a drug metabolized by CYP2C8, it may decrease the drug clearance. The interaction of paclitaxel and clopidogrel was previously reported by Bergmann et al (3) in a case study; the clearance of paclitaxel was reduced 38% by the co-administration of clopidogrel. Despite this warning of the potential drug interactions of the two agents, follow-up clinical studies are lacking.

The variation in the background of the cases in this study makes a simple comparison difficult. Paclitaxel + carboplatin therapy (TC therapy) was used as the standard regimen for treatment of ovarian cancer and lung cancer. TC therapy is associated with a relatively high rate of neutropenia compared to other paclitaxel regimens (grade 3 or 4 leukopenia: 59%, grade 3 or 4 neutropenia: 89–92%, febrile neutropenia: 9%) (4,5). However, TC therapy administration for >6 courses has reported a rate of 87% neutropenia and is well tolerated (4). Although comparisons between different regimens are difficult, in previous studies, patients received more carboplatin (AUC 6 and 7.5) compared to the patients in the present study. The paclitaxel doses were similar to previous studies (175 and 180 mg/m2) and the majority of patients in the present study. Therefore, the neutropenia risk is considered lower compared to these studies. However, in the present study, neutropenia of grade 3 or higher presented in all cases, and 50% discontinued treatment with severe adverse events such as febrile neutropenia. This suggests that the adverse events are amplified by the drug interactions of paclitaxel and clopidogrel. A larger study that can control for patient background is required in order to further quantify this drug interaction.

For the 1 case involving paclitaxel + nedaplatin therapy, it was possible to compare the average neutrophil counts prior and subsequent to clopidogrel administration. The case also used aspirin, atorvastatin and lansoplazole, following percutaneous coronary intervention. Except for clopidogrel, these drugs cannot be considered to influence drug interaction with paclitaxel, and bone marrow suppression. The neutrophil reduction rate was significantly higher following the combination treatment of clopidogrel and paclitaxel compared to prior to clopidogrel administration. Infection did not occur in this case, but the average number of neutrophils at day 8 was <500 counts/mm3 with clopidogrel. In general, infection rates increase when neutrophil counts fall <500 counts/mm3, and the frequency and severity of infections are inversely proportional to the number of neutrophils (12). Thus, when neutropenia is severe due to the administration of clopidogrel, it is likely that the risk of infection is also greatly increased.

The present study has certain limitations. One of them is the small sample size (8 cases). Patient backgrounds were not matched in each case, due to the different regimens. Additionally, only 1 patient could be evaluated who received paclitaxel with and without clopidogrel. Therefore, the impact of aging is evident in prior and subsequent comparison of a single case. Furthermore, the study was not a pharmacogenetic and pharmacokinetic study. Therefore, more studies are required.

The drug interaction of paclitaxel and clopidogrel cannot be clinically negligible, as the data suggest that there is an increased risk of severe adverse events. Therefore, therapeutic strategies should be considered to avoid the combination of these two agents where possible. When a combination is required, it is necessary to monitor for adverse events carefully.

References