Neurotoxicity and low paclitaxel clearance associated with concomitant clopidogrel therapy in a 60‐year‐old Caucasian woman with ovarian carcinoma

Abstract

Aim

The aim of the present case report was to describe a novel pharmacokinetic drug–drug interaction between the antiplatelet agent clopidogrel and the antineoplastic agent paclitaxel.

Methods

The patient was identified in a previously described cohort of 93 patients with ovarian carcinoma treated with paclitaxel. The effect of clopidogrel acyl‐β‐D‐glucuronide on the metabolism of paclitaxel was assessed in human liver microsomes. The analysis of clopidogrel in plasma and the quantification of paclitaxel and 6α‐hydroxypaclitaxel in in vitro samples were performed by liquid chromatography tandem mass spectrometry.

Results

The patient was a 60‐year‐old female treated with an unknown dose of clopidogrel at the time of paclitaxel therapy. Clopidogrel was present in all three of the plasma samples obtained during paclitaxel dosing. Estimated unbound paclitaxel clearance was 238 l h⁻¹, which was only 62% of the cohort geometric mean (385 l h⁻¹; range 176–726). She was hospitalized three times, developed severe neuropathy and paclitaxel treatment was subsequently discontinued. In vitro, 30‐min preincubation with 100 μM clopidogrel acyl‐β‐D‐glucuronide inhibited the depletion rate of 0.5 μM paclitaxel by 51% and the formation rate of 6α‐hydroxypaclitaxel by 77%.

Conclusion

This is the first report of a clopidogrel–paclitaxel interaction, suggesting that clinically used doses of clopidogrel can reduce the cytochrome P450 2C8 (CYP2C8)‐mediated systemic clearance of paclitaxel, leading to an increased risk of paclitaxel toxicity. Caution should be exercised whenever the simultaneous use of paclitaxel and clopidogrel cannot be avoided.

What is Already Known About This Subject

• Neurotoxicity and bonemarrow suppression are dose limiting toxicities of paclitaxel.

• Paclitaxel is predominantly eliminated by CYP2C8.

• The acyl-beta-D-glucoronide metabolite of clopidogrel is a strong inhibitor of CYP2C8 in vitro.

What This Study Adds

• In vitro, clopidogrel acyl‐β‐D‐glucuronide inhibits the overall depletion of paclitaxel by 50%, and CYP2C8 specific hydroxylation by 77%.

• A patient is described who was treated concomitantly with paclitaxel and clopidogrel and subsequently developed toxicity so severe that paclitaxel was cessated.

• It is concluded that a clinically significant interaction between clopidogrel and paclitaxel is likely as well as plausible.

Introduction

Paclitaxel is an antineoplastic agent frequently used in the treatment of solid tumours. The development of neuropathy has been associated with low paclitaxel clearance 1. Paclitaxel is mainly metabolized by cytochrome P450 (CYP) 2C8 (by 6‐α‐hydroxylation) and to a lesser extent by CYP3A4 (by p‐3´‐hydroxylation) in vitro 2, 3. Recently, the widely used antiplatelet agent clopidogrel was found to be a strong inhibitor of CYP2C8, due to its acyl‐β‐D‐glucuronide metabolite, which is a strong metabolism‐dependent CYP2C8 inhibitor in vitro 4.

Case report

We present the case of the only clopidogrel user (dose unknown) who was identified in a previously described cohort of 93 ovarian carcinoma patients scheduled for six to nine courses of paclitaxel 175 mg m⁻² plus carboplatin (area under the curve 5–6 mg·min·ml⁻¹), every third week 5, 6. The clopidogrel user was diagnosed with FIGO stage IIIc disease. Comedication included metoclopramide, ondansetron, lisinopril, hydrochlorothiazide, salicylic acid, citalopram, simvastatin, paracetamol, tramadol and esomeprazole. Baseline biochemistry results including albumin, alanine aminotransferase, alkaline phosphatase and bilirubin were unremarkable. Her genotype was CYP2C8*1/CYP2C8*3, and her estimated clearance of unbound paclitaxel was 238 l h⁻¹ [cohort geometric mean (range): 385 l h⁻¹ (176–726)] – i.e. the second lowest in the cohort 5. She had a trough neutrophil count of 0.6 ×10⁹ l⁻¹ [cohort median (10th–90th percentile): 0.72 ×10⁹ l⁻¹ (0.11–2.07 ×10⁹ l⁻¹)]. She was hospitalized thrice during chemotherapy owing to Common Terminology Criteria (CTCAE) grade 3 nausea and vomiting. Paclitaxel was discontinued after four cycles owing to grade 3 neuropathy. Grade 3 toxicity generally represents severe symptoms, limiting self‐care and activities of daily living. In the cohort, 18% of the patients were admitted to hospital and 17% discontinued paclitaxel owing to toxicity. Grade 3 neuropathy, nausea and vomiting occurred in 17%, 2% and 4% of the patients, respectively. After approval from The Regional Scientific Ethical Committee for Southern Denmark (S‐VF‐20 050 083), all three of the patient's original plasma samples were assayed for clopidogrel 7. Clopidogrel was found in all the samples, and noncompliance was therefore eliminated. In addition, we studied the effect of clopidogrel acyl‐β‐D‐glucuronide on the metabolism of paclitaxel in human liver microsomes (HLM). Preincubation with 100 μM clopidogrel acyl‐β‐D‐glucuronide for 30 min inhibited the depletion rate of 0.5 μM paclitaxel by 51% and the formation rate of 6α‐hydroxypaclitaxel by 77% (Figure 1). The experiment was carried out by premixing clopidogrel acyl‐β‐D‐glucuronide or control for 3 min with HLM (2 mg ml⁻¹). After incubation, samples were taken at different time points by moving the incubation mixture to a stop solution (acetonitrile containing paclitaxel‐d5 and HCOOH). Pseudo‐first‐order depletion constants were determined for the depletion rate of 0.5 μM paclitaxel using time points at 0–30 min after adding paclitaxel. The 6α‐hydroxypaclitaxel formation rate was calculated based on its concentration at 7.5 min after adding paclitaxel.

Figure 1.

In vitro inhibition experiments in human liver microsomes (HLM). (A) Depletion of 0.5 μM paclitaxel, and (B) formation of 6α‐hydroxypaclitaxel, in the absence (CONTROL) and presence (CLOP‐G) of 100 μM clopidogrel acyl‐β‐D‐glucuronide. Clopidogrel acyl‐β‐D‐glucuronide (100 μM) or control was first preincubated for 30 min with HLM (2 mg ml⁻¹) and β‐nicotinamide adenine dinucleotide phosphate, reduced form (NADPH) (1 mM). Paclitaxel (0.5 μM) was then added and the mixture was further incubated for 1 h. Paclitaxel and 6α‐hydroxypaclitaxel were quantified using a Shimadzu Nexera liquid chromatograph coupled to a Shimadzu 8050 mass spectrometer (Shimadzu, Kyoto, Japan). The data points represent mean ± standard deviation values of triplicate incubations.

Discussion and conclusion

This is the first case report of severe paclitaxel toxicity and very low paclitaxel clearance in a patient treated simultaneously with clopidogrel, and, overall, the first report of an interaction between paclitaxel and a CYP2C8 inhibitor. Our in vitro experiments conformed well to the clinical case, demonstrating that clopidogrel acyl‐β‐D‐glucuronide inhibited the depletion of paclitaxel by 50%, and the 6α‐hydroxylation of paclitaxel, a CYP2C8‐specific marker reaction, by 77% in HLM. Given that the paclitaxel concentration (0.5 μM) used in vitro is within its clinically relevant concentration range, and that the 77% inhibition of CYP2C8 is similar to the estimated inhibitory effect of clinically used clopidogrel doses, the in vitro results are likely to be representative of a clinical situation. Until formal studies have determined the clinical significance of the interaction, caution should be exercised whenever simultaneous use of paclitaxel and clopidogrel cannot be avoided.

Competing Interest

All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: no support from any organization for the submitted work; JB has a patent Use of gemfibrozil in low doses as a pharmacokinetic enhancer (CYP2C8 inhibitor) pending; no other relationships or activities that could appear to have influenced the submitted work.

This work was supported by the Danish Ministry of Interior Affairs and Health (2001–2007) (#2006‐12103‐276], The Danish Research Agency (#271‐05‐0266) and The Academy of Finland (#278123).

Bergmann, T. K. , Filppula, A. M. , Launiainen, T. , Nielsen, F. , Backman, J. T. , and Brosen, K. (2016) Neurotoxicity and low paclitaxel clearance associated with concomitant clopidogrel therapy in a 60‐year‐old Caucasian woman with ovarian carcinoma. Br J Clin Pharmacol, 81: 313–315. doi: 10.1111/bcp.12795.