Interaction between paclitaxel and warfarin

M. E. Thompson and M. S. Highley*

Department of Cancer Medicine, Ninewells Hospital, Dundee, UK

*E-mail: m.s.highley@dundee.ac.uk

Paclitaxel is now routinely employed in the treatment of cancers of the ovary, breast and lung [1]. It is metabolised by the hepatic cytochrome P450 system and binds to plasma proteins. We report an increase in the international normalised ratio (INR) in a patient receiving warfarin, following the administration of paclitaxel.

A 75-year-old female presented with a deep venous thrombosis and a pleural effusion. She was commenced on warfarin, with a target INR of 2.5–3.0, and was stabilised on 2 mg daily. Investigations revealed stage IV ovarian cancer, and paclitaxel and carboplatin was initiated 2 months after starting warfarin. She had a history of duodenal ulceration, for which she was taking ranitidine 150 mg twice daily.

Paclitaxel 175 mg/m2 was given over 3 h, followed by carboplatin at a target dose of an area under the curve of 5 mg·min/ml. Oral dexamethasone 20 mg was administered the night before and the morning of treatment. Ondansetron, 8 mg twice daily, was given as an antiemetic on the day of treatment. Prior to the paclitaxel, cimetidine 300 mg was infused over 15 min, followed by 10 mg chlorpheniramine over a similar time period.

A pre-chemotherapy INR of 3.0 increased to 5.2 on day 2 of the first cycle. The warfarin was discontinued and recommenced on day 8. A post-treatment rise was observed after all subsequent cycles of paclitaxel and carboplatin (Figure 1). The dose of paclitaxel was reduced to 135 mg/m2 on the third and following cycles, which were also delayed by 1 week, due to thrombocytopaenia. On the third cycle, i.v. ranitidine was administered rather than cimetidine, but there was still a rise in the INR. The daily dose of warfarin was 5 mg for most of the last four cycles, but was reduced on days 3 and 4 of the fifth and sixth cycles, to minimise the increase in the INR.



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Figure 1. Change in INR with paclitaxel administration.

 
Carboplatin is not known to interact with warfarin. Regular prolonged administration of cimetidine can inhibit the metabolism of warfarin, producing a rise in the INR [2]. However, a single dose prior to paclitaxel is unlikely to produce an increase the following day, and the INR also increased when ranitidine was given. Paclitaxel is 95–98% bound to plasma proteins, as indicated by in vitro data [3], and could therefore displace warfarin from protein binding sites. Both warfarin and paclitaxel are metabolised by the cytochrome P450 system, but whilst warfarin is oxidised primarily by CYP2C9 and CYP1A2, paclitaxel is metabolised via CYP2C8 and CYP3A4. Interactions between paclitaxel and other anticancer agents have been reported, but of other drug classes, so far only interactions with the anticonvulsants phenytoin, carbamazepine and phenobarbital have been described [4].

The early increase in the INR suggests that displacement of warfarin from protein binding sites by paclitaxel is the most important mechanism of this apparent interaction. In patients receiving warfarin and paclitaxel, the INR must be monitored closely.

M. E. Thompson & M. S. Highley*

Department of Cancer Medicine, Ninewells Hospital, Dundee, UK (*E-mail: m.s.highley{at}dundee.ac.uk)

References

1. Crown J, O’Leary M. The taxanes: an update. Lancet 2000; 355: 1176–1178.[CrossRef][ISI][Medline]

2. Serlin MJ, Sibeon RG, Mossman S et al. Cimetidine: interaction with oral anticoagulants. Lancet 1979; 2: 317–319.[CrossRef][Medline]

3. Sonnichsen DS, Relling MV. Clinical pharmacokinetics of paclitaxel. Clin Pharmacokinet 1994; 27: 256–269.[ISI][Medline]

4. Baker AF, Dorr RT. Drug interactions with the taxanes: clinical implications. Cancer Treat Rev 2001; 27: 221–233.[CrossRef][ISI][Medline]