High-dose methotrexate clearance following prior vancomycin administration: no significant interaction in the absence of overt renal impairment

J. Shamash*, S. Joel, L. Lundholm, L. Millard and T. Oliver

Department of Medical Oncology, St. Bartholomew’s Hospital, London, UK

*E-mail: brenda.bunbury@bartsandthelondon.nhs.uk

We read with interest the clinical cases described by R. Blum et al. [1]. We are currently conducting a study into high-risk and relapsed germ-cell tumours. This protocol requires the use of high-dose methotrexate (MTX), and as we use vancomycin as part of our empirical antibiotic therapy, we have reviewed our cases for evidence of the interaction described. The GAMEC protocol used involved the administration of cisplatin 100 mg/m2, etoposide 360 mg/m2 divided doses over 4 days, actinomycin 1 mg/m2 and MTX 10 g/m2 on weeks 1, 3, 6, 8 and 10, and cisplatin 50 mg/m2 on weeks 2 and 4. The cisplatin was administered 36 h after MTX if the serum creatinine had not risen by more than 15% above the pretreatment concentration. The MTX dose was adjusted according to glomerular filtration rate: >120 ml/min, 10 g/m2; 100–120 ml/min, 8 g/m2; 80–99 ml/min, 6 g/m2; 60–79 ml/min, 5g/m2; 40–59 ml/min, 3.5 g/m2. Antibiotics were given for febrile neutropenia, with first-line antibiotics being ceftazidime and gentamicin, and second line being ceftazidime and vancomycin. As part of the protocol, in addition to MTX levels being measured at 12, 24 and 48 h as required, some patients underwent a detailed pharmacokinetic study to assess MTX clearance.

We identified eight patients who received high-dose MTX following administration of vancomycin for previous neutropenia. All but one received high-dose MTX within 10 days of previous vancomycin administration. The serial MTX levels of these patients, with their serum creatinines and MTX doses, are shown in Table 1.


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Table 1. Patients’ serial methotrexate levels, serum creatinines and methotrexate doses
 
For the three patients where detailed pharmacokinetic data were available, MTX total plasma clearance before and after vancomycin administration were: patient 6, 5.9 versus 5.6 l/h; patient 7, 3.0 versus 3.9 l/h; patient 8, 8.8 versus 8.1 l/h, respectively. An additional patient was studied on only one occasion following vancomycin. For these four patients the median MTX clearance was 5.4 l/h (range 3.9–8.8), compared with 6.7 l/h (range 1.7–8.5) in the 15 patients who were studied but did not receive vancomycin (P = 0.87). One patient clearly showed impaired clearance of MTX after vancomycin administration (patient 1; 48 h MTX, 32 µmol/L), but showed no change in EDTA clearance (71 ml/min before the first cycle compared with 65 ml/min before the second cycle). Although vancomycin could have contributed to his impaired MTX clearance, the cisplatin and a known underlying ureteric obstruction were probably more significant.

Our data differ from those described by Blum et al. in that the doses of MTX were slightly lower, although still well into the high-dose range. In addition, our protocol did not involve ifosfamide, a drug which is known to cause cumulative renal tubular damage, particularly in combination with cisplatin [2, 3], and which may have contributed to the effect described. We note that sampling was more prolonged in both of the cases described than in our own studies, and therefore may have detected delayed elimination, reflecting slow MTX clearance from a deep compartment, such as patients with third space fluid.

It would be useful to know whether other investigators have encountered the interaction described by Blum et al. because protocols involving high-dose MTX are often intensive, leading to febrile neutropenia, and vancomycin remains an important empirical antibiotic in this context.

In conclusion, the suggestion that a repeat EDTA should be performed following vancomycin administration if high-dose MTX is used again, cannot be supported by our experience.

J. Shamash*, S. Joel, L. Lundholm, L. Millard & T. Oliver

Department of Medical Oncology, St Bartholomew’s Hospital, London, UK (*E-mail: jonathan{at}jshamash.demon.co.uk)

References

1. Blum R, Seymour JF, Toner G. Significant impairment of high-dose methotrexate clearance following vancomycin administration in the absence of overt renal impairment. Ann Oncol 2002; 13: 327–330.[Abstract/Free Full Text]

2. Arndt C, Morgenstern B, Hawkins D et al. Renal function following combination chemotherapy with ifosfamide and cisplatin in patients with osteogenic sarcoma. Med Pediatr Oncol 1999; 32: 93–96.[CrossRef][ISI][Medline]

3. Koch Nogueira PC, Hadj-Aissa A, Schell M et al. Long-term nephrotoxicity of cisplatin, ifosfamide, and methotrexate in osteosarcoma. Pediatr Nephrol 1998; 12: 572–575.[CrossRef][ISI][Medline]





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