High-dose Cisplatin with amifostine: ototoxicity and pharmacokinetics.
OBJECTIVE
Ototoxicity is a common side effect of high-dose cisplatin treatment. Thiol-containing chemoprotectors ameliorate cisplatin ototoxicity under experimental conditions. The trial was initiated to test the efficacy of amifostine protection in high-dose cisplatin treatment (125-150 mg/m) for metastatic malignant melanoma, to correlate the ototoxic outcome with cisplatin pharmacokinetics, and to evaluate the importance of using a selective analytical method for the quantification of cisplatin.


METHODS
Prospective study of 15 patients with stage IV malignant melanoma.


METHODS
Clinical follow-up of therapeutic response, pure-tone audiometry, and analysis of cisplatin and its monohydrated complex in blood ultrafiltrate by liquid chromatography with postcolumn derivatization were performed. Ultrafiltered blood platinum was analyzed by inductively coupled plasma mass spectrometry.


RESULTS
Ototoxicity and gastrointestinal toxicity were the most prominent side effects. Three patients ultimately required hearing aids. All patients had audiometric changes at one or more frequencies after the second treatment course, and all but one patient reported auditory symptoms. No correlation was found between hearing loss and blood cisplatin pharmacokinetics. Platinum levels determined by inductively coupled plasma mass spectrometry were higher than total platinum levels calculated from cisplatin and monohydrated complex concentrations obtained by liquid chromatography analysis.


CONCLUSIONS
Ototoxicity was unacceptable despite amifostine treatment. Cisplatin pharmacokinetics during the first treatment course were not predictive of hearing loss. Amifostine caused a lowering of dose-normalized area under the concentration-time curve for cisplatin and monohydrated complex. Use of the unselective inductively coupled plasma mass spectrometry analysis leads to an overestimation of active drug. Selective analysis of cisplatin is especially important when evaluating cisplatin pharmacokinetics during chemoprotector treatment.
Department of Otolaryngology-Head and Neck Surgery, Karolinska Institute, Stockholm, Sweden. Andreas.Ekborn@ks.se
Andreas
A
Ekborn
Johan
J
Hansson
Hans
H
Ehrsson
Staffan
S
Eksborg
Inger
I
Wallin
Gunnar
G
Wagenius
Göran
G
Laurell
D000328:Adult; D000368:Aged; D004999:Amifostine / Q000009:adverse effects / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D001301:Audiometry, Pure-Tone; D001309:Auditory Threshold / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006319:Hearing Loss, Sensorineural / Q000097:blood / Q000139:chemically induced* / Q000517:prevention & control; D006801:Humans; D008297:Male; D008545:Melanoma / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D008657:Metabolic Clearance Rate / Q000187:drug effects; D008875:Middle Aged; D009367:Neoplasm Staging; D018696:Neuroprotective Agents / Q000009:adverse effects / Q000627:therapeutic use*; D011446:Prospective Studies; D012878:Skin Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology
D000970:Antineoplastic Agents; D018696:Neuroprotective Agents; D004999:Amifostine; D002945:Cisplatin