Cisplatin induced ototoxicity : Pharmacokinetics, prediction and prevention

Abstract: Cisplatin is an anticancer drug used against a number of malignancies e.g. testicular cancer, ovarian cancer and some paediatric malignancies. The main dose limiting side effects of cisplatin are oto- and neurotoxicity. Cisplatin is regarded as the most common cause of ototoxicity in Sweden today. Cisplatin ototoxicity manifests clinically as a hearing loss beginning in the high frequency region and involving successively lower frequencies. Tinnitus is another common complaint. There is a high interindividual variability in susceptibility to the ototoxic effect, a rough dose dependence and indications that the mode of administration affects the toxic effects. The aim of the thesis has been to study cisplatin ototoxicity especially as related to the pharmacokinetics of the drug and to prediction and prevention of ototoxicity. The first hypothesis was that mode of administration affects the side effect profile of cisplatin. The pharmacokinetics of cisplatin and the monohydrated complex of cisplatin (MHC) a toxic biotransformation product of cisplatin were determined after a bolus injection or a one-hour infusion of cisplatin to guinea pigs. It was found that the interindividual variability in susceptibility to the ototoxic effect was far greater than the variability in pharmacokinetics, suggesting that other factors are more important for the degree of hearing loss. MHC has been suggested as the major cause of cisplatin side effects but has previously not been purified in sufficient amounts for animal studies of toxicity. This was effected by separation on a porous graphitic column. MHC caused an ABR thresholds shift, an increase in creatinine and a weight loss in the animals similar to those seen after administration of cisplatin in the double dose. Thus, MHC is approximately twice as toxic as cisplatin. The antitumour effect of cisplatin is often assumed to be proportional to the systemic exposure to the drug. D-methionine has recently been advocated as a protectant against cisplatin toxicity. However, i.v. administration of D-methionine 1 hour before cisplatin caused a 30% decrease in the systemic exposure to cisplatin and an even greater reduction in MHC exposure. Our results indicate that the previously observed protection from cisplatin ototoxicity by systemic D-methionine can be explained by a lowered systemic exposure to cisplatin. Local administration of a cytoprotective agent to the inner ear offers a possibility to prevent cisplatin-induced ototoxicity without risk of interference with the antitumour effect. Thiourea (TU) has unique properties that make it an interesting candidate for local protection against cisplatin ototoxicity. Ears administered TU by a direct intracochlear infusion demonstrated significantly lower OHC loss as compared to untreated ears but similar ABR. Thus, TU demonstrates partial protection against cisplatin-induced ototoxicity. A trial was initiated to test the efficacy of high dose cisplatin treatment (125 mg/m2) with amifostine (Ethyol®) protection in 15 patients with metastatic malignant melanoma. The most prominent side effects were ototoxic and in spite of amifostine treatment ototoxicity was unacceptable. After the second treatment all but one patient reported auditory symptoms and three patients ultimately required a hearing aid. No correlation was found on the individual level between subsequent hearing loss and plasma pharmacokinetics during the first course. An effect of amifostine on cisplatin pharmacokinetics was suggested as the analysis of platinum levels showed higher values than those obtained by selective analysis of cisplatin, corroborating the findings in the D-methionine study.