ETOPOSIDE DOSAGE AND PHARMACODYNAMICS

Etoposide is a schedule-dependent cytotoxic drug with high single agen t activity in small-cell lung cancer and lymphoma. Despite its clear d ose-dependent myelosuppressive activity, dose-dependent evidence of it s anti-tumour activity is harder to demonstrate. A number of reports h ave correlated haematological toxicity with pharmacokinetic and physio logical parameters, which explains some of the variability in dynamic effects that exists between patients. Recent reports have also suggest ed that anti-tumour response may be related to plasma etoposide concen tration. In our own studies we have investigated factors that influenc e the pharmacodynamic effects of etoposide, principally with regard to haematological toxicity, and these studies have highlighted a number of patient groups who are at risk. Impaired renal function causes a re duction in clearance of etoposide, resulting in increased systemic exp osure and more profound myelotoxicity. A 30% dose reduction in this gr oup is recommended to normalise the area under the plasma concentratio n-time curve (AUC). Patients with low serum albumin concentrations (<3 5 g/l) also showed significantly worse haematological toxicity, but wi th no apparent change in total drug pharmacokinetics. There was, howev er, an increase in the free drug fraction in this group due to decreas ed protein binding, such that the free drug AUC was similar to that fo und in patients with renal dysfunction. This would also indicate that a dose reduction of around 30%-40% is required in this patient group. Patients with normal albumin levels but liver enzyme values (aspartate transaminase or gammaglutamyl transpeptidase) more than 3 times the u pper limit of normal also had a less marked but significant increase i n neutropenia. In patients with normal organ function, age was the onl y significant factor in predicting the degree of leukopenia/neutropeni a, and increasing age was also associated with decreasing drug clearan ce and an increase in drug AUC. A small dose reduction and/or careful monitoring is required in this patient group. Further studies are requ ired to elucidate further the relationship between the pharmacokinetic s of etoposide and its pharmacodyamics, particularly with regard to an ti-tumour activity, and to determine the role of individualised therap y, based on a pharmacokinetic parameter, in reducing the dynamic varia bility and optimising the use of this drug.