[Clinical pharmacokinetics and practical consequences of optimal use of medroxyprogesterone acetate]

Medroxyprogesterone acetate (MPA) is one of the major drugs used in endocrine therapy for advanced breast cancer. However, its optimal dose is still not clearly established. Response to treatment and drug-related side effects were analyzed as a function of plasma MPA concentrations during prolonged MPA administration. MPA plasma concentrations were measured (HPLC assay) at steady state (Css min) in 129 patients (mean age 63 years, 34-87) treated by MPA (111 being treated orally exclusively, with daily doses ranging from 400 to 2000 mg). A wide inter-patient variability was noted in MPA Css min for the 70 patients receiving 1000 mg/day per os: median 51 ng/ml, range 10-269 ng/ml. Intra-patient analysis of the evolution of MPA Css min during prolonged treatment showed relative stability of MPA concentrations (mean coefficient of variation = 21%). A weak but nevertheless significant correlation was demonstrated between oral doses and MPA Css min (P = 0.016). Thirty-five percent of patients (45/129) developed MPA-related side effects which were associated with the highest plasma MPA concentrations: medians were 81 and 32 ng/ml for toxic and non-toxic treatments respectively (P < 0.001). Moreover, the cumulative incidence of side-effects constantly increases with the elevation of Css min. Objective response was assessable in 55 patients treated by MPA exclusively. Plasma MPA concentrations were significantly different between patients with PD and those with either CR, PR or SD: medians were 46 and 65 ng/ml respectively (P = 0.025). The cumulative incidence of objective response increases up to 70 ng/ml. Analysis of toxicity and response as a function of the oral dose did not reveal any significant relationship. These data suggested an optimal therapeutic window for MPA Css min located within 50-70 ng/ml. This study demonstrates that, as opposed to the administered dose, plasma MPA concentration is a determining factor for toxicity and response to therapy.