Pharmacokinetic approach to the selection of dose schedules for medroxyprogesterone acetate in clinical oncology

Abstract

The pharmacokinetic and bioavailability properties of medroxyprogesterone acetate (MPA) after single PO and IM doses in man were used as a basis to predict, on a theoretical pharmacokinetic basis, the blood level profile of the drug during repeated dose administration with various dosage schedules. Because of the unusually long-lasting depot effect of IM MPA, a different build-up process of blood levels is expected during repeated IM or PO administration, and this should be taken into account when dose schedules for use in clinical oncology are selected. As regards the IM route, dose schedules based on 4 weeks' treatment with daily injections of 500-1,000 mg followed by a maintenance therapy with 1,000 mg/week are suggested, since they permit rapid achievement and maintenance of relatively high plasma levels. A similar plasma level profile can be obtained with oral MPA provided that daily doses twice as large as the IM doses are given during the first month of treatment and continued during the maintenance period. The serum levels observed in 25 patients with advanced breast cancer treated with MPA given IM or PO according to various dose schedules and recent literature data are very close to the serum level profiles predicted on a theoretical pharmacokinetic basis.

Adjuvant Treatment with High Dose Medroxyprogesterone Acetate in Node-Negative Early Breast Cancer A 3-year Interim Report on a Randomized Trial (I)

“…In an adjuvant situation, HD-MPA given i.m. for 6 months would in fact accomplish exposure to the drug for at least 3 more months (14,15). With regard to the dose chosen, it has been shown in advanced breast cancer that no further tumor regression could be obtained from daily MPA doses over 500 mg during the loading phase (6).…”

A Randomized Controlled Comparative Study of Oral Medroxyprogesterone Acetate 1,200 and 600 mg in Patients with Advanced or Recurrent Breast Cancer

“…The median serum concentration of MPA in the 1,200-mg treatment group was almost double that of the 600-mg group, but there was wide interpatient variation. This has also been reported in pharmacokinetic studies of measuring serum concentrations [19, 20]. The variation may be explained by individual differences in MPA absorption and metabolism.…”

Clinical Significance of Differences in Bioavailability of Medroxyprogesterone Acetate Preparations

“…As predicted from pharmacokinetic data, high blood concentrations can be achieved (Tamassia et al 1982) and high response rates were reported. The question remained as to the optimum dosage and route of administration of medroxyprogesterone acetate to achieve maximum response.…”

“…Concentrations rose throughout the study when the intramuscular route was used, while steady-state was reached after approximately 10 days of oral therapy (Camaggi et al 1983). It was predicted that steady-state would be reached after 6 to 8 months of continuous intramuscular therapy, and a schedule of daily intramuscular injections for 1 month to achieve a high blood concentration, followed by a once-weekly maintenance dose, was suggested (Tamassia et al 1982). It was noted that there was a very wide variation in plasma concentrations between patients, particularly after oral administration, and it was thought that response might relate to the blood concentration achieved.…”