Effect of repeated bolus and continuous doxorubicin administration on bone and soft tissue concentrations- a randomized study evaluated in a tumour-free porcine model.

Abstract

Purpose: The aim of this study was to evaluate plasma and bone- and soft-tissue concentrations of doxorubicin following two administrations of either bolus or continuous infusion administered at a three-week interval. The achievement of adequate concentration at target sites is believed to be positively correlated to effect, and it has been suggested that concentrations are affected by the number of administrations.

Methods: Eighteen female pigs were included in the study and randomized into two groups of nine receiving either a bolus or continuous infusion. The animals received a dosage of 2 mg/kg on day 1 and on day 22. From day 1 to 10, doxorubicin concentrations, as well as kidney and liver function, were monitored with plasma samples (total concentrations). On day 22, doxorubicin was measured in plasma samples (total concentration) and microdialysates (unbound concentrations) from subcutaneous tissue, muscle, synovial fluid of the knee joint, cancellous bone, and intravenously.

Results: On day 22, the pharmacokinetic profiles were comparable between the two groups except for plasma AUC_{0 - 12 h}, which was higher after continuous infusion, and intravenous C_max, which was higher after bolus infusion. Bone- and soft tissue concentrations were below 0.10 µg/mL. Except for mean plasma (total) concentration at the 6 h timepoint on day 1 and 22 in the continuous group, which was higher after the first administration (p = 0.037), no differences in plasma concentrations were found between the two administrations.

Conclusion: Low mean tissue doxorubicin concentrations and similar pharmacokinetic profiles were found between the bolus and continuous infusion groups. Thus, similar anti-neoplastic efficacy is to be expected with both administration types.