Antitumour activity and plasma kinetics of bleomycin by continuous and intermittent administration.

Y M Peng,T E Moon,H S Chen,D S Alberts,N Mason

doi:10.1038/bjc.1980.110

Abstract

We have studied the cytotoxicity of bleomycin (4--10 u/kg/day for 6 days) given by continuous i.p. infusion (using an osmotic minipump) compared to daily i.p. bolus administration, against P388 leukaemic spleen colony-forming-units(LCFU-S). Continuous i.p. bleomycin at 8 u/kg/day caused a 0.5 log greater reduction of LCFU-S than did an identical dose given by intermittent bolus administration. The infusion minipump provided constant bleomycin plasma levels of 0.62 +/- 0.03 mu/ml and a total plasma AUC (area under the plasma decay curve) of 89.0 mu.h/ml for 6 days at 8 u/kg/day. Intermittent bolus bleomycin at 8 u.kg/day had a terminal-phase plasma t1/2 of 15 min and a total 6-day plasma AUC of 90.8mu.h/ml. These pharmacokinetic data validate the osmotic minipump as a constant drug-delivery system, and suggest that the two administration schedules resulted in equal total bleomycin dosages. Although high peak bleomycin plasma levels (i.e. 32 mu/ml) were achieved with the intermittent bolus administration, continuous-infusion bleomycin's greater inhibition of LCFU-S was probably related to the drug's schedule-dependent cell-killing characteristics. The results of this study provide further rationale for the continuing use of infusion bleomycin schedules in cancer patients.

Highlights

There is some evidence that continuous i.v. infusion (C.i.v.) vs intermittent i.v. push (I.i.v.) bleomycin is associated with similar response rates and less systemic toxicity in patients with squamous-cell cancer of the cervix (Baker et al, 1978)
The animal was first anaesthetized with pentobarbital, a small incision was made in the abdomen, the minipump filled with bleomycin (2-10 u/kg/day) was inserted i.p. and the incision was closed with surgical clips
We were able to use these minipumps to deliver a constant infusion of bleomycin for 6 days

Summary

Introduction

BLEOMYCIN has proven effectiveness against several human cancers when administered either intermittently (i.v., i.m., s.c. or i.p.) or by continuous infusion (Prestayko & Crooke, 1979; Alberts et al, 1979). There is some evidence that continuous i.v. infusion (C.i.v.) vs intermittent i.v. push (I.i.v.) bleomycin (when combined with mitomycin C and vincristine) is associated with similar response rates and less systemic toxicity in patients with squamous-cell cancer of the cervix (Baker et al, 1978). (J.s.c.) bleomycin caused longer survival and slower tumour growth rates and pulmonary toxicity in mice bearing Lewis lung carcinoma (Sikic et al, 1978).

Results

Conclusion