Clinical pharmacokinetics of mitoxantrone after intraperitoneal administration |
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Authors: | J Dieter Nagel Freek J Varossieau Ria Dubbelman Wim W ten Bokkel Huinink J Gordon McVie |
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Institution: | (1) Department of Pediatric Oncology and Hematology, University Clinic of Bonn, Adenauerallee 119, W-5300 Bonn, Germany;(2) Netherlands Cancer Institute, Department of Experimental Therapy, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands;(3) Cancer Research Campaign, 2 Carlton House Terrace, SWIY 5AR London, U.K. |
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Abstract: | Summary The pharmacokinetics of intraperitoneally (i.p.) injected mitoxantrone was determined in plasma and peritoneal dialysate taken from five patients presenting with cancer confined to the peritoneal cavity over a sampling period of 1 week. The drug was given through a Tenckhoff catheter as a 15-min infusion and the peritoneal dialysate was removed after a dwell time of 4 h; the doses delivered varied between 20 and 50 mg/m2. Dose-limiting local toxicity was moderate. The HPLC technique used for mitoxantrone determinations proved to be sensitive within the range of 0.3–4,000 ng/ml. Median values obtained for the pharmacokinetic parameters of mitoxantrone in peritoneal dialysate were:t
1/2 (distribution), 56.4 min (range, 16.8–235.8 min);t
1/2 (elimination), 128 h (range, 28.3–171.0 h); VdSS (volume of distribution at steady state), 24.8 l (range, 17.0–232.5 l);
ss (volume of distribution at steady state corrected for the body surface area in square meters), 14.4 l/m2 (range, 10.6–129.2 l/m2); and clearance, 0.25 l/h (range, 0.16–0.59 l/h). For plasma the median values were:t
1/2 (absorption), 58.8 min (range, 45.6–87.0 min);t
1/2 (distribution), 2.5 h (range, 1.4–6.3 h);t
1/2 (elimination), 44.1 h (range, 9.1–91 h); VdSS, 2,152 l (range, 352–19,733 l);
ss, 1,345 l/m2 (range, 220–11,606 l/m2); and clearance, 117 l/h (range, 51–1,609 l/h). After 168 h the median plasma concentration was 1 ng/ml. The median peak concentration in peritoneal dialysate was 490 ng/ml. Considering the moderate toxicity observed and the concentrations achieved in the peritoneal dialysate, removal of the dialysate after certain dwell times seems reasonable to be a reasonable approach for the optimization of i.p. treatment with mitoxantrone. |
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