Clinical pharmacokinetics of mitoxantrone after intraperitoneal administration

Abstract

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: t1/2 beta (distribution), 56.4 min (range, 16.8-235.8 min); t1/2 gamma (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); delta'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: t1/2 alpha (absorption), 58.8 min (range, 45.6-87.0 min); t1/2 beta (distribution), 2.5 h (range, 1.4-6.3 h); t1/2 gamma (elimination), 44.1 h (range, 9.1-91 h); Vdss, 2,152 l (range, 352-19,733 l); delta'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.

Intraperitoneal Therapy for Peritoneal Cancer

“…The ratios of drug AUC in the peritoneal cavity and AUC in systemic blood are 12 for cisplatin, 10 for carboplatin, 65 for melphalan, 65 for etoposide, 75 for mitomycin C, 367 for 5-fluorouracil, 500 for doxorubicin, 915 for mitoxantrone and 1000 for paclitaxel dissolved in Cremophor EL ® (BASF Corp., Germany)/ethanol [32–38]. However, the ratios between drug concentrations in tumors and plasma are much lower; IP treatments of cis-platin in animals yielded two- to three-times higher concentrations in tumor periphery, but no improvement in tumor center, compared with intravenous treatments [39,40].…”

“…Intraperitoneal therapy has been under development for several decades; most clinical studies were conducted in patients with ovarian or gastrointestinal cancer [32–38]. IP therapy has been administered in various settings.…”

Versatility of Particulate Carriers: Development of Pharmacodynamically Optimized Drug-Loaded Microparticles for Treatment of Peritoneal Cancer

“…IP therapy has been under development for several decades and has shown survival benefits in selected patient groups (5,(16)(17)(18)(19)(20). Most studies, conducted in patients with ovarian or gastrointestinal cancer, used IP therapy preoperatively to downstage the disease to facilitate surgical debulking and intraoperatively and postoperatively to treat residual small and microscopic tumors (21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36). Hyperthermia intraoperative IP chemotherapy, where the drug solution (e.g., cisplatin, mitomycin C) is heated to 41-43°C to enhance drug uptake and antitumor efficacy, has also been used.…”

Intraperitoneal Mitoxantrone or Floxuridine: Effects on Time-to-Failure and Survival in Patients with Minimal Residual Ovarian Cancer after Second-Look Laparotomy—A Randomized Phase II Study by the Southwest Oncology Group

“…In fact, others have concluded that mitoxantrone is worthy of further exploration reassessments were documented in a small number of patients. Encouraging therapeutic results have been observed given alone [17][18][19][20][21][22] or in combination with interferon-a [23]. A negative report with the intraperitoneal administra-with this drug by the ip route in other settings [29][30][31][32].…”