Mitoxantrone pharmacokinetics

This royal-blue-colored drug is an anthracenedione that inhibits DNA topoisomerase II. The pharmacokinetics of mitoxantrone may best be described by a three-compartment model, with an a half-life of 3 to 10 minutes, a 3 half life of 0.3 to 3 hours, and a median terminal half-life of 12 days. Biliary elimination appears to be the primary route of elimination, with less than 10% of the drug eliminated by the kidney.23 Mitoxantrone has shown clinical activity in the treatment of acute leukemias, breast and prostate cancer, and non-Hodgkin s lymphomas. Myelosuppression, mucositis, nausea and vomiting, and cardiac toxicity are side effects of this drug. The total cumulative dose limit is 160 mg/m2 for patients who have not received prior anthracycline or mediastinal radiation. Patients who have received prior doxorubicin or daunorubicin therapy should not receive a cumulative dose greater than 120 mg/m2 of mitoxantrone. Patients should be counseled that their urine will turn a blue-green color. 

The characterization of a mitoxantrone-resistant breast cancer cell line that displayed an efflux-based MDR phenotype without expression of Pgp or MRPl led to the discovery of BCRP. This transporter, also known as mitoxantrone resistance protein (MXR) or placenta-specific ABC transporter (ABCP), is a half-transporter acting as a homo- or heterodimer to form an active transporter [22]. The substrate specificity of BCRP overlaps somewhat with that of Pgp and MRPl, suggesting a similar role in the pharmacokinetic of chemotherapeutic drugs. In fact, the overexpression of BCRP in tumor cells confers resistance to mitoxantrone, topotecan, SN38, flavopiridol, doxorubicin, bisantrene, etoposide, and methotrexate [16]. 

The pharmacokinetics of mitoxantrone 10 mg/m daily were compared with mitoxantrone 6 mg/m (a 40% reduction in dose) with high-dose ciclosporin in children. The ciclosporin recipients had a 42% reduction in mitoxantrone clearance, a 12% inerease in mitoxantrone AUC, and similar toxicity. ... 

LacayoNJ, Lum BL, BectonDL, Weinstein H, Ravindranath Y, Chang MN, BomgaarsL, Lau-er SJ, Sikic BL Pharmacokinetic interactions of cyclosporine with etoposide and mitoxantrone in children with acute myeloid leukem ia. Leukemia (2002) 16, 920-7. 

Guohua A, Morrie ME. 2012. A physiologically based pharmacokinetic model of mitoxantrone in mice and scale-np to humans a semi-mechanistic model on corporating DNA and protein binding. AAPS J 14 352-354. 

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