Abstract
We conducted a pharmacokinetic (PK) study of mitoxantrone (Novantrone®), a clinically well-established anticancer agent, in mice and developed a mechanism-based PBPK (physiologically based pharmacokinetic) model to describe its disposition. Mitoxantrone concentrations in plasma and six organs (lung, heart, liver, kidney, spleen, and brain) were determined after a 5 mg/kg i.v. dose. We evaluated three different PBPK models in order to characterize our experimental data: model 1 containing Kp values, model 2 incorporating a deep binding compartment, and model 3 incorporating binding of mitoxantrone to DNA and protein. Among the three models, only model 3 with DNA and protein binding captured all the experimental data well. The estimated binding affinity for DNA (K DNA) and protein (K macro) were 0.0013 and 1.44 μM, respectively. Predicted plasma and tissue AUC values differed from observed values by <19 %, except for heart (60 %). Model 3 was further used to simulate plasma mitoxantrone concentrations in humans for a 12-mg/m2 dose, using human physiological parameters. The simulated results generally agreed with the observed time course of mitoxantrone plasma concentrations in patients after a standard dose of 12 mg/m2. In summary, we reported for the first time a mechanism-based PBPK model of mitoxantrone incorporating macromolecule binding which may have clinical applicability in optimizing clinical therapy. Since mitoxantrone is a substrate of the efflux transporters ABCG2 and ABCB1, the incorporation of efflux transporters may also be necessary to characterize the data obtained in low-dose studies.
Similar content being viewed by others
References
Smith IE. Mitoxantrone (novantrone): a review of experimental and early clinical studies. Cancer Treat Rev. 1983;10:103–15.
Batra VK, Morrison JA, Woodward DL, Siverd NS, Yacobi A. Pharmacokinetics of mitoxantrone in man and laboratory animals. Drug Metab Rev. 1986;17:311–29.
Durr FE, Wallace RE, Citarella RV. Molecular and biochemical pharmacology of mitoxantrone. Cancer Treat Rev. 1983;10(Suppl B):3–11.
Young CW, Raymond V. Clinical assessment of the structure-activity relationship of anthracyclines and related synthetic derivatives. Cancer Treat Rep. 1986;70:51–63.
Scott LJ, Figgitt DP. Mitoxantrone: a review of its use in multiple sclerosis. CNS Drugs. 2004;18:379–96.
Ehninger G, Schuler U, Proksch B, Zeller KP, Blanz J. Pharmacokinetics and metabolism of mitoxantrone. A review. Clin Pharmacokinet. 1990;18:365–80.
De Isabella P, Palumbo M, Sissi C, Capranico G, Carenini N, Menta E, Oliva A, Spinelli S, Krapcho AP, Giuliani FC, et al. Topoisomerase II DNA cleavage stimulation, DNA binding activity, cytotoxicity, and physico-chemical properties of 2-aza- and 2-aza-oxide-anthracenedione derivatives. Mol Pharmacol. 1995;48:30–8.
Thielmann HW, Popanda O, Gersbach H, Gilberg F. Various inhibitors of DNA topoisomerases diminish repair-specific DNA incision in UV-irradiated human fibroblasts. Carcinogenesis. 1993;14:2341–51.
Foye WO, Vajragupta O, Sengupta SK. DNA-binding specificity and RNA polymerase inhibitory activity of bis(aminoalkyl)anthraquinones and bis(methylthio)vinylquinolinium iodides. J Pharm Sci. 1982;71:253–7.
Lu K, Savaraj N, Loo TL. Pharmacological disposition of 1,4-dihydroxy-5-8-bis[[2 [(2-hydroxyethyl)amino]ethyl]amino]-9,10-anthracenedione dihydrochloride in the dog. Cancer Chemother Pharmacol. 1984;13:63–6.
Reszka R, Beck P, Fichtner I, Hentschel M, Richter J, Kreuter J. Body distribution of free, liposomal and nanoparticle-associated mitoxantrone in B16-melanoma-bearing mice. J Pharmacol Exp Ther. 1997;280:232–7.
Ehninger G, Proksch B, Heinzel G, Schiller E, Weible KH, Woodward DL. The pharmacokinetics and metabolism of mitoxantrone in man. Invest New Drugs. 1985;3:109–16.
Richard B, Fabre G, Fabre I, Cano JP. Excretion and metabolism of mitoxantrone in rabbits. Cancer Res. 1989;49:833–7.
Alberts DS, Peng YM, Leigh S, Davis TP, Woodward DL. Disposition of mitoxantrone in cancer patients. Cancer Res. 1985;45:1879–84.
Sharom FJ. ABC multidrug transporters: structure, function and role in chemoresistance. Pharmacogenomics. 2008;9:105–27.
Gerlowskiand LE, Jain RK. Physiologically based pharmacokinetic modeling: principles and applications. J Pharm Sci. 1983;72:1103–27.
Gustafson DL, Rastatter JC, Colombo T, Long ME. Doxorubicin pharmacokinetics: macromolecule binding, metabolism, and excretion in the context of a physiologic model. J Pharm Sci. 2002;91:1488–501.
Bradshaw-Pierce EL, Eckhardt SG, Gustafson DL. A physiologically based pharmacokinetic model of docetaxel disposition: from mouse to man. Clin Cancer Res. 2007;13:2768–76.
Zaharko DS, Dedrick RL, Bischoff KB, Longstreth JA, Oliverio VT. Methotrexate tissue distribution: prediction by a mathematical model. J Natl Cancer Inst. 1971;46:775–84.
Li J, Gwilt P. The effect of malignant effusions on methotrexate disposition. Cancer Chemother Pharmacol. 2002;50:373–82.
Bischoff KB, Dedrick RL, Zaharko DS, Longstreth JA. Methotrexate pharmacokinetics. J Pharm Sci. 1971;60:1128–33.
Farris FF, Dedrick RL, King FG. Cisplatin pharmacokinetics: applications of a physiological model. Toxicol Lett. 1988;43:117–37.
Shah DK, Balthasar JP. Physiologically based pharmacokinetic model for topotecan in mice. J Pharmacokinet Pharmacodyn. 2011;38:121–42.
An G, Morris ME. HPLC analysis of mitoxantrone in mouse plasma and tissues: application in a pharmacokinetic study. J Pharm Biomed Anal. 2010;51:750–3.
Davies B, Morris T. Physiological parameters in laboratory animals and humans. Pharm Res. 1993;10:1093–5.
Goormaghtigh E, Chatelain P, Caspers J, Ruysschaert JM. Evidence of a specific complex between adriamycin and negatively-charged phospholipids. Biochim Biophys Acta. 1980;597:1–14.
Courtade S, Marinetti GV, Stotz E. The structure and abundance of rat tissue cardiolipins. Biochim Biophys Acta. 1967;137:121–34.
Kawai R, Mathew D, Tanaka C, Rowland M. Physiologically based pharmacokinetics of cyclosporine A: extension to tissue distribution kinetics in rats and scale-up to human. J Pharmacol Exp Ther. 1998;287:457–68.
Terasaki T, Iga T, Sugiyama Y, Hanano M. Pharmacokinetic study on the mechanism of tissue distribution of doxorubicin: interorgan and interspecies variation of tissue-to-plasma partition coefficients in rats, rabbits, and guinea pigs. J Pharm Sci. 1984;73:1359–63.
Terasaki T, Iga T, Sugiyama Y, Hanano M. Experimental evidence of characteristic tissue distribution of adriamycin. Tissue DNA concentration as a determinant. J Pharm Pharmacol. 1982;34:597–600.
Peng YM, Ormberg D, Alberts DS, Davis TP. Improved high-performance liquid chromatography of the new antineoplastic agents bisantrene and mitoxantrone. J Chromatogr. 1982;233:235–47.
Larson RA, Daly KM, Choi KE, Han DS, Sinkule JA. A clinical and pharmacokinetic study of mitoxantrone in acute nonlymphocytic leukemia. J Clin Oncol. 1987;5:391–7.
Alberts DS, Peng YM, Leigh S, Davis TP, Woodward DL. Disposition of mitoxantrone in patients. Cancer Treat Rev. 1983;10(Suppl B):23–7.
Lown JW, Hanstock CC. High field 1H-NMR analysis of the 1:1 intercalation complex of the antitumor agent mitoxantrone and the DNA duplex [d(CpGpCpG)]. J Biomol Struct Dyn. 1985;2:1097–106.
Kapuscinski J, Darzynkiewicz Z. Relationship between the pharmacological activity of antitumor drugs Ametantrone and mitoxantrone (Novatrone) and their ability to condense nucleic acids. Proc Natl Acad Sci U S A. 1986;83:6302–6.
Rentsch KM, Schwendener RA, Pestalozzi BC, Sauter C, Wunderli-Allenspach H, Hanseler E. Pharmacokinetic studies of mitoxantrone and one of its metabolites in serum and urine in patients with advanced breast cancer. Eur J Clin Pharmacol. 1998;54:83–9.
Rentsch KM, Horber DH, Schwendener RA, Wunderli-Allenspach H, Hanseler E. Comparative pharmacokinetic and cytotoxic analysis of three different formulations of mitoxantrone in mice. Br J Cancer. 1997;75:986–92.
Wang YF, Ahmad A, Abu-Qare AW, Dudkowski C, Ayoub JE, Zhang A, Ahmad I. Rapid determination of liposomal and non-liposomal mitoxantrone in mouse plasma. Preclinica. 2004;2:279–86.
Mao Q, Unadkat JD. Role of the breast cancer resistance protein (ABCG2) in drug transport. AAPS J. 2005;7:E118–33.
Zhang S, Yang X, Morris ME. Flavonoids are inhibitors of breast cancer resistance protein (ABCG2)-mediated transport. Mol Pharmacol. 2004;65:1208–16.
Minderman H, Suvannasankha A, O'Loughlin KL, Scheffer GL, Scheper RJ, Robey RW, Baer MR. Flow cytometric analysis of breast cancer resistance protein expression and function. Cytometry. 2002;48:59–65.
Acknowledgment
Supported in part by a grant from the Susan G. Komen Breast Cancer Foundation (BCTR0601385). We thank Dr. Donald Mager and Dr. Chao Xu for their valuable suggestions in the PBPK model construction.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
An, G., Morris, M.E. A Physiologically Based Pharmacokinetic Model of Mitoxantrone in Mice and Scale-up to Humans: a Semi-Mechanistic Model Incorporating DNA and Protein Binding. AAPS J 14, 352–364 (2012). https://doi.org/10.1208/s12248-012-9344-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1208/s12248-012-9344-7