Doxorubicin pharmacokinetics

Fundaro A. et al.. Non-stealth and stealth solid lipid nanoparticles (SLN) carrying doxorubicin pharmacokinetics and tissue distribution after i.v. administration to rats,... 

Ratain, M.J., Robert, J., and van der Vijgh, W.J.F. Limited sampling models for doxorubicin pharmacokinetics. Journal of Clinical Oncology 1991 9 871-876. 

Holmes FA, Madden T, Newman RA, Valero V, Theriault RL, Fraschini G, Walters RS, Booser DJ, Buzdar AU, Willey J, Hortobagyi GN. Sequence-dependent alteration of doxorubicin pharmacokinetics by paclitaxel in a phase I study of paclitaxel and doxorubicin in patients with metastatic breast cancer. Oncol (1996) 14, 2713-21. 

Ri s CE, Ei el S, Wesley M, Wiemik PH, Bachur NR. Doxorubicin pharmacokinetics prodilorpeiBzine and barbiturate effects. Clin Pharmacol Ther( 9 )3, 263. 

Fundaro, A., CavaUi, R., Bargoni, A., Vighetto, D., Zara, G., Gasco, M. Non-stealth and stealth solid Upid nanoparticles (SEN) carrying doxorubicin Pharmacokinetics and tissue distribution after i.v. administration to rats. Pharmacol. Res. 2000,42 (4), 337-343. 

Liposomal doxorubicin is an irritant, not a vesicant, and is dosed differently from doxorubicin, so clinicians need to be very careful when prescribing these two drugs. The pharmacokinetics of liposomal doxorubicin are best described by a two-compartment model, with a terminal half-life of 30 to 90 hours.20 Liposomal doxorubicin has shown significant activity in the treatment of breast and ovarian cancer, along with multiple myeloma and Kaposi s sarcoma. Side effects include mucositis, myelosuppression, alopecia, and palmar-plantar erythrodysesthesia. The liposomal doxorubicin may be less cardiotoxic than doxorubicin. 

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. 

Paclitaxel also may be given concurrently with doxorubicin or epirubicin as a combination regimen. Pharmacokinetic interactions make these regimens more difficult to give. 

Bibby DC, Talmadge JE, Dalai MK, Kurz SG, Chytil KM, Barry SE, Shand DG, Steiert M (2005) Pharmacokinetics and biodistribution of RGD-targeted doxorubicin-loaded nanoparticles in tumor-bearing mice. International Journal of Pharmaceutics 293 281-290. 

Minchin RF, Johnston MR, Aiken MA, Boyd MR (1984) Pharmacokinetics of doxorubicin in isolated lung of dogs and humans perfused in vivo. J Pharmacol Exp Ther 229 193-198. 

Gabizon A, Shmeeda H, Barenholz Y. Pharmacokinetics of pegylated liposomal Doxorubicin review of animal and human studies. Clin Pharmacokinetics 2003 42 419 36. 

Coukell AJ, Spencer CM. Polyethylene glycol-liposomal doxorubicin. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in the management of AIDS-related Kaposi s sarcoma. Drugs 1997 53 520. 

Gabizon AA, Barenholz Y, Bialer M. Prolongation of the circulation time of doxorubicin encapsulated in liposomes containing polyethylene glycol-derivatized phospholipid pharmacokinetic studies in rodents and dogs. Pharm Res 1993 10(5) 703. 

Charrois GJ, Allen TM. Drug release rate influences the pharmacokinetics, biodistribution, therapeutic activity, and toxicity of pegylated liposomal doxorubicin formulations in murine breast cancer. Biochim Biophys Acta 2004 1663(1-2) 167. 

Bao A, Goins B, Klipper R, Negrete G, Phillips WT. Direct Tc labeling of pegylated liposomal doxorubicin (Doxil) for pharmacokinetic and non-invasive imaging studies. J Pharmacol Exp Ther 2004 308 419. 

A phase I clinical and pharmacokinetic study of PKl comprising doxorubicin covalently bound to N-(2-hydroxypropyl)-methacrylamide copolymer by a peptidyl linker, was carried out in 36 patients with refractory or resistant cancers [94], PKl demonstrated anti-tumour activity, and that polymer-drug conjugation decreased doxorubicin dose-limiting toxicities. Phase II studies are in progress. 

Zara G.P., Intravenous administration to rahhits of non-stealth and stealth doxorubicin loaded sohd hpid nanoparticles at increasing concentrations of stealth agent pharmacokinetics and distrihution of doxoruhicin in hrain and other tissues, J. Drug Targeting, 10, 327, 2002. 

Matsumura Y, Hamaguchi T, Ura T, Muio K, Yamada Y, Shimada Y, Shitao K, Okusaka T, Ueno H, Ikeda M, Watanahe N. Phase I clinical trial and pharmacokinetic evaluation of NK911, a micelle-encapsulated doxorubicin. Br J Cancer 2004 91 1775-1781. 

Northfelt DW, Martin FJ, Working P, Volberding PA, Russell J, Newman M, Amantea MA, Kaplan LD. Doxorubicin encapsulated in liposomes containing surface-bound polyethylene glycol pharmacokinetics, tumor localization, and safety in patients with AIDS-related Kaposi s sarcoma. J Clin Pharmacol 1996 36 55-63. 

Herceptin with cisplatin, doxorubicin or epirubicin plus cyclophosphamide, or paclitaxel. A comparison of serum levels of trastuzumab given in combination with various chemotherapeutic agents did not suggest the possibility of any pharmacokinetic interactions except in combination with paclitaxel. Although not statistically signihcant, mean serum trough concentrations of trastuzumab were consistently elevated, about 1.5-fold, when Herceptin was administered in combination with paclitaxel. However, trastuzumab and paclitaxel were used concurrently in clinical trials with positive outcome results. The concurrent administration of anthracyclines, cyclophosphamide, and trastuzumab increased the incidence and severity of cardiac dysfunction during clinical trials. 

The pharmacokinetics fCD and HlftCD after intravenous administration have been assessed (Frijlinket al., 1990). As determined at doses of 25,100, and 200 mg/kg in permanently cannulated rats, plasma levels of both CDs decreased rapidly upon injection. Within 24 h after administration, most of the doses were excreted unchanged via urine. There was no evidence forsigniLcant metabolism of the intravenously administered CDs. The pharmacokinetics and the tissue concentrations of methyl-p-cyclodextrin (MEBCD) and doxorubicin (DOX) in rabbits following administration of MEBCD and DOX, alone or in combination were studied (Grosse et al., 1999). Results indicated that DOX did not modify MEBCD pharmacokinetic proLle, but MEBCD reduced signiLcantly the distribution half-life of DOX. Tissue determination showed that MEBCD did not enhanced the cardiac accumulation of DOX. 

Kwon and Kataoka (1995) summarized earlier studies ofthe pharmacokinetics and disposition polyethylene oxid -aspartate)-doxorubicin conjugates (PEGAsp-DOX) (Yokoyama et al.,... 

Danson, S., D. Ferry, V. Alakhov, J. Margison, D. Kerr, D. Jowle, M. Brampton, G. Halbert, and M. Ranson. 1994. Phase I dose escalation and pharmacokinetic study of pluronic polymer-bound doxorubicin (SP1049C) in patients with advanced canBerJ. Cancer. 90 2085-2091. 

Peck, R.A., et al. 2001. Phase I and pharmacokinetic study of the novel MDR1 and MRP1 inhibitor biricodar administered alone and in combination with doxorubicin. J Clin Oncol 19 3130. 

Vasey, P. A., Kaye, S. B., Morrison, R., et al. Phase I clinical and pharmacokinetic study of PK1 [lV-(2-hydroxypropyl)methacrylamide copolymer doxorubicin] First member of a new class of chemotherapeutic agents-drug-polymer conjugates. Cancer Research Campaign Phase I/II Committee. Clin. Cancer Res. 5(l) 83-94. 1999. 

Oral verapamil has been shown to increase peak plasma levels, prolong the terminal half-life, and increase the volume of distribution at steady state of doxorubicin (282). Gigante et al. (283) performed similar studies in which the pharmacokinetics of doxorubicin in combination with verapamil given at high doses intravenously were followed for 17 patients with advanced neoplasms. The steady-state concentration and systemic and renal clearances were found to be statistically similar for various doses of verapamil and doxorubicin, and for doxorubicin administered alone. 

Cyclosporin A readily inhibits CYP3A metabolism and may lead to significant pharmacokinetic interactions (288). Several studies have been performed using cyclosporin A as a P-gp modulator in combination with etoposide, doxorubicin, and paclitaxel as described below. 

The effects of cyclosporin A on the pharmacokinetics of etoposide have been determined and were shown to be dose dependent. A variable range of cyclosporin A concentrations was obtained (297-5073 ng/mL), and it was observed that patients with higher cyclosporin A concentrations also had larger increases in etoposide AUC (290). Results from studies using clinically relevant plasma concentrations of cyclosporin A (1000-5000 ng/mL) as a P-gp inhibitor resulted in mean 48%, 52%, and 52% decreases in the systemic, renal, and nonrenal clearances of intravenously administered etoposide (232,290). Similar decreases in the systemic, renal, and nonrenal clearances of doxorubicin were observed with administration of cyclosporin A (232,291). 

Sparreboom A, Planting AS, Jewell RC, et al. Clinical pharmacokinetics of doxorubicin in combination with GF120918, a potent inhibitor of MDR1 P-glycoprotein. Anticancer Drugs 1999 10(8) 719-728. 

Gigante M, Toffoli G, Boiocchi M. Pharmacokinetics of doxorubicin co-adminis-tered with high-dose verapamil. Br J Cancer 1995 71(1) 134—136. 

Giaccone G, Linn SC, Welink J, et al. A dose-finding and pharmacokinetic study of reversal of multidrug resistance with SDZ PSC 833 in combination with doxorubicin in patients with solid tumors. Clin Cancer Res 1997 3(11) 2005—2015. 

Tranchand B, Catimel G, Lucas C, et al. Phase I clinical and pharmacokinetic study of S9788, a new multidrug-resistance reversal agent given alone and in combination with doxorubicin to patients with advanced solid tumors. Cancer Chemother Pharmacol 1998 41(4) 281-291. 

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