Abstract
Purpose
Liposomal encapsulation of doxorubicin is designed to increase safety and tolerability by decreasing cardiac and gastrointestinal toxicity through decreased exposure of these tissues to doxorubicin, while effectively delivering drug to the tumor. We conducted an open-label phase I study to determine the pharmacokinetic profile of a single dose of liposome-encapsulated doxorubicin (Myocet) in patients with various solid tumors. Safety and tolerability were monitored.
Experimental design
Patients received a single intravenous infusion of Myocet 75 mg/m2. Plasma samples were analyzed for concentration of liposome-encapsulated doxorubicin, total doxorubicin, and doxorubicinol.
Results
A total of 18 patients aged 20–73 years (median 60 years) participated; 17 were evaluable for pharmacokinetic analysis. The most common primary tumor was soft tissue sarcoma (22%). Total body clearance for total doxorubicin was 5.6 l/h/m2 while the volume (Vss) was 82 l/m2. The terminal half-life was 52.6 h. Based on the AUC and Cmax values for total doxorubicin and encapsulated doxorubicin, an estimated 85% of circulating doxorubicin was encapsulated. Doxorubicinol was detected in all patients; the mean AUC was 2.03±1.10 μmol/l/h. The mean 48-h urinary excretion of doxorubicin was 6.44% of the dose. The most common adverse events were nausea (94%), fatigue (78%) and vomiting (67%). Cardiotoxicity (measured as ten-point fall in LVEF to <50%) was observed in one patient. Pharmacokinetic values did not correlate with hematological, laboratory or demographic variables.
Conclusions
The pharmacokinetic profile of Myocet suggests that the liposomal formulation results in a longer half-life with less free drug available for tissue distribution than conventional doxorubicin, consistent with the enhanced therapeutic index observed in clinical studies.
Similar content being viewed by others
References
Singal PK, Iliskovic N (1998) Doxorubicin-induced cardiomyopathy. N Engl J Med 339:900–905
Swenson CE, Bolcsak LE, Batist G, Guthrie TH Jr, Tkaczuk KH, Boxenbaum H, Welles L, Chow S-C, Bhamra R, Chasikin P (2003) Pharmacokinetics of doxorubicin administered i.v. as Myocet (TLC D-99; liposome-encapsulated doxorubicin citrate) compared with conventional doxorubicin when given in combination with cyclophosphamide in patients with metastatic breast cancer. Anticancer Drugs 14:239–246
Batist G, Ramakrishnan G, Rao CS, Chandrasekharan A, Gutheil J, Guthrie T, Shah P, Khojasteh A, Nair MK, Hoelzer K (2001) Reduced cardiotoxicity and preserved antitumor efficacy of liposome-encapsulated doxorubicin and cyclophosphamide compared with conventional doxorubicin and cyclophosphamide in a randomized, multicenter trial of metastatic breast cancer. J Clin Oncol 19:1444–1454
Harris L, Batist G, Belt R, Rovira D, Navari R, Azarnia N, Welles L, Winer E (2002) Liposome-encapsulated doxorubicin compared with conventional doxorubicin in a randomized multicenter trial as first-line therapy of metastatic breast carcinoma. Cancer 94:25–36
Chabner BA, Allegra CJ, Curt GA, Calabresi P (1996) Antineoplastic agents. In: Hardman JG, Limbird LE (eds) Goodman and Gilman’s the pharmacological basis of therapeutics, 9th edn. McGraw-Hill, New York, pp 1264–1266
Takanashi S, Bachur N (1976) Adriamycin metabolism in man. Evidence from urinary metabolites. Drug Metab Dispos 4:79–87
Mross K, Maessen P, van der Vijgh WJF, Gall H, Boven E, Pinedo HM (1988) Pharmacokinetics and metabolism of epidoxorubicin and doxorubicin in humans. J Clin Oncol 6:517–526
Speth PAJ, Van Hoesel QGCM, Haanen C (1988) Clinical pharmacokinetics of doxorubicin. Clin Pharmacokinet 15:15–31
Loo TL, Freireich EJ (1995) Cancer chemotherapeutic drugs. In: PL Munson (ed) Principles of pharmacology: basic concepts and clinical application. Chapman & Hall, New York, pp 1475–1516
Robert J (1998) Anthracyclines. In: Grochow LB, Ames MM (eds) A clinician’s guide to chemotherapy: pharmacokinetics and pharmacodynamics. William and Wilkins, Philadelphia
Gibaldi M, Perrier D (1982) Pharmacokinetics, 2nd edn. Dekker
Chan KKH, Gibaldi M (1982) Estimation of statistical moments and steady-state volume of distribution for a drug given by intravenous infusion. J Pharmacokinet Biopharm 10:551–558
Robert J, Gianni L (1993) Pharmacokinetics and metabolism of anthracyclines. Cancer Surv 17:219–252
Camaggi CM, Comparsi R, Strocchi E, Testoni F, Angelelli B, Pannuti F (1988) Epirubicin and doxorubicin comparative metabolism and pharmacokinetics. A cross-over study. Cancer Chemother Pharmacol 21:221–228
Jacquet J-M, Bressolle F, Galtier M, Bourrier M, Donadio D, Jourdan J, Rossi JF (1990) Doxorubicin and doxorubicinol: intra- and inter-individual variations of pharmacokinetic parameters. Cancer Chemother Pharmacol 27:219–225
Piscitelli SC, Rodvold KA, Rushing DA, Tewksbury DA (1993) Pharmacokinetics and pharmacodynamics of doxorubicin in patients with small cell lung cancer. Clin Pharmacol Ther 53:555–561
Amantea MA, Forrest A, Northfeldt DW, Mamelok R (1997) Population pharmacokinetics and pharmacodynamics of pegylated-liposomal doxorubicin in patients with AIDS-related Kaposi’s sarcoma. Clin Pharmacol Ther 61:301–311
Hamilton A, Biganzoli L, Coleman R, Mauriac L, Hennebert P, Awada A, Nooij M, Beex L, Piccart M, Van Hoorebeeck I, et al (2002) EORTC 10968: a phase I clinical and pharmacokinetic study of polyethylene glycol liposomal doxorubicin (Caelyx, Doxil) at a 6-week interval in patients with metastatic breast cancer. Ann Oncol 13:910–918
Keller AM, Mennel RG, Nabholtz JM, Georgoulias V, Emanuel DJ, Tendler CL (2001) Phase III trial of pegylated liposomal doxorubicin (Caelyx/Doxil) for the treatment of patients with advanced breast cancer who have failed a prior taxane-containing chemotherapy regimen. Proceedings of the Annual Meeting of the American Society of Clinical Oncology, abstract 115
Lyass O, Uziely B, Ben-Yosef R, Tzemach D, Heshing NI, Lotem M, Brufman G, Gabizon A (2000) Correlation of toxicity with pharmacokinetics of pegylated liposomal doxorubicin (Doxil) in metastatic breast carcinoma. Cancer 89:1037–1047
Lotem M, Hubert A, Lyass O, Goldenhersh MA, Ingber A, Peretz T, Gabizon A (2000) Skin toxic effects of polyethylene glycol-coated liposomal doxorubicin. Arch Dermatol 136:1475–1480
Hong RL, Tseng YL (2001) Phase I and pharmacokinetic study of a stable, polyethylene-glycolated liposomal doxorubicin in patients with solid tumors: the relation between pharmacokinetic property and toxicity. Cancer 91:1826–1833
Mross K (1993) Klinische und pharmakologische Untersuchungen zur Pharmakokinetik, Metabolisierung, Pharmakodynamik und Toxizität von Anthrazyklinen W. Zuckschwerdt Verlag München, Aktuelle Onkologie 76
Massing U, Fuxius S (2000) Liposomal formulations of anticancer drugs: selectivity and effectiveness. Drug Resist Updat 3:171–177
Gabizon A, Catane R, Uziely B, Kaufman B, Safra T, Cohen R, Martin F, Huang F, Barenholz Y (1994) Prolonged circulation time and enhanced accumulation in malignant exudates of doxorubicin encapsulated in polyethylene-glycol coated liposomes. Cancer Res 54:987–992
Mross K, Gierlich T, Häring B, März W, Unger C (2002) Clinical and pharmacokinetics study with liposomal doxorubicin (DL-1) in patients with advanced metastatic cancer—results from a phase-I study. Int J Clin Pharmacol Ther 40:387–388
Acknowledgement
This study was sponsored by The Liposome Company, Princeton, NJ, USA (now Medeus Pharmaceuticals, Inc.).
Author information
Authors and Affiliations
Corresponding author
Additional information
The Liposome Company is now Medeus Pharmaceuticals, Inc.
Rights and permissions
About this article
Cite this article
Mross, K., Niemann, B., Massing, U. et al. Pharmacokinetics of liposomal doxorubicin (TLC-D99; Myocet) in patients with solid tumors: an open-label, single-dose study. Cancer Chemother Pharmacol 54, 514–524 (2004). https://doi.org/10.1007/s00280-004-0825-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00280-004-0825-y