This Article Full Text (PDF) References Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Saved Citations Download to citation manager Request Permissions Request Reprints Add to My Marked Citations Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Citing Articles via Scopus Google Scholar Articles by Amantea, M Articles by Working, P K Search for Related Content PubMed PubMed Citation Articles by Amantea, M Articles by Working, P K Social Bookmarking                         What's this?

Relationship of dose intensity to the induction of palmar-plantar erythrodysesthia by pegylated liposomal doxorubicin in dogs

SEQUUS Pharmaceuticals, Inc., Menlo Park, California, USA

M S Newman

SEQUUS Pharmaceuticals, Inc., Menlo Park, California, USA

T M Sullivan

Battelle, Columbus, Ohio, USA

A Forrest

Clinical Pharmacokinetics Laboratory, Millard Fillmore Hospital, Buffalo, New York, USA

P K Working

SEQUUS Pharmaceuticals, Inc., Menlo Park, California, USA

1 The multiple dose pharmacokinetics of pegylated liposomal doxorubicin (PL-DOX), known as DOXIL® (US) and CAELYX® (EU), was characterized in dogs and a pharmacokinetic/pharmacodynamic model to identify a relationship between drug exposure and the probability of observing treatment-related palmarplantar erythrodysesthesia (PPE) was developed.

2 Twenty dogs were assigned to PL-DOX groups (2/sex/ group) that received intravenous PL-DOX doses of 0.5 mg/kg q1, 2, or 4 weeks; 1.0 mg/kg q2weeks; or 1.5 mg/kg q4weeks for 12 weeks. Blood was collected for HPLC analysis of doxorubicin concentration pre-dose and periodically up to 120 h after dosing three times during treatment.

3 Plasma drug concentration was modeled using iterative 2-stage analysis. Dermal lesions (PPE) were scored twice weekly for six regions of each dog using a 0-6 severity scale; maximum severity was 36. PPE score data were modeled using an approach in which the% probability of PPE was related to a hypothetical effect site by a series of Hill-type functions.

4 Pharmacokinetics were best modeled as a one-compartment open model. Vss (ml/kg), CLt (ml/hr/kg) and half-life (h) were 44.1, 1.39 and 23.1, respectively. Cmax increased linearly with dose. CLt decreased with repeated doses.

5 A two-compartment pharmacodynamic model, which correctly predicted 97% of the observed lesion severity, was developed to establish the relationship of lesion severity to dose intensity (a measure of drug exposure incorporating the effect of both dose level and dosing frequency, which can be expressed in units of mg/kg/week). The model demonstrated that maximal PPE was positively correlated with dose intensity, the major factor that affects the incidence and severity of dermal lesions.

6 The model can be used to predict acceptable dose intensities in humans utilizing body surface area conversion factors and comparative AUCs for dogs and humans. It predicts that a dose intensity of 10-12.5 mg/m² of PL-DOX will be well tolerated in patients. The results of recent clinical studies are consistent with this prediction.

Key Words: CAELYX® • DOXIL® • pegylated liposomal doxorubicin • palmar-plantar erythrodysesthia

Human & Experimental Toxicology, Vol. 18, No. 1, 17-26 (1999)
DOI: 10.1177/096032719901800103


CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				D Lorusso, A Di Stefano, V Carone, A Fagotti, S Pisconti, and G Scambia Pegylated liposomal doxorubicin-related palmar-plantar erythrodysesthesia ('hand-foot' syndrome) Ann. Onc., July 1, 2007; 18(7): 1159 - 1164. [Abstract] [Full Text] [PDF]

				G. J. R. Charrois and T. M. Allen Multiple Injections of Pegylated Liposomal Doxorubicin: Pharmacokinetics and Therapeutic Activity J. Pharmacol. Exp. Ther., September 1, 2003; 306(3): 1058 - 1067. [Abstract] [Full Text] [PDF]

				R. Banerjee Liposomes: Applications in Medicine J Biomater Appl, July 1, 2001; 16(1): 3 - 21. [Abstract] [PDF]

				L. K. McLoon and J. D. Wirtschafter Doxil-Induced Chemomyectomy: Effectiveness for Permanent Removal of Orbicularis Oculi Muscle in Monkey Eyelid Invest. Ophthalmol. Vis. Sci., May 1, 2001; 42(6): 1254 - 1257. [Abstract] [Full Text]

				M. Lotem, A. Hubert, O. Lyass, M. A. Goldenhersh, A. Ingber, T. Peretz, and A. Gabizon Skin Toxic Effects of Polyethylene Glycol-Coated Liposomal Doxorubicin Arch Dermatol, December 1, 2000; 136(12): 1475 - 1480. [Abstract] [Full Text] [PDF]

				K. J. Harrington, G. Rowlinson-Busza, K. N. Syrigos, R. G. Vile, P. S. Uster, A. M. Peters, and J. S. W. Stewart Pegylated Liposome-encapsulated Doxorubicin and Cisplatin Enhance the Effect of Radiotherapy in a Tumor Xenograft Model Clin. Cancer Res., December 1, 2000; 6(12): 4939 - 4949. [Abstract] [Full Text]

				D. C. Drummond, O. Meyer, K. Hong, D. B. Kirpotin, and D. Papahadjopoulos Optimizing Liposomes for Delivery of Chemotherapeutic Agents to Solid Tumors Pharmacol. Rev., December 1, 1999; 51(4): 691 - 744. [Abstract] [Full Text] [PDF]