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Antimicrobial Agents and Chemotherapy, August 2000, p. 2068-2076, Vol. 44, No. 8
0066-4804/00/$04.00+0

Dose-Dependent Pharmacokinetics of Amphotericin B Lipid Complex in Rabbits

Thomas J. Walsh,1,* Andre J. Jackson,2 James W. Lee,1 Michael Amantea,1 Tin Sein,1 John Bacher,3 and Loren Zech4,dagger

Mycology Unit and Immunocompromised Host Section1 and Laboratory of Mathematical Biology,4 National Cancer Institute, and Veterinary Resource Program,3 National Institutes of Health, Bethesda, Maryland, and Division of Bioequivalence, Center for Drug Evaluation and Research, Rockville, Maryland2

Received 7 October 1998/Returned for modification 13 October 1999/Accepted 8 May 2000

Amphotericin B lipid complex (ABLC) was recently approved by the Food and Drug Administration for treatment of patients with invasive fungal infections who are intolerant of or refractory to conventional amphotericin B therapy. Little is known, however, about the pharmacokinetics of this new antifungal compound. We therefore investigated the pharmacokinetics of ABLC in comparison with those of conventional desoxycholate amphotericin B (DAmB) in rabbits. The pharmacokinetics of DAmB in a rabbit model were similar to those previously reported in humans. The pharmacokinetics of ABLC differed substantially from those of DAmB. Plasma amphotericin B levels following ABLC administration were 10 times lower than those following administration of an equal dosage of DAmB. The levels of ABLC in whole blood were approximately 40 times greater than those in plasma. The ABLC model differed from the DAmB model by (i) a dose- and time-dependent uptake and return between the plasma compartment and apparent cellular components of the blood-sediment compartment and (ii) time-dependent tissue uptake and return to plasma from serially connected compartments. Following infusion of ABLC, there was a nonlinear uptake into the apparent cellular components of the blood-sediment compartment. This uptake was related to the reciprocal of the integral of the total amount of drug infused (i.e., the more drug infused the greater the fractional uptake between 0.5 and 5 mg/kg of body weight for ABLC). The transfer of drug from plasma to the cellular components of the blood-sediment compartment resulted in initial uptake followed by rapid redistribution back to the plasma. The study describes a detailed model of the pharmacokinetics of ABLC and characterizes a potential role of the cellular components of the blood-sediment compartment in the distribution of this new antifungal compound in tissue.

* Corresponding author. Mailing address: Pediatric Oncology Branch, Bldg. 10, Room BN240, National Institutes of Health, Bethesda, MD 20892. Phone (301) 402-0023. Fax: (301) 402-0575. E-mail: Walsht{at}mail.NIH.GOV.

dagger Deceased.

Antimicrobial Agents and Chemotherapy, August 2000, p. 2068-2076, Vol. 44, No. 8
0066-4804/00/$04.00+0


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