Dose-Dependent Pharmacokinetics of Amphotericin B Lipid Complex in Rabbits

Abstract

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.Invasive fungal infections have emerged as important causes of morbidity and mortality in immunocompromised hosts (14,15). Desoxycholate amphotericin B (DAmB) remains the treatment of choice for treatment of many life-threatening opportunistic mycoses. However, dose-limiting nephrotoxicity often compromises the ability to administer DAmB, resulting in therapeutic failures. Certain lipid formulations of amphotericin B can be administered at higher dosages with reduced nephrotoxicity (6, 9, 13, 17).Amphotericin B lipid complex (ABLC or Abelcet; The Liposome Company, Princeton, N.J.) was developed to reduce the toxicity and maximize the therapeutic utility of amphotericin B in the treatment of invasive fungal infections (10). The preparation of ABLC consists of amphotericin B complexed with two lipids in a 1:1 drug-to-lipid molar ratio. These lipids, dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylglycerol (DMPG), are present in a 7:3 molar ratio.Amphotericin B lipid complex 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 am...

Polyene Antibiotics Physical Chemistry and Their Effect on Lipid Membranes; Impacting Biological Processes and Medical Applications

“…Most preclinical studies consistently indicate that liposomal AmB increases drug disposition in organs such as the lung and central nervous system [ 380 , 381 , 382 ]. Clinical trial results, on the other hand, indicate that liposomal AmB and AmB lipid complexes have better bioavailability, tolerability, and safety compared with AmB deoxycholate [ 207 , 208 , 383 , 384 , 385 ]. Studies conducted in patients have shown the presence of high concentrations of liposomal AmB in the liver, spleen, kidney, thyroid, bone marrow, and lung [ 386 ].…”

Weekly high-dose liposomal amphotericin B (L-AmB) in critically ill septic patients with multiple Candida colonization: The AmBiDex study

“…Moreover, given the pharmacokinetic and pharmacodynamics properties of high-dose L-AmB with its associated long half-life and a dose-dependent efficacy against Candida species, these delivery procedures would allow an optimization of the concentrations at the site(s) of infection(s). [ 18 , 19 ] Such administration regimen was only evaluated in an hematological patient population for the prophylaxis of invasive fungal infections[ 20 , 21 ], or in the treatment of invasive aspergillosis [ 19 , 22 ]. It has also been studied for prophylaxis in patients undergoing liver transplantation[ 23 ], in treatment of visceral leishmaniasis in the HIV patient population[ 24 ], treatment of mucormycosis[ 25 ], or even in the neonates setting [ 26 ].…”