Physiologically Based Pharmacokinetic Model of Amphotericin B Disposition in Rats Following Administration of Deoxycholate Formulation (Fungizone®): Pooled Analysis of Published Data

Abstract

Abstract. The time course of tissue distribution of amphotericin B (AmB) has not been sufficiently characterized despite its therapeutic importance and an apparent disconnect between plasma pharmacokinetics and clinical outcomes. The goals of this work were to develop and evaluate a physiologically based pharmacokinetic (PBPK) model to characterize the disposition properties of AmB administered as deoxycholate formulation in healthy rats and to examine the utility of the PBPK model for interspecies scaling of AmB pharmacokinetics. AmB plasma and tissue concentration-time data, following single and multiple intravenous administration of Fungizone® to rats, from several publications were combined for construction of the model. Physiological parameters were fixed to literature values. Various structural models for single organs were evaluated, and the whole-body PBPK model included liver, spleen, kidney, lung, heart, gastrointestinal tract, plasma, and remainder compartments. The final model resulted in a good simultaneous description of both single and multiple dose data sets. Incorporation of three subcompartments for spleen and kidney tissues was required for capturing a prolonged half-life in these organs. The predictive performance of the final PBPK model was assessed by evaluating its utility in predicting pharmacokinetics of AmB in mice and humans. Clearance and permeability-surface area terms were scaled with body weight. The model demonstrated good predictions of plasma AmB concentration-time profiles for both species. This modeling framework represents an important basis that may be further utilized for characterization of formulation-and disease-related factors in AmB pharmacokinetics and pharmacodynamics.

A Physiologically Based Pharmacokinetic Model of Amiodarone and its Metabolite Desethylamiodarone in Rats: Pooled Analysis of Published Data

“…Data pooling is a common strategy for building PBPK models [44,60,61], with obvious advantages. First, more tissues can be included in the model using the combined dataset.…”

“…Evidently, it is not practical to measure the accurate drug concentration in this compartment. Considering that muscle constitutes about half of the volume of the rest of body compartment [43], drug concentration in muscle was used to approximately represent the concentration in the rest of body compartment, as numerous PBPK models did [44][45][46].…”

“…A permeability-limited model [44] was used to describe the drug distribution into each tissue (Fig. 1b, liver used as an example).…”

Mixed nanomicelles as potential carriers for systemic delivery of Z-GP-Dox, an FAPα-based doxorubicin prodrug: formulation and pharmacokinetic evaluation

“…The plasma flow and organ volume values used for model fitting were taken from the literature. 27 The plasma cardiac output (Q co ) for rats was calculated as 2.69 L/hour. The mass balance equations (1)(2)(3)(4)(5)(6)(7)(8) for the model are shown as follows: …”

Pharmacokinetics and tissue distribution of amphotericin B following oral administration of three lipid-based formulations to rats

“…It was previously reported that AmB shows significant tissue distribution and prolonged tissue storage as evidenced by a high volume of distribution, slow rates of transfer from a peripheral compartment when compared to rate of distribution from the central compartment, as well as high tissue concentrations relative to plasma 37 . The distribution of AmB is highly dependent on the pharmaceutical formulation, plasma protein binding, blood flow to the organs and the disease condition 31,[38][39][40] .…”