Physiologically based pharmacokinetic model of amphotericin B disposition in rats following administration of deoxycholate formulation (Fungizone®): pooled analysis of published data

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.

Fig. 1

Model structures evaluated for major target organs (liver, kidney, and spleen). a Model A, single “well-stirred” compartment where the venous plasma concentration is in instant equilibrium with the tissue concentration governed by a partition coefficient (Kp). b Model B, two subcompartments (vascular and extravascular) with a permeability-limited distribution (PS). c Model C, three subcompartments (vascular, extravascular, and deep tissue) characterized by permeability-limited distribution and rates of association with (k _a) and dissociation from (k _d) deep tissue subcompartment. Q _ti, plasma flow rate to the organ

Fig. 2

Schematic of the whole-body PBPK model used to characterize the biodistribution of AmB in rats, mice, and humans. Q _ti, plasma flow rate to the organ; Cl _ti, organ clearance

Fig. 3

Time course of AmB in the spleen of rats following single IV bolus administration. The symbols represent data extracted from references (white circle, (13) and white square, (16)), and lines are model-predicted profiles after fitting single-organ spleen data to model B (dotted line) and model C (dashed line)

Fig. 4

Time course of plasma AmB in rats following single IV bolus administration. Symbols represent data extracted from references (white circle, (13); white square, (16); and triangles, (3)), and lines are whole-body PBPK model predicted profiles after fitting to single dose data (dashed line) and simultaneous fitting to the single and multiple dose data (solid line)

Fig. 5

Time course of AmB in different tissues of rats following single IV bolus administration. Symbols represent data extracted from references (white circle, (13); white square, (16); and triangle, (3)), and lines are whole-body PBPK model predicted profiles after fitting to single dose data (dashed line) and simultaneous fitting to the single and multiple dose data (solid line)

Fig. 6

Time course of AmB in different tissues of rats following multiple IV bolus administration. Symbols represent data extracted from reference (black circle, (17)), and lines are whole-body PBPK model predicted profiles after simulation using parameters estimated from single dose data (dashed–dotted line) and simultaneous fitting to the single and multiple dose data (solid line). For the remainder compartment, symbols represent concentration in muscle tissue

Fig. 7

Time course of plasma AmB concentrations in mice and humans following single IV bolus administration. Symbols represent data extracted from references (black square, (20) and black square, (12)), and lines are whole-body PBPK model predicted profiles after simulation using interspecies scaling of parameters estimated using rat data