Francine Johansson Azeredo (1), Miguel Adelino da Silva Filho (1), Christian Assunção da Silva (1), Hartmut Derendorf (2), Eryvaldo Sócrates Tabosa do Egito (1)
(1) Programa de Pós Graduação em Ciências da Saúde, UFRN, Natal-RN, 59012-570, Brazil; (2) Department of Pharmaceutics, University of Florida, Gainesville-FL, 32603, United States of America;
Objectives: The aim of this study was to model the time-kill curves of static concentrations of a novel formulation containing Amphotericin B (AmB) against Candida albicans in order to better analyze its pharmacological effect and to compare this effect to the free AmB one by PK-PD model approach [1].
Methods: The super-aggregated formulation containing AmB was prepared by heating the AmB micelle system as previously described [2]. The prepared formulation (AmB-DOC-H) activity against C. albicans ATCC 90027 was analyzed in an in vitro PD study. In vitro time-kill curves were obtained by counting the number of colony forming units (CFU) as a function of time after yeast exposition to AmB concentrations multiple of MIC (0.25, 0.5, 1 and 2 times MIC). Experiments were followed in triplicate for 24 h. We adapted a published Emax model to describe the time course of the fungicidal activity of AmB and its resistance [3] using the software NONMEM v. 7.0 (ICON®, USA).
Results: Both free AmB and AmB- DOC-H MICs against C. albicans were 0.25 µg/mL. The PK/PD model that better described the AmB-DOC-H fungicidal effect has compartments for drug-susceptible fungus (S), susceptible fungus that need a growing lag time (Slag) and insusceptible fungus (R) with first order rate constants for growth (knet) and one that stimulates the transfer from the proliferating stage into the resting stage (kSR). All the population Pk-PD parameters obtained from the modeling were estimated with acceptable precision, showing values of 1.58 h-1 (9%) and 1.22 h-1 (7%) for Emax of free AmB and AmB-DOC-H, respectively. The values of EC50 were 0.0326 µg/mL (18%) and 0.0801 µg/mL (17%) of free AmB and AmB-DOC-H.
Conclusions: A PK/PD model that incorporates both the C. albicans lag time of growth and rate of transfer to resting stage was used so it could well characterize the observed time courses of fungicidal killing over a wide range of concentration-time profiles, indicating that these factors needs to be considered when proposing dosing regimen for this drug. Moreover, AmB- DOC-H showed a promising potency against C.albicans according to the estimated EC50 value which was higher than the estimated for the free AmB.
References:
[1] Schmidt S, Schuck E, Kumar V, Burkhardt V, Derendorf H. Integration of pharmacokinetic/pharmacodynamic modeling and simulation in the development of new anti-infective agents – minimum inhibitory concentration versus time-kill curves. Exp Opin Drug Discov (2007) 2 (6): 849-60
[2] Silva-Filho MA, Siqueira SDVS, Freire LB, de Araujo IB, de Holanda e Silva KG, Medeiros AC, Araujo-Filho I, Oliveira AG, do Egito EST. How can micelle systems be rebuilt by a heating process?. Int J Nanomed (2012) 7: 141-150
[3] Mohamed AF, Nielsen EI, Cars O, Friberg AE. Pharmacokinetic-Pharmacodynamic Model for Gentamicin and Its Adaptive Resistance with Predictions of Dosing Schedules in Newborn Infants. Antimicrob Agents Chemother (2012) 56: 179-188.
Reference: PAGE 24 (2015) Abstr 3370 [www.page-meeting.org/?abstract=3370]
Poster: Drug/Disease modeling - Infection