Pharmacokinetic and pharmacodynamic modeling of anidulafungin (LY303366): Reappraisal of its efficacy in neutropenic animal models of opportunistic mycoses using optimal plasma sampling

A. H. Groll, D. Mickiene, R. Petraitiene, V. Petraitis, C. A. Lyman, J. S. Bacher, S. C. Piscitelli, T. J. Walsh

Research output: Contribution to journalArticle

Abstract

The compartmental pharmacokinetics of anidulafungin (VER-002; formerly LY303366) in plasma were characterized with normal rabbits, and the relationships between drug concentrations and antifungal efficacy were assessed in clinically applicable infection models in persistently neutropenic animals. At intravenous dosages ranging from 0.1 to 20 mg/kg of body weight, anidulafungin demonstrated linear plasma pharmacokinetics that fitted best to a three-compartment open pharmacokinetic model. Following administration over 7 days, the mean (± standard error of the mean) peak plasma concentration (Cmax) increased from 0.46 ± 0.02 μg/ml at 0.1 mg/kg to 63.02 ± 2.93 μg/ml at 20 mg/kg, and the mean area under the concentration-time curve from 0 h to infinity (AUC0-∞) rose from 0.71 ± 0.04 to 208.80 ± 24.21 μg · h/ml. The mean apparent volume of distribution at steady state (Vss) ranged from 0.953 ± 0.05 to 1.636 ± 0.22 liter/kg (nonsignificant [NS]), and clearance ranged from 0.107 ± 0.01 to 0.149 ± 0.00 liter/kg/h (NS). Except for a significant prolongation of the terminal half-life and a trend toward an increased Vss at the higher end of the dosage range after multiple doses, no significant differences in pharmacokinetic parameters were noted in comparison to single-dose administration. Concentrations in tissue at trough after multiple dosing (0.1 to 10 mg/kg/day) were highest in lung and liver (0.85 ± 0.16 to 32.64 ± 2.03 and 0.32 ± 0.05 to 43.76 ± 1.62 μg/g, respectively), followed by spleen and kidney (0.24 ± 0.65 to 21.74 ± 1.86 and 0-24 values, higher plasma concentrations at the end of the dosing interval, and a smaller volume of distribution (P <0.05 to 0.193 for the various comparisons among dosage groups). Pharinacodynamic modeling using the residual fungal tissue burden in the main target sites as the primary endpoint and Cmax, AUC0-24, time during the dosing interval of 24 h with plasma drug concentration equaling or exceeding the MIC or the minimum fungicidal concentration for the isolate, and tissue concentrations as pharmacodynamic parameters showed predictable pharmacokinetic-pharmacodynamic relationships in experimental disseminated candidiasis that fitted well with an inhibitory sigmoid maximum effect pharmacodynamic model (r2, 0.492 to 0.819). However, no concentration-effect relationships were observed in experimental pulmonary aspergillosis using the residual fungal burden in lung tissue and survival as parameters of antifungal efficacy. Implementation of optimal plasma sampling in discriminative animal models of invasive fungal infections and pharmacodynamic modeling is a novel approach that holds promise of improving and accelerating our understanding of the action of antifungal compounds in vivo.

Original languageEnglish (US)
Pages (from-to)2845-2855
Number of pages11
JournalAntimicrobial Agents and Chemotherapy
Volume45
Issue number10
DOIs
StatePublished - 2001
Externally publishedYes

Fingerprint

anidulafungin
Mycoses
Animal Models
Pharmacokinetics
Pulmonary Aspergillosis
Tissue Survival
Lung
Candidiasis
Sigmoid Colon
Pharmaceutical Preparations
Half-Life
Spleen
Body Weight
Rabbits
Kidney
Liver

ASJC Scopus subject areas

  • Pharmacology (medical)

Cite this

Pharmacokinetic and pharmacodynamic modeling of anidulafungin (LY303366) : Reappraisal of its efficacy in neutropenic animal models of opportunistic mycoses using optimal plasma sampling. / Groll, A. H.; Mickiene, D.; Petraitiene, R.; Petraitis, V.; Lyman, C. A.; Bacher, J. S.; Piscitelli, S. C.; Walsh, T. J.

In: Antimicrobial Agents and Chemotherapy, Vol. 45, No. 10, 2001, p. 2845-2855.

Research output: Contribution to journalArticle

Groll, A. H. ; Mickiene, D. ; Petraitiene, R. ; Petraitis, V. ; Lyman, C. A. ; Bacher, J. S. ; Piscitelli, S. C. ; Walsh, T. J. / Pharmacokinetic and pharmacodynamic modeling of anidulafungin (LY303366) : Reappraisal of its efficacy in neutropenic animal models of opportunistic mycoses using optimal plasma sampling. In: Antimicrobial Agents and Chemotherapy. 2001 ; Vol. 45, No. 10. pp. 2845-2855.
@article{425b2dcd0f574b61a3ed992ca47a9ae5,
title = "Pharmacokinetic and pharmacodynamic modeling of anidulafungin (LY303366): Reappraisal of its efficacy in neutropenic animal models of opportunistic mycoses using optimal plasma sampling",
abstract = "The compartmental pharmacokinetics of anidulafungin (VER-002; formerly LY303366) in plasma were characterized with normal rabbits, and the relationships between drug concentrations and antifungal efficacy were assessed in clinically applicable infection models in persistently neutropenic animals. At intravenous dosages ranging from 0.1 to 20 mg/kg of body weight, anidulafungin demonstrated linear plasma pharmacokinetics that fitted best to a three-compartment open pharmacokinetic model. Following administration over 7 days, the mean (± standard error of the mean) peak plasma concentration (Cmax) increased from 0.46 ± 0.02 μg/ml at 0.1 mg/kg to 63.02 ± 2.93 μg/ml at 20 mg/kg, and the mean area under the concentration-time curve from 0 h to infinity (AUC0-∞) rose from 0.71 ± 0.04 to 208.80 ± 24.21 μg · h/ml. The mean apparent volume of distribution at steady state (Vss) ranged from 0.953 ± 0.05 to 1.636 ± 0.22 liter/kg (nonsignificant [NS]), and clearance ranged from 0.107 ± 0.01 to 0.149 ± 0.00 liter/kg/h (NS). Except for a significant prolongation of the terminal half-life and a trend toward an increased Vss at the higher end of the dosage range after multiple doses, no significant differences in pharmacokinetic parameters were noted in comparison to single-dose administration. Concentrations in tissue at trough after multiple dosing (0.1 to 10 mg/kg/day) were highest in lung and liver (0.85 ± 0.16 to 32.64 ± 2.03 and 0.32 ± 0.05 to 43.76 ± 1.62 μg/g, respectively), followed by spleen and kidney (0.24 ± 0.65 to 21.74 ± 1.86 and 0-24 values, higher plasma concentrations at the end of the dosing interval, and a smaller volume of distribution (P <0.05 to 0.193 for the various comparisons among dosage groups). Pharinacodynamic modeling using the residual fungal tissue burden in the main target sites as the primary endpoint and Cmax, AUC0-24, time during the dosing interval of 24 h with plasma drug concentration equaling or exceeding the MIC or the minimum fungicidal concentration for the isolate, and tissue concentrations as pharmacodynamic parameters showed predictable pharmacokinetic-pharmacodynamic relationships in experimental disseminated candidiasis that fitted well with an inhibitory sigmoid maximum effect pharmacodynamic model (r2, 0.492 to 0.819). However, no concentration-effect relationships were observed in experimental pulmonary aspergillosis using the residual fungal burden in lung tissue and survival as parameters of antifungal efficacy. Implementation of optimal plasma sampling in discriminative animal models of invasive fungal infections and pharmacodynamic modeling is a novel approach that holds promise of improving and accelerating our understanding of the action of antifungal compounds in vivo.",
author = "Groll, {A. H.} and D. Mickiene and R. Petraitiene and V. Petraitis and Lyman, {C. A.} and Bacher, {J. S.} and Piscitelli, {S. C.} and Walsh, {T. J.}",
year = "2001",
doi = "10.1128/AAC.45.10.2845-2855.2001",
language = "English (US)",
volume = "45",
pages = "2845--2855",
journal = "Antimicrobial Agents and Chemotherapy",
issn = "0066-4804",
publisher = "American Society for Microbiology",
number = "10",

}

TY - JOUR

T1 - Pharmacokinetic and pharmacodynamic modeling of anidulafungin (LY303366)

T2 - Reappraisal of its efficacy in neutropenic animal models of opportunistic mycoses using optimal plasma sampling

AU - Groll, A. H.

AU - Mickiene, D.

AU - Petraitiene, R.

AU - Petraitis, V.

AU - Lyman, C. A.

AU - Bacher, J. S.

AU - Piscitelli, S. C.

AU - Walsh, T. J.

PY - 2001

Y1 - 2001

N2 - The compartmental pharmacokinetics of anidulafungin (VER-002; formerly LY303366) in plasma were characterized with normal rabbits, and the relationships between drug concentrations and antifungal efficacy were assessed in clinically applicable infection models in persistently neutropenic animals. At intravenous dosages ranging from 0.1 to 20 mg/kg of body weight, anidulafungin demonstrated linear plasma pharmacokinetics that fitted best to a three-compartment open pharmacokinetic model. Following administration over 7 days, the mean (± standard error of the mean) peak plasma concentration (Cmax) increased from 0.46 ± 0.02 μg/ml at 0.1 mg/kg to 63.02 ± 2.93 μg/ml at 20 mg/kg, and the mean area under the concentration-time curve from 0 h to infinity (AUC0-∞) rose from 0.71 ± 0.04 to 208.80 ± 24.21 μg · h/ml. The mean apparent volume of distribution at steady state (Vss) ranged from 0.953 ± 0.05 to 1.636 ± 0.22 liter/kg (nonsignificant [NS]), and clearance ranged from 0.107 ± 0.01 to 0.149 ± 0.00 liter/kg/h (NS). Except for a significant prolongation of the terminal half-life and a trend toward an increased Vss at the higher end of the dosage range after multiple doses, no significant differences in pharmacokinetic parameters were noted in comparison to single-dose administration. Concentrations in tissue at trough after multiple dosing (0.1 to 10 mg/kg/day) were highest in lung and liver (0.85 ± 0.16 to 32.64 ± 2.03 and 0.32 ± 0.05 to 43.76 ± 1.62 μg/g, respectively), followed by spleen and kidney (0.24 ± 0.65 to 21.74 ± 1.86 and 0-24 values, higher plasma concentrations at the end of the dosing interval, and a smaller volume of distribution (P <0.05 to 0.193 for the various comparisons among dosage groups). Pharinacodynamic modeling using the residual fungal tissue burden in the main target sites as the primary endpoint and Cmax, AUC0-24, time during the dosing interval of 24 h with plasma drug concentration equaling or exceeding the MIC or the minimum fungicidal concentration for the isolate, and tissue concentrations as pharmacodynamic parameters showed predictable pharmacokinetic-pharmacodynamic relationships in experimental disseminated candidiasis that fitted well with an inhibitory sigmoid maximum effect pharmacodynamic model (r2, 0.492 to 0.819). However, no concentration-effect relationships were observed in experimental pulmonary aspergillosis using the residual fungal burden in lung tissue and survival as parameters of antifungal efficacy. Implementation of optimal plasma sampling in discriminative animal models of invasive fungal infections and pharmacodynamic modeling is a novel approach that holds promise of improving and accelerating our understanding of the action of antifungal compounds in vivo.

AB - The compartmental pharmacokinetics of anidulafungin (VER-002; formerly LY303366) in plasma were characterized with normal rabbits, and the relationships between drug concentrations and antifungal efficacy were assessed in clinically applicable infection models in persistently neutropenic animals. At intravenous dosages ranging from 0.1 to 20 mg/kg of body weight, anidulafungin demonstrated linear plasma pharmacokinetics that fitted best to a three-compartment open pharmacokinetic model. Following administration over 7 days, the mean (± standard error of the mean) peak plasma concentration (Cmax) increased from 0.46 ± 0.02 μg/ml at 0.1 mg/kg to 63.02 ± 2.93 μg/ml at 20 mg/kg, and the mean area under the concentration-time curve from 0 h to infinity (AUC0-∞) rose from 0.71 ± 0.04 to 208.80 ± 24.21 μg · h/ml. The mean apparent volume of distribution at steady state (Vss) ranged from 0.953 ± 0.05 to 1.636 ± 0.22 liter/kg (nonsignificant [NS]), and clearance ranged from 0.107 ± 0.01 to 0.149 ± 0.00 liter/kg/h (NS). Except for a significant prolongation of the terminal half-life and a trend toward an increased Vss at the higher end of the dosage range after multiple doses, no significant differences in pharmacokinetic parameters were noted in comparison to single-dose administration. Concentrations in tissue at trough after multiple dosing (0.1 to 10 mg/kg/day) were highest in lung and liver (0.85 ± 0.16 to 32.64 ± 2.03 and 0.32 ± 0.05 to 43.76 ± 1.62 μg/g, respectively), followed by spleen and kidney (0.24 ± 0.65 to 21.74 ± 1.86 and 0-24 values, higher plasma concentrations at the end of the dosing interval, and a smaller volume of distribution (P <0.05 to 0.193 for the various comparisons among dosage groups). Pharinacodynamic modeling using the residual fungal tissue burden in the main target sites as the primary endpoint and Cmax, AUC0-24, time during the dosing interval of 24 h with plasma drug concentration equaling or exceeding the MIC or the minimum fungicidal concentration for the isolate, and tissue concentrations as pharmacodynamic parameters showed predictable pharmacokinetic-pharmacodynamic relationships in experimental disseminated candidiasis that fitted well with an inhibitory sigmoid maximum effect pharmacodynamic model (r2, 0.492 to 0.819). However, no concentration-effect relationships were observed in experimental pulmonary aspergillosis using the residual fungal burden in lung tissue and survival as parameters of antifungal efficacy. Implementation of optimal plasma sampling in discriminative animal models of invasive fungal infections and pharmacodynamic modeling is a novel approach that holds promise of improving and accelerating our understanding of the action of antifungal compounds in vivo.

UR - http://www.scopus.com/inward/record.url?scp=0034812542&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0034812542&partnerID=8YFLogxK

U2 - 10.1128/AAC.45.10.2845-2855.2001

DO - 10.1128/AAC.45.10.2845-2855.2001

M3 - Article

C2 - 11557479

AN - SCOPUS:0034812542

VL - 45

SP - 2845

EP - 2855

JO - Antimicrobial Agents and Chemotherapy

JF - Antimicrobial Agents and Chemotherapy

SN - 0066-4804

IS - 10

ER -