Silke Gastine (1), William Hope (2), Andreas H. Groll (3), Georg Hempel (1)
(1) Institute of Pharmaceutical and Medical Chemistry – Department of Clinical Pharmacy, Westfälische Wilhelms-Universität Münster, Münster, Germany, (2) Antimicrobial Pharmacodynamics and Therapeutics, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, United Kingdom, (3) nfectious Disease Research Program, Center for Bone Marrow Transplantation, and Department of Pediatric Hematology/Oncology, University Children's Hospital Münster, Münster, Germany
Objectives: As one of the latest triazole antifungal agents Posaconazole shows activity against both Aspergillus spp. and Candida spp. [1]. Posaconazole is widely used in treatment and prophylaxis of invasive fungal infections.To monitor pharmacodynamics of antifungal substances in-vivo, it has been shown, that the polysaccharide galactomannan is a valid PD surrogate regarding aspergillosis [2]. Being part of the fungal cell wall, galactomannan is released during fungal growth and thus declines with the drugs effect. Although current guidelines suggest therapeutic drug monitoring to ensure adequate Posaconazole exposure [3], there is some uncertainty about therapeutic targets for both prophylaxis and treatment of established disease.
Methods: The PKPD of Posaconazole was investigated for the treatment and prophylaxis of invasive pulmonary aspergillosis due to Aspergillus fumigatus in persistently neutropenic rabbits [4]. A total of 46 rabbits were included in the study. They were divided into four arms: healthy (n= 6), prophylaxis (n= 9), treatment (n= 16) and control (n= 15). The healthy arm received a single 20 mg/kg dose of Posaconazole with subsequent pharmacokinetic sampling. All other groups received pulmonary inoculation either the day before treatment or four days after the start of prophylaxis. Antifungal therapy consisted of Posaconazole at 2, 6, and 20 mg/kg of body weight orally. No Posaconazole was administered in the control group, but inoculation was performed as a control for both the treatment and the prophylaxis setting.
To evaluate the pharmacodynamics, galactomannan levels were collected every other day during the study. Nonparametric PKPD model building was performed using the Pmetrics Package in R [5]. In a first step the structure of the PK model was explored. Up to three compartments as well as linear and non-linear elimination were tested. Subsequently, a PD model describing galactomannan was added. Separate PD models as well as simultaneous modelling were tested to depict galactomannan levels in the treatment, prophylaxis and control group.
Results: A one-compartment model with first order oral absorption from a depot compartment and linear elimination best described the pharmacokinetics of Posaconazole (r2=0.934, individual predictions).
Final parameter means (SD) of the PK part of the model were: Clearance 0.60 (0.57) L/h, central volume of distribution 117 (98.6) L. Ka was fixed to 0.35 1/h, derived from estimations with PK only.
The pharmacodynamic effect of Posaconazole plasma concentrations on galactomannan levels was best described by dynamic Hill-functions reflecting growth and kill of the fungus (r2=0.864, individual predictions).
Final parameter means (SD) of the PD part of the model were: population maximal growth reflected by galactomannan index (GAI) 6.58 (1.73) , hill coefficient for growth 196 (98.4), hill coefficient for kill 55.8 (88.2), maximum rate of growth 0.03 (0.02) GAI/h, maximum rate of kill 1.97 (1.69) GAI/h, C50 for growth 0.19 (0.13) mg/L , C50 for kill 3.99 (1.95) mg/L, inital galactomannan concentration 0.1 (0.1) GAI.
Conclusions: The nonparametric population PKPD model adequately describes Posaconazole pharmacokinetics and its pharmacodynamic effect on fungal growth, reflected by galactomannan. It is possible to simultaneously predict the efficacy of Posaconazole PKPD for prophylaxis and treatment, as well as the evolvement of galactomannan levels in the control group. This model provides a further insight into drug exposures, that are important for the prevention and treatment of invasive pulmonary aspergillosis.
References:
[1] EUCAST European committee on antimicrobial susceptibility testing. Posaconazole. 2017
[2] Howard et al. Pharmacokinetics and pharmacodynamics of posaconazole for invasive pulmonary aspergillosis: clinical implications for antifungal therapy. J Infect Dis. 2011
[3] Mellinghof et al. Primary prophylaxis of invasive fungal infections in patients with haematological malignancies: 2017 update of the recommendations of the Infectious Diseases Working Party (AGIHO) of the German Society for Haematology and Medical Oncology (DGHO). Annals of Hematology. 2017
[4] Petraitiene et al. Antifungal activity and pharmacokinetics of posaconazole (SCH 56592) in treatment and prevention of experimental invasive pulmonary aspergillosis: Correlation with galactomannan antigenemia. Antimicrobial Agents and Chemotherapy. 2001
[5] Neely et al. Accurate Detection of Outliers and Subpopulations With Pmetrics, a Nonparametric and Parametric Pharmacometric Modeling and Simulation Package for R. Therapeutic Drug Monitoring. 2012
Reference: PAGE 27 (2018) Abstr 8699 [www.page-meeting.org/?abstract=8699]
Poster: Drug/Disease Modelling - Infection