Modeling of renal failure, dialysis, inhalation and mechanical ventilation: Development of a whole-body physiologically-based pharmacokinetic (PBPK) model for ICU patients with and without renal failure receiving inhalatively administered Amikacin via a tracheal tube.
Thomas Wendl(1), Christoph Niederalt(1), Corina Becker(2), Heino Staß(2), Rolf Burghaus(2), Jörg Lippert(1), Stefan Willmann(1)
(1) Bayer Technology Services GmbH, Competence Center Systems Biology and Computational Solutions, D-51368 Leverkusen, Germany; (2) Bayer HealthCare AG, Clinical Pharmacology / Clinical Pharmacokinetics, D-42096 Wuppertal, Germany
Objectives: Aim of this study was to establish a whole-body PBPK model for inhalative administration of Amikacin to renally impaired volunteers and to intubated and mechanically ventilated ICU patients with ventilator associated pneumonia (VAP).
Methods: : A whole-body PBPK model for inhalative administration of Amikacin to healthy volunteers was parameterized using the software tools PK-Sim® and MoBi® [1] to account for renal failure and inhalation via a tracheal tube, common findings in intensive care unit (ICU) patients. Renal failure was taken into account by reduction of glomerular filtration rate (GFR), a continuous veno-venous hemodiafiltration (CVVHDF) by insertion of an additional clearance into the venous blood plasma and hemodialysis by a temporary operation of a plasma clearance process. Systemic uptake from alveolar lining fluid (ALF) was adjusted to measured concentration time profiles in ICU patients after inhalation of Amikacin via the tracheal tube [2, 3].
Results: The whole-body-PBPK model for inhaled Amikacin combined with a reduction of renal clearance and in some cases inclusion of hemodialysis is able to describe the measured plasma concentration-time profiles of Amikacin in renally impaired volunteers. To describe inhalation in intubated and mechanically ventilated ICU patients, a reduction of the fraction deposited in the alveoli as well as an increase in paracellular lung uptake is necessary. An increase of paracellular uptake could be explained by inflation of the lungs through the ventilator. A model accounting for both, the reduced clearance of renally impaired and fast systemic uptake in mechanically ventilated ICU patients is able to predict the PK of Amikacin in intubated and mechanically ventilated ICU patients with acute renal failure with great accuracy. This is shown in a visual predictive check with clinical data.
Conclusions: The established PBPK model can be used to predict time-resolved concentrations of Amikacin in pulmonary lining fluids, lung interstitium and lung cells of intubated and mechanically ventilated ICU patients, and therefore, allows for estimation of local efficacy.
References:
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[2] Luyt CE, Eldon MA, Stass H, Gribben D, Corkery K, Chastre J (2011) Pharmacokinetics and Tolerability of Amikacin Administered as BAY41-6551 Aerosol in subjects with chronic kidney disease, submitted to “journal of aerosol medicine and pulmonary drug delivery”,
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[4] Luyt et al. (2011) Pharmacokinetics and Tolerability of Amikacin Administered as BAY41-6551 Aerosol in Mechanically Ventilated Patients with Gram-Negative Pneumonia and Acute Renal Failure, submitted to “journal of aerosol medicine and pulmonary drug delivery”.