1. LIPOPHILIC AND PROTEIN BOUND ANTIBIOTICS ARE MORE LIKELY TO HAVE ALTERED PHARMACOKINETCIS DURING ECMO
Kiran Shekar, Jason Roberts, Sara Diab, Adrian Barnett, Kimble Dunster, Susan Ghassabian, Charles McDonald, Rylan Hayes, Sam Foley, Steve Wallis, Dan Mullany, David Platts, Gabriela Simonova, Lin Fung, Maree Smith, John Fraser
Critical Care Research Group, Adult Intensive Care Services, The Prince Charles Hospital and The University of Queensland, Brisbane, Queensland, Australia
Introduction: Experiments in ex vivo ECMO circuits have identified partition coefficient (logP, marker of lipophilicity) and protein binding (PB) as key drug factors affecting pharmacokinetics (PK) during ECMO. We investigated the role of these drug properties in altering PK in healthy and critically ill sheep on ECMO.
The significant physiologic differences between [cardiac output (p=0.01), mean arterial blood pressure (<0.001), fluid balance (p<0.001) and serum protein concentrations(<0.001)] between E24H and SE24H did not appear to independently influence steady state volume of distribution (Vss), or clearance (CL). There were no significant biochemical differences in hepatic or renal function between the groups.
While logP significantly influenced Vss, AUC0-t and mean resident time (MRT); PB significantly influenced CL and AUC 0-t in healthy and lung injury sheep when compared with HS. (Fig 3, Table 1)
Methods: PK sampling was performed in healthy ambulatory sheep (HS, n=7), healthy sheep on ECMO (E24H, n=7) and in sheep with smoke inhalation acute lung injury (SE24H, n=6) on ECMO (Fig 1). The sheep received eight study antibiotics [ceftriaxone (CTX), gentamicin (GTM), meropenem (MRP), vancomycin (VCM), doripenem (DRP), ciprofloxacin (CRF), fluconazole (FCZ), caspofungin (CPF)]. Plasma drug concentrations were determined using validated LC-MS/MS techniques. PK data obtained from a non-compartmental analysis was used to build regression models and to examine the influence of pathophysiology, logP and PB.
Fig 3 Increased steady state volume of distribution (Vss) in healthy(E24H) and critically ill sheep (SE24H) on ECMO when compared with healthy sheep (HS).
Fig 1. Following smoke inhalation sheep were supported with venovenous ECMO
Results: The ECMO sheep (both E24H and SE24H) generally had significantly reduced exposure to the study drugs (Fig 2), when compared with HS.
Table 1. Linear regression results for predicting PK parameters based on drug properties (logP) and protein binding (PB). Cmax –maximum plasma concentration; Cmin-minimum plasma concentration.
Conclusion: Lipophilic and protein-bound drugs exhibited significantly altered PK during ECMO both in healthy and critically ill sheep. Clinical population PK studies should prioritise these drugs first to generate evidence based dosing guidelines for antibiotic drug dosing during ECMO.
Fig 2 Study drug exposure represented as area under the curve (AUC) 0-t in healthy
sheep (HS) and healthy (E24H) and critically ill sheep (SE24H) on ECMO.