Population Pharmacokinetics and Dose Optimization of Teicoplanin during Venoarterial Extracorporeal Membrane Oxygenation

Abstract

The pharmacokinetics (PK) of drugs are known to be significantly altered in patients receiving extracorporeal membrane oxygenation (ECMO). However, clinical studies of the PK of drugs administered during ECMO are scarce, and the proper dosing adjustment has yet to be established. We developed a population PK model for teicoplanin, investigated covariates influencing teicoplanin exposure, and suggested an optimal dosing regimen for ECMO patients. Samples for PK analysis were collected from 10 adult patients, and a population PK analysis and simulations were performed to identify an optimal teicoplanin dose needed to provide a Ͼ50% probability of target attainment at 72 h using a trough concentration target of Ͼ10 g/ml for mild to moderate infections and a trough concentration target of Ͼ15 g/ml for severe infections. Teicoplanin was well described by a two-compartment PK model with first-order elimination. The presence of ECMO was associated with a lower central volume of distribution, and continuous renal replacement therapy (CRRT) was associated with a higher peripheral volume of distribution. For mild to moderate infections, an optimal dose was a loading dose (LD) of 600 mg and a maintenance dose (MD) of 400 mg for ECMO patients not receiving CRRT and an LD of 800 mg and an MD of 600 mg for those receiving CRRT. For severe infections, an optimal dose was an LD of 1,000 mg and an MD of 800 mg for ECMO patients not receiving CRRT and an LD of 1,200 mg and an MD of 1,000 mg for those receiving CRRT. In conclusion, doses higher than the standard doses are needed to achieve fast and appropriate teicoplanin exposure during ECMO. (This study has been registered at ClinicalTrials.gov under identifier NCT02581280.)

Permissive fluid volume in adult patients undergoing extracorporeal membrane oxygenation treatment

“…Cannulations for all ECMO supports were performed by cardiovascular surgeons with limited cut-down using the Seldinger technique [ 30 ]. Either the CAPIOX EBS (Terumo Co., Ltd., Tokyo, Japan) or the QUADROX PLS (Maquet GmbH, Rastatt, Germany) system was used in all patients.…”

Antimicrobial therapy during ECMO – customised dosing with therapeutic drug monitoring: The way to go?

“…An in-depth knowledge on ECMO and critical illness-related PK changes is required to inform antibiotic dosing in these patients and thankfully, important breakthroughs have been made in this area of research. An emerging body of literature over the last 10 years describes the PK of antibiotics in critically ill adult patients on ECMO support (Table 1) [6][7][8][9][10][11][12][13][14][15][16][17]. These clinical PK data, in combination with existing ex vivo and in vivo animal model data [4,5], outline four key findings in relation to ECMO and antibiotic PK: (a) physicochemical properties of drugs influence the degree of drug loss/sequestration in ECMO circuits whereby lipophilic (e.g., fentanyl) and highly-protein bound drugs (e.g., ceftriaxone) would be most vulnerable to these losses; (b) earlier neonatal and paediatric PK data cannot be extrapolated to the critically ill adult population; (c) modern ECMO circuitry has minimal adsorption and impact on the PK of most antibiotics and; (d) altered PK changes in ECMO patients are more reflective of critical illness rather than ECMO itself.…”

Drug Disposition and Pharmacotherapy in Neonatal ECMO: From Fragmented Data to Integrated Knowledge

“…In this prospective population PK evaluation, the predictive target attainment was reduced during ECMO for every simulated dosing, despite the Vd was lower and Cl was not affected by the extracorporeal circuit (159). Based on the hydrophilic profile of the drug, the hemodilution and protein binding could be addressed as the main drivers for teicoplanin disposition on ECMO (159).…”

“…Another glycopeptide antimicrobial which may be used during neonatal ECMO is teicoplanin. Although specific neonatal data of teicoplanin disposition in the extracorporeal setting are lacking, the evidence from an adult PK study suggests the need for higher doses during ECMO (159). In this prospective population PK evaluation, the predictive target attainment was reduced during ECMO for every simulated dosing, despite the Vd was lower and Cl was not affected by the extracorporeal circuit (159).…”

“…Although specific neonatal data of teicoplanin disposition in the extracorporeal setting are lacking, the evidence from an adult PK study suggests the need for higher doses during ECMO (159). In this prospective population PK evaluation, the predictive target attainment was reduced during ECMO for every simulated dosing, despite the Vd was lower and Cl was not affected by the extracorporeal circuit (159). Based on the hydrophilic profile of the drug, the hemodilution and protein binding could be addressed as the main drivers for teicoplanin disposition on ECMO (159).…”