Population pharmacokinetics of linezolid and correlation with efficacy and safety parameters in patients with acute respiratory distress syndrome on veno-venous extracorporal membrane oxygenation

Abstract

Veno-venska ekstrakorporalna membranska oksigenacija (V-V ECMO) je sve više zastupljena u zbrinjavanju respiratorne insuficijencije kod kritično oboljelih. Ipak, uticaj ovog oblika terapijske podrške na farmakokinetiku (FK) i doziranje lijekova, posebno linezolida, još uvijek nije dovoljno istražena oblast. Cilj istraživanja je da se procijeni opravdanost primjene viših doza linezolida, u poređenju sa standardnim, kod kritično oboljelih sa akutnim respiratornim distres sindromom (ARDS) uzrokovanim COVID-19, koji su istovremeno bili na V-V ECMO podršci. U istraživanje su prospektivno uključeni bolesnici sa dijagnostikovanim COVID-19 i ARDS uz terapijski model vvECMO podrške sa istovremenom intravenskom primjenom linezolida 600 mg/8 h. Kriterijumi za isključivanje su bili: osobe mlađe od 18 godina, poznata alergija na linezolid, trudnoća, terapijska izmjena plazme u posljednjih 24 sata i nadomjesna bubrežna terapija. Za analizu FK linezolida od svakog bolesnika u stanju ravnoteže lijeka prikupljeno je po šest uzoraka krvi u definisanim vremenskim tačkama. Prikupljeni su svi demografski i klinički podaci neophodni za procjenu uticaja istih na FK linezolida. Nelinearnim modeliranjem kombinovanih efekata razvijen je i validiran populacioni FK model, korišten za Monte Karlo simulacije (5000 virtualnih bolesnika) za generisanje individualnih FK parametara i koncentracijskih profila nakon režima doziranja 600 mg/8 h i 600 mg/12 h. Za procjenu vjerovatnoće postizanja ciljnih vrijednosti farmakokinetičkog-farmakodinamičkog (FK-FD) indeksa (PTA) korišteni su sljedeći targeti: 85%T>MIC, fAUC24/MIC≥80 i fAUC24/MIC≥100. Izračunata je i kumulativna frakcija odgovora (CFR) za različite Gram-pozitivne bakterije. Praćeni su i bezbjednosni aspekti na osnovu promjene nivoa trombocita i razvoj trombocitopenije u odnosu na vrijeme započinjanja vvECMO i linezolida uz istovremenu primjenu. Ukupno su analizirane 53 koncentracije linezolida. Pokazana je visoka korelacija izmjeđu Cmin i AUC24. FK parametri linezolida nisu značajno odstupali u odnosu na ne-ECMO bolesnike i nije pronađen značajan uticaja kovarijata na FK parameter. Nakon doznog režima linezolida 600 mg/8 h predviđeno je jednako i veće postizanje FK-FD ciljne vrijednosti 85%T>MIC za MIC=2 mg/L kod 90%, dok je kod bolesnika koji su primali standardni dozni režim 85%T>MIC zabilježen kod dvije trećine bolesnika. fAUC24/MIC≥80 postignut je kod skoro tri puta većeg broja bolesnika primjenom linezolida 600 mg/8 h za istu vrijednost MIC-a. Prisustvo trombocitopenije sa značajnim smanjenjem broja tombocita zabilježeno je kod ukupno 81,8% bolesnika. Rezultati istraživanja ukazaju da dozni režim linezolida 600 mg/8 h u odnosu na standardni ima prednost kod istovremene primjene vvECMO terapijskog modela za postizanje FK-FD ciljnih vrijednosti linezolida i dobijanja adekvatnog terapijskog odgovora. Terapijsko praćenje koncentracije linezolida u serumu i broja trombocita je neophodno kako bi se zadovoljili bezbjednosni aspekti uz maksimalan terapijski efekat linezolida kod kritično oboljelih sa ARDS na V-V ECMO podršci.Veno-venous extracorporeal membrane oxygenation (V-V ECMO) is increasingly used in managing respiratory failure in critically ill patients. However, the impact of this form of therapeutic support on the pharmacokinetics (PK) and dosing of medications, especially linezolid, remains an insufficiently explored area. This study aims to evaluate the rationale for administering higher doses of linezolid, compared to standard doses, in critically ill patients with acute respiratory distress syndrome (ARDS) caused by COVID-19, who are concurrently supported by V-V ECMO. The study prospectively included patients with COVID-19, ARDS, on a therapeutic V-V ECMO support model with concurrent intravenous administration of linezolid 600 mg every 8 hours. Exclusion criteria were: individuals under 18 years, known allergy to linezolid, pregnancy, therapeutic plasma exchange in the last 24 hours, and renal replacement therapy. For the analysis of linezolid PK, six blood samples were collected from each patient at steady state at defined time points. All demographic and clinical data necessary for assessing their impact on linezolid PK were collected. A population PK model was developed and validated using nonlinear modeling of combined effects, which was then employed in Monte Carlo simulations (5,000 virtual patients) to generate individual PK parameters and concentration profiles after dosing regimens of 600 mg every 8 hours and 600 mg every 12 hours. The probability of achieving target pharmacokinetic-pharmacodynamic (PK-PD) index values (PTA) was assessed using the following targets: 85%T>MIC, fAUC24/MIC≥80 i fAUC24/MIC≥100. The cumulative fraction of response (CFR) was also calculated for various Gram-positive bacteria. Safety aspects were monitored based on changes in platelet levels and development of thrombocytopenia in relation to the initiation of V-V ECMO and linezolid with concurrent application. A total of 53 linezolid concentrations were analyzed. A high correlation was found between Cmin and AUC24. Linezolid PK parameters did not significantly deviate from those in non-ECMO patients, and no significant impact of covariates on PK parameters was found. After the linezolid dosing regimen of 600 mg every 8 hours, the probability of achieving PK-PD target value of 85%T>MIC for MIC =2 mg/L was predicted to be 90%, while two-thirds of the patients on the standard dosing regimen reached 85%T>MIC. fAUC24/MIC≥80 was achieved in nearly three times more patients with the 600 mg every 8 hours linezolid regimen for the same MIC value. Thrombocytopenia occurred in 81.8% of patients with a significant reduction in platelet count. This study indicates that the linezolid dosing regimen of 600 mg every 8 hours, compared to the standard, is advantageous when using the V-V ECMO therapeutic model to achieve linezolid PK-PD target values and adequate therapeutic response. Therapeutic monitoring of linezolid serum concentrations and platelet counts is necessary to satisfy safety aspects while maximizing therapeutic effects in critically ill patients with ARDS on V-V ECMO