Viktor Rognås (1), Johan Spånberg (1), Emanuele Durante-Mangoni (2), Leonard Leibovici (3), Yehuda Carmeli (4), George L Daikos (5), Mical Paul (6,7), Mats O Karlsson (1), Lena E Friberg (1)
(1) Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden, (2) Internal Medicine, University of Campania ‘L Vanvitelli’, and AORN dei Colli-Monaldi Hospital, Napoli, Italy, (3) Department of Medicine, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel, (4) Sackler Faculty of Medicine, Tel Aviv University, Ramat-Aviv, Israel, (5) First Department of Medicine, Laikon General Hospital, Athens, Greece, (6) Institute of Infectious Diseases, Rambam Health Care Campus, Haifa, Israel, (7) The Ruth and Bruce Rappaport Faculty of Medicine, Techion – Israel Institute of Technology, Haifa, Israel
Objectives: A recent randomized clinical trial, AIDA [1], compared colistin monotherapy versus combination therapy with meropenem. Patients included in the study were critically ill adults with bacteremia, ventilator-associated pneumonia, hospital-acquired pneumonia, or urosepsis caused by carbapenem-non-susceptible Gram-negative bacteria. Survival analysis of the AIDA data indicated that, contrary to expectations, higher colistin exposure correlated positively with a higher hazard of death [2]. A subsequent analysis of organ failure (SOFA) scores pointed in the same direction[3]. These findings might be confounded by kidney function, since colistin is known to be nephrotoxic[4] and its prodrug CMS is renally cleared. Here we aimed to develop a model relating colistin exposure to changes in creatinine. Another aim was to discern what structural and statistical model that best explain the variability in serum creatinine (SCr) in the studied patient population.
Methods: The AIDA study [1] contributed colistin and creatinine measurements from 309 critically ill patients, not on dialysis, in the ages 18–95 years (median 67 years). Recruited patients had gram-negative bacterial infections that were carbapenem resistant (MIC ≥ 2 mg/L), and colistin susceptible (MIC ≤ 2 mg/L). Both treatment arms were given colistin (9 MU loading dose, 4.5 MU q12h maintenance dose, 30 min infusion), and patients in the second arm were also given meropenem. Early colistin PK measurements were used to predict rolling daily (24 hour) exposures (AUC) for each subject [2]. The number of SCr measurements per patient ranged from 1 to 8 observations from screening and up to 28 days after randomization. Measured SCr ranged from 0.10–7.23 mg/dL, median 0.91 mg/dL.
A turn-over model was applied to describe the endogenous changes in SCr over time. Baseline SCr was used to calculate creatinine clearance (CrCL) using the Cockcroft-Gault equation. Volume of distribution for SCr was fixed to subjects total body water (60% of body weight for males, 55% for females). Disease progression (change in SCr over time) was adjusted for. The daily colistin exposure was tested to have a delayed effect on CrCL by application of an effect compartment model. The effect of colistin on CrCL was described by a Hill equation. Inter-individual variability (IIV) was evaluated on all parameters, along with covariances.
Covariates were explored using full random effects modeling (FREM) and step-wise covariate modeling (SCM) through the PsN QA-tool. Studied covariates included the age, sex and weight of the subject, as well as study sites and treatment arm.
Results: Estimated typical baseline SCr was 0.90 mg/dL. Disease progression was modelled with an empirical function, in which CrCL is allowed to increase or decrease towards an asymptote. Estimated maximum inhibition of CrCL by colistin (Imax) was 73%. The colistin concentration in the effect compartment that gave rise to half Imax (C50) was 1.44 mg/L, with a Hill coefficient of 2.44. The effect compartment half-life (delay) was estimated to 2 weeks. Individual predictions versus time plots, as well as the VPC, showed that the model adequately described the data. Estimated baseline half-life of SCr ranged from 4–11 hours (IQR), median 6 hours. Estimated baseline CrCL ranged from 48–130 mL/min (IQR), median 84 mL/min. Steady state colistin concentrations of 2, 4 and 6 mg/L would after 14 days lead to a decrease in CrCL of 25, 47 and 62% respectively. No additional covariates were found significant.
Conclusions: A turn-over model for SCr (adjusted for disease progression) with effect compartment for colistin exposure affecting CrCL, best described the data. The model could characterize the change in in CrCL over time for patients getting progressively worse or better throughout the study period.
References:
[1] Paul M, et al. Colistin alone versus colistin plus meropenem for treatment of severe infections caused by carbapenem-resistant Gram-negative bacteria: an open-label, randomised controlled trial. Lancet Infect Dis 2018;18:391–400. https://doi.org/10.1016/S1473-3099(18)30099-9.
[2] Kristoffersson A, et al. Population pharmacokinetics of colistin and the relation to survival in critically ill patients infected with colistin susceptible and carbapenem-resistant bacteria. Clin Microbiol Infect (Accepted)
[3] Rognås V, et al. Bounded Integer approach to model time-varying SOFA scores from patients with carbapenem resistant infections, Stockholm, Sweden: 2019.
[4] Forrest A, et al. Pharmacokinetic/Toxicodynamic Analysis of Colistin-Associated Acute Kidney Injury in Critically Ill Patients. Antimicrob Agents Chemother 2017;61:e01367-17, /aac/61/11/e01367-17.atom. https://doi.org/10.1128/AAC.01367-17.
Reference: PAGE () Abstr 9543 [www.page-meeting.org/?abstract=9543]
Poster: Drug/Disease Modelling - Infection