Colistin Population Pharmacokinetics after Application of a Loading Dose of 9 MU Colistin Methanesulfonate in Critically Ill Patients

Abstract

Colistin has been revived, in the era of extensively drug-resistant (XDR) Gram-negative infections, as the last-resort treatment in critically ill patients. Recent studies focusing on the optimal dosing strategy of colistin have demonstrated the necessity of a loading dose at treatment initiation (D. Plachouras, M. Karvanen, L. E. Friberg, E. Papadomichelakis, A. Antoniadou, I. Tsangaris, I. Karaiskos, G. Poulakou, F. Kontopidou, A. Armaganidis, O. Cars, and H. Giamarellou, Antimicrob Agents Chemother 53:3430-3436, 2009, http://dx.doi.org/10.1128/AAC.01361-08; A. F. Mohamed, I. Karaiskos, D. Plachouras, M. Karvanen, K. Pontikis, B. Jansson, E. Papadomichelakis, A. Antoniadou, H. Giamarellou, A. Armaganidis, O. Cars, and L. E. Friberg, Antimicrob Agents Chemother 56:4241- 4249, 2012, http://dx.doi.org/10.1128/AAC.06426-11; S. M. Garonzik, J. Li, V. Thamlikitkul, D. L. Paterson, S. Shoham, J. Jacob, F. P. Silveira, A. Forrest, and R. L. Nation, Antimicrob Agents Chemother 55:3284-3294, 2011, http://dx.doi.org/10.1128/AAC.01733-10). In 19 critically ill patients with suspected or microbiologically documented infections caused by XDR Gram-negative strains, a loading dose of 9 MU colistin methanesulfonate (CMS) (∼ 270 mg colistin base activity) was administered with a maintenance dose of 4.5 MU every 12 h, commenced after 24 h. Patients on renal replacement were excluded. CMS infusion was given over 30 min or 1 h. Repeated blood sampling was performed after the loading dose and after the 5th or 6th dose. Colistin concentrations and measured CMS, determined after hydrolization to colistin and including the partially sulfomethylated derivatives, were determined with a liquid chromatography-tandem mass spectrometry assay. Population pharmacokinetic analysis was conducted in NONMEM with the new data combined with data from previous studies. Measured colistimethate concentrations were described by 4 compartments for distribution and removal of sulfomethyl groups, while colistin disposition followed a 1-compartment model. The average observed maximum colistin A plus B concentration was 2.65 mg/liter after the loading dose (maximum time was 8 h). A significantly higher availability of the measured A and B forms of colistimethate and colistin explained the higher-than-expected concentrations in the present study compared to those in previous studies. Creatinine clearance was a time-varying covariate of colistimethate clearance. The incidence of acute renal injury was 20%.

FIG 1

Observed colistimethate and colistin plasma concentration data in the three studies included in the model development (6, 7). The data from the current study are shown in the two right panels. inf, infusion; MU, million IU; q8h, every 8 h; q12h, every 12 h. (Reprinted from reference with permission of the publisher.)

FIG 2

Final structural model describing disposition of CMS and colistin. CMS (CMS₁) and its derivatives (CMS₂) occur in two states and distribute in both a central and peripheral compartment. For the previous studies (6, 7), a portion of the CMS dose (F2) was estimated to enter in the form of derivatives, while F2 was negligible for the new study. In addition, F1 for the new study was higher than F1 plus F2 for the previous studies. Vc, central volume of distribution; Vp, peripheral volume of distribution.

FIG 3

Prediction-corrected visual predictive check for the final model. Dots represent the observed data, and lines represent the 5th, 50th, and 95th percentiles of the observed data. The shaded areas are the 95% confidence intervals of the 5th, 50th, and 95th percentiles as calculated from 500 simulations from the final PK model. LD, loading dose; MD, maintenance dose. Data from studies 1 and 2 were collected earlier (6, 7), and study 3 is the current study.

FIG 4

Predicted profiles of colistimethate (top) and colistin (bottom) following the first dose and on day 5 (steady state) for the three dosing regimens available to generate the population PK model. In all predictions, an infusion time of 30 min was applied, and CL_CR was set to 80 ml/min. F1 and F2 are the fractions of the administered dose that enters the CMS compartments as A or B forms (Fig. 2). F3 is the corresponding fraction directly entering the colistin compartment (applied in the 4th column). The two left columns show the predictions based on the estimated fractions of F1 and F2 in the current study, and the new formulation is set to include 100% A or B forms of CMS. The old formulation is set to include the estimated relative percentage of 61% A or B forms of CMS. The two right columns are two hypothetical scenarios where a part of the dose enters the CMS2 compartment (F2 > 0; 3rd and 4th columns) or colistin compartment (F3 > 0; 4th column).