Anders N Kristoffersson and Lena E Friberg
Department of Pharmaceutical Biosciences, Uppsala University
Objectives: As part of the EU funded AIDA project a multicenter, open-label, randomized 360 patient clinical trial (180 patients in each arm) has been initiated with the aim to compare colistin alone vs. colistin plus meropenem against severe infections caused by carbapenem-resistant bacteria [1]. The aim of this work was to propose a sparse sampling pharmacokinetic (PK) schedule for colistin and its prodrug CMS by application of optimal design (OD) methodology and to make an interim analysis from the study data to evaluate the design.
Methods: The CMS dosing schedule was a 9 MU loading dose, and a 4.5 MU twice daily maintenance dose given as 30 min infusions. The two sampling points were optimized for individual exposure determination of colistin in PopED [2] using the MAPocc [3] method to handle inter occasion variability (IOV) present in the PK model [4], with sampling allowed 15 min post end of infusion and until the start of the next infusion. Samples from the first 98 included patients have been assayed and were used to evaluate the design based on precision and distribution shrinkage (SH) of the individual parameter estimates as reported by NONMEM [5].
Results: The optimal sampling times were found to be at 45 min and 10 h post start of first and second of infusions respectively, and predicted to give satisfactory precision and SH in the most important colistin exposure determinant, the individual apparent clearance (CL/fm) estimate. Twenty-six of the patients adhered to the optimal sampling protocol while 44 entered the study after initiation of colistin treatment and the remaining 28 did not conform to the sampling schedule. The precision and SH in the individual CL estimate was best for the group entering the study after initiation of treatment, but was satisfactory for all groups (reduction in uncertainty vs. the population variability by >39% and a SH <30%).
Conclusions: An optimized PK sampling schedule was developed and found to result in individual CL estimates with low SH. The result brings confidence for the ability to evaluate covariates that may affect CL as well the relationship between colistin exposure and microbiological and clinical outcomes. Analysis is ongoing of the remaining patients and a full report including covariate data is intended to be submitted at the end of the year.
Acknowledgments: This project was funded by the EU-project AIDA (grant Health-F3-2011-278348) to LEF
References:
[1] Y. Dickstein, L. Leibovici, D. Yahav, N. Elyakim-Raz, G.L. Daikos, A. Skiada, A. Antoniadou, Y. Carmeli, A. Nutman, I. Levi, A. Adler, E. Durante-Mangoni, R. Andini, G. Cavezza, J.W. Mouton, R.A. Wijma, U. Theuretzbacher, L.E. Friberg, A.N. Kristoffersson, O. Zusman, F. Kopel, Y. Dishon, S. Altunin, M. Paul, and the AIDA consortium. Multicenter open-label randomized controlled trial to compare colistin alone with colistin plus meropenem for the treatment of severe infections caused by carbapenem-resistant Gram-negative infections (AIDA): study protocol. BMJ Open (in press 2016).
[2] J. Nyberg, S. Ueckert, E.A. Stromberg, S. Hennig, M.O. Karlsson, and A.C. Hooker. PopED: an extended, parallelized, nonlinear mixed effects models optimal design tool. Comput Methods Programs Biomed. 108:789-805 (2012).
[3] A. Kristoffersson, L. Friberg, and J. Nyberg. Inter occasion variability in individual optimal design. Journal of Pharmacokinetics and Pharmacodynamics. 42:735-750 (2015).
[4] 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. Application of a loading dose of colistin methanesulfonate in critically ill patients: population pharmacokinetics, protein binding, and prediction of bacterial kill. Antimicrob Agents Chemother. 56:4241-4249 (2012).
[5] R.B. Bauer. NONMEM users guide. Introduction to NONMEM 7, ICON Development Solutions, Elicott City, Maryland, 2010.
Reference: PAGE 25 () Abstr 5962 [www.page-meeting.org/?abstract=5962]
Poster: Methodology - Study Design