Salim Bouchene

A Population WB-PBPK Model of Colistin and its Prodrug CMS in Pigs: Focus on the Renal Distribution and Excretion

PurposeThe objective was the development of a whole-body physiologically-based pharmacokinetic (WB-PBPK) model for colistin, and its prodrug colistimethate sodium (CMS), in pigs to explore their tissue distribution, especially in kidneys.MethodsPlasma and tissue concentrations of CMS and colistin were measured after systemic administrations of different dosing regimens of CMS in pigs. The WB-PBPK model was developed based on these data according to a non-linear mixed effect approach and using NONMEM software. A detailed sub-model was implemented for kidneys to handle the complex disposition of CMS and colistin within this organ.ResultsThe WB-PBPK model well captured the kinetic profiles of CMS and colistin in plasma. In kidneys, an accumulation and slow elimination of colistin were observed and well described by the model. Kidneys seemed to have a major role in the elimination processes, through tubular secretion of CMS and intracellular degradation of colistin. Lastly, to illustrate the usefulness of the PBPK model, an estimation of the withdrawal periods after veterinary use of CMS in pigs was made.ConclusionsThe WB-PBPK model gives an insight into the renal distribution and elimination of CMS and colistin in pigs; it may be further developed to explore the colistin induced-nephrotoxicity in humans.

A Whole-Body Physiologically Based Pharmacokinetic Model for Colistin and Colistin Methanesulfonate in Rat

Colistin is a polymyxin antibiotic used to treat patients infected with multidrug‐resistant Gram‐negative bacteria (MDR‐GNB). The objective of this work was to develop a whole‐body physiologically based pharmacokinetic (WB‐PBPK) model to predict tissue distribution of colistin in rat. The distribution of a drug in a tissue is commonly characterized by its tissue‐to‐plasma partition coefficient, Kp. Colistin and its prodrug, colistin methanesulfonate (CMS) Kp priors, were measured experimentally from rat tissue homogenates or predicted in silico. The PK parameters of both compounds were estimated fitting in vivo their plasma concentration–time profiles from six rats receiving an i.v. bolus of CMS. The variability in the data was quantified by applying a nonlinear mixed effect (NLME) modelling approach. A WB‐PBPK model was developed assuming a well‐stirred and perfusion‐limited distribution in tissue compartments. Prior information on tissue distribution of colistin and CMS was investigated following three scenarios: Kp was estimated using in silico Kp priors (I) or Kp was estimated using experimental Kp priors (II) or Kp was fixed to the experimental values (III). The WB‐PBPK model best described colistin and CMS plasma concentration–time profiles in scenario II. Colistin‐predicted concentrations in kidneys in scenario II were higher than in other tissues, which was consistent with its large experimental Kp prior. This might be explained by a high affinity of colistin for renal parenchyma and active reabsorption into the proximal tubular cells. In contrast, renal accumulation of colistin was not predicted in scenario I. Colistin and CMS clearance estimates were in agreement with published values. The developed model suggests using experimental priors over in silico Kp priors for kidneys to provide a better prediction of colistin renal distribution. Such models might serve in drug development for interspecies scaling and investigate the impact of disease state on colistin disposition.