Evaluating the stability of colistin and colistin methanesulphonate in human plasma under different conditions of storage

202

208

A previous pharmacokinetic study on dosing of colistin methanesulfonate (CMS) at 240 mg (3 million units [MU]) every 8 h indicated that colistin has a long half-life, resulting in insufficient concentrations for the first 12 to 48 h after initiation of treatment. A loading dose would therefore be beneficial. The aim of this study was to evaluate CMS and colistin pharmacokinetics following a 480-mg (6-MU) loading dose in critically ill patients and to explore the bacterial kill following the use of different dosing regimens obtained by predictions from a pharmacokinetic-pharmacodynamic model developed from an in vitro study on Pseudomonas aeruginosa. The unbound fractions of colistin A and colistin B were determined using equilibrium dialysis and considered in the predictions. Ten critically ill patients (6 males; mean age, 54 years; mean creatinine clearance, 82 ml/min) with infections caused by multidrug-resistant Gram-negative bacteria were enrolled in the study. The pharmacokinetic data collected after the first and eighth doses were analyzed simultaneously with the data from the previous study (total, 28 patients) in the NONMEM program. For CMS, a two-compartment model best described the pharmacokinetics, and the half-lives of the two phases were estimated to be 0.026 and 2.2 h, respectively. For colistin, a one-compartment model was sufficient and the estimated half-life was 18.5 h. The unbound fractions of colistin in the patients were 26 to 41% at clinical concentrations. Colistin A, but not colistin B, had a concentration-dependent binding. The predictions suggested that the time to 3-log-unit bacterial kill for a 480-mg loading dose was reduced to half of that for the dose of 240 mg.

Section: Discussionmentioning

confidence: 53%

Application of a Loading Dose of Colistin Methanesulfonate in Critically Ill Patients: Population Pharmacokinetics, Protein Binding, and Prediction of Bacterial Kill

Mohamed

Karaiskos

Plachouras

et al. 2012

202

208

“…Urine samples voided over the 12-h predose period and 24-h postdose period were collected. To minimize any potential in vitro conversion of CMS to colistin (23), samples for CMS and colistin concentration analysis were immediately stored on ice and processed at 4°C prior to storage at Ϫ80°C, pending high-performance liquid chromatography (HPLC) analysis. The samples were analyzed for CMS and colistin concentrations within 4 months of the completion of the study (23).…”

Section: Methodsmentioning

confidence: 99%

Pulmonary and Systemic Pharmacokinetics of Inhaled and Intravenous Colistin Methanesulfonate in Cystic Fibrosis Patients: Targeting Advantage of Inhalational Administration

Yapa

Patel

et al. 2014

142

dThe purpose of this study was to define the pulmonary and systemic pharmacokinetics of colistin methanesulfonate (CMS) and formed colistin following intravenous (i.v.) and inhaled administration in cystic fibrosis (CF) patients. Six CF subjects were administered nebulized CMS doses of 2 and 4 million IU and an i.v. CMS infusion of 150 mg of colistin base activity. Blood plasma, sputum, and urine samples were collected for 12 to 24 h postdose. To assess the tolerability of the drug, lung function tests, blood serum creatinine concentrations, and adverse effect reports were recorded. All doses were well tolerated in the subjects. The pharmacokinetic parameters for CMS following i.v. delivery were consistent with previously reported values. Sputum concentrations of formed colistin were maintained at <1.0 mg/liter for 12 h postdose. Nebulization of CMS resulted in relatively high sputum concentrations of CMS and formed colistin compared to those resulting from i.v. administration. The systemic availability of CMS was low following nebulization of 2 and 4 million IU (7.93% ؎ 4.26% and 5.37% ؎ 1.36%, respectively), and the plasma colistin concentrations were below the limit of quantification. Less than 2 to 3% of the nebulized CMS dose was recovered in the urine samples in 24 h. The therapeutic availability and drug targeting index for CMS and colistin following inhalation compared to i.v. delivery were significantly greater than 1. Inhalation of CMS is an effective means of targeting CMS and formed colistin for delivery to the lungs, as high lung exposure and minimal systemic exposure were achieved in CF subjects.

“…Samples were collected in heparinized blood collection tubes, placed on ice, and centrifuged at 4°C within 1 h of collection. The resulting plasma was stored at Ϫ70 to Ϫ80°C to prevent in vitro conversion of CMS to colistin (11). For patients on either HD or CRRT, the total volume of dialysate collected across a collection interval was measured or calculated from known flow rates.…”

Section: Patients and Study Designmentioning

confidence: 99%

“…CMS and colistin concentrations in plasma were quantified by previously reported high-performance liquid chromatographic methods (21)(22). Plasma CMS and colistin concentrations were quantified within 4 months of collection to avoid in vitro conversion of CMS to colistin (11). The accuracies of the plasma colistin assay at the low, medium, and high quality control concentrations were 106%, 100%, and 103% of target concentrations, respectively, with corresponding precision (CV) of 6.27%, 7.85%, and 6.48%.…”

Section: Patients and Study Designmentioning

confidence: 99%

Population Pharmacokinetics of Colistin Methanesulfonate and Formed Colistin in Critically Ill Patients from a Multicenter Study Provide Dosing Suggestions for Various Categories of Patients

Garonzik

Thamlikitkul

et al. 2011

Self Cite

641

858

With increasing clinical emergence of multidrug-resistant Gram-negative pathogens and the paucity of new agents to combat these infections, colistin (administered as its inactive prodrug colistin methanesulfonate [CMS]) has reemerged as a treatment option, especially for critically ill patients. There has been a dearth of pharmacokinetic (PK) data available to guide dosing in critically ill patients, including those on renal replacement therapy. In an ongoing study to develop a population PK model for CMS and colistin, 105 patients have been studied to date; these included 12 patients on hemodialysis and 4 on continuous renal replacement therapy. For patients not on renal replacement, there was a wide variance in creatinine clearance, ranging from 3 to 169 ml/min/1.73 m 2 . Each patient was treated with a physicianselected CMS dosage regimen, and 8 blood samples for PK analysis were collected across a dosage interval on day 3 or 4 of therapy. A linear PK model with two compartments for CMS and one compartment for formed colistin best described the data. Covariates included creatinine clearance on the total clearance of CMS and colistin, as well as body weight on the central volume of CMS. Model-fitted parameter estimates were used to derive suggested loading and maintenance dosing regimens for various categories of patients, including those on hemodialysis and continuous renal replacement. Based on our current understanding of colistin PK and pharmacodynamic relationships, colistin may best be used as part of a highly active combination, especially for patients with moderate to good renal function and/or for organisms with MICs of >1.0 mg/liter.