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Purpose: Quantification of pharmacodynamic interactions is key in combination therapies, yet conventional checkerboard experiments with up to 10 by 10 combinations are labor-intensive. Therefore, this study provides optimized experimental rhombic checkerboard designs to enable an efficient interaction screening with significantly reduced experimental workload. Methods: Based on the general pharmacodynamic interaction (GPDI) model implemented in Bliss Independence, a novel rhombic 'dynamic' checkerboard design with quantification of bacteria instead of turbidity as endpoint was developed. In stochastic simulations and estimations (SSE), the precision and accuracy of interaction parameter estimations and classification rates of conventional reference designs and the newly proposed rhombic designs based on effective concentrations (EC) were compared. Results: Although a conventional rich design with 20-times as many combination scenarios provided estimates of interaction parameters with higher accuracy, precision and classification rates, the optimized rhombic designs with one natural growth scenario, three monotherapy scenarios per combination partner and only four combination scenarios were still superior to conventional reduced designs with twice as many combination scenarios. Additionally, the rhombic designs were able to identify whether an interaction occurred as a shift on maximum effect or EC50 with > 98%. Overall, effective concentration-based designs were found to be superior to traditional standard concentrations, but were more challenged by strong interaction sizes exceeding their adaptive concentration ranges. Conclusion: The rhombic designs proposed in this study enable a reduction of resources and labor and can be a tool to streamline higher throughput in drug interaction screening. [ABSTRACT FROM AUTHOR]

In this review, we provide an updated summary on colistin pharmacokinetics and pharmacodynamics. Colistin is an old molecule that is frequently used as last-line treatment for infections caused by multidrug-resistant Gram-negative bacteria. Colistin is a decapeptide administered either as a prodrug, colistin methanesulfonate (CMS), when used intravenously, or as colistin sulfate when used orally. Because colistin binds to laboratory materials, many experimental issues are raised and studies on colistin can be tricky. Due to its large molecular weight and its cationic properties at physiological pH, colistin passes through physiological membranes poorly and is mainly distributed within the extracellular space. Renal clearance of colistin is very low, but the dosing regimen should be adapted to the renal function of the patient because CMS is partly eliminated by the kidney. Therapeutic drug monitoring of colistin is warranted because the pharmacokinetics of colistin are very variable, and because its therapeutic window is narrow. Resistance of bacteria to colistin is increasing worldwide in parallel to its clinical and veterinary uses and a plasmid-mediated resistance mechanism (MCR-1) was recently described in animals and humans. In vitro, bacteria develop various resistance mechanisms rapidly when exposed to colistin. The use of a loading dose might reduce the emergence of resistance but the use of colistin in combination also seems necessary. [ABSTRACT FROM AUTHOR]

Purpose: The objective of this study was to compare two different nebulizers: Eflow rapid® and Pari LC star® by scintigraphy and PK modeling to simulate epithelial lining fluid concentrations from measured plasma concentrations, after nebulization of CMS in baboons. Methods: Three baboons received CMS by IV infusion and by 2 types of aerosols generators and colistin by subcutaneous infusion. Gamma imaging was performed after nebulisation to determine colistin distribution in lungs. Blood samples were collected during 9 h and colistin and CMS plasma concentrations were measured by LC-MS/MS. A population pharmacokinetic analysis was conducted and simulations were performed to predict lung concentrations after nebulization. Results: Higher aerosol distribution into lungs was observed by scintigraphy, when CMS was nebulized with Pari LC® star than with Eflow Rapid® nebulizer. This observation was confirmed by the fraction of CMS deposited into the lung (respectively 3.5% versus 1.3%).CMS and colistin simulated concentrations in epithelial lining fluid were higher after using the Pari LC star® than the Eflow rapid® system. Conclusions: A limited fraction of CMS reaches lungs after nebulization, but higher colistin plasma concentrations were measured and higher intrapulmonary colistin concentrations were simulated with the Pari LC Star® than with the Eflow Rapid® system. [ABSTRACT FROM AUTHOR]

The objective of this study was to explore correlations between a variety of covariates and oxaliplatin ultrafilterable and blood pharmacokinetic parameters. Data from 40 patients receiving oxaliplatin combined with 5-fluorouracil and levofolinic acid as standard treatment for advanced colorectal cancer were analysed. Plasma ultrafilterable, blood, and urine platinum concentrations were determined by flameless atomic absorption spectrophotometry. Data were analysed according to a population pharmacokinetic method using the NONMEM program. The best fit for oxaliplatin plasma ultrafilterable clearance (CL) was given by the following equation, which considers four covariates: body surface area (BSA, in metres squared), age (in years), sex (0 if male, 1 if female), and serum creatinine (Scr, in micromoles per liter): CL (l/h)=5.49xBSA+4.55xBSAx(140–AGE)x(1–0.15xSEX)/Scr. By taking into account these covariates, the interindividual variability in CL decreased from 43% to 33%. Renal clearance represented 34% of the overall elimination. This value was obtained by recovering urine over only 5 h from the beginning of the infusion and modelling the data using NONMEM. We would recommend the use of this methodology for pharmacokinetic studies in oncology in which renal clearances of the drug are presently rarely explored. The oxaliplatin blood concentrations versus time observed during the three-cycle period were well-described by a three-compartment model with first-order elimination from the central compartment. No significant intrapatient pharmacokinetic variability was observed between cycles. The relationship we obtained using the population approach between oxaliplatin CL and covariates may allow rational reduction of oxaliplatin dose in cases of elevated serum creatinine levels. [ABSTRACT FROM AUTHOR]

Purpose: The 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.Methods: Plasma 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.Results: The 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.Conclusions: The 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. [ABSTRACT FROM AUTHOR]