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• W100095440 abstract "The global aim of this PhD thesis is to explore a number of methodologies to optimise the assessment of renal function and investigate the renal elimination of drugs. It is unclear in the literature whether cystatin C (CysC) is a better predictor of renal impairment than serum creatinine (SCr). A systematic review was undertaken to compare the diagnostic accuracy of CysC versus SCr which identified 27 population-groups in 24 studies (total number of people, n=2007) that compared the diagnostic accuracy of CysC with SCr. Metatesti?½ and RevMani?½ were the softwares applied in this meta-analysis study. The diagnostic odds ratios (DORs) (95%CI) of predicting renal dysfunction derived from a Moses-Littenberg linear regression model were 3.99 (3.41-4.57) for CysC and 2.79 (2.12-3.46) for SCr. The diagnostic accuracy for impaired renal function favours CysC, however, CysC does not offer a statistically significant advantage over SCr, the confidence intervals of the DORs overlap. Further studies should be undertaken to find an endogenous marker of GFR that has a higher accuracy of predicting renal dysfunction than CysC and SCr. It has been suggested that Intensive Care Unit (ICU) patients have different pharmacokinetics (PK) compared to healthy volunteers, which could be the result of supra-physiological renal function for renally eliminated drugs. Two population pharmacokinetic (popPK) models were developed for cefepime and cefpirome administered as 2 g every 12 h as a 3 min. intravenous infusion. Both popPK models for cefepime and cefpirome were 3-compartment with zeroorder input which best described the concentration-time data and accounted for between subject and between occasion variability in this population. The popPK models were used to simulate, via Monte Carlo simulations (n=1000), free-drug concentrations of cefepime and cefpirome for two administration methods: (1) intermittent bolus administration (IBA); (2) continuous infusion (CI). Concentration-time profiles were evaluated by the probability of achieving free-drug concentrations above the MIC for greater than 65% of the dosing interval, defined as the probability of target attainment (PTA). Finally, the PTA expectation values for each antimicrobial and each dosing administration were evaluated using MIC distributions of E. coli, K. pneumoniae, P. aeruginosa, and A. baumannii. When cefepime and cefpirome are administered via IBA or CI for E. coli and K. pneumoniae, both should be successful in current dosing scheduled in achieving the bactericidal target. However, against P. aeruginosa, a daily dose of 4 g/day of cefepime administered as CI is required to achieve a PTA expectation value of >90%, while for cefpirome, doses greater than 6 g/day administered as CI may need to be considered to optimise therapy in ICU patients. For the treatment of A. baumannii, doses of cefepime and cefpirome greater than 6 g/day administered as CI are required to maximize therapeutic outcome in ICU patients. Pharmaceutical companies are often not able to optimally use data obtained from phase I PK studies to design their future phase II studies. Using fluconazole as an example drug, two existing studies were identified and used to illustrate techniques for achieving this, i) fluconazole administered to healthy volunteers (analogous to a phase I study) and ii) fluconazole administered to people with HIV infection (analogous to a phase II study). Optimal study design techniques were used to develop a parsimonious phase II study design based on minimising dosing arms and number of blood samples per patient that were present from the actual HIV study. Those involved in optimising the study design were blinded to the actual HIV study results. Five (competing) models were developed from the phase I (healthy volunteer) data that were expected to accommodate for possible differences that may be present in the phase II (HIV) study. A parsimonious design was found that performed well across all five competing models and this design was compared against the actual HIV study (full design). The model developed from the optimised parsimonious design was shown to perform as well as the model developed from the HIV full study design. The study design presented illustrates that cost-effective studies that provide acceptable parameter precision are achievable even when there is considerable uncertainty in the model and parameter space. This provides a useful way for phase II studies to be designed based on data obtained during preliminary phase I studies." @default.
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• W100095440 date "2007-01-01" @default.
• W100095440 modified "2023-09-27" @default.
• W100095440 title "Optimising the assessment of renal function and determining the renal elimination of drugs using various methodologies" @default.
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