Towards effective pharmacotherapy targeting septic patients on midazolam or vancomycin using a modeling and simulation approach

Yoke Lin Lo (2011). Towards effective pharmacotherapy targeting septic patients on midazolam or vancomycin using a modeling and simulation approach PhD Thesis, School of Pharmacy, The University of Queensland.

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Author Yoke Lin Lo
Thesis Title Towards effective pharmacotherapy targeting septic patients on midazolam or vancomycin using a modeling and simulation approach
School, Centre or Institute School of Pharmacy
Institution The University of Queensland
Publication date 2011-03
Thesis type PhD Thesis
Supervisor Associate Professor Dr. Bruce G Charles
Dr. Toong-Chow Lee
Total pages 233
Total colour pages 14
Total black and white pages 219
Subjects 11 Medical and Health Sciences
Abstract/Summary In recent years, the use of population pharmacokinetic approach has greatly improved the scope and efficiency for obtaining information on which improved therapeutic dosing regimens can be based. Structural and variability models can be fitted to the data to obtain population as well as individual estimates of the pharmacokinetics. This approach is especially useful where there are very limited amounts of data per individual as occurs in critical care settings or pediatric population where intensive blood sampling is logistically difficult, unsafe, or unethical. Profound pathophysiologic and metabolic changes including multi-organ system failure as a result of overwhelming inflammatory response accompanied by severe sepsis and septic shock may result in a very complex drug disposition pattern in these patients. Midazolam is a sedative agent with a short duration of action. Nonetheless, cases of prolonged sedation after discontinuation of midazolam have been reported in patients with severe sepsis or septic shock. Similarly, neonatal sepsis is the major cause of mortality and morbidity in neonatal intensive care units. Hitherto, there has been no data on the pharmacokinetics of vancomycin in very premature Malaysian neonates, despite the widespread use of this antibiotic in the country. Dosing practices have relied solely on literature data from Caucasian infants. Accordingly, the general aims of this thesis were, firstly, to determine the pharmacokinetic profile of midazolam in adult septic patients with various degrees of severity in sepsis syndrome; and secondly, to examine the pharmacokinetics of vancomycin in premature Malaysian infants so that improved dosage regimens might be developed. The first study involved prospectively collected data from 55 critically ill, adult, septic patients receiving midazolam by continuous intravenous infusion for the induction and maintenance of sedation in a general ICU. A 6-compartment model best described the pharmacokinetics of midazolam and its major metabolites. Serum and urine concentrations of midazolam, 1-hydroxymidazolam and 1-hydroxymidazolam glucuronide were estimated by a newly developed and validated liquid chromatography-mass spectrometry assay method. Population and individual estimates of clearance and distribution volume and factors which affected the variability of these parameters were estimated. The imprecision and bias of the model were estimated and the predictive performance of the population model was evaluated by standard methods. Body weight, which reflects the severity of fluid retention, coagulation and renal function status, as well as the need for noradrenaline administration were important factors in explaining the between-subject variability of the pharmacokinetic parameters of midazolam and its metabolites. Typical population parameter estimates of clearance were: midazolam to other sites, 3.55 L/h; midazolam to 1-hydroxymidazolam, 3.77 L/h; 1-hydroxymidazolam, 16.2 L/h and 1-hydroxymidazolam glucuronide, 13.4 L/h. The central and peripheral distribution volumes were 15.1 L/70-kg and 67.2 L/70-kg respectively while the inter-compartmental clearance was 34.4 L/h. The bioavailability of midazolam was 0.8 as per previously reported data and the absorption rate constant was 0.97 h-1. A large between-subject variability and residual unexplained variability were observed. There was no appreciable model misspecification or bias. In the second study, data were collected retrospectively from the routine therapeutic drug monitoring records of 116 premature, newborn infants. Vancomycin concentrations were estimated by fluorescence polarization immunoassay. A one-compartment infusion model with first-order elimination best described the serum vancomycin concentration data (n=835 points). Typical population parameter estimates of clearance and volume of distribution for a 1-kg premature neonate with a postmenstrual age of 30 weeks were 0.043 L/h and 0.52 L, respectively. The estimated population vancomycin elimination half-life was 8.5 h. There was a 20% reduction in clearance for small-for-gestational age infants, compared to appropriate-for-gestational age infants. The between-occasion variability for clearance was 16.7%. The predictive capability of the final model as assessed by visual inspective checks and non-parametric bootstrapping was found to be satisfactory. Improved dosage regimens based on AUC24/MIC≥400 values were formulated by incorporating body size, postmenstrual and small-for-gestational age using Monte Carlo simulations with the model estimated pharmacokinetic parameters. In conclusion, the research reported in this thesis has established that a multi-compartment model could be successfully used to estimate the pharmacokinetic responses of midazolam and its metabolites simultaneously in sera and urine in critically ill patients with various degrees of sepsis syndrome severity. Factors that influenced the pharmacokinetic parameters of midazolam in these patients were identified, but the variability in the pharmacokinetic parameters remained high. In addition, the population pharmacokinetic parameters of vancomycin in very premature infants were determined, and improved dosing regimens of vancomycin for these infants were successfully formulated using retrospective data obtained from routine therapeutic drug monitoring. The predictive performance of these two population pharmacokinetic models was evaluated and no model misspecification or bias was detected.
Keyword midazolam
premature neonates
population pharmacokinetics
modeling and simulations
dosage guidelines
Additional Notes Page no. that should be printed in colour: 38, 104-107, 110-111, 134, 139, 146-149, 164 Page no. that should be printed in landscape: 174, 219

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Created: Mon, 28 Mar 2011, 16:01:00 EST by Ms Yoke Lin Lo on behalf of Library - Information Access Service