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Title: Pharmacometric models of oral ciprofloxacin for children with malnutrition
Author: Ungphakorn, Wanchana
Awarding Body: University of Strathclyde
Current Institution: University of Strathclyde
Date of Award: 2012
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Abstract:
Children with severe malnutrition typically suffer from numerous associated complications. Among these, septicaemia, especially with Gram-negative organisms, remains the major concern because it is associated with a high mortality rate. The World Health Organization (WHO) has been releasing standard guidelines for the treatment of bacterial infections for many years; however, it has been found that the mortality rate remains high even if these guidelines are followed. Ciprofloxacin is a fluoroquinolone antimicrobial agent that has been considered as alternative treatment option. However, to date, data around the pharmacokinetics (PK) of ciprofloxacin, as well as other drugs, are limited in malnourished children. The aim of this thesis was to develop pharmacokinetic models for describing and predicting the PK of drugs in such children. A population analysis was performed by using ciprofloxacin concentration-time data obtained from 52 malnourished children. It was found that a one-compartment model, with first-order absorption and a lag, adequately described the data. The final population model included the effect of body weight, high mortality risk and serum sodium concentration on clearance (CL), and the effect of body weight and sodium concentration on volume of distribution (V). Inclusion of these factors reduced inter-individual variability in CL from 50% to 38%, and in V from 49% to 43%. Absorption rate (ka) was poorly estimated and highly variable. Internal validation techniques, including nonparametric bootstrap, a visual predictive check, normalised prediction distribution error and a jackknife analysis, were used to assess the stability and robustness of the final population model. The results of these analyses indicated that the model was stable and had a favourable predictive performance for CL and V. To develop new dosage regimens, the population model was used to perform a 10,000-patient Monte Carlo simulation. The probabilities of achieving the therapeutic target AUC0-24/MIC ratio and the expected population response were then iv determined. The results showed that PK-PD breakpoints were 0.06-0.125 mg/L and 0.25-0.5 mg/L for Gram-negative and Gram-positive organisms, respectively. The overall response with the 30 mg/kg/day dose was 80% for Escherichia coli, Klebsiella pneumoniae and Salmonella species, but <60% for Pseudomonas aeruginosa and Streptococcus pneumoniae. The results suggested that an oral dose of ciprofloxacin 10 mg/kg three times daily (30 mg/kg/day) may be appropriate for the management of septicaemia in severely malnourished children. Discrepancies of susceptibility breakpoints between reference sources were also found, i.e., PK-PD, CLSI and EUCAST, and these discrepancies were most pronounced for P. aeruginosa and S. pneumoniae. The population model was alsmpartment model, with first-order absorption and a lag, adequately described the data. The final population model included the effect of body weight, high mortality risk and serum sodium concentration on clearance (CL), and the effect of body weight and sodium concentration on volume of distribution (V). Inclusion of these factors reduced inter-individual variability in CL from 50% to 38%, and in V from 49% to 43%. Absorption rate (ka) was poorly estimated and highly variable. Internal validation techniques, including nonparametric bootstrap, a visual predictive check, normalised prediction distribution error and a jackknife analysis, were used to assess the stability and robustness of the final population model. The results of these analyses indicated that the model was stable and had a favourable predictive performance for CL and V. o used to determine optimal design for future population PK studies. A number of design options and design variables were examined. The results suggest that the optimal number of groups was three and two for three- and four-sample designs, respectively. When using two groups, it was possible to vary the number of individuals in each group. If permission was given to obtain up to five samples from each patient, one group of participants would be adequate. Only samples taken after the first dose gave sufficient information. The expected coefficient of variation (CV) of all parameters was under 10% with sample sizes of 25 and 40 for five- and four-sample designs, respectively. For three samples, the CV for ka remained above 20%, although the sample size was increased to 100. It was also found that the optimal designs were highly dependent on the prior information, so prior knowledge of drug concentration-time profiles should be used with optimal design methods when designing population PKt model, with first-order absorption and a lag, adequately described the data. The final population model included the effect of body weight, high mortality risk and serum sodium concentration on clearance (CL), and the effect of body weight and sodium concentration on volume of distribution (V). Inclusion of these factors reduced inter-individual variability in CL from 50% to 38%, and in V from 49% to 43%. Absorption rate (ka) was poorly estimated and highly variable. Internal validation techniques, including nonparametric bootstrap, a visual predictive check, normalised prediction distribution error and a jackknife analysis, were used to assess the stability and robustness of the final population model. The results of these analyses indicated that the model was stable and had a favourable predictive performance for CL and V. studies. In order to predict the disposition of other drugs in a malnourished population, whole body physiologically based pharmacokinetic (WBPBPK) models were developed by using ciprofloxacine as a model drug. The WBPBPK model was initially developed for healthy adults and then scaled to healthy and malnourished children. Kp values were calculated using the Poulin method, the Rodgers method and empirical method. The results showed that, for healthy adults and children, the predicted versus observed concentration-time profiles were well described with intravenous (IV bolus v and short infusion) models. Oral predictions were also in good agreement with the data from the literature, but peak concentrations were more rapidly achieved with a higher dose. Unlike the Poulin method, the concentration-time profiles predicted using Kp from the Rodgers method and the empirical methods were similar, and closely resembled the observed data. When models were scaled for malnutrition, inter-individual variability was higher, especially during the absorption phase. However, PK profiles were still adequately described. The models developed in this thesis are useful tools for describing and predicting drug PK in malnourished children. However, due to the scarcity of data, further studies to characterise the alteration of drug kinetics, particularly during the absorption process, might improve the performance of the models. Application of these models to other drugs and data is also required to substantiate the predictive performance of the model.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.576297  DOI: Not available
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