METHOD: Compartmental models were fitted. The final model was determined based on the objective function value and inspection of goodness-of-fit plots. The bias and precision of parameter estimates were compared between SAEM and FOCEi using stochastic simulations and estimations. For robustness, parameters were re-estimated as the initial estimates were perturbed 100 times and resultant changes evaluated.
RESULTS: The absorption kinetics of metformin depend significantly on food status. Under the fasted state, the first-order absorption into the central compartment was preceded by zero-order infusion into the depot compartment, whereas for the fed state, the absorption into the depot was instantaneous followed by first-order absorption from depot into the central compartment. The means of relative mean estimation error (rMEE) ( ME E SAEM ME E FOCEi ) and rRMSE ( RMS E SAEM RMS E FOCEi ) were 0.48 and 0.35, respectively. All parameter estimates given by SAEM appeared to be narrowly distributed and were close to the true value used for simulation. In contrast, the distribution of estimates from FOCEi were skewed and more biased. When initial estimates were perturbed, FOCEi estimates were more biased and imprecise.
DISCUSSION: nlmixr is reliable for NLMEM. SAEM was superior to FOCEi in terms of bias and precision, and more robust against initial estimate perturbations.
METHODS: Patients were recruited from four hospitals. Clinical data were recorded and blood samples were taken for PK and genetic studies. Population PK parameters were estimated by nonlinear mixed-effects modelling in Monolix®. Models were evaluated using the difference in objective function value, goodness-of-fit plots, visual predictive check and bootstrap analysis. Monte Carlo simulation was conducted to evaluate different dosing regimens for IVIG.
RESULTS: A total of 30 blood samples were analysed from 10 patients. The immunoglobulin G concentration data were best described by a one-compartment model with linear elimination. The final model included both volume of distribution (Vd) and clearance (CL) based on patient's individual weight. Goodness-of-fit plots indicated that the model fit the data adequately, with minor model mis-specification. Genetic polymorphism of the FcRn gene and the presence of bronchiectasis did not affect the PK of IVIG. Simulation showed that 3-4-weekly dosing intervals were sufficient to maintain IgG levels of 5 g L-1 , with more frequent intervals needed to achieve higher trough levels.
CONCLUSIONS: Body weight significantly affects the PK parameters of IVIG. Genetic and other clinical factors investigated did not affect the disposition of IVIG.
OBJECTIVE: The aim of this proof-of-concept study was to evaluate whether combining population pharmacokinetic and machine learning approaches could provide a more accurate prediction of the clearance of renally eliminated drugs in individual neonates.
METHODS: Six drugs that are primarily eliminated by the kidneys were selected (vancomycin, latamoxef, cefepime, azlocillin, ceftazidime, and amoxicillin) as 'proof of concept' compounds. Individual estimates of clearance obtained from population pharmacokinetic models were used as reference clearances, and diverse machine learning methods and nested cross-validation were adopted and evaluated against these reference clearances. The predictive performance of these combined methods was compared with the performance of two other predictive methods: a covariate-based maturation model and a postmenstrual age and body weight scaling model. Relative error was used to evaluate the different methods.
RESULTS: The extra tree regressor was selected as the best-fit machine learning method. Using the combined method, more than 95% of predictions for all six drugs had a relative error of < 50% and the mean relative error was reduced by an average of 44.3% and 71.3% compared with the other two predictive methods.
CONCLUSION: A combined population pharmacokinetic and machine learning approach provided improved predictions of individual clearances of renally cleared drugs in neonates. For a new patient treated in clinical practice, individual clearance can be predicted a priori using our model code combined with demographic data.
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