Clin Pharmacokinet
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Since 2007, it is mandatory for the pharmaceutical companies to submit a Paediatric Investigation Plan to the Paediatric Committee at the European Medicines Agency for any drug in development in adults, and it often leads to the need to conduct a pharmacokinetic study in children. Pharmacokinetic studies in children raise ethical and methodological issues. Because of limitation of sampling times, appropriate methods, such as the population approach, are necessary for analysis of the pharmacokinetic data. The choice of the pharmacokinetic sampling design has an important impact on the precision of population parameter estimates. Approaches for design evaluation and optimization based on the evaluation of the Fisher information matrix (M(F)) have been proposed and are now implemented in several software packages, such as PFIM in R. ⋯ PFIM was a useful tool to find an optimal sampling design in children, considering clinical constraints. Even if it was not forecasted initially by the investigators, this approach showed that it was really necessary to include a late sampling time for all children. Moreover, we described an approach to evaluate designs assuming expected proportions of BLQ data are omitted.
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Multicenter Study
Population pharmacokinetic-pharmacodynamic analysis of neutropenia in cancer patients receiving PM00104 (Zalypsis(®)).
PM00104 (Zalypsis(®)) is a novel marine-derived compound that has shown antineoplastic activity against a number of human tumour cell lines. Myelosuppression was found to be a PM00104 dose-limiting toxicity during phase I studies. The objective of this study was to characterize the time course of neutropenia after intravenous PM00104 administration in cancer patients. ⋯ The time course of neutropenia following PM00104 was well characterized by the model developed. The model-predicted time course of the ANCs and its variability confirmed that neutropenia is reversible, of short duration and non-cumulative.
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Therapeutic hypothermia can influence the pharmacokinetics and pharmacodynamics of drugs, the discipline which is called thermopharmacology. We studied the effect of therapeutic hypothermia on the pharmacokinetics of phenobarbital in asphyxiated neonates, and the clinical efficacy and the effect of phenobarbital on the continuous amplitude-integrated electroencephalography (aEEG) in a prospective study. ⋯ A one-compartmental population pharmacokinetic/pharmacodynamic model was developed using a multi-level Markov transition model. No (clinically relevant) effect of moderate therapeutic hypothermia on phenobarbital pharmacokinetics could be identified. The observed responsiveness was 66%. While we still advise an initial loading dose of 20 mg/kg, clinicians should not be reluctant to administer an additional dose of 10-20 mg/kg. An additional dose should be given before switching to a second-line anticonvulsant drug. Based on our pharmacokinetic/pharmacodynamic model, administration of phenobarbital under hypothermia seems to reduce the transition rate from a continuous normal voltage (CNV) to discontinuous normal voltage aEEG background level in hypothermic asphyxiated newborns, which may be attributed to the additional neuroprotection of phenobarbital in infants with a CNV pattern.
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The principles of allometry can be applied within a given species (intra-species scaling), for example extrapolation of pharmacokinetic parameters from adults to adolescents and older children (>5 years of age). Similarly, allometric scaling may also be used to predict pharmacokinetic parameters from normal weight subjects to the obese. The objective of this investigation was to evaluate the predictive performance of several allometric methods for the prediction of drug clearance (CL) and volume of distribution (Vd) in the obese from normal weight subjects. ⋯ The study indicated that allometric scaling can be applied to predict CL in the obese from normal weight subjects with high accuracy. The predicted CL can then be used to select a dose to initiate a clinical trial (pharmacokinetics, safety and efficacy).
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Given the alarming increase in obesity among children undergoing surgery, the main aim of this study was to characterize propofol clearance in a cohort of morbidly obese children and adolescents in relation to their age and body weight characteristics. ⋯ In the population pharmacokinetic model for propofol in morbidly obese children and adolescents, TBW proved to be the most significant determinant for clearance. As a result, it is anticipated that dosage of propofol for maintenance of anaesthesia in morbidly obese children and adolescents should be based on TBW using an allometric function. TRIAL REGISTRATION NUMBER (CLINICALTRIALS.GOV): NCT00948597.