Paediatric anaesthesia
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Paediatric anaesthesia · Mar 2011
Review Case ReportsBuprenorphine TTS for children--a review of the drug's clinical pharmacology.
The transdermal therapeutic system (TTS) with buprenorphine is currently being used 'off-label' to treat chronic pediatric pain. We compiled available pharmacokinetic (PK), pharmacodynamic (PD), and clinical pediatric data on buprenorphine to rationalize treatment regimens. ⋯ Buprenorphine is of interest in pediatric postoperative pain and cancer pain control because of its multiple administration routes, long duration of action, and metabolism largely independent of renal function. There is little reason to expect buprenorphine effects in children out of infancy are fundamentally different to those in adults. From the limited pediatric data available, it appears that buprenorphine has no higher adverse potential than the more commonly used opioids. There is an urgent need for focused PK, PD, and safety studies in children before use in children becomes more widespread.
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Paediatric anaesthesia · Mar 2011
ReviewRole of modeling and simulation in pediatric investigation plans.
Ethical and practical constraints encourage the optimal use of resources in pediatric drug development. Modeling and simulation has emerged as a promising methodology acknowledged by industry, academia, and regulators. We previously proposed a paradigm in pediatric drug development, whereby modeling and simulation is used as a decision tool, for study optimization and/or as a data analysis tool. ⋯ Extrapolation of efficacy from different age groups is often used in pediatric medicinal development as another means to alleviate the burden of clinical trials in children, and this can be aided by modeling and simulation to supplement clinical data. The regulatory assessment is finally judged on clinical grounds such as feasibility, ethical issues, prioritization of studies, and unmet medical need. The regulators are eager to expand the use of modeling and simulation to elucidate safety issues, to evaluate the effects of disease (e.g., renal or hepatic dysfunction), and to qualify mechanistic models that could help shift the current medicinal development paradigm.
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Physiological-based pharmacokinetic models have been used to describe midazolam clearance (CL) maturation. There are no maturation descriptors of CL from neonate to adulthood based on reported estimates at different ages. ⋯ Previously published pharmacokinetic parameters can be used to develop maturation models that address gaps in current knowledge regarding the influence of age on a drug's disposition. If a midazolam sedation target concentration of 0.1 mg·l(-1) , similar to that given to adults, is assumed, then we might anticipate steady-state infusion rates of 0.014 mg·kg(-1) ·h(-1) in neonates, 0.05 mg·kg(-1) ·h(-1) in a 1-year-old, 0.06 mg·kg(-1) ·h(-1) in a 5-year-old and 0.05 mg·kg(-1) ·h(-1) in a 12-year-old child. Age-related pharmacodynamic differences that will affect dose and the impact of active metabolites on response are not yet quantified.
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Details of the development of conventional analytical methods for the determination of drugs in pediatric plasma/serum samples via microassays are presented. Examples of the development of small-volume sampling and the use of the newer detection systems such as LC/MS/MS for enhanced detection are presented. Dried blood spot sampling has conventionally been used for the study of inborn errors of metabolism using Guthrie cards. ⋯ The application of the methodology in pharmacokinetic/pharmacodynamic studies is discussed. The utilization of solid-phase microextraction and stir bar sorptive extraction in drug analysis is presented. Clinical applications of these methodologies are reported including the development of in vivo solid-phase microextraction.