Clin Pharmacokinet
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Tacrolimus is an immunosuppressive drug used for the prevention of the allograft rejection in kidney transplant recipients. It exhibits a narrow therapeutic index and large pharmacokinetic variability. Tacrolimus is mainly metabolized by cytochrome P450 (CYP) 3A4 and 3A5 and effluxed via ATP-binding cassette (ABC) transporters such as P-glycoprotein (P-gp), encoded by ABCB1 gene. The influence of CYP3A5*3 on the pharmacokinetics of tacrolimus has been well characterized. On the other hand, the contribution of polymorphisms in other genes is controversial. In addition, the involvement of other efflux transporters than P-gp in tacrolimus disposition is uncertain. The present study was designed to investigate the effects of genetic polymorphisms of CYP3As and efflux transporters on the pharmacokinetics of tacrolimus. ⋯ This is the first report showing that MRP2/ABCC2 has a crucial impact on the pharmacokinetics of tacrolimus in a haplotype-specific manner. Determination of the ABCC2 as well as CYP3A5 genotype may be useful for more accurate tacrolimus dosage adjustment.
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Pharmacokinetics play an integral role in the pediatric drug development process. The determination of pharmacokinetic parameters, particularly clearance, in different age groups directly informs dosing strategies for subsequent efficacy trials. Allometric scaling for prediction of pediatric clearance from the observed clearance in adults has been used in this effort. Clinical trial simulation, a powerful tool used to inform clinical trial design, requires both an estimate of clearance along with an estimate of the expected pharmacokinetic variability. The standard deviations (SD) of individual clearance values for adults are typically used and may lead to inaccurate predictions by not taking into account the more widespread distribution of factors such as body weight in the pediatric population. The objective of this study was to assess the accuracy of allometric prediction of drug clearance as well as methods for predicting clearance variability in children 6 years of age and older. ⋯ Allometric scaling may be a useful tool during pediatric drug development to predict drug clearance and dosing requirements in children 6 years of age and older. A novel methodology is reported that employs virtual adult and pediatric populations and adult pharmacokinetic data to accurately predict clearance variability in specific pediatric subpopulations. This approach has important implications for both clinical trial simulations and sample size determination for pediatric pharmacokinetic studies.
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In almost 30 years since the introduction of HMG-CoA reductase inhibitors (statins), no other class of lipid modulators has entered the market. Elevation of high-density lipoprotein-cholesterol (HDL-C) via inhibiting cholesteryl ester transfer protein (CETP) is an attractive strategy for reducing the risk of cardiovascular events in high-risk patients. Transfer of triglyceride and cholesteryl ester (CE) between lipoproteins is mediated by CETP; thus inhibition of this pathway can increase the concentration of HDL-C. ⋯ In view of the heterogeneity in HDL particle size, charge, and composition, the mere concentration of HDL-C may not be a good surrogate marker for HDL functionality. Recent clinical studies have reported that increased HDL functionality inversely correlates with the development of atherosclerotic plaque. Future development of CETP inhibitors may therefore benefit from the use of biomarkers of HDL functionality.
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Major changes in cytochrome P450 (CYP) 3A activity may be expected in the first few months of life with, later, relatively limited changes. In this analysis we studied the maturation of in vivo CYP3A-mediated clearance of midazolam, as model drug, from preterm neonates of 26 weeks gestational age (GA) to adults. ⋯ An in-vivo maturation function for midazolam clearance from premature neonates to adults has been developed. This function can be used to derive evidence-based doses for children, and to simulate exposure to midazolam and possibly other CYP3A substrates across the pediatric age range in population pharmacokinetic models or physiologically based pharmacokinetic models.
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Randomized Controlled Trial
Population pharmacokinetics of tranexamic acid in paediatric patients undergoing craniosynostosis surgery.
Tranexamic acid (TXA) effectively reduces blood loss and transfusion requirements during craniofacial surgery. The pharmacokinetics of TXA have not been fully characterized in paediatric patients and dosing regimens remain diverse in practice. A mixed-effects population analysis would characterize patient variability and guide dosing practices. ⋯ A two-compartment model with covariates bodyweight and age adequately characterized the disposition of TXA. A loading dose of 10 mg/kg over 15 min followed by a 5 mg/kg/h maintenance infusion was simulated to produce steady-state TXA plasma concentrations above the 16 μg/mL threshold. This dosing scheme reduces the initial high peaks observed with the larger dose of 50 mg/kg over 15 min used in our previous clinical study.