Expert opinion on drug metabolism & toxicology
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Expert Opin Drug Metab Toxicol · Aug 2014
ReviewTailored tools to improve pharmacotherapy in infants.
Extensive within-population variability is the essence of neonatal pharmacology. Despite this, infants remain one of the last therapeutic orphans. Together with additional legal initiatives, tailoring of already available tools (modeling, covariates, pharmacovigilance) may significantly improve pharmacotherapy in infants. ⋯ Knowledge on pharmacotherapy in infants is lagging. Tailoring available tools to the specific characteristics (maturation) and clinical needs (newly emerging covariates) of infants is feasible but needs creativity and a multidisciplinary collaboration between modelers, academia, clinical researchers and, obviously, the public, including parents.
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Expert Opin Drug Metab Toxicol · Jul 2014
ReviewPharmacokinetic and pharmacodynamic evaluation of donepezil for the treatment of Alzheimer's disease.
Donepezil is a highly selective acetylcholinesterase inhibitor and one of the only four drugs currently approved for treatment of Alzheimer's dementia. Providing high bioavailability and a very long half-time, donepezil is regarded as effective and well tolerable in Alzheimer's disease patients, even in difficult clinical conditions such as hepatic or renal impairment. It moderately improves cognitive and global functioning scores in patients with mild to moderate Alzheimer's disease over the course of 6 - 12 months, with open-label extension studies suggesting effects of even longer duration. ⋯ Donepezil is one of the most frequently prescribed anti-dementia drugs. The recent additional approval of the 23 mg formulation will expand its use in patients with moderate to severe Alzheimer's disease. After numerous Phase III study failures of novel disease-modifying drugs for Alzheimer's disease, donepezil is likely going to stay a first-line therapeutic option in Alzheimer's disease in the upcoming years.
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Expert Opin Drug Metab Toxicol · Jul 2014
ReviewEvaluation of ranirestat for the treatment of diabetic neuropathy.
Pharmacologic maintenance of normoglycemia in diabetes cannot prevent the eventual complications mainly due to protein glycation-induced cell death, dysregulated antioxidant defense and signal transduction in affected tissues. The rate-limiting enzyme of this process, aldose reductase, is therefore a pharmacologic target. To date, nine inhibitors of this enzyme have been developed. Ranirestat has completed two Phase III clinical trials. The objective of this evaluation is to summarize and provide expert opinion on the status of ranirestat with an emphasis on its pharmacokinetics in the context of its potential effects to prevent/treat diabetic complications. ⋯ Ranirestat is a well-tolerated front-line inhibitor. It reproducibly exhibits some degree of measurable objective beneficial outcomes in diabetic neuropathy. It is the furthest advanced in clinical trials with some depth of supporting preclinical data. Trials in subjects with newly diagnosed neuropathy along with the identification of objective biomarkers/measurements of efficacy will be critical in identifying the real value and effect of ranirestat.
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Expert Opin Drug Metab Toxicol · Jul 2014
EditorialThe emergent role of metabolic phenotyping in dynamic patient stratification.
The role that metabolic phenotyping can increasingly play in patient stratification and personalised medicine is discussed. The background to the general approach, comprehensive and simultaneous analysis of small-molecule metabolites in biofluids, tissues and tissue extracts combined with suitable multivariate statistical models, is summarised. The main techniques used (NMR and mass spectrometry) are cited, and the implementation of dedicated phenome centres is explained. Finally, the advantages and limitations, opportunities and drawbacks of the approach are discussed.
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Expert Opin Drug Metab Toxicol · Apr 2014
ReviewModels for evaluating the pharmacokinetics and pharmacodynamics for β-blockers.
β-blocker therapy plays an important role in the treatment of various diseases, including hypertension, myocardial infarction and heart failure. Although all β-blockers shared their ability to competitively block β1-adrenoceptor, this therapeutic class showed great heterogeneity in their pharmacokinetic (PK) and pharmacodynamic (PD) properties. ⋯ PK models and PK/PD modeling have clearly contributed to characterization of the PK and PD properties of β-blockers. Differences in cardiovascular actions between classical β-blockers and vasodilatory β-blockers need to be further studied in order to confirm the clinical benefits of the new-generation of β-blockers. PK/PD modeling may contribute to clarify the importance of heterogeneity of PK and PD properties of β-blockers potentially improving the selection of the adequate agent and dose regimen in the treatment of cardiovascular diseases.