Clinical pharmacology and therapeutics
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Clin. Pharmacol. Ther. · Jan 2010
Comment ReviewBiomarker qualification via public-private partnerships.
Biomarkers linked to patient outcomes (safety and efficacy) have an increasingly important role in drug development. Consequently, validation and qualification of such biomarkers are essential, often requiring large data sets from well-controlled randomized clinical trials. In the December 2009 issue of Clinical Pharmacology & Therapeutics, investigators utilizing data from four pharmaceutical companies and working under the auspices of the Biomarkers Consortium described the utility of adiponectin as an early predictor of glycemic control in diabetic patients taking peroxisome proliferator-activated receptor (PPAR) agonists. This work illustrates the advantages of large public-private partnerships for biomarker qualification.
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Clin. Pharmacol. Ther. · Jan 2010
Comparative StudyComparison of critical drug-drug interaction listings: the Department of Veterans Affairs medical system and standard reference compendia.
The objective of this study was to evaluate the agreement among the US Department of Veterans Affairs (VA) listing of "critical" drug-drug interactions (DDIs) and two standard drug-interaction compendia. A list of critical DDIs, as defined by the VA, was compared with two standard commercially available compendia (Micromedex DRUG-REAX and Drug Interactions: Analysis and Management (DIAM)) in order to determine the level of agreement among the systems. Of 982 DDIs classified as critical by the VA, only 136 DDIs (13.7%) were considered critical in all three systems. Our conclusion was that, overall, there is poor agreement among the compendia and the VA system.
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Clin. Pharmacol. Ther. · Dec 2009
Clinical trial simulations in pediatric patients using realistic covariates: application to teduglutide, a glucagon-like peptide-2 analog in neonates and infants with short-bowel syndrome.
Teduglutide, a synthetic glucagon-like peptide-2 (GLP-2) analog with activity relating to the regeneration, maintenance, and repair of the intestinal epithelium, is currently being evaluated for the treatment of short-bowel syndrome (SBS), Crohn's disease, and other gastrointestinal disorders. On the basis of promising results from teduglutide studies in adults with SBS and from studies in neonatal and juvenile animal models, a pediatric multiple-dose phase I clinical study was designed to determine the safety, efficacy, and pharmacokinetics of teduglutide in pediatric patients with SBS who have undergone resection for necrotizing enterocolitis, malrotation, or intestinal atresia. This report details the application of clinical trial simulations coupled with a novel approach using generalized additive modeling for location, scale, and shape (GAMLSS) that facilitates the simulation of demographic covariates specific to the targeted patient populations. The goal was to optimize phase I dosing strategies and the likelihood of achieving target exposure and therapeutic effect.
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Clin. Pharmacol. Ther. · Dec 2009
Meta AnalysisUtility of adiponectin as a biomarker predictive of glycemic efficacy is demonstrated by collaborative pooling of data from clinical trials conducted by multiple sponsors.
This study, conducted under the Metabolic Disorders Steering Committee of the Biomarkers Consortium (a public-private partnership managed by the Foundation for the National Institutes of Health (FNIH)), analyzed blinded data on 2,688 type 2 diabetes (T2D) patients from randomized clinical trials conducted by four pharmaceutical companies. An increase in the levels of adiponectin was observed after peroxisome proliferator-activated receptor (PPAR)-agonist treatment (P < 0.0001), but not after treatment with non-PPAR drugs. This increase correlated with decreases in levels of glucose, hemoglobin A(1c) (Hb(A1c)), hematocrit, and triglycerides, and increases in levels of blood urea nitrogen, creatinine, and high-density lipoprotein cholesterol (HDL-C). ⋯ Logistic regression demonstrated that an increase in the level of adiponectin predicts a decrease in the level of Hb(A1c). These analyses confirm previously demonstrated relationships between adiponectin levels and metabolic parameters and support the robust predictive utility of adiponectin across the spectrum of glucose tolerance. Cross-company precompetitive collaboration is a feasible and powerful approach to biomarker qualification.
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Clin. Pharmacol. Ther. · Dec 2009
Randomized Controlled TrialEscitalopram is a weak inhibitor of the CYP2D6-catalyzed O-demethylation of (+)-tramadol but does not reduce the hypoalgesic effect in experimental pain.
Tramadol is O-demethylated to the active metabolite (+)-O-desmethyltramadol ((+)-M1) via CYP2D6, an enzyme that is weakly inhibited by escitalopram. We investigated the possibility of a pharmacokinetic (PK) and pharmacodynamic (PD) effect of escitalopram on tramadol metabolism. Fifteen healthy subjects completed this randomized, double-blind, three-phase, crossover trial. ⋯ The median area under plasma concentration-time curve extrapolated to infinity (AUC(0-infinity)) of (+)-M1 was 2.75 micromol/l.h after placebo pretreatment compared with 1.95 micromol/l.h after escitalopram (P = 0.0027). The mean AUEC(1-12) of CPT were 4,140 and 4,388 cm.s after placebo and escitalopram, respectively (P = 0.71). Although escitalopram is a weak inhibitor of CYP2D6, it does not impair the analgesic effect of tramadol.