Clinical pharmacology and therapeutics
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Clin. Pharmacol. Ther. · Mar 2008
Comparative StudyDisease severity is a major determinant for the pharmacodynamics of propofol in critically ill patients.
As oversedation is still common and significant variability between and within critically ill patients makes empiric dosing difficult, the population pharmacokinetics and pharmacodynamics of propofol upon long-term use are characterized, particularly focused on the varying disease state as determinant of the effect. Twenty-six critically ill patients were evaluated during 0.7-9.5 days (median 1.9 days) using the Ramsay scale and the bispectral index as pharmacodynamic end points. NONMEM V was applied for population pharmacokinetic and pharmacodynamic modeling. ⋯ Deeper levels of sedation were found with an increasing SOFA score. With severe illness, critically ill patients will need downward titration of propofol. In patients with cardiac failure, the propofol dosages should be reduced by 38%.
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Clin. Pharmacol. Ther. · Mar 2008
Randomized Controlled Trial Comparative StudyIntravenous parecoxib rapidly leads to COX-2 inhibitory concentration of valdecoxib in the central nervous system.
Evidence in animal studies supports widespread induction of cyclooxygenase-2 (COX-2) in the central nervous system (CNS) following tissue injury, probably mediated by cytokines, transducing the signal across the blood-brain barrier. CNS COX-2 blockade is a possible therapeutic target for drugs that are able to reach adequate CNS levels and abolish the prostaglandin E2-induced central sensitization. This human pharmacokinetic study investigated valdecoxib cerebrospinal fluid (CSF) and plasma concentrations over time in 37 patients following 40 mg of single-dose intravenous parecoxib. ⋯ Valdecoxib was first detectable in the CSF at 15 min postdosing, increased rapidly until 50 min, and thereafter remained between 6 and 14 ng/ml. This is the first human study demonstrating CNS COX-2 inhibitor penetration as early as 15 min. CSF valdecoxib concentration rapidly reached in vitro IC50 (inhibitory concentration 50) (1.57 ng/ml) by 17 min and remained consistently higher thereafter.
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Clin. Pharmacol. Ther. · Feb 2008
ReviewInnovative early development regulatory approaches: expIND, expCTA, microdosing.
The Food and Drug Administration (FDA) Critical Path Initiative as well as the European Medicines Agency Road Map to 2010 (ref. 2) call for opportunities for more efficient drug development. One of the initiatives that has emerged in this context is the elaboration through guidance of exploratory investigational new drugs (INDs)/clinical trial applications (CTAs). This article reviews the history of these emerging guidances as well as the experience to date in their use by the industry.
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Clin. Pharmacol. Ther. · Feb 2008
Clinical TrialInfluence of CYP2C9 and VKORC1 1173C/T genotype on the risk of hemorrhagic complications in African-American and European-American patients on warfarin.
The association of CYP2C9 and VKORC1 1173C/T genotype and risk of hemorrhage among African Americans and European Americans is presented. This association was evaluated using Cox proportional hazard regression with adjustment for demographics, comorbidity, and time-varying covariates. Forty-four major and 203 minor hemorrhages occurred over 555 person-years among 446 patients (60.6+/-15.6 years, 50% men, 227 African Americans). ⋯ The risk of major hemorrhage was 5.3-fold (95% CI: 0.4-64.0) higher before stabilization of therapy, 2.2-fold (95% CI: 0.7-6.5) after stabilization, and 2.4-fold (95% CI: 0.8-7.4) during all periods when anticoagulation was not stable. The variant VKORC1 1173C/T genotype did not confer a significant increase in risk for major (HR 1.7; 95% CI: 0.7-4.4) or minor (HR 0.8; 95% CI: 0.5-1.3) hemorrhage. The variant CYP2C9 genotype is associated with an increased risk of major hemorrhage, which persists even after stabilization of therapy.
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Clin. Pharmacol. Ther. · Feb 2008
Clinical TrialInfluence of OATP1B1 genotype on the pharmacokinetics of rosuvastatin in Koreans.
This study was carried out to determine whether polymorphisms of organic anion-transporting polypeptide 1B1 (OATP1B1) have an effect on rosuvastatin pharmacokinetics in Koreans. Among 200 subjects genotyped for OATP1B1 c.388A>G, and c.521T>C, 30 subjects were selected for the rosuvastatin pharmacokinetic study. ⋯ There were no significant differences in rosuvastatin-lactone pharmacokinetics among the three groups. The pharmacokinetic exposure of rosuvastatin was higher in the OATP1B1*15/*15 subjects than the others, suggesting a potential association between the OATP1B1 genetic polymorphisms and altered rosuvastatin pharmacokinetics in Korean populations.