Clin Pharmacokinet
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Clinical Trial
Use of target controlled infusion to derive age and gender covariates for propofol clearance.
Attempts to describe the variability of propofol pharmacokinetics in adults and to derive population covariates have been sparse and limited mainly to experiments based on bolus doses or infusions in healthy volunteers. This study aimed to identify age and gender covariates for propofol when given as an infusion in anaesthetized patients. ⋯ We achieved a relatively simple and practical covariate model in which the variability of pharmacokinetics within the study population could be ascribed principally to variability in clearance from the central compartment. Pharmacokinetic simulation predicted an improved performance of the TCI system when employing the derived covariates model, especially in elderly female patients.
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To characterize levetiracetam pharmacokinetics, identify significant covariate relationships and identify doses in children that achieve blood concentrations similar to those observed in adults. ⋯ The most influential covariate of levetiracetam pharmacokinetics in children is bodyweight. A starting dose of levetiracetam 10 mg/kg twice daily ensures the same exposure in children as does 500 mg twice daily in adults.
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Randomized Controlled Trial Multicenter Study Comparative Study
Population pharmacokinetics and pharmacodynamics of rivaroxaban--an oral, direct factor Xa inhibitor--in patients undergoing major orthopaedic surgery.
There is a clinical need for novel oral anticoagulants with predictable pharmacokinetics and pharmacodynamics. Rivaroxaban is an oral direct Factor Xa (FXa) inhibitor in clinical development for the prevention and treatment of thromboembolic disorders. This analysis was performed to characterize the population pharmacokinetics and pharmacodynamics of rivaroxaban in patients participating in two phase II, double-blind, randomized, active-comparator-controlled studies of twice-daily rivaroxaban for the prevention of venous thromboembolism after total hip- or knee-replacement surgery. ⋯ This population analysis in patients undergoing major orthopaedic surgery demonstrated that rivaroxaban has predictable, dose-dependent pharmacokinetics that were well described by an oral one-compartment model and affected by expected covariates. Rivaroxaban exposure could be assessed using the prothrombin time, if necessary, but not the international normalized ratio. The findings suggested that fixed dosing of rivaroxaban may be possible in patients undergoing major orthopaedic surgery.
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Randomized Controlled Trial Multicenter Study Comparative Study
A clinical comparison of slow- and rapid-escalation treprostinil dosing regimens in patients with pulmonary hypertension.
Subcutaneous treprostinil is an effective treatment for pulmonary arterial hypertension (PAH). A previous pivotal study indicated that infusion site pain was dose dependent and resulted in suboptimal dose escalation by week 12 and a reduced clinical benefit. We hypothesized that a rapid-escalation treprostinil dosing regimen would be as safe and effective as a slow-escalation dosing regimen. ⋯ The rapid-dosing regimen is as safe and effective as the slow-escalation regimen and may be associated with even better clinical outcomes. Infusion site pain is not dose dependent.
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Coumarin derivatives, including warfarin, acenocoumarol and phenprocoumon, are the drugs of choice for long-term treatment and prevention of thromboembolic events. The management of oral anticoagulation is challenging because of a large variability in the dose-response relationship, which is in part caused by genetic polymorphisms. The narrow therapeutic range may result in bleeding complications or recurrent thrombosis, especially during the initial phase of treatment. ⋯ Genetic polymorphism in further enzymes and structures involved in the effect of anticoagulants such as gamma-glutamylcarboxylase, glutathione S-transferase A1, microsomal epoxide hydrolase and apolipoprotein E appear to be of negligible importance. Despite the clear effects of CYP2C9 and VKORC1 variants, these polymorphisms explain less than half of the interindividual variability in the dose response to oral anticoagulants. Thus, while individuals at the extremes of the dose requirements are likely to benefit, the overall clinical merits of a genotype-adapted anticoagulant treatment regimen in the entire patient populations remain to be determined in further prospective clinical studies.