Clin Pharmacokinet
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Meta Analysis
Population pharmacokinetics meta-analysis of recombinant human erythropoietin in healthy subjects.
The aim of this analysis was to develop a population pharmacokinetic model to describe the pharmacokinetics of recombinant human erythropoietin (rHuEPO) in healthy subjects, after intravenous and subcutaneous administration over a wide dose range, and to examine the influence of demographic characteristics and other covariates on the pharmacokinetic parameters of rHuEPO. ⋯ The population pharmacokinetic model developed is suitable to describe the pharmacokinetic behaviour of rHuEPO after intravenous and subcutaneous administration in healthy subjects, over a wide dose range.
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Randomized Controlled Trial
Safety, pharmacokinetics and pharmocodynamics of recombinant human porphobilinogen deaminase in healthy subjects and asymptomatic carriers of the acute intermittent porphyria gene who have increased porphyrin precursor excretion.
Acute intermittent porphyria is an autosomal dominant disorder caused by deficient activity of the third enzyme in the haem biosynthetic pathway, porphobilinogen deaminase. It is characterised by acute, potentially life-threatening neurological attacks that are precipitated by various drugs, reproductive hormones and other factors. During acute attacks, the porphyrin precursors 5-aminolevulinic acid and porphobilinogen accumulate and are excreted at high concentrations in the urine. Current treatment is based on glucose loading and parenteral haem replenishment, which reduce the accumulation of 5-aminolevulinic acid and porphobilinogen. Recently, a new form of treatment based on porphobilinogen deaminase enzyme replacement therapy has been shown to be effective in an acute intermittent porphyria mouse model which, during phenobarbital (phenobarbitone) induction of haem biosynthesis, mimics the biochemical pattern of acute porphyric attacks. The objective of the present study was to investigate the safety, pharmacokinetics and pharmacodynamics of recombinant human porphobilinogen deaminase (P 9808), administered to healthy subjects and asymptomatic porphobilinogen deaminase-deficient subjects with high concentrations of porphobilinogen, the substrate of porphobilinogen deaminase. ⋯ The recombinant human porphobilinogen deaminase enzyme preparation was found to be safe to administer and effective for removal of the accumulated metabolite porphobilinogen from plasma and urine. The pharmacokinetic profile of recombinant human porphobilinogen deaminase showed dose proportionality, and the elimination half-life was about 2.0 hours for the two highest doses. Thus, clinical grounds were established for investigation of the therapeutic efficacy of the enzyme during periods of overt disease in patients with acute intermittent porphyria.
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Meta Analysis
Population pharmacokinetic meta-analysis of trabectedin (ET-743, Yondelis) in cancer patients.
To characterise the population pharmacokinetics of trabectedin (ET-743, Yondelis(R)) in cancer patients. ⋯ The integration of trabectedin pharmacokinetic data demonstrated linear elimination, dose-proportionality up to 1.8 mg/m(2) and time-independent pharmacokinetics. The pharmacokinetic impact of dexamethasone and sex covariates is probably limited given the moderate to large interindividual pharmacokinetic variability of trabectedin. The antiemetic and hepatoprotective effects are still a valid rationale to recommend dexamethasone as a supportive treatment for trabectedin.
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Controlled Clinical Trial
Mechanism-based pharmacokinetic-pharmacodynamic modelling of the reversal of buprenorphine-induced respiratory depression by naloxone : a study in healthy volunteers.
Respiratory depression is a potentially life-threatening adverse effect of opioid therapy. It has been postulated that the difficulty of reversing buprenorphine-induced respiratory depression is caused by slow receptor association-dissociation kinetics at the opioid mu receptor. The aim of this study was to characterise the pharmacodynamic interaction between buprenorphine and naloxone in healthy volunteers. ⋯ Because of the slow receptor association-dissociation kinetics of buprenorphine in combination with the fast elimination kinetics of naloxone, naloxone is best administered as a continuous infusion for reversal of buprenorphine-induced respiratory depression.
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Clinical Trial
Effect of severe renal failure and haemodialysis on the pharmacokinetics of levosimendan and its metabolites.
Levosimendan is a calcium sensitiser developed for the treatment of congestive heart failure. It increases myocardial contractility, reduces the filling pressure and dilates both the peripheral and coronary vessels. The circulating metabolites of levosimendan, OR-1855 and OR-1896, are formed and eliminated slowly after intravenous administration of levosimendan. The aim of this study was to investigate the effect of impaired renal function and haemodialysis on the pharmacokinetics of levosimendan, OR-1855 and OR-1896. ⋯ The t(1/2) of the levosimendan metabolites was prolonged 1.5-fold and their AUC and C(max) were 2-fold in patients with severe CRF and ESRD patients undergoing haemodialysis as compared with healthy subjects. These results suggest that the dose should be reduced when levosimendan is used for the treatment of congestive heart failure in patients with severe renal insufficiency.