Clin Pharmacokinet
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Randomized Controlled Trial Comparative Study Clinical Trial
Absence of interaction of fondaparinux sodium with aspirin and piroxicam in healthy male volunteers.
Patients undergoing major orthopaedic surgery who are being treated with fondaparinux sodium for prevention of venous thromboembolism may be receiving treatment for coronary artery disease or chronic inflammatory disease of the joints or arthritis. Two separate studies assessed any possible interaction between fondaparinux sodium at steady state and aspirin (acetylsalicylic acid) or piroxicam in healthy volunteers. ⋯ Neither aspirin nor piroxicam influenced the pharmacokinetics of fondaparinux sodium at steady state. Two hours after administration, prolongation of bleeding time with aspirin alone or with aspirin plus fondaparinux sodium was significantly greater than with fondaparinux sodium alone (p = 0.003 and p = 0.004, respectively). No significant differences were observed between aspirin alone or aspirin + fondaparinux sodium in effect on bleeding time. A small decrease in collagen-induced platelet aggregation was observed after administration of piroxicam alone or piroxicam + fondaparinux sodium. A small effect on aPTT was observed; it was similar for fondaparinux sodium whether administered alone or in combination with either aspirin or piroxicam. No serious adverse events were reported.
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Randomized Controlled Trial Multicenter Study Comparative Study Clinical Trial
The pharmacokinetics of fondaparinux sodium in healthy volunteers.
Fondaparinux sodium is the first in a new class of synthetic factor Xa inhibitors that binds reversibly with high affinity to antithrombin III. It has been investigated for the prevention and treatment of arterial and venous thrombotic disorders and approved for use at a dose of 2.5mg once daily in the prevention of venous thromboembolism in major orthopaedic surgery. The pharmacokinetics of fondaparinux sodium were determined in eight studies in young and elderly healthy volunteers. ⋯ The favourable pharmacokinetic profile of fondaparinux sodium is likely to play an important role in the major advance that the drug represents in the prevention and treatment of thrombotic disorders.
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Randomized Controlled Trial Clinical Trial
Absence of interaction of fondaparinux sodium with digoxin in healthy volunteers.
Fondaparinux sodium is the first of a new class of antithrombotic agents: the selective factor Xa inhibitors. Coadministration with digoxin may occur in clinical practice and both drugs are excreted almost completely by the renal route. In this study we assessed the possible pharmacokinetic and pharmacodynamic interaction of fondaparinux sodium with digoxin at steady state in healthy male volunteers. ⋯ The pharmacokinetic profiles of both digoxin and fondaparinux sodium were unaffected by coadministration. Bioequivalence was concluded, based on the 90% confidence intervals of the ratio of adjusted geometric means calculated for the 2-by-2 comparison of peak concentration, area under the concentration-time curve and cumulative urinary excretion, which lay within the 0.80 to 1.25 reference interval. There were no clinically significant fluctuations in vital signs and ECG parameters. The coadministration of digoxin with fondaparinux sodium was well tolerated and no significant changes were observed in vital signs.
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Cytochrome P450 2C19 (CYP2C19) is the main (or partial) cause for large differences in the pharmacokinetics of a number of clinically important drugs. On the basis of their ability to metabolise (S)-mephenytoin or other CYP2C19 substrates, individuals can be classified as extensive metabolisers (EMs) or poor metabolisers (PMs). Eight variant alleles (CYP2C19*2 to CYP2C19*8) that predict PMs have been identified. ⋯ CYP2C19 is a major enzyme in proguanil activation to cycloguanil, but there are no clinical data that suggest that PMs of CYP2C19 are at a greater risk for failure of malaria prophylaxis or treatment. Diazepam clearance is clearly diminished in PMs or when inhibitors of CYP2C19 are coprescribed, but the clinical consequences are generally minimal. Finally, many studies have attempted to identify relationships between CYP2C19 genotype and phenotype and susceptibility to xenobiotic-induced disease, but none of these are compelling.
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Sepsis and septic shock are accompanied by profound changes in the organism that may alter both the pharmacokinetics and the pharmacodynamics of drugs. This review elaborates on the mechanisms by which sepsis-induced pathophysiological changes may influence pharmacological processes. Drug absorption following intramuscular, subcutaneous, transdermal and oral administration may be reduced due to a decreased perfusion of muscles, skin and splanchnic organs. ⋯ Changes in drug effect during septic conditions may theoretically result from changes in pharmacodynamics due to changes in the affinity of the receptor for the drug or alterations in the intrinsic activity at the receptor. The lack of valid pharmacological studies in patients with sepsis and septic shock makes drug administration in these patients a difficult challenge. The patient's underlying pathophysiological condition may guide individual dosage selection, which may be guided by measuring plasma concentration or drug effect.