Clin Pharmacokinet
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Review Comparative Study
Pharmacodynamic and pharmacokinetic properties of enoxaparin : implications for clinical practice.
Enoxaparin is a low-molecular-weight heparin (LMWH) that differs substantially from unfractionated heparin (UFH) in its pharmacodynamic and pharmacokinetic properties. Some of the pharmacodynamic features of enoxaparin that distinguish it from UFH are a higher ratio of anti-Xa to anti-IIa activity, more consistent release of tissue factor pathway inhibitor, weaker interactions with platelets and less inhibition of bone formation. ⋯ Clinical studies have confirmed that these pharmacological advantages translate into improved outcomes. There are important pharmacokinetic and pharmacodynamic differences between enoxaparin, other LMWHs and UFH, and therefore these molecules cannot be regarded as interchangeable.
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Review Comparative Study
Fosphenytoin: clinical pharmacokinetics and comparative advantages in the acute treatment of seizures.
Fosphenytoin is a phosphate ester prodrug developed as an alternative to intravenous phenytoin for acute treatment of seizures. Advantages include more convenient and rapid intravenous administration, availability for intramuscular injection, and low potential for adverse local reactions at injection sites. Drawbacks include the occurrence of transient paraesthesias and pruritus at rapid infusion rates, and cost. ⋯ Close monitoring and reduction in the infusion rate by 25-50% are recommended when intravenous loading doses of fosphenytoin are administered in these patients. The potential exists for clinically significant interactions when fosphenytoin is coadministered with other highly protein bound drugs. The pharmacokinetic properties of fosphenytoin permit the drug to serve as a well tolerated and effective alternative to parenteral phenytoin in the emergency and non-emergency management of acute seizures in children and adults.
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Comparative Study
Intranasal diamorphine as an alternative to intramuscular morphine: pharmacokinetic and pharmacodynamic aspects.
Diamorphine is a semisynthetic derivative of morphine that is currently licensed for use in the treatment of moderate to severe acute pain, administered by the intramuscular, intravenous or subcutaneous routes. It is highly water-soluble and has a number of properties that render it suitable for administration via the nasal route. Administration via the intranasal route is well described for other drugs, but has only recently been evaluated in a clinical setting for diamorphine. ⋯ The pharmacokinetic and pharmacodynamic properties of intranasal diamorphine, and particularly the ability to administer it without a needle (and therefore reduce the incidence of transmissible infection), have made this a popular route for abuse amongst opioid addicts. In this setting, however, the intranasal route is not free from adverse events, including deaths. The primary clinical need in the paediatric population is for a well tolerated, effective and expedient analgesic agent that is safe to use; intranasal diamorphine has pharmacokinetic properties that would make it suitable for such a clinical indication and, in clinical evaluations to date, appears to be promising.
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Four elements are crucial to successful pharmacokinetic-pharmacodynamic (PK/PD) modelling and simulation for efficient and effective rational drug development: (i) mechanism-based biomarker selection and correlation to clinical endpoints; (ii) quantification of drug and/or metabolites in biological fluids under good laboratory practices (GLP); (iii) GLP-like biomarker method validation and measurements and; (iv) mechanism-based PK/PD modelling and validation. Biomarkers can provide great predictive value in early drug development if they reflect the mechanism of action for the intervention even if they do not become surrogate endpoints. PK/PD modelling and simulation can play a critical role in this process. ⋯ Protocol design to produce sufficient data for PK/PD modelling would be more complex than that of PK. Knowledge of mechanism from discovery and preclinical studies are helpful for planning clinical study designs in cascade, sequential, crossover or replicate mode. The appropriate combination of biomarker identification and selection, bioanalytical methods development and validation for drugs and biomarkers, and mechanism-based PK/PD models for fitting data and predicting future clinical endpoints/outcomes provide powerful insights and guidance for effective and efficient rational drug development, toward safe and efficacious medicine for individual patients.
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Review
Stereoselectivity in the pharmacodynamics and pharmacokinetics of the chiral antimalarial drugs.
Several of the antimalarial drugs are chiral and administered as the racemate. These drugs include chloroquine, hydroxychloroquine, quinacrine, primaquine, mefloquine, halofantrine, lumefantrine and tafenoquine. Quinine and quinidine are also stereoisomers, although they are given separately rather than in combination. ⋯ Because of their low hepatic extraction ratios, stereoselective plasma protein binding also contributes to the stereoselectivity in the metabolism of these drugs. Chiral metabolites are formed from some parent antimalarial drugs, although stereoselective aspects of the pharmacokinetics of the metabolites are not well understood. It is concluded that knowledge of the stereoselective aspects of these agents may be helpful in better understanding their mechanisms of action and possibly optimising their clinical safety and/or effectiveness.