Clin Pharmacokinet
-
The direct factor Xa (FXa) inhibitors rivaroxaban, apixaban and edoxaban, and the thrombin inhibitor dabigatran etexilate (dabigatran) have gained approval for use in several indications, most notably for the prevention and treatment of venous thromboembolism (VTE) and for the prevention of stroke in patients with atrial fibrillation. Hepatic impairment can affect the disposition of these anticoagulants considerably not only because of the hepatic metabolism of the direct FXa inhibitors but also because moderate to severely impaired hepatic function will affect coagulation. This review describes the key pharmacological properties of novel oral anticoagulants with special attention to patients with impaired hepatic function. ⋯ Dabigatran is contraindicated in patients with hepatic impairment or liver disease expected to have any impact on survival. Currently, edoxaban is not available in the US or European markets. However, the Japanese label did not restrict use in hepatic dysfunction but advises care in patients with severe hepatic impairment.
-
Randomized Controlled Trial
Population pharmacokinetics of losmapimod in healthy subjects and patients with rheumatoid arthritis and chronic obstructive pulmonary diseases.
Losmapimod is an orally available, potent p38 mitogen-activated protein kinase inhibitor. It is in development as an anti-inflammatory drug in different therapeutic areas. Clinical studies have shown that losmapimod is well tolerated and safe in humans and several studies have shown its pharmacological effect in the target diseases. The aim of this work was to develop a population pharmacokinetic model and to explore the covariates affecting the pharmacokinetics of losmapimod using data collected from healthy volunteers and patients with rheumatoid arthritis (RA) and chronic obstructive pulmonary diseases (COPD). ⋯ The population pharmacokinetic model described in this work well characterized the pharmacokinetic profile of losmapimod following administration of a single oral dose and repeated oral doses in healthy subjects and patients with RA and COPD. Although sex, bodyweight and age were significant factors influencing some pharmacokinetic parameters of losmapimod, the relatively small magnitude of the effect did not result in concerns for dose adjustment.
-
Randomized Controlled Trial Comparative Study Clinical Trial
A population pharmacokinetic and pharmacodynamic study of a peripheral κ-opioid receptor agonist CR665 and oxycodone.
Peripherally acting opioids, particularly peripheral κ-opioid agonists, may be effective for treating visceral pain by activating receptors expressed on afferent nerves within the gut. ⋯ The results are consistent with the peripheral selectivity of CR665, as well as the possibility that peripheral actions of oxycodone contribute to its visceral analgesic efficacy.
-
New oral anticoagulants (OACs) that directly inhibit Factor Xa (FXa) or thrombin have been developed for the long-term prevention of thromboembolic disorders. These novel agents provide numerous benefits over older vitamin K antagonists (VKAs) due to major pharmacological differences. VKAs are economical and very well characterized, but have important limitations that can outweigh these advantages, such as slow onset of action, narrow therapeutic window and unpredictable anticoagulant effect. ⋯ The risk of metabolic drug-drug interactions also appears to differ between OACs: VKAs > rivaroxaban > apixaban > dabigatran. The convenience of the new OACs has translated into improvements in efficacy and safety as shown in phase III randomized trials. The new anticoagulants so far offer the greatest promise and opportunity for the replacement of VKAs.
-
Fentanyl was structurally designed by Paul Janssen in the early 1960s as a potent opioid analgesic (100-fold more potent than morphine). It is a full agonist at μ-opioid receptors and possesses physicochemical properties, in particular a high lipophilicity (octanol:water partition coefficient >700), which allow it to cross quickly between plasma and central nervous target sites (transfer half-life of 4.7-6.6 min). It undergoes first-pass metabolism via cytochrome P450 3A (bioavailability ~30 % after rapid swallowing), which can be circumvented by non-intravenous formulations (bioavailability 50-90 % for oral transmucosal or intranasal formulations). ⋯ Thanks to the development of non-intravenous pharmaceutical formulations, fentanyl has become one of the most successful opioid analgesics, and can be regarded as an example of a successful reformulation strategy of an existing drug based on pharmacokinetic research and pharmaceutical technology. This development broadened the indications for fentanyl beyond the initial restriction to intra- or perioperative clinical uses. The clinical utility of fentanyl could be expanded further by more comprehensive mathematical characterizations of its parametric pharmacokinetic input functions as a basis for the rational selection of fentanyl formulations for individualized pain therapy.