Clin Pharmacokinet
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Randomized Controlled Trial Clinical Trial
Microdosed Cocktail of Three Oral Factor Xa Inhibitors to Evaluate Drug-Drug Interactions with Potential Perpetrator Drugs.
The aim of this study was to prove the suitability of simultaneously administered microdoses of the factor Xa inhibitors (FXaIs) rivaroxaban, apixaban and edoxaban (100 µg in total). To evaluate drug-drug interactions, the impact of ketoconazole, a known strong inhibitor of cytochrome P450 3A4 and P-glycoprotein, was studied. ⋯ EudraCT 2016-003024-23.
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Randomized Controlled Trial
Population-Pharmacokinetic Modeling of Tildrakizumab (MK-3222), an Anti-Interleukin-23-p19 Monoclonal Antibody, in Healthy Volunteers and Subjects with Psoriasis.
Tildrakizumab is an anti-interleukin-23p19 monoclonal antibody recently approved for the treatment of chronic plaque psoriasis. ⋯ The pharmacokinetics of tildrakizumab behaves like a typical monoclonal antibody without requiring dosage adjustment.
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Multicenter Study
Pharmacokinetics of the BCL-2 Inhibitor Venetoclax in Subjects with Hepatic Impairment.
Venetoclax is a selective B cell lymphoma-2 inhibitor. It is approved for treatment of chronic lymphocytic leukemia and is being investigated for other hematological malignancies. Venetoclax is predominantly eliminated by the liver; therefore, there is a need to investigate the effect of hepatic insufficiency on venetoclax pharmacokinetics. ⋯ No venetoclax dosage adjustment is required in subjects with mild or moderate hepatic impairment. In subjects with severe hepatic impairment, a 50% dose reduction of venetoclax is recommended to account for higher exposures and the longer half-life.
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Upadacitinib is a selective Janus kinase (JAK) 1 inhibitor being developed as an orally administered treatment for patients with moderate to severe rheumatoid arthritis (RA) and other autoimmune disorders. These analyses characterized the population pharmacokinetics of upadacitinib across phase I-III clinical trials using data for immediate-release (IR) and extended-release (ER) formulations. ⋯ A robust population pharmacokinetic model was developed for upadacitinib using a large dataset from phase I-III clinical trials in healthy volunteers and subjects with RA. None of the identified covariates had a clinically meaningful effect on upadacitinib exposures. The model is appropriate to use for simulations and to evaluate the exposure-response relationship of upadacitinib.
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Ixazomib, the first oral proteasome inhibitor, is approved in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma (MM) who have received at least one prior therapy. Ixazomib is a selective, potent, and reversible inhibitor of the 20S proteasome, and preferentially binds to and inhibits the β5 chymotrypsin-like proteolytic site. Ixazomib absorption is rapid, with a median time to reach maximum plasma concentration of approximately 1 h post-dose. ⋯ Non-cytochrome P450 (CYP)-mediated metabolism appears to be the major clearance mechanism for ixazomib. Drug-drug interaction studies have shown no meaningful effects of strong inhibitors of CYP3A on ixazomib PK; however, the strong inducer rifampin caused a clinically relevant reduction in ixazomib exposure, supporting the recommendation to avoid concomitant administration of ixazomib with strong CYP3A inducers. Exposure-response analyses of data from the phase III TOURMALINE-MM1 registrational study demonstrate a favorable benefit-risk profile for the approved dose and regimen of weekly ixazomib 4 mg on days 1, 8, and 15 of each 28-day cycle.