15 research outputs found
CYP-mediated drug-drug interactions with evacetrapib, an investigational CETP inhibitor: in vitro prediction and clinical outcome
AIMS Evacetrapib is a cholesteryl ester transfer protein (CETP) inhibitor under development for reducing cardiovascular events in patients with high risk vascular disease. CETP inhibitors are likely to be utilized as âadd-onâ therapy to statins in patients receiving concomitant medications, so the potential for evacetrapib to cause clinically important drugâdrug interactions (DDIs) with cytochromes P450 (CYP) was evaluated. METHODS The DDI potential of evacetrapib was investigated in vitro, followed by predictions to determine clinical relevance. Potential DDIs with possible clinical implications were then investigated in the clinic. RESULTS In vitro, evacetrapib inhibited all of the major CYPs, with inhibition constants (Ki) ranging from 0.57 ÎŒM (CYP2C9) to 7.6 ÎŒM (CYP2C19). Evacetrapib was a time-dependent inhibitor and inducer of CYP3A. The effects of evacetrapib on CYP3A and CYP2C9 were assessed in a phase 1 study using midazolam and tolbutamide as probe substrates, respectively. After 14 days of daily dosing with evacetrapib (100 or 300 mg), midazolam exposures (AUC) changed by factors (95% CI) of 1.19 (1.06, 1.33) and 1.44 (1.28, 1.62), respectively. Tolbutamide exposures (AUC) changed by factors of 0.85 (0.77, 0.94) and 1.06 (0.95, 1.18), respectively. In a phase 2 study, evacetrapib 100 mg had minimal impact on AUC of co-administered simvastatin vs. simvastatin alone with a ratio of 1.25 (1.03, 1.53) at steady-state, with no differences in reported hepatic or muscular adverse events. CONCLUSIONS Taken together, the extent of CYP-mediated DDI with the potential clinical dose of evacetrapib is weak and clinically important DDIs are not expected to occur in patients taking concomitant medications.Ellen A. Cannady, Jeffrey G. Suico, Ming-Dauh Wang, Stuart Friedrich, Jessica R. F. Rehmel, Stephen J. Nicholls, Kathryn A. Kruege
An alternative method for measuring velocities in open-channel flows: perfomance evaluation of a Pitot tube compared to an acoustic meter
âThat's a Good QuoteâWhat's the Source?â: Integrating Media Technology Research and Presentation Skills in a High School Social Studies Class
The greater in vivo antiplatelet effects of prasugrel as compared to clopidogrel reflect more efficient generation of its active metabolite with similar antiplatelet activity to that of clopidogrel?s active metabolite
Evaluation of the Pharmacokinetics and Pharmacodynamics of Prasugrel in Japanese Elderly Subjects
Benchmarking laboratory observation uncertainty for in-pipe storm sewer discharge measurements
Cytochrome P450 3A Inhibition by Ketoconazole Affects Prasugrel and Clopidogrel Pharmacokinetics and Pharmacodynamics Differently
Successful arthroscopic treatment of shoulder osteochondrosis in the dog
Fourteen shoulder joints in 12 dogs were treated arthroscopically for osteochondrosis. The arthroscopic procedure included removal of all osteochondral flaps and curettage of the edges of the subchondral defect. Histological examination of biopsy samples from eight joints revealed synovitis in all cases. Arthroscopic surgery of shoulder osteochondrosis in the dog proved to be a less time consuming procedure than arthrotomy with minimal soft tissue trauma and allowed a rapid return to function of the patients