Pharmacokinetic–pharmacodynamic studies of the 11β‐hydroxysteroid dehydrogenase type 1 inhibitor MK‐0916 in healthy subjects. (December 2013)

• Record Type: Journal Article
• Authors: Wright, D. Hamish; Stone, Julie A.; Crumley, Tami M.; Wenning, Larissa; Zheng, Wei; Yan, Kerri; Yang, Amy Yifan; Sun, Li; Cilissen, Caroline; Ramael, Steven; Hermanowski‐Vosatka, Anne; Langdon, Ronald B.; Gottesdiener, Keith M.; Wagner, John A.; Lai, Eseng
• Is Part Of: British journal of clinical pharmacology. Volume 76:Number 6(2013:Dec.)
• Page Start: 917
• Page End: 931
• Publication Date: 2013-12
• Subjects: Pharmacology -- Periodicals; Drugs -- Periodicals; 615.1
• DOI: 10.1111/bcp.12131
• Languages: English
• ISSNs: 0306-5251

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="bcp12131-sec-0001" sec-type="section"> <title>Aims</title> <p>To characterize pharmacokinetic parameters of MK‐0916 and its safety and tolerability in lean, healthy male subjects following single and multiple oral doses. To assess (by stable‐isotope labelling) the <italic>in vivo</italic> inhibition of cortisone‐to‐cortisol conversion following oral MK‐0916.</p> </sec> <sec id="bcp12131-sec-0002" sec-type="section"> <title>Methods</title> <p>Data are presented from two randomized, controlled, double‐blind, rising‐dose phase I studies. In the first study, subjects received single oral doses of 0.4–100 mg MK‐0916 (<italic>n</italic> = 16). In the second study, subjects received 0.2–225 mg MK‐0916 followed by daily doses of 0.2–100 mg for 13 days beginning on day 2 or day 15 (<italic>n</italic> = 80). Plasma and urine drug concentrations were measured for pharmacokinetic analysis. For pharmacodynamic analysis, concentrations of plasma [<sup>13</sup>C<sub>4</sub>]cortisol were measured by high‐pressure liquid chromatography and tandem mass spectrometry following a single oral dose of 5 mg [<sup>13</sup>C<sub>4</sub>]cortisone.</p> </sec> <sec id="bcp12131-sec-0003" sec-type="section"> <title>Results</title> <p>Doses ≥3 mg were rapidly absorbed (time at which maximal concentration was achieved in plasma, 1.1–1.8 h). Exposure (measured as the area under the concentration–time curve from 0 to 168 h) increased approximately in proportion to dose. Values for the maximal plasma concentration and the plasma concentration at 24 h increased in excess of dose proportionality at doses <6 mg and roughly in proportion to dose at doses >6 mg. In subjects dosed with 6 mg MK‐0916 once daily for 14 days, the mean trough plasma concentration was 240 n<sc>m</sc> and <italic>in vivo</italic> cortisone‐to‐cortisol conversion was inhibited by 84%. The relationship between plasma MK‐0916 and hepatic 11β‐hydroxysteroid dehydrogenase type 1 inhibition was well represented by a simple <italic>E</italic><sub>max</sub> model with an IC<sub>50</sub> of 70.4 n<sc>m</sc>. Exposure to MK‐0916 was generally well tolerated.</p> </sec> <sec id="bcp12131-sec-0004" sec-type="section"> <title>Conclusions</title> <p>These findings indicate that 11β‐hydroxysteroid dehydrogenase type 1 is effectively inhibited in human subjects by doses of MK‐0916 that are well tolerated.</p> </sec> </abstract>