Pharmacokinetic–pharmacodynamic studies of the 11β‐hydroxysteroid dehydrogenase type 1 inhibitor MK‐0916 in healthy subjects

Abstract

AIMSTo 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 in vivo inhibition of cortisone-to-cortisol conversion following oral MK-0916. METHODSData 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 (n = 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 (n = 80). Plasma and urine drug concentrations were measured for pharmacokinetic analysis. For pharmacodynamic analysis, concentrations of plasma [13 C4]cortisol were measured by high-pressure liquid chromatography and tandem mass spectrometry following a single oral dose of 5 mg [ 13 C4]cortisone. RESULTSDoses Ն3 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 nM and in vivo cortisone-to-cortisol conversion was inhibited by 84%. The relationship between plasma MK-0916 and hepatic 11b-hydroxysteroid dehydrogenase type 1 inhibition was well represented by a simple Emax model with an IC50 of 70.4 nM. Exposure to MK-0916 was generally well tolerated. CONCLUSIONSThese findings indicate that 11b-hydroxysteroid dehydrogenase type 1 is effectively inhibited in human subjects by doses of MK-0916 that are well tolerated. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• The intracellular enzyme 11b-hydroxysteroid dehydrogenase type 1 converts the inactive glucocorticoid cortisone into the active hormone cortisol in many tissues, including the liver and adipocytes. It is thought that increased conversion of cortisone to cortisol contributes to pathophysiology associated with the metabolic syndrome.• MK-0916 is an inhibitor of 11b-hydroxysteroid dehydrogenase type 1 that has been evaluated clinically as a potential therapy for type 2 diabetes, obesity or hypertension. WHAT THIS STUDY ADDS• In lean, healthy male subjects, MK-0916 was well tolerated when given in oral doses that were sufficient to provide profound inhibition of hepatic conversion of cortisone to cortisol.• Multiple-dose administration of 6 mg day -1 MK-0916 provided mean plasma concentrations >200 nM at all times, a plasma drug concentration that inhibited systemic 11b-hydroxysteroid dehydrogenase type 1 by 84%.

Inhibitors of 11β-Hydroxysteroid Dehydrogenase Type 1 as Potential Drugs for Type 2 Diabetes Mellitus—A Systematic Review of Clinical and In Vivo Preclinical Studies

“…In subjects receiving 6 mg of MK-0916 once daily was observed an 84% liver inhibition of cortisone-cortisol conversion. In addition, doses equal to or higher than 1.58 mg/day caused a 31-42% reduction in allo-THF + THF ratio /THE [26]. Oral MK-0916 administration appeared to be well tolerated and no serious AE was reported.…”

“…The first study was an initial investigation which primarily evaluated the safety in subjects given single oral doses of 0.4-100 mg of MK-0916. In the second study, in which subjects received 0.2-225 mg of MK-0916 followed by daily doses of 0.2-100 mg for 13 days, a primary goal was to evaluate the hepatic 11β-HSD1 inhibition [26]. In subjects receiving 6 mg of MK-0916 once daily was observed an 84% liver inhibition of cortisone-cortisol conversion.…”

“…In addition, the referred AE were mild to moderate in intensity. These included drowsiness and fatigue, reported in a subject administered placebo, and disorientation and hypogeusia, nightmares and abdominal pain in a subject administered MK-0916 [26].…”

Clinical Pharmacokinetics and the Impact of Genetic Polymorphism on a CYP2C19 Substrate, BMS-823778, in Healthy Subjects

“…The reason for the dose-dependent AI is unknown. One possibility is the existence of high-affinity, low-capacity binding sites (Wright et al, 2013) for BMS-823778. Extensive tissue distribution of BMS-923778 to these binding sites limits the exposure of BMS-823778 at low doses.…”

Cibler la voie métabolique du cortisol comme action thérapeutique dans le diabète de type 2

“…-Un autre inhibiteur de la 11βHSD1 a été testé chez l'homme, le MK-0916 [29]. Des résultats encourageants ont été observés chez le patient obèse DT2 traité par le MK-0916, avec une réduction de -0,3 % du taux d'HbA1c, associée à une diminution du poids et de la pression artérielle [30].…”