Pharmacokinetics and pharmacodynamics of MK-5046, a bombesin receptor subtype-3 (BRS-3) agonist, in healthy patients

Abstract

MK-5046 is an orally active, potent, selective agonist of the orphan G protein-coupled receptor bombesin receptor subtype-3 (BRS-3) that is under evaluation for treatment of obesity. We report the safety, tolerability, pharmacokinetics, and pharmacodynamics of oral doses of MK-5046 (10-160 mg) in a double-blind, randomized, placebo-controlled study in healthy and obese male volunteers. MK-5046 exposure increased dose proportionally, and MK-5046 was eliminated with an apparent terminal half-life of 1.5 to 3.5 hours. Single doses transiently increased blood pressure. Patients reported adverse events (erections and feeling hot, cold, and/or jittery) that coincided with time of occurrence (T(max)) and increased with increasing dose. No changes were observed in body temperature, heart rate, plasma glucose levels, or feelings of hunger/satiety. The blood pressure and thermal experiences attenuated with a second dose 6 hours after the first. Additionally, the erections suggest a possible, unanticipated, role for BRS-3 in reproductive physiology. Oral administration of MK-5046 achieves plasma concentrations that are projected to activate BRS-3 and therefore should be suitable for exploring its biological role in humans.

Figure 1

Plasma concentration-time profiles of MK-5046 after ingestion of single oral doses by male patients. Large plots are linear scale; insets are the same data using a log scale. (A) Single doses administered in the fasted state. Data are arithmetic means; n = 6 (N = 12 for 40 and 160 mg) healthy male patients/group of the indicated doses. (B) Single doses of 40 mg administered in fasted state (•) and after standard, high-fat breakfast (◦). Data are arithmetic means; n = 6 healthy male patients/group. (C) Single doses administered in the fasted state to cohorts with different mean body mass indexes (BMIs); (26.4 kg/m², closed symbols; 32.8 kg/m², open symbols). Data are arithmetic means; n = 6 patients/group.

Figure 2

Plasma concentration-time profiles of MK-5046 in fasted state and after ingestion of two 120-mg oral doses taken 6 hours apart in healthy (•, n = 6/group) and obese (◦, n = 5/group) male patients. Data are arithmetic means. Large plot is linear scale; inset is the same data using a log scale.

Figure 3

Effect of MK-5046 on blood pressure, heart rate, and body temperature. Data are change from the baseline (0 hours, which is nominally 0800) for placebo (red circles; n = 27, except n = 22 at the 5- and 6-hour points), 120 mg (open triangles; n = 12/group), 120 mg twice (black squares; second dose at 6 hours, n = 11/group), and 160 mg (open diamonds; n = 12/group) MK-5046 doses. Data are arithmetic mean ± standard error. Placebo time points sampled only with the twice-dosing cohort had an n = 5 and were omitted.

Figure 4

MK-5046 plasma concentration and blood pressure 1 hour after dosing. Change in blood pressure from predose to 1 hour after dosing is graphed as a function of MK-5046 plasma concentration at 1 hour after dosing. Because of attenuation with a second dose, only first dose data were included in this analysis. E_max best-fit curves (solid lines) are graphed as follows: ΔSBP = 23.33*MK-5046/(MK-5046 + 1842) and ΔDBP = 8.561*MK-5046/(MK-5046 + 315.3).

Figure 5

MK-5046 adverse experiences (AEs) as a function of dose administered and time. (A) The percentage of patients receiving the indicated doses who experienced one or more of the indicated AEs is indicated. The following groups of Medical Dictionary for Regulatory Activities (MedDRA) Preferred Terms were used to define the AE. Cold: chills, cold sweat, and feeling cold; Hot: feeling hot, flushing, hot flush, and hyperhidrosis; Jittery: feeling jittery, muscle tightness, muscle twitching, nervousness, and tremor. Any includes all of the cold, hot, and jittery terms. The Preferred Term “chills” includes the Lower Level Term “shivering,” but similar Lower Level Terms (eg, shaky feelings, shaking, tremor, and muscle tightness) are classified as “jittery.” (B) Time course of AE. The AE prevalence was assessed using time intervals of 15 minutes. The number of patients experiencing one or more of the indicated AEs is shown. Patients receiving placebo are omitted. When 120 mg was dosed twice, the 2 postdose periods are treated separately. (C) The percentage of patients receiving the indicated doses who experienced one or more erections is indicated.