Cannabinoid 1 receptor (CB1R) inverse agonists are emerging as a potential obesity therapy. However, the physiological mechanisms by which these agents modulate human energy balance are incompletely elucidated. Here, we describe a comprehensive clinical research study of taranabant, a structurally novel acyclic CB1R inverse agonist. Positron emission tomography imaging using the selective CB1R tracer [(18)F]MK-9470 confirmed central nervous system receptor occupancy levels ( approximately 10%-40%) associated with energy balance/weight-loss effects in animals. In a 12-week weight-loss study, taranabant induced statistically significant weight loss compared to placebo in obese subjects over the entire range of evaluated doses (0.5, 2, 4, and 6 mg once per day) (p < 0.001). Taranabant treatment was associated with dose-related increased incidence of clinical adverse events, including mild to moderate gastrointestinal and psychiatric effects. Mechanism-of-action studies suggest that engagement of the CB1R by taranabant leads to weight loss by reducing food intake and increasing energy expenditure and fat oxidation.
We studied the time course for the reversal of rifampin's effect on the pharmacokinetics of oral midazolam (a cytochrome P450 (CYP) 3A4 substrate) and digoxin (a P-glycoprotein (P-gp) substrate). Rifampin increased midazolam metabolism, greatly reducing the area under the concentration-time curve (AUC(0-∞)). The midazolam AUC(0-∞) returned to baseline with a half-life of ~8 days. Rifampin's effect on the AUC(0-3 h) of digoxin was biphasic: the AUC(0-3 h) increased with concomitant dosing of the two drugs but decreased when digoxin was administered after rifampin. Digoxin was found to be a weak substrate of organic anion-transporting polypeptide (OATP) 1B3 in transfected cells. Although the drug was transported into isolated hepatocytes, it is not likely that this transport was through OATP1B3 because the transport was not inhibited by rifampin. However, rifampin did inhibit the P-gp-mediated transport of digoxin with a half-maximal inhibitory concentration (IC(50)) below anticipated gut lumen concentrations, suggesting that rifampin inhibits digoxin efflux from the enterocyte to the intestinal lumen. Pharmacokinetic modeling suggested that the effects on digoxin are consistent with a combination of inhibitory and inductive effects on gut P-gp. These results suggest modifications to drug-drug interaction (DDI) trial designs.
F-MK-6240 is a highly selective, subnanomolar-affinity Positron Emission Tomography (PET) tracer for imaging neurofibrillary tangles (NFTs). Plasma kinetics, brain uptake, and preliminary quantitative analysis of F-MK-6240 in healthy elderly subjects (HE), subjects with clinically probable Alzheimer disease (AD), and amnestic mild cognitive impairment (MCI) were characterized in a first-in-human study. Dynamic PET scans of up to 150 min were performed in 4 cognitively normal HE, 4 AD and 2 MCI subjects, after bolus injection of 152-169 MBq F-MK-6240 to evaluate tracer kinetics and distribution in brain. Regional standardized uptake value ratio (SUVR) and distribution volume ratio (DVR) were determined using the cerebellar cortex as a reference region. Total distribution volume () was assessed by compartmental modeling using radiometabolite corrected input function in a subgroup of 6 subjects. F-MK-6240 had rapid brain uptake with peak standardized uptake value of 3-5, followed by a uniformly quick washout from all brain regions in HE; slower clearance was observed in regions commonly associated with NFT deposition in AD. In AD, SUVR measured between 60-90 min postinjection was high (approximately 2-4) in regions associated with NFT deposition; whereas, in HE, SUVR was approximately 1 across all brain regions suggesting high tracer selectivity for binding NFTs in vivo.F-MK-6240 VT was approximately 2- to 3-fold higher in neocortical and medial temporal brain regions of AD compared with HE, and stabilized by 60 min in both groups. DVR estimated by Logan reference tissue model or compartmental modeling correlated well (R >0.9) to SUVR for AD. F-MK-6240 exhibited favorable kinetics with high-binding levels to brain regions with a plausible pattern for NFT deposition in AD. In comparison, negligible tracer binding was observed in HE. This pilot study suggests simplified ratio methods such as SUVR can be employed to quantify NFT binding. These results support further clinical development ofF-MK-6240 for potential application in longitudinal studies.
The acceptance and use of either surrogate end points (SEPs) or efficient clinical end points are associated with greater and more rapid availability of new medicines as compared with disease situations for which clinical end points are inefficient or no surrogates exist. This review of the history of the development, qualification, and acceptance of key SEPs shows that both successes and failures had three key characteristics: (i) apparent biologic plausibility, (ii) prognostic value for the outcome of the disease, and (iii) an association between changes in the SEP and changes in outcome with therapeutic intervention--the three factors recommended for SEPs in the International Conference on Harmonisation's "Statistical Principles for Clinical Trials." We recommend that only prognostic value be an absolute prerequisite for surrogacy, because therapeutic interventions may not exist a priori, and biological plausibility can be subjective. Ideally, all three of these factors would be traded off against one another in a consistent and transparent risk-management process.
Taranabant is a cannabinoid-1 receptor inverse agonist for the treatment of obesity. This study evaluated the safety, pharmacokinetics, and pharmacodynamics of taranabant (5, 7.5, 10, or 25 mg once daily for 14 days) in 60 healthy male subjects. Taranabant was rapidly absorbed, with a median t(max) of 1.0 to 2.0 hours and a t(1/2) of approximately 74 to 104 hours. Moderate accumulation was observed in C(max) (1.18- to 1.40-fold) and AUC(0-24 h) (1.5- to 1.8-fold) over 14 days for the 5-, 7.5-, and 10-mg doses, with an accumulation half-life ranging from 15 to 21 hours. Steady state was reached after 13 days. After multiple-dose administration, plasma AUC(0-24 h) and C(max) of taranabant increased dose proportionally (5-10 mg) and increased somewhat less than dose proportionally for 25 mg. Taranabant was generally well tolerated up to doses of 10 mg and exhibited multiple-dose pharmacokinetics consistent with once-daily dosing.
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