Aubrey Stoch

The acyclic CB1R inverse agonist taranabant mediates weight loss by increasing energy expenditure and decreasing caloric intake

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.

Rifampin's Acute Inhibitory and Chronic Inductive Drug Interactions: Experimental and Model-Based Approaches to Drug–Drug Interaction Trial Design

We studied the time course for the reversal of rifampins 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 (AUC0–∞). The midazolam AUC0–∞ returned to baseline with a half‐life of ~8 days. Rifampins effect on the AUC0–3 h of digoxin was biphasic: the AUC0–3 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 (IC50) 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.

The Value, Qualification, and Regulatory Use of Surrogate End Points in Drug Development

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 Harmonisations “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.

Multiple-Dose Pharmacokinetics, Pharmacodynamics, and Safety of Taranabant, a Novel Selective Cannabinoid-1 Receptor Inverse Agonist, in Healthy Male Volunteers

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 tmax of 1.0 to 2.0 hours and a t1/2 of approximately 74 to 104 hours. Moderate accumulation was observed in Cmax (1.18‐ to 1.40‐fold) and AUC0–24 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 AUC0–24 h and Cmax 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.

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamic Properties of Taranabant, a Novel Selective Cannabinoid‐1 Receptor Inverse Agonist, for the Treatment of Obesity: Results From a Double‐Blind, Placebo‐Controlled, Single Oral Dose Study in Healthy Volunteers

Taranabant is a novel cannabinoid CB‐1 receptor (CB1R) inverse agonist in clinical development for the treatment of obesity. This double‐blind, randomized, placebo‐controlled, single oral dose study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of taranabant (0.5–600 mg) in 24 healthy male volunteers. Single‐dose AUC0‐∞ and Cmax values for taranabant increased approximately linearly ith dose up to 200 mg, with slightly less than dose‐proportional increases in AUC0‐∞ and Cmax values for doses >200 mg. Plasma taranabant had a biphasic disposition, with a median tmax of 1 to 2.5 hours and a terminal elimination tl/2 of 38 to 69 hours. Coadministration of taranabant with a high‐fat meal led to a 14% increase in Cmax and a 74% increase in AUC0‐∞, Clinical adverse experiences ssociated with single doses of taranabant were generally mild and transient. Of the 198 clinical adverse experiences reported, the most common drug‐related ones were nausea (36), headache (22), drowsiness (14), abdominal discomfort/abdominal pain/stomachache (14), hiccups (9), dizziness (8), decreased appetite (7), increased bowel movement (7), mood change (6), tiredness (4), vomiting (4), and sweating increased (4). Taranabant has pharmacokinetic characteristics suitable for a once‐daily dosing regimen.

Efavirenz modulation of sleep spindles and sleep spectral profile

Non‐nucleoside reverse transcriptase inhibitors are important antiretroviral agents for the treatment of human immunodeficiency virus. Some non‐nucleoside reverse transcriptase inhibitors, in particular efavirenz, have prominent effects on sleep, cognition and psychiatric variables that limit their tolerability. To avoid confounds due to drug–drug and drug–disease interactions, we assessed the effects of efavirenz in healthy volunteers on sleep, cognition and psychological endpoints during the first week of treatment. Forty healthy male subjects were randomized to receive placebo or efavirenz 600 mg nightly for 7 days after completion of a 3‐day placebo run‐in period. Treatment with efavirenz was associated with reduced time to sleep onset in the Maintenance of Wakefulness Test, an increase in non‐rapid eye movement sleep, a large exposure‐related decrease in sigma band spectral density and sleep spindle density during non‐rapid eye movement sleep, and reduced performance on an attention switching task. Because efavirenz has been shown to have serotonin 2A receptor partial‐agonist properties, we reasoned that antagonism of serotonin 2A receptor signalling in the thalamic reticular nucleus, which generates sleep spindles and promotes attention, may be responsible. Consistent with predictions, treatment of healthy volunteers with a single dose of a serotonin 2A receptor antagonist was found to significantly suppress sigma band spectral density in an exposure‐related manner and modulated the overall spectral profile in a manner highly similar to that observed with efavirenz, consistent with the notion that efavirenz exhibits serotonin 2A receptor partial‐agonist pharmacology in humans.

A randomized, crossover, placebo-controlled clinical trial to assess the sensitivity of the CRCDS Mini-Sim to the next-day residual effects of zopiclone.

Objectives: We sought to validate Cognitive Research Corporation’s Driving Simulator (CRCDS Mini-Sim) for studies of drug safety with respect to driving ability. Methods: A total of 30 healthy subjects were randomized to receive placebo or 7.5 mg zopiclone, a hypnotic known to impair driving, in random order during the 2 treatment periods of a 2 period crossover design. Results: Evening administration of 7.5 mg zopiclone increased next-day standard deviation of lateral lane position (SDLP) by 2.62 cm on average compared with evening administration of placebo, and caused significant effects on symmetry analysis. The magnitude of the change in SDLP is highly similar to changes previously observed using on-the-road driving methods. Conclusions: Further validation of the CRCDS Mini-Sim is warranted to develop this platform for drug safety studies.

Influence of taranabant, a cannabinoid-1 receptor inverse agonist, on pharmacokinetics and pharmacodynamics of warfarin

IntroductionThe pharmacokinetic/pharmacodynamic effects of warfarin were assessed in the presence and absence of taranabant, an orally active, highly selective, potent, cannabinoid-1 receptor inverse agonist, which was being developed for the treatment of obesity.MethodsTwelve subjects were assigned to two open-label treatments in fixed sequence separated by a 14-day washout. Treatment A was single-dose warfarin 30 mg on day 1. Treatment B was multiple-dose taranabant 6 mg each day for 21 days (days −14 to day 7) with coadministration of singledose warfarin 30 mg on day 1. Blood samples were collected predose and up to 168 hours postdose for assay of R(+)-and S(−)-warfarin and prothrombin time/international normalized ratio (PT/INR).ResultsThe geometric mean ratios (GMR; warfarin+taranabant/warfarin 90% confidence interval [CI] primary endpoints) for area under the curve (AUC)0-∞ for R(+)-and S(−)-warfarin were 1.10 (90% CI: 1.03, 1.18) and 1.06 (90% CI: 1.00, 1.13), respectively. The GMRs (warfarin+taranabant/warfarin) for the maximum plasma concentration (Cmax) of S(−)-and R(+)-warfarin were 1.16 (90% CI: 1.05, 1.28) and 1.17 (90% CI: 1.07, 1.29), respectively. For R(+)-and S(−)-warfarin, the 90% CIs for AUC0-∞ GMRs fell within the prespecified bounds. Taranabant did not produce a clinically meaningful effect on PT/INR.ConclusionNo clinically significant alterations of the pharmacokinetics of R(+)-and S(−)-warfarin were seen following coadministration of multipledose taranabant 6 mg and single-dose warfarin 30 mg.

First-in-human brain imaging of Alzheimer dementia patients and elderly controls with 18F-MK-6240, a PET tracer targeting neurofibrillary tangle pathology

18F-MK-6240 (18F-labeled 6-(fluoro)-3-(1H-pyrrolo[2,3-c]pyridin-1-yl)isoquinolin-5-amine) is a highly selective, subnanomolar-affinity PET tracer for imaging neurofibrillary tangles (NFTs). Plasma kinetics, brain uptake, and preliminary quantitative analysis of 18F-MK-6240 in healthy elderly (HE) subjects, subjects with clinically probable Alzheimer disease (AD), and subjects with amnestic mild cognitive impairment were characterized in a study that is, to our knowledge, the first to be performed on humans. Methods: Dynamic PET scans of up to 150 min were performed on 4 cognitively normal HE subjects, 4 AD subjects, and 2 amnestic mild cognitive impairment subjects after a bolus injection of 152–169 MBq of 18F-MK-6240 to evaluate tracer kinetics and distribution in brain. Regional SUV ratio (SUVR) and distribution volume ratio 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. Results: 18F-MK-6240 had rapid brain uptake with a peak SUV of 3–5, followed by a uniformly quick washout from all brain regions in HE subjects; slower clearance was observed in regions commonly associated with NFT deposition in AD subjects. In AD subjects, SUVR between 60 and 90 min after injection was high (approximately 2–4) in regions associated with NFT deposition, whereas in HE subjects, SUVR was approximately 1 across all brain regions, suggesting high tracer selectivity for binding NFTs in vivo. 18F-MK-6240 total distribution volume was approximately 2- to 3-fold higher in neocortical and medial temporal brain regions of AD subjects than in HE subjects and stabilized by 60 min in both groups. Distribution volume ratio estimated by the Logan reference tissue model or compartmental modeling correlated well (R2 > 0.9) to SUVR from 60 to 90 min for AD subjects. Conclusion: 18F-MK-6240 exhibited favorable kinetics and high binding levels to brain regions with a plausible pattern for NFT deposition in AD subjects. In comparison, negligible tracer binding was observed in HE subjects. This pilot study suggests that simplified ratio methods such as SUVR can be used to quantify NFT binding. These results support further clinical development of 18F-MK-6240 for potential application in longitudinal studies.

Dose-dependent quantitative effects of acute fructose administration on hepatic de novo lipogenesis in healthy humans

Fructose feeding increases hepatic de novo lipogenesis (DNL) and is associated with nonalcoholic fatty liver disease. Little is known, however, about individual variation in susceptibility to fructose stimulation of DNL. In this three-period crossover study, 17 healthy male subjects were enrolled to evaluate the within- and between-subject variability of acute fructose feeding on hepatic fractional DNL. During each assessment, [1-13C1]acetate was infused to measure DNL in the fasting state and during fructose feeding. Subjects randomly received a high dose of fructose (10 mg·kg fat-free mass-1·min-1) on two occasions and a low dose (5 mg·kg fat-free mass-1·min-1) on another. Fructose solutions were administered orally every 30 min for 9.5 h. Ten subjects completed all three study periods. DNL was assessed as the fractional contribution of newly synthesized palmitate into very-low-density lipoprotein triglycerides using mass isotopomer distribution analysis. Mean fasting DNL was 5.3 ± 2.8%, with significant within- and between-subject variability. DNL increased dose dependently during fructose feeding to 15 ± 2% for low- and 29 ± 2% for high-dose fructose. The DNL response to high-dose fructose was very reproducible within an individual ( r = 0.93, P < 0.001) and independent of fasting DNL. However, it was variable between individuals and significantly correlated to influx of unlabeled acetyl-CoA ( r = 0.7, P < 0.001). Unlike fasting DNL, fructose-stimulated DNL is a robust and reproducible measure of hepatic lipogenic activity for a given individual and may be a useful indicator of metabolic disease susceptibility and treatment response.