The Pharmacology of TD-8954, a Potent and Selective 5-HT(4) Receptor Agonist with Gastrointestinal Prokinetic Properties.

This study evaluated the in vitro and in vivo pharmacological properties of TD-8954, a potent and selective 5-HT(4) receptor agonist. TD-8954 had high affinity (pK(i) = 9.4) for human recombinant 5-HT(4(c)) (h5-HT(4(c))) receptors, and selectivity (>2,000-fold) over all other 5-hydroxytryptamine (5-HT) receptors and non-5-HT receptors, ion channels, enzymes and transporters tested (n = 78). TD-8954 produced an elevation of cAMP in HEK-293 cells expressing the h5-HT(4(c)) receptor (pEC(50) = 9.3), and contracted the guinea pig colonic longitudinal muscle/myenteric plexus preparation (pEC(50) = 8.6). TD-8954 had moderate intrinsic activity in the in vitro assays. In conscious guinea pigs, subcutaneous administration of TD-8954 (0.03-3 mg/kg) increased the colonic transit of carmine red dye, reducing the time taken for its excretion. Following intraduodenal dosing to anesthetized rats, TD-8954 (0.03-10 mg/kg) evoked a dose-dependent relaxation of the esophagus. Following oral administration to conscious dogs, TD-8954 (10 and 30 µg/kg) produced an increase in contractility of the antrum, duodenum, and jejunum. In a single ascending oral dose study in healthy human subjects, TD-8954 (0.1-20 mg) increased bowel movement frequency and reduced the time to first stool. It is concluded that TD-8954 is a potent and selective 5-HT(4) receptor agonist in vitro, with robust in vivo stimulatory activity in the gastrointestinal (GI) tract of guinea pigs, rats, dogs, and humans. TD-8954 may have clinical utility in patients with disorders of reduced GI motility.

Population pharmacokinetic/pharmacodynamic model of subcutaneous adipose 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) activity after oral administration of AMG 221, a selective 11ß-HSD1 inhibitor.

Inhibition of 11ß-HSD1 is hypothesized to improve measures of insulin sensitivity and hepatic glucose output in patients with type II diabetes. AMG 221 is a potent, small molecule inhibitor of 11ß-HSD1. The objective of this analysis is to describe the pharmacokinetic/pharmacodynamic (PK/PD) relationship between AMG 221 and 11ß-HSD1 inhibition in ex vivo adipose tissue samples. Healthy, obese subjects were administered a single dose of 3, 30, or 100 mg of oral AMG 221 (n = 44) or placebo (n = 11). Serial blood samples were collected over 24 hours. Subcutaneous adipose tissue samples were collected by open biopsy. Population PK/PD analysis was conducted using NONMEM. The inhibitory effects (mean ± standard error of the estimate) of AMG 221 on 11ß-HSD1 activity were directly related to adipose concentrations with I(max) (the maximal inhibition of 11ß-HSD1 activity) and IC50 (the plasma AMG 221 concentration associated with 50% inhibition of enzyme activity) of 0.975 ± 0.003 and 1.19 ± 0.12 ng/mL, respectively. The estimated baseline 11ß-HSD1 enzyme activity was 755 ± 61 pmol/mg. An equilibration rate constant (k(eo)) of 0.220 ± 0.021 h⁻¹ described the delay between plasma and adipose tissue AMG 221 concentrations. AMG 221 potently blocked 11ß-HSD1 activity, producing sustained inhibition for the 24-hour study duration as measured in ex vivo adipose samples. Early characterization of concentration-response relationships can support rational selection of dose and regimen for future studies.

Practice effects and the use of alternate forms in serial neuropsychological testing.

Accurate understanding of practice characteristics, performance stability, and error on neuropsychological tests is essential to both valid clinical assessment and maximization of signal detection for clinical trials of cognitive enhancing drugs. We examined practice effects in 28 healthy adults. As part of a larger study using donepezil and simulating a Phase I trial, participants were randomized into: placebo, no-treatment and donepezil. Donepezil results are presented elsewhere. Neuropsychological tests were administered in a fixed order for 6 weeks, with alternate forms available for most tests. Despite alternate forms, ANOVAs revealed significant improvements for the pooled control group (placebo and no-treatment) on all tests except Letter Number Sequencing and Trails B. Learning occurred principally in the first three to four sessions. PASAT and Stroop interference showed the greatest learning. Thus, serial assessment with alternate forms may attenuate retest effects on some tests, but continued learning occurs on novel tests or those in which an advantageous test-taking strategy can be identified. Alternate forms and baseline practice sessions may help control early, rapid improvements in clinical trials.

Neuropsychological test performance in healthy elderly volunteers before and after donepezil administration: a randomized, controlled study.

Neuropsychological performance was examined in healthy elderly participants administered the cholinesterase inhibitor donepezil. Of principal interest was examination of the sensitivity of a series of neuropsychological measures to detect cognitive changes after drug administration using typical phase I research parameters (eg, a small sample over a short treatment period). In this double-blind parallel study over a period of 6 weeks, 26 healthy elderly participants (aged 55 to 75 years) were randomized into 1 of 2 arms (14 donepezil and 12 placebo) and completed 14 days of donepezil (5 mg, twice a day) or placebo (twice a day). A battery of neuropsychological tests was administered on days 0, 14 (prerandomization), 28 (end of treatment), and 42 (washout). After 2 weeks of donepezil treatment (day 28), subjects in the donepezil group performed slightly but significantly worse on 2 tests of speed, attention, and short-term memory (P < 0.05) compared with the placebo group. No significant improvement in performance was present on any test during treatment with donepezil. These results are consistent with a previous study in healthy young participants in which transient mild worsening on some cognitive tests during donepezil administration was observed, possibly caused by perturbation of an already optimized cholinergic system in healthy participants. These results are important to consider when designing clinical development plans for putative cognitive-enhancing drugs; in addition, these results raise questions about when the optimal point to begin treatment is for patients who have not yet met criteria for dementia.

Neuropsychological test performance in healthy volunteers before and after donepezil administration.

Participants in early Phase I clinical trials for drugs designed to enhance cognition are typically healthy volunteers. If improvement can be detected with a battery of cognitive tests in healthy volunteers, such a battery could be a pharmacodynamic marker in the future development of the compound for treatment of cognitive disorders. In the present exploratory study, a battery of neuropsychological (NP) tests was used to determine if changes in cognition from a pharmacological intervention could be detected in healthy volunteers. A drug with known cognitive-enhancing effects in Alzheimer's disease, donepezil, was compared with placebo and no treatment arms. Carry-over effects of repeated test administration were also assessed. In this double-blind study, 27 healthy adults were randomized into one of three arms (eight donepezil, nine placebo and 10 no treatment) and completed 14 days of donepezil (5 mg q.h.s.) or placebo (q.h.s.). A battery of NP tests was administered on days 0, 7, 14 (randomization), 21, 28 (end of treatment) and 42 (washout). There were no differences in performance between the placebo and the no treatment arms. However, on day 21, subjects in the donepezil group performed slightly but significantly worse on some tests of speed, attention and memory (p < 0.05) compared to the pooled control group (placebo and no treatment arms). No improvement in performance was present while on donepezil at days 21 or 28. While the results are counter to expectations, some tests in the battery did detect a cognitive change (transient mild worsening during drug administration) in healthy volunteers.