- Email: [email protected]
Safety, tolerability, and pharmacokinetics of a potent and selective 5-ht6 receptor antagonist, SUVN-502, following multiple ascending doses in healthy elderly subjects, and effect of gender and food on single-dose pharmacokinetics
P748
Poster Presentations: P3
Background: Cholinesterase inhibitors (ChEIs), Donepezil, Gal-
antamine, and Rivastigmine are first-line drugs for the treatment of Alzheimer’s disease (AD) patients. Donepezil and Galantamine inhibit acetylcholinesterase. Rivastigmine can block both acetylcholinesterase and butyrylcholinesterase. ChEIs improve the cognitive function of AD patients. However, ChEIs sometimes cause adverse effects including diarrhea, nausea, vomiting, and bradycardia. We hypothesized that low creatinine clearance (Clcr) should be the risk factor of adverse effects by ChEIs. Usually, ChEIs reduce serum cholinesterase (ChE) levels. Therefore, we examined an association between the reduction of serum ChE levels and Clcr among the AD patients who underwent ChEIs therapy. Methods: Three hundred fifty one AD patients (168 men, 183 women, mean age: 75.8 6 9.6) were enrolled in this study. Body weight (BW), serum creatinine (cr), and serum ChE were examined. Clcr was estimated by the Cockcroft-Gault (CG) equation. The degree of reduction of ChE after ChEIs therapy, Donepezil, Galantamine, or Rivastigmine was also compared. Statistical analysis was performed by using PASW Statistics 18 (SPSS Inc., Chicago, IL, USA), with p < 0.05 considered significant. Results: Average reduction ratio of ChE by ChEIs, Donepezil, Galantamine, and Rivastigmine were 0.865, 0.9435, and 0.6845, respectively (ANOVA, P<0.001). Unexpectedly, there was no correlation between the reduction ratio of ChE and Clcr. Conclusions: There was no correlation between reduction ratio of ChE and Clcr after ChEs therapy. However, Rivastigmine lowered serum ChE most among the three ChEIs. This result implies that serum butyrylcholinesterase was inhibited by Rivastigmine.
M1 of SUVN-502 were quantified in plasma using a validated LC-MS/MS method. Results: SUVN-502 was well tolerated up to the highest tested dose of 100 mg/day following single or repeated oral administration in healthy elderly male, and adult male and female subjects. There was no significant effect of gender and food on the pharmacokinetics of SUVN-502 and M1 of SUVN-502 after single oral administration of 100 mg SUVN-502. Following multiple administration of 50 or 100 mg of SUVN-502, steady state was reached within 2-4 days for SUVN-502 and 4-6 days for metabolite M1 of SUVN502. The exposure of SUVN-502 was comparable between Day 14 and Day 1, while exposure of metabolite M1 of SUVN-502 were approximately 1.6 to 2.5 fold higher on Day 14 compared to Day 1. Upon repeated administration for 14 days, SUVN-502 and the metabolite M1 of SUVN-502 had mean half-life of w13 and w 37 hours respectively. Conclusions: SUVN-502 has shown a favorable safety and pharmacokinetic profile after single and repeated dose administration. Gender and food did not have any clinically meaningful effect on pharmacokinetic parameters of SUVN-502. SUVN502 and M1 of SUVN-502 achieved the projected efficacy concentrations and attained steady state from seven days upon multiple administrations in elderly subjects. SUVN-502 is well tolerated in humans with adequate plasma exposure for efficacy and favorable pharmacokinetics suitable for once a day oral administration.
P3-297
P3-296
SAFETY, TOLERABILITY, AND PHARMACOKINETICS OF A POTENT AND SELECTIVE 5-HT6 RECEPTOR ANTAGONIST, SUVN-502, FOLLOWING MULTIPLE ASCENDING DOSES IN HEALTHY ELDERLY SUBJECTS, AND EFFECT OF GENDER AND FOOD ON SINGLEDOSE PHARMACOKINETICS
Ramakrishna Nirogi, Koteshwara Mudigonda, Kiran Kumar Penta, Gopinadh Bhyrapuneni, Devender Reddy Ajjala, Nageswararao Muddana, Veera Raghava Chowdary Palacharla, Vinod Kumar Goyal, Santosh Kumar Pandey, Renny Abraham, Pradeep Jayarajan, Rajesh Kumar Badange, Ramasastry Kambhampati, Suven Life Sciences Ltd, Hyderabad, India. Contact e-mail: [email protected] Background: Serotonin receptor subtype 6 antagonists improve
the cognitive performances in animal models and patients suffering from Alzheimer’s disease (AD). SUVN-502 and its circulatory metabolite M1 of SUVN-502 are potent and selective 5-HT6 antagonists exhibiting cognitive enhancement in rodent models. SUVN-502 is being developed for the treatment of cognitive deficits associated with AD. Methods: SUVN-502 was studied in a single-center, multi-faceted, phase 1 clinical trial (US IND) to evaluate its safety, tolerability, and pharmacokinetics after multiple ascending doses in healthy elderly male subjects. Subjects were dosed with 50 or 100 mg orally for 14 days. The effect of gender and food on SUVN-502 pharmacokinetics following 100 mg single oral dose was also evaluated in healthy subjects. SUVN-502 and its active metabolite
STABILITY IN COGNITIVE AND NEUROBEHAVIORAL ASSESSMENTS BETWEEN SCREEN AND BASELINE IN AN ALZHEIMER’S DISEASE TRIAL
Jo Cara Pendergrass1, Steven D. Targum1,2, Kristen Drake2, Lisa Fosdick2, Constantine Lyketsos3, Cynthia Munro3, Gwenn S. Smith3 and Andres M. Lozano2,4, 1Clintara, LLC, Boston, MA, USA; 2Functional Neuromodulation, Ltd, Charlottesville, VA, USA; 3Johns Hopkins University School of Medicine, Baltimore, MD, USA; 4University of Toronto/Toronto Western Research Institute, Toronto, ON, Canada. Contact e-mail: [email protected] Background: Confidence in study findings is dependent on the
reliability of key study measures at baseline. In Alzheimer’s disease (AD) studies, primary measures often include the ADAS-Cog (Alzheimer’s Disease Assessment Scale-Cognitive) and CDR (Clinical Dementia Rating scale). We examined the stability of the ADAS-Cog and CDR prior to randomization in an AD clinical trial. Methods: Analyses were conducted as part of the phase II ADvance study (ClinicalTrials.gov identifier NCT01608061). ADvance is a 12-month double-blind, randomized feasibility study of deep brain stimulation targeting the fornix (DBS-f) in subjects with mild probable AD. As part of entry criteria, eligible participants must have an ADAS-cog11 score of 12-24 (inclusive at screen and baseline) and CDR global score of 0.5-1.0 at screen. Analyses included intra-class correlations and assessment of total and individual item scores for the ADAS-Cog and CDR at screen and baseline prior to neurosurgical DBS-f implant. Results: Data were available from 42 AD patients who had complete assessments at screen and baseline. The mean ADAS-Cog-11 score was 17.45 6 3.55 (SD) and 16.88 6 2.85 at screen and baseline,
Poster Presentations: P3
Background: Cholinesterase inhibitors (ChEIs), Donepezil, Gal-
antamine, and Rivastigmine are first-line drugs for the treatment of Alzheimer’s disease (AD) patients. Donepezil and Galantamine inhibit acetylcholinesterase. Rivastigmine can block both acetylcholinesterase and butyrylcholinesterase. ChEIs improve the cognitive function of AD patients. However, ChEIs sometimes cause adverse effects including diarrhea, nausea, vomiting, and bradycardia. We hypothesized that low creatinine clearance (Clcr) should be the risk factor of adverse effects by ChEIs. Usually, ChEIs reduce serum cholinesterase (ChE) levels. Therefore, we examined an association between the reduction of serum ChE levels and Clcr among the AD patients who underwent ChEIs therapy. Methods: Three hundred fifty one AD patients (168 men, 183 women, mean age: 75.8 6 9.6) were enrolled in this study. Body weight (BW), serum creatinine (cr), and serum ChE were examined. Clcr was estimated by the Cockcroft-Gault (CG) equation. The degree of reduction of ChE after ChEIs therapy, Donepezil, Galantamine, or Rivastigmine was also compared. Statistical analysis was performed by using PASW Statistics 18 (SPSS Inc., Chicago, IL, USA), with p < 0.05 considered significant. Results: Average reduction ratio of ChE by ChEIs, Donepezil, Galantamine, and Rivastigmine were 0.865, 0.9435, and 0.6845, respectively (ANOVA, P<0.001). Unexpectedly, there was no correlation between the reduction ratio of ChE and Clcr. Conclusions: There was no correlation between reduction ratio of ChE and Clcr after ChEs therapy. However, Rivastigmine lowered serum ChE most among the three ChEIs. This result implies that serum butyrylcholinesterase was inhibited by Rivastigmine.
M1 of SUVN-502 were quantified in plasma using a validated LC-MS/MS method. Results: SUVN-502 was well tolerated up to the highest tested dose of 100 mg/day following single or repeated oral administration in healthy elderly male, and adult male and female subjects. There was no significant effect of gender and food on the pharmacokinetics of SUVN-502 and M1 of SUVN-502 after single oral administration of 100 mg SUVN-502. Following multiple administration of 50 or 100 mg of SUVN-502, steady state was reached within 2-4 days for SUVN-502 and 4-6 days for metabolite M1 of SUVN502. The exposure of SUVN-502 was comparable between Day 14 and Day 1, while exposure of metabolite M1 of SUVN-502 were approximately 1.6 to 2.5 fold higher on Day 14 compared to Day 1. Upon repeated administration for 14 days, SUVN-502 and the metabolite M1 of SUVN-502 had mean half-life of w13 and w 37 hours respectively. Conclusions: SUVN-502 has shown a favorable safety and pharmacokinetic profile after single and repeated dose administration. Gender and food did not have any clinically meaningful effect on pharmacokinetic parameters of SUVN-502. SUVN502 and M1 of SUVN-502 achieved the projected efficacy concentrations and attained steady state from seven days upon multiple administrations in elderly subjects. SUVN-502 is well tolerated in humans with adequate plasma exposure for efficacy and favorable pharmacokinetics suitable for once a day oral administration.
P3-297
P3-296
SAFETY, TOLERABILITY, AND PHARMACOKINETICS OF A POTENT AND SELECTIVE 5-HT6 RECEPTOR ANTAGONIST, SUVN-502, FOLLOWING MULTIPLE ASCENDING DOSES IN HEALTHY ELDERLY SUBJECTS, AND EFFECT OF GENDER AND FOOD ON SINGLEDOSE PHARMACOKINETICS
Ramakrishna Nirogi, Koteshwara Mudigonda, Kiran Kumar Penta, Gopinadh Bhyrapuneni, Devender Reddy Ajjala, Nageswararao Muddana, Veera Raghava Chowdary Palacharla, Vinod Kumar Goyal, Santosh Kumar Pandey, Renny Abraham, Pradeep Jayarajan, Rajesh Kumar Badange, Ramasastry Kambhampati, Suven Life Sciences Ltd, Hyderabad, India. Contact e-mail: [email protected] Background: Serotonin receptor subtype 6 antagonists improve
the cognitive performances in animal models and patients suffering from Alzheimer’s disease (AD). SUVN-502 and its circulatory metabolite M1 of SUVN-502 are potent and selective 5-HT6 antagonists exhibiting cognitive enhancement in rodent models. SUVN-502 is being developed for the treatment of cognitive deficits associated with AD. Methods: SUVN-502 was studied in a single-center, multi-faceted, phase 1 clinical trial (US IND) to evaluate its safety, tolerability, and pharmacokinetics after multiple ascending doses in healthy elderly male subjects. Subjects were dosed with 50 or 100 mg orally for 14 days. The effect of gender and food on SUVN-502 pharmacokinetics following 100 mg single oral dose was also evaluated in healthy subjects. SUVN-502 and its active metabolite
STABILITY IN COGNITIVE AND NEUROBEHAVIORAL ASSESSMENTS BETWEEN SCREEN AND BASELINE IN AN ALZHEIMER’S DISEASE TRIAL
Jo Cara Pendergrass1, Steven D. Targum1,2, Kristen Drake2, Lisa Fosdick2, Constantine Lyketsos3, Cynthia Munro3, Gwenn S. Smith3 and Andres M. Lozano2,4, 1Clintara, LLC, Boston, MA, USA; 2Functional Neuromodulation, Ltd, Charlottesville, VA, USA; 3Johns Hopkins University School of Medicine, Baltimore, MD, USA; 4University of Toronto/Toronto Western Research Institute, Toronto, ON, Canada. Contact e-mail: [email protected] Background: Confidence in study findings is dependent on the
reliability of key study measures at baseline. In Alzheimer’s disease (AD) studies, primary measures often include the ADAS-Cog (Alzheimer’s Disease Assessment Scale-Cognitive) and CDR (Clinical Dementia Rating scale). We examined the stability of the ADAS-Cog and CDR prior to randomization in an AD clinical trial. Methods: Analyses were conducted as part of the phase II ADvance study (ClinicalTrials.gov identifier NCT01608061). ADvance is a 12-month double-blind, randomized feasibility study of deep brain stimulation targeting the fornix (DBS-f) in subjects with mild probable AD. As part of entry criteria, eligible participants must have an ADAS-cog11 score of 12-24 (inclusive at screen and baseline) and CDR global score of 0.5-1.0 at screen. Analyses included intra-class correlations and assessment of total and individual item scores for the ADAS-Cog and CDR at screen and baseline prior to neurosurgical DBS-f implant. Results: Data were available from 42 AD patients who had complete assessments at screen and baseline. The mean ADAS-Cog-11 score was 17.45 6 3.55 (SD) and 16.88 6 2.85 at screen and baseline,