- Email: [email protected]
EFFECT OF FOOD ON THE PHARMACOKINETICS OF RVT-101 IN HEALTHY ADULT SUBJECTS
Poster Presentations: Tuesday, July 26, 2016
biogenesis include erythropoietin and pioglitazone. Erythropoietin activates eNOS, causing production of nitric oxide (NO), which then triggers transcription of genes involved in mitochondrial biogenesis (3). Thiazolidinediones, e.g., pioglitazone, induce mitochondrial biogenesis by increasing expression of PPAR-1a-coactivator, the principle regulator of mitochondrial biogenesis. (4). Treatment using concurrent combinations having different targets is more effective than sequentially using single agents. A clinical trial would test the hypothesis that a combination of lithium, erythropoietin, and pioglitazone, might impede the progression of MCI to AD, or of early to more advanced AD. Conclusions: Dysfunctional mitochondria underlie AD and may be disposed, by combining lithium, erythropoietin, and pioglitazone to enhance mitophagy, which then stimulates production of new organelles by enhancing mitochondrial biogenesis. 1. Nixon, J Cell Sci 2007;120:4081-4091. 2. Sarkar, J Cell Biol 2011;101:514-519. 3. Burger, Cardiovasc Res 2006;72:51-59. 4. Gosh, Mol Pharmacol 2007;71:1695-1702.
P3-014
EFFECT OF FOOD ON THE PHARMACOKINETICS OF RVT-101 IN HEALTHY ADULT SUBJECTS
Stephen C. Piscitelli1, Lori Jones1, Brendan Johnson1, Ilise Lombardo2, Lawrence Friedhoff2, 1Roivant Sciences, Inc., New York, NY, USA; 2Axovant Sciences, Inc., New York, NY, USA. Contact e-mail: [email protected] Background: RVT-101 is an oral, potent antagonist of the 5-hy-
droxytryptamine 6 (5-HT6) serotonin receptor currently being evaluated in a pivotal phase 3 study for the treatment of Alzheimer’s disease. RVT-101 promotes the release of acetylcholine, glutamate, and other neurotransmitters providing a complementary mechanism of action with cholinesterase inhibitors. The effect of a high fat meal on the pharmacokinetics of the phase 3 tablet formulation was evaluated. Methods: This was an open-label, randomized, single dose, two-period, balanced crossover study to assess the effect of food on the pharmacokinetics of RVT-101 in healthy adult subjects. Subjects were randomized to receive a 35 mg oral dose in two separate dosing periods. In one period, the dose was administered after an overnight fast. In the other period, the dose was administered within 30 minutes after the start of a meal with fat comprising approximately 53% of total caloric content (approximately 870 calories). A wash out period of at least 10 days was required between each dose. Safety assessments were performed throughout each period and serial PK samples were collected for 168 hours following each dose of study drug. Results: Twelve subjects (10 males, 2 females) with ages ranging from 20 to 50 years were enrolled and completed the study. RVT-101 was well tolerated. There were no Grade 2-4 adverse events and no withdrawals due to adverse events. The presence of food did not affect the pharmacokinetics of RVT-101. The AUC(0-N) was 3645 ng*h/ml fasted and 3769 ng*h/ml with food (ratio 0.97, 90% confidence interval 0.76-1.24). Cmax was 105 ng/ml and 104 ng/ml fasted and fed, respectively (ratio 1.01, 90% confidence interval 0.77-1.33). Conclusions: RVT-101 can be given without regard to meals and easily added to existing medication schedules providing a convenient once daily dosing regimen for patients and caregivers.
P3-015
RESEARCH PARTICIPATION AND PERCEPTIONS AMONG COMMUNITY MEMBERS WHO REPORT A HISTORY OF DEMENTIA
Sadaf Milani, Linda B. Cottler, Catherine Striley, University of Florida, Gainesville, FL, USA. Contact e-mail: [email protected]
P823
Background: The prevalence of dementia in individuals aged 60 or older around the world ranges from 5-7%. As the population ages, the prevalence of dementia will increase. More research is needed, however, low research participation rates, especially among minorities, hinder progress. Methods: Data were acquired from HealthStreet, a community engagement program at University of Florida which relies on Community Health Workers to assess health conditions and concerns of community residents in North East and North Central Florida. Participants who completed an intake from November 2011 to January 2016 were included in this cross sectional analysis (n¼7,034). Likelihood to participate in different types of health research studies, trust in research and trust in researchers was assessed. Since participants reporting dementia were judged as competent to consent, their dementia was likely mild. Results: Of the 7,034 respondents, 1.4% reported a lifetime history of dementia. Community members reporting dementia were more likely to report previous participation in a health research study (22.8%) compared to all other HealthStreet participants (17.6%). Among those reporting dementia, 73.3% said that they were definitely interested in participating in a research study compared to only 51.0% of total HealthStreet participants; they were also more willing to participate in a study without compensation (89.1%) compared to all HealthStreet participants (77.7%). Over half of those reporting dementia were female (53.5%) and their mean age was 53.0. Approximately half of these individuals were African American (49.5%), followed by Caucasian (45.5%) and other (5.0%). Conclusions: Community members reporting dementia were consistently more likely to have participated in and to desire future participation in health research compared to all other HealthStreet participants. This high interest in health research among those with dementia should lead to requests to participate. Community dwelling populations are very likely willing to participate, but they need to be invited to do so; Coordinators and PIs should do so. HealthStreet provides a model program that recruits older populations into health research. While this analysis shows that interest in research participation among this population is high, barriers to their research participation need to be identified.
P3-016
SUVN-D4010, A POTENT AND SELECTIVE 5-HT4 RECEPTOR PARTIAL AGONIST: SAFETY, TOLERABILITY AND PHARMACOKINETICS IN HUMANS
Pradeep Jayarajan, Gopinadh Bhyrapuneni, Koteshwara Mudigonda, Kiran Kumar Penta, NageswaraRao Muddana, Veera Raghava Chowdary Palacharla, Vijay Benade, Renny Abraham, Ramkumar Subramanian, Vinod Kumar Goyal, Santosh Kumar Pandey, Rajesh Kumar Boggavarapu, Devender Reddy Ajjala, Mohammed Abdul Rasheed, Ramakrishna Nirogi, Suven Life Sciences Ltd, Hyderabad, India. Contact e-mail: pradeep@ suven.com Background: SUVN-D4010 is a potent, selective and orally
bioavailable 5-HT4receptor partial agonist. Efficacy of SUVND4010 has been proved in preclinical models of cognition where it improved the episodic, working and emotional memory in rats as well as increased brain acetylcholine levels. A significant increase in cortical sAPPa and decrease in amyloid-b protein levels was also seen. SUVN-D4010 is being developed for the treatment of cognitive deficits associated with Alzheimer’s disease (AD). Methods: SUVN-D4010 was studied in a single-center, multifaceted, phase 1 clinical trial (US IND) to evaluate its safety, tolerability, and pharmacokinetics after single and multiple ascending doses in healthy adult male subjects. For evaluation after single
biogenesis include erythropoietin and pioglitazone. Erythropoietin activates eNOS, causing production of nitric oxide (NO), which then triggers transcription of genes involved in mitochondrial biogenesis (3). Thiazolidinediones, e.g., pioglitazone, induce mitochondrial biogenesis by increasing expression of PPAR-1a-coactivator, the principle regulator of mitochondrial biogenesis. (4). Treatment using concurrent combinations having different targets is more effective than sequentially using single agents. A clinical trial would test the hypothesis that a combination of lithium, erythropoietin, and pioglitazone, might impede the progression of MCI to AD, or of early to more advanced AD. Conclusions: Dysfunctional mitochondria underlie AD and may be disposed, by combining lithium, erythropoietin, and pioglitazone to enhance mitophagy, which then stimulates production of new organelles by enhancing mitochondrial biogenesis. 1. Nixon, J Cell Sci 2007;120:4081-4091. 2. Sarkar, J Cell Biol 2011;101:514-519. 3. Burger, Cardiovasc Res 2006;72:51-59. 4. Gosh, Mol Pharmacol 2007;71:1695-1702.
P3-014
EFFECT OF FOOD ON THE PHARMACOKINETICS OF RVT-101 IN HEALTHY ADULT SUBJECTS
Stephen C. Piscitelli1, Lori Jones1, Brendan Johnson1, Ilise Lombardo2, Lawrence Friedhoff2, 1Roivant Sciences, Inc., New York, NY, USA; 2Axovant Sciences, Inc., New York, NY, USA. Contact e-mail: [email protected] Background: RVT-101 is an oral, potent antagonist of the 5-hy-
droxytryptamine 6 (5-HT6) serotonin receptor currently being evaluated in a pivotal phase 3 study for the treatment of Alzheimer’s disease. RVT-101 promotes the release of acetylcholine, glutamate, and other neurotransmitters providing a complementary mechanism of action with cholinesterase inhibitors. The effect of a high fat meal on the pharmacokinetics of the phase 3 tablet formulation was evaluated. Methods: This was an open-label, randomized, single dose, two-period, balanced crossover study to assess the effect of food on the pharmacokinetics of RVT-101 in healthy adult subjects. Subjects were randomized to receive a 35 mg oral dose in two separate dosing periods. In one period, the dose was administered after an overnight fast. In the other period, the dose was administered within 30 minutes after the start of a meal with fat comprising approximately 53% of total caloric content (approximately 870 calories). A wash out period of at least 10 days was required between each dose. Safety assessments were performed throughout each period and serial PK samples were collected for 168 hours following each dose of study drug. Results: Twelve subjects (10 males, 2 females) with ages ranging from 20 to 50 years were enrolled and completed the study. RVT-101 was well tolerated. There were no Grade 2-4 adverse events and no withdrawals due to adverse events. The presence of food did not affect the pharmacokinetics of RVT-101. The AUC(0-N) was 3645 ng*h/ml fasted and 3769 ng*h/ml with food (ratio 0.97, 90% confidence interval 0.76-1.24). Cmax was 105 ng/ml and 104 ng/ml fasted and fed, respectively (ratio 1.01, 90% confidence interval 0.77-1.33). Conclusions: RVT-101 can be given without regard to meals and easily added to existing medication schedules providing a convenient once daily dosing regimen for patients and caregivers.
P3-015
RESEARCH PARTICIPATION AND PERCEPTIONS AMONG COMMUNITY MEMBERS WHO REPORT A HISTORY OF DEMENTIA
Sadaf Milani, Linda B. Cottler, Catherine Striley, University of Florida, Gainesville, FL, USA. Contact e-mail: [email protected]
P823
Background: The prevalence of dementia in individuals aged 60 or older around the world ranges from 5-7%. As the population ages, the prevalence of dementia will increase. More research is needed, however, low research participation rates, especially among minorities, hinder progress. Methods: Data were acquired from HealthStreet, a community engagement program at University of Florida which relies on Community Health Workers to assess health conditions and concerns of community residents in North East and North Central Florida. Participants who completed an intake from November 2011 to January 2016 were included in this cross sectional analysis (n¼7,034). Likelihood to participate in different types of health research studies, trust in research and trust in researchers was assessed. Since participants reporting dementia were judged as competent to consent, their dementia was likely mild. Results: Of the 7,034 respondents, 1.4% reported a lifetime history of dementia. Community members reporting dementia were more likely to report previous participation in a health research study (22.8%) compared to all other HealthStreet participants (17.6%). Among those reporting dementia, 73.3% said that they were definitely interested in participating in a research study compared to only 51.0% of total HealthStreet participants; they were also more willing to participate in a study without compensation (89.1%) compared to all HealthStreet participants (77.7%). Over half of those reporting dementia were female (53.5%) and their mean age was 53.0. Approximately half of these individuals were African American (49.5%), followed by Caucasian (45.5%) and other (5.0%). Conclusions: Community members reporting dementia were consistently more likely to have participated in and to desire future participation in health research compared to all other HealthStreet participants. This high interest in health research among those with dementia should lead to requests to participate. Community dwelling populations are very likely willing to participate, but they need to be invited to do so; Coordinators and PIs should do so. HealthStreet provides a model program that recruits older populations into health research. While this analysis shows that interest in research participation among this population is high, barriers to their research participation need to be identified.
P3-016
SUVN-D4010, A POTENT AND SELECTIVE 5-HT4 RECEPTOR PARTIAL AGONIST: SAFETY, TOLERABILITY AND PHARMACOKINETICS IN HUMANS
Pradeep Jayarajan, Gopinadh Bhyrapuneni, Koteshwara Mudigonda, Kiran Kumar Penta, NageswaraRao Muddana, Veera Raghava Chowdary Palacharla, Vijay Benade, Renny Abraham, Ramkumar Subramanian, Vinod Kumar Goyal, Santosh Kumar Pandey, Rajesh Kumar Boggavarapu, Devender Reddy Ajjala, Mohammed Abdul Rasheed, Ramakrishna Nirogi, Suven Life Sciences Ltd, Hyderabad, India. Contact e-mail: pradeep@ suven.com Background: SUVN-D4010 is a potent, selective and orally
bioavailable 5-HT4receptor partial agonist. Efficacy of SUVND4010 has been proved in preclinical models of cognition where it improved the episodic, working and emotional memory in rats as well as increased brain acetylcholine levels. A significant increase in cortical sAPPa and decrease in amyloid-b protein levels was also seen. SUVN-D4010 is being developed for the treatment of cognitive deficits associated with Alzheimer’s disease (AD). Methods: SUVN-D4010 was studied in a single-center, multifaceted, phase 1 clinical trial (US IND) to evaluate its safety, tolerability, and pharmacokinetics after single and multiple ascending doses in healthy adult male subjects. For evaluation after single