scholarly journals Pharmacokinetics and Safety of an Improved Oral Formulation of Paltusotine, a Selective, Non-Peptide Somatostatin Receptor 2 (SST2) Agonist for the Treatment of Acromegaly

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A524-A524
Author(s):  
Rosa Luo ◽  
Gerald Burke ◽  
Cosina Mui ◽  
Sepehr Shakib ◽  
Christine Ferrara-Cook ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Somatostatin Receptor ◽  
Systemic Exposure ◽  
Dose Proportionality ◽  
Tablet Formulation ◽  
High Fat ◽  
Capsule Formulation ◽  
Post Dose ◽  
High Calorie ◽  
Dose Proportional

Abstract Depot injection formulations of peptide somatostatin receptor ligands (SRLs) are routinely used to treat acromegaly and neuroendocrine tumors (NETs). Paltusotine (CRN00808), an orally administered small molecule nonpeptide selective somatostatin receptor 2 (SST2) agonist has been shown to maintain GH and IGF-1 levels in acromegaly patients previously on depot SRLs (ACROBAT Edge NCT03789656). In this study, a capsule formulation was used, which did not exhibit dose proportional pharmacokinetics (PK) at doses >40 mg, required a 2-hour post-dose fast in overnight fasted patients, and had the potential for reduced bioavailability when taken with proton-pump inhibitors (PPI). A spray-dried dispersion (SDD) tablet formulation was developed with improved solubility in the physiological pH range and its performance was evaluated in healthy volunteers. Male and female healthy volunteers who met inclusion/exclusion criteria were enrolled in a single-center Phase 1 study (ANZCTR registration ACTRN12619001562167). A Cohort of 12 subjects was administered a single dose of paltusotine in a four-period cross-over design. Periods 1 and 2 assessed the effect of lansoprazole (a PPI) on PK of 20 mg dose of paltusotine SDD tablets. In Period 3, 20 mg dose of paltusotine SDD tablets was co-administered with a high fat, high-calorie meal. In Period 4, a 60 mg dose of paltusotine SDD tablets was administered to assess dose proportionality. In a separate cohort of subjects (n=12; also, a 4-period cross-over design), the relative bioavailability of capsules and SDD tablets was assessed, and the effect of food administration 0.5, 1, and 2 hour post-dose was evaluated. Subsequently, in another cohort of 12 subjects (a 3-period cross-over design), dose proportionality of the SDD tablets was evaluated at 40 mg and 80 mg dose with a 1-hour post-dose fast. A 4 hours post-dose fast was also assessed for the 80 mg dose. Pharmacokinetics and safety of paltusotine were evaluated. Paltusotine was generally well tolerated in this study. SDD tablets exhibited dose proportional increase in total systemic exposure (AUC) up to a dose of 80 mg. Healthy volunteers pretreated with the PPI, lansoprazole (15 mg bid for 3 days), and co-administered with paltusotine SDD tablets exhibited a small decrease (approximately 25%) in systemic exposure to paltusotine compared with the same subjects that had washed out from the PPI-pretreatment. SDD tablets exhibited significant reduction in systemic exposure when co-administered with a high-fat, high-calorie meal. However, the SDD formulation was less sensitive to timing of post-dose food administration compared to the capsule formulation. These data suggest that the SDD tablet formulation of paltusotine improves flexibility in dose administration, can be co-administered with PPIs and other agents that increase stomach pH, and reduces the post-dose fasting requirement.

scholarly journals High-Fat Breakfast Increases Bioavailability of Albendazole Compared to Low-Fat Breakfast: Single-Dose Study in Healthy Subjects

2021 ◽  
Vol 12 ◽  
Author(s):  
Dolores Ochoa ◽  
Miriam Saiz-Rodríguez ◽  
Esperanza González-Rojano ◽  
Manuel Román ◽  
Sergio Sánchez-Rojas ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Systemic Exposure ◽  
High Fat ◽  
Low Fat ◽  
Time Curve ◽  
Single Dose Study ◽  
Albendazole Sulfoxide ◽  
Dose Study ◽  
Two Stages ◽  
Oral Doses

Purpose: Albendazole is a benzimidazole carbamate drug with anthelmintic and antiprotozoal activity against intestinal and tissue parasites. It has been described that the administration with meals increases albendazole absorption. Our aim was to compare the systemic exposure in healthy volunteers of two albendazole formulations after a single oral dose under fed conditions and to evaluate the effect of breakfast composition on albendazole and albendazole sulfoxide bioavailability.Methods: 12 healthy volunteers were included in a 4-period, 4-sequence, crossover, open, randomized, bioequivalence clinical trial, including two stages to compare two formulations of albendazole. Single oral doses of 400 mg albendazole were administered under fed conditions (a low-fat breakfast in first stage and a high-fat breakfast in the second) separated by 7-day washout periods. Plasma albendazole and albendazole sulfoxide concentrations were measured by HPLC-MS/MS.Findings: Albendazole absorption was clearly influenced by the meal composition. A high-fat breakfast increased albendazole and albendazole sulfoxide area under the concentration–time curve (AUC) and maximum concentration (Cmax) by double, compared to a low-fat breakfast. The bioavailability of the two formulations was very similar, although the sample size was not sufficient to demonstrate bioequivalence because the intraindividual variability of albendazole was approximately 60%.Implications: The higher albendazole and albendazole sulfoxide levels when administered with a high-fat meal could be of importance in clinical practice. Since albendazole labeling recommends its administration with meals, it is necessary to insist on taking it with a fatty meal so that the effectiveness of albendazole is not compromised.

scholarly journals 1288. Phase 1 First-in-Human Single- and Multiple-Ascending Dose Trial Demonstrates Pharmacokinetics (PK) and Tolerability of SPR720, an Oral DNA GyrB Inhibitor for Mycobacterial Infections

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S659-S659
Author(s):  
Angela Talley ◽  
Archie Thurston ◽  
Grayson Moore ◽  
Myriah M Satterfield ◽  
Erika L Manyak ◽  
...  
Keyword(s):  
Adverse Events ◽  
Healthy Volunteers ◽  
Controlled Trial ◽  
Phase 1 ◽  
Safety Data ◽  
Elderly Subjects ◽  
Independent Contractor ◽  
Serious Adverse Events ◽  
Healthy Elderly ◽  
Dose Proportional

Abstract Background SPR720 (phosphate pro-drug of SPR719) is a novel aminobenzimidazole bacterial DNA gyrase (GyrB) inhibitor in development for non-tuberculous mycobacterial lung disease (NTM-LD) and pulmonary tuberculosis. SPR719 has broad-spectrum activity versus clinically relevant mycobacteria in vitro and in murine and hollow fiber (HF) infection models. In this first-in-human single ascending dose (SAD) /multiple ascending dose (MAD) study, the safety, tolerability and pharmacokinetics (PK) of SPR720/SPR719 were evaluated in healthy volunteers. Methods This was a Phase 1 randomized, double-blind, placebo-controlled trial with 7 SAD cohorts (including a food effect cohort) and 5 MAD cohorts. Healthy volunteers (n=8/cohort, 3:1 randomization) received SPR720 or placebo in single oral doses of ranging from 100 mg to 2000 mg or repeat total daily doses ranging from 500 mg to 1500 mg for 7 or 14 days. Safety monitoring and PK sampling occurred throughout the trial. Plasma and urine concentrations of SPR720/SPR719 were measured by validated LC-MS/MS methods. PK parameters were calculated using non-compartmental analysis. Results A total of 96 subjects (including 8 healthy elderly subjects, age ≥ 65 years) were randomized and received study drug. SPR720 was well-tolerated at daily doses up to 1000 mg for up to 14 days. Across SAD/MAD cohorts, the most common adverse events were gastrointestinal (nausea, vomiting and diarrhea) and headache, all of mild or moderate severity and dose dependent. No serious adverse events were reported. Across SAD cohorts, a dose proportional and greater-than-dose proportional increase in SPR719 plasma Cmax and AUC0-24, respectively were observed. SPR720 was rapidly absorbed with a mean SPR719 t1/2 of 2.9-4.5 h. Dosing with food decreased SPR719 plasma AUC by ~20%. No clinically meaningful effect of age on plasma AUC was observed. In the MAD cohorts, SPR719 plasma exposure declined approximately 40% between Day 1 and Day 7, suggesting induction of an elimination pathway. However, plasma AUC0-24 was similar at Days 7 and 14. Conclusion Together with HF pharmacodynamic data, human PK and safety data for SPR720 suggest that predicted therapeutic exposures can be attained with a well-tolerated once-daily dose. Further evaluation in a Phase 2 NTM-LD trial is planned. Disclosures Angela Talley, MD, Spero Therapeutics (Employee, Shareholder) Archie Thurston, Jr., PhD, Spero Therapeutics (Consultant) Grayson Moore, BA, RN, Spero Therapeutics, Inc. (Shareholder, Independent Contractor) Vipul Kumar, PhD, Spero Therapeutics (Employee, Shareholder) Suzanne Stokes, PhD, Spero Therapeutics (Employee, Shareholder) Aaron Dane, MSc, Spero theraputics (Consultant) David Melnick, MD, Spero Therapeutics (Employee)Spero Therapeutics (Employee)

S-OXIDATION OF THIORIDAZINE TO PSYCHOACTIVE METABOLITES: AN ORAL DOSE-PROPORTIONALITY STUDY IN HEALTHY VOLUNTEERS

1988 ◽  
Vol 6 (3-4) ◽  
Author(s):  
B.S. Chakraborty ◽  
E.M. Hawes ◽  
G. McKay ◽  
J.W. Hubbard ◽  
E.D. Korchinski ◽  
...  
Keyword(s):  
Oral Dose ◽  
Healthy Volunteers ◽  
Dose Proportionality ◽  
S Oxidation

scholarly journals A 5-Day High-Fat, High-Calorie Diet Impairs Insulin Sensitivity in Healthy, Young South Asian Men but Not in Caucasian Men

Diabetes ◽  
2013 ◽  
Vol 63 (1) ◽  
pp. 248-258 ◽  
Author(s):  
L. E. H. Bakker ◽  
L. D. van Schinkel ◽  
B. Guigas ◽  
T. C. M. Streefland ◽  
J. T. Jonker ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
South Asian ◽  
High Fat ◽  
Asian Men ◽  
Caucasian Men ◽  
Calorie Diet ◽  
High Calorie Diet ◽  
High Calorie

scholarly journals Pharmacokinetics of EDP-420 after Multiple Oral Doses in Healthy Adult Volunteers and in a Bioequivalence Study

2009 ◽  
Vol 53 (8) ◽  
pp. 3218-3225 ◽  
Author(s):  
Li-Juan Jiang ◽  
Yat Sun Or
Keyword(s):  
Systemic Exposure ◽  
Bioequivalence Study ◽  
Respiratory Pathogens ◽  
Capsule Formulation ◽  
Dose Study ◽  
Effect Of Food ◽  
Tract Infections ◽  
Oral Doses

ABSTRACT EDP-420 (also known as EP-013420, or S-013420) is a first-in-class bridged bicyclolide currently in clinical development for the treatment of respiratory tract infections (RTI) and has previously shown favorable pharmacokinetic (PK) and safety profiles after the administration of single oral doses of a suspension to healthy volunteers. Here we report its PK profile after the administration of multiple oral doses of a suspension to healthy adults. Bioequivalence between suspension and capsule formulations, as well as the effect of food, is also reported. The most important PK features of EDP-420 observed in these clinical studies are its long half-life of 17 to 18 h and its high systemic exposure, which support once-daily dosing and treatment durations potentially shorter than those of most other macrolide antibiotics. EDP-420 is readily absorbed following oral administration in both suspension and capsule formulations. In the multiple-oral-dose study, steady state was achieved on day 1 by using a loading dose of 400 mg/day, followed by 2 days of 200 mg/day. A high-fat meal had no effect on the bioavailability of EDP-420 administered in a capsule formulation. EDP-420 was well tolerated, with no serious or severe adverse events reported, and no subject was discontinued from the study due to an adverse event. Based on its human PK and safety profiles, together with its in vitro/in vivo activities against common respiratory pathogens, EDP-420 warrants further development, including trials for clinical efficacy in the treatment of RTI.

scholarly journals The computational form of craving is a selective multiplication of economic value

2018 ◽  
Vol 115 (16) ◽  
pp. 4122-4127 ◽  
Author(s):  
Anna B. Konova ◽  
Kenway Louie ◽  
Paul W. Glimcher
Keyword(s):  
Economic Value ◽  
Food Craving ◽  
World Food ◽  
High Fat ◽  
Computational Framework ◽  
Size Number ◽  
Experimental Tool ◽  
Behavioral Signature ◽  
Computational Form ◽  
High Calorie

Craving is thought to be a specific desire state that biases choice toward the desired object, be it chocolate or drugs. A vast majority of people report having experienced craving of some kind. In its pathological form craving contributes to health outcomes in addiction and obesity. Yet despite its ubiquity and clinical relevance we still lack a basic neurocomputational understanding of craving. Here, using an instantaneous measure of subjective valuation and selective cue exposure, we identify a behavioral signature of a food craving-like state and advance a computational framework for understanding how this state might transform valuation to bias choice. We find desire induced by exposure to a specific high-calorie, high-fat/sugar snack good is expressed in subjects’ momentary willingness to pay for this good. This effect is selective but not exclusive to the exposed good; rather, we find it generalizes to nonexposed goods in proportion to their subjective attribute similarity to the exposed ones. A second manipulation of reward size (number of snack units available for purchase) further suggested that a multiplicative gain mechanism supports the transformation of valuation during laboratory craving. These findings help explain how real-world food craving can result in behaviors inconsistent with preferences expressed in the absence of craving and open a path for the computational modeling of craving-like phenomena using a simple and repeatable experimental tool for assessing subjective states in economic terms.

A Pharmacokinetic Bioequivalence Study Comparing Sublingual Riluzole (BHV‐0223) and Oral Tablet Formulation of Riluzole in Healthy Volunteers

2019 ◽  
Vol 9 (4) ◽  
pp. 476-485
Author(s):  
Irfan Qureshi ◽  
Meghan Lovegren ◽  
Victoria Wirtz ◽  
Richard Larouche ◽  
Mario Tanguay ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Bioequivalence Study ◽  
Tablet Formulation ◽  
Oral Tablet

Effect of a high-fat meal on the relative bioavailability of H3B-6527, a novel FGFR4 inhibitor, in healthy volunteers

2018 ◽  
Vol 83 (1) ◽  
pp. 91-96 ◽  
Author(s):  
Nathalie Rioux ◽  
Amy Kim ◽  
Darrell Nix ◽  
Todd Bowser ◽  
Markus Warmuth ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Relative Bioavailability ◽  
High Fat ◽  
Fat Meal

scholarly journals USL255 extended‐release topiramate: Dose‐proportional pharmacokinetics and tolerability in healthy volunteers

Epilepsia ◽  
2014 ◽  
Vol 55 (7) ◽  
pp. 1069-1076 ◽  
Author(s):  
Annie M. Clark ◽  
Mark B. Halvorsen ◽  
Tricia L. Braun ◽  
Krista M. Johnson ◽  
James C. Cloyd
Keyword(s):  
Healthy Volunteers ◽  
Extended Release ◽  
Dose Proportional

Pharmacological issues concerning olaparib capsule and tablet formulations in treating ovarian cancer: Are they really the same drug?

2020 ◽  
Vol 26 (4) ◽  
pp. 967-971
Author(s):  
Gianluca Perego ◽  
Renata Nozza ◽  
Emanuela Oggionni ◽  
Mary Cabiddu ◽  
Cinzia Scolari ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Parp Inhibitor ◽  
Tablet Formulation ◽  
Tolerability Profile ◽  
Pill Burden ◽  
Capsule Formulation ◽  
Moderate Severity ◽  
Platinum Sensitive ◽  
Pharmacokinetic Properties ◽  
Tablet Formulations

Olaparib is a first-in-class PARP inhibitor that has demonstrated efficacy as maintenance therapy in patients with ovarian cancer. It has been approved as a capsule formulation and after the publication of data from SOLO2 study became available also as tablet formulation. Due to different pharmacokinetic properties, these different formulations cannot be considered bioequivalent nor interchangeable. The tablet formulation has improved bioavailability, reducing pill burden and offering a more convenient dosage regimen. Furthermore, olaparib tablet formulation had a manageable tolerability profile if compared to capsule one, with most of adverse events of mild or moderate severity. Under this light, olaparib tablet formulation is a useful maintenance strategy for recurrent, platinum-sensitive ovarian cancer, providing a more convenient dosing option than the capsule formulation.

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