Single Ascending Dose Study Research Articles

Characterization of JNJ-42847922, a Selective Orexin-2 Receptor Antagonist, as a Clinical Candidate for the Treatment of Insomnia.

Dual orexin receptor antagonists have been shown to promote sleep in various species, including humans. Emerging research indicates that selective orexin-2 receptor (OX2R) antagonists may offer specificity and a more adequate sleep profile by preserving normal sleep architecture. Here, we characterized JNJ-42847922 ([5-(4,6-dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-fluoro-6-[1,2,3]triazol-2-yl-phenyl)-methanone), a high-affinity/potent OX2R antagonist. JNJ-42847922 had an approximate 2-log selectivity ratio versus the human orexin-1 receptor. Ex vivo receptor binding studies demonstrated that JNJ-42847922 quickly occupied OX2R binding sites in the rat brain after oral administration and rapidly cleared from the brain. In rats, single oral administration of JNJ-42847922 (3-30 mg/kg) during the light phase dose dependently reduced the latency to non-rapid eye movement (NREM) sleep and prolonged NREM sleep time in the first 2 hours, whereas REM sleep was minimally affected. The reduced sleep onset and increased sleep duration were maintained upon 7-day repeated dosing (30 mg/kg) with JNJ-42847922, then all sleep parameters returned to baseline levels following discontinuation. Although the compound promoted sleep in wild-type mice, it had no effect in OX2R knockout mice, consistent with a specific OX2R-mediated sleep response. JNJ-42847922 did not increase dopamine release in rat nucleus accumbens or produce place preference in mice after subchronic conditioning, indicating that the compound lacks intrinsic motivational properties in contrast to zolpidem. In a single ascending dose study conducted in healthy subjects, JNJ-42847922 increased somnolence and displayed a favorable pharmacokinetic and safety profile for a sedative/hypnotic, thus emerging as a promising candidate for further clinical development for the treatment of insomnia.

Population pharmacokinetic/pharmacodynamic assessment of pharmacological effect of a selective estrogen receptor β agonist on total testosterone in healthy men.

LY500307 is a highly selective estrogen receptor β (ERβ) agonist, which loses its selectivity at high dose and leads to undesirable suppression of total testosterone (TT) concentration. The objective of the present analysis was to define the LY500307 dose with minimal effect on TT METHODS: LY500307 and TT concentrations were obtained from a single ascending-dose study in a total of 30 healthy male subjects. LY500307 (in the range of 0.5 to 500 mg) or placebo was administered orally as a single dose on 2 occasions with a 3-week washout period. A population pharmacokinetics/pharmacodynamics (PK/PD) model that integrated Fourier series in an indirect response model was developed to describe the circadian rhythm of TT and the exposure-response relationship of LY500307 on TT. The maximum TT suppression (Emax ) was approximately 28.6%. The potency (EC50 ) of LY500307 on TT suppression was approximately 1.69 ng/mL with a 95%CI of 0.871 to 4.44 ng/mL. This model could provide inferences on LY500307 dose levels that would result in various magnitudes of TT suppression. Population PK/PD modeling is a highly sensitive tool to detect exposure-response relationships on top of the complicated and highly variable circadian rhythm of TT.

Journal of Diabetes News

Journal of Diabetes News

SP647FIRST-TIME-IN-HUMAN PHASE 1 CLINICAL TRIAL IN HEALTHY VOLUNTEERS WITH SNF472, A NOVEL INHIBITOR OF VASCULAR CALCIFICATION

Introduction: SNF472, an intravenous formulation of phytate, is being developed for the prevention of vascular calcification in patients with end-stage renal failure on hemodialysis. It acts by preventing the formation and growth of hydroxyapatite crystals. Extensive non-clinical investigations have shown adequate evidence of efficacy and safety to warrant a first study in humans. Methods: A double-blind, randomized, single ascending dose study was performed in two cohorts of eight healthy male volunteers. Single ascending doses of 0.5, 5, 9 and 12 mg/kg of SNF 472 were administered by a four hour infusion in a leap-frog design. Apart from standard safety parameters and pharmacokinetics, a potential biomarker of calcification that assesses the potential for the formation of hydroxyapatite crystals ex vivo, by artificially increasing the calcium phosphorus product of blood samples from the subjects ex vivo, was used to assess pharmacodynamics. Results: The only adverse event of note was mild dose dependent local venous irritation. This is not anticipated to be an issue in the target population as SNF472 will be administered into the tubing delivering blood to the dialysis column. At a dose of 0.5 mg/kg SNF472 plasma concentrations were below the limit of detection. At the 5, 9 and 12 mg/kg doses, mean maximum plasma concentrations above the anticipated EC50 (5µM) were achieved. With the 12 mg/kg dose concentrations were 10-fold more than the EC50. In terms of the biomarker, the doses of 5, 9 and 12 mg/kg were on a plateau and reduced hydroxyapatite crystal formation by 80%. Conclusions: The findings support continuation of the development program, the next steps being a single dose and multiple dose studies in hemodialysis patients.

Utilizing Physiologically Based Pharmacokinetic Modeling to Inform Formulation and Clinical Development for a Compound with pH-Dependent Solubility

ARRY-403 is a glucokinase activator developed for the treatment of diabetes. Less than dose-proportional exposure was observed during single ascending dose studies with ARRY-403. A physiologically based pharmacokinetic (PBPK) model for ARRY-403 was developed through integration of in vitro physicochemical data with precipitation time estimations based on results from the single ascending dose studies; PBPK modeling indicated that the primary cause of the less than dose-proportional exposure was dose-limited absorption because of pH-dependent solubility. The impact of dose, particle size, and fasted or fed state on ARRY-403 exposure was examined through sensitivity analyses and used to refine the PBPK model. On the basis of the marked pH-dependent solubility of ARRY-403, the refined PBPK model was used to simulate the effects of acid-reducing agents (ARAs) on ARRY-403 exposure, as these agents are widely available and could be coadministered with ARRY-403. The simulations indicated that a clinical study with an ARA was warranted; in a clinical study, famotidine had a marked effect on ARRY-403 exposure. This approach, based on the "predict, learn, and confirm" paradigm, demonstrates the utility of integrating physicochemical properties, in vitro experiments, and clinical results using PBPK to inform formulation development and to guide clinical study design.

Single and multiple dose pharmacokinetics and tolerability of HX-1171, a novel antioxidant, in healthy volunteers.

BackgroundHX-1171 (1-O-hexyl-2,3,5-trimethylhydroquinone) is a promising antioxidant with therapeutic potential for hepatic fibrosis. The aim of this study was to investigate the tolerability and pharmacokinetics of HX-1171 in healthy volunteers.MethodsA randomized, single-blind, placebo-controlled, dose escalation study was conducted in 83 subjects. In the single ascending dose study, 20, 40, 80, 160, 300, 600, 1,200, 1,500 or 2,000 mg of HX-1171 was administered to 67 subjects. In the multiple ascending dose study, 500 or 1,000 mg was administered to 16 subjects for 14 days. The plasma and urine concentrations of HX-1171 were determined by using a validated liquid chromatography-mass spectrometry method. Pharmacokinetic parameters were obtained by non-compartmental analysis. Tolerability was assessed based on physical examinations, vital signs, clinical laboratory tests, and electrocardiograms.ResultsAdverse events reported in the study were all mild in intensity and resolved without any sequelae. HX-1171 was rapidly and minimally absorbed with a median time at maximal concentration of 0.63–1.50 hours and slowly eliminated with a terminal half-life of 21.12–40.96 hours. Accumulation index ranged from 2.0 to 2.2 after repeated dosing for 14 days. For both the single and multiple doses administrations, urinary concentrations indicated that less than 0.01% of the HX-1171 administered was excreted in urine.ConclusionHX-1171 was well tolerated and minimally absorbed in healthy volunteers. The pharmacokinetic profile of HX-1171 was consistent with once-a-day dosing.

Pharmacokinetics, pharmacodynamics and food effect of LB30870, a novel direct thrombin inhibitor, after single oral doses in healthy men

1. The safety, tolerability, pharmacokinetics, pharmacodynamics, and food effect of LB30870, a new selective thrombin inhibitor, were studied in 16 healthy men.2. A double-blind, placebo-controlled single ascending dose study was done at oral doses of 5, 15, 30, 60, 120, and 240 mg under fasting conditions. An open, randomized, balanced cross-over food effect study was done at 60 mg dose. Plasma and urinary concentrations were measured up to 48 h post-dose. Coagulation and thrombin activity markers were measured at selected time points.3. Cmax of LB30870 was at 1.3–3.0 h post-dose with a mean apparent terminal half-life (t1/2) of 2.8–4.1 h. AUC after doses above 15 mg appeared greater than dose-proportional. In fed state, AUC showed 80% reduction relative to fasting condition.4. At doses 60 and 120 mg, peak activated partial thromboplastin time (aPTT) increased by 1.5- and 2-fold, respectively, from baseline. The aPTT and international normalized ratio (INR) were concentration-dependent, with less within-individual variability than ecarin clotting time (ECT), prothrombin time (PT), or thrombin time (TT).5. Single oral doses of LB30870 up to 240 mg were well tolerated. The food effect must be overcome if LB30870 is to be used as an oral anti-coagulant.

Clinical Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of the Novel Factor Xa Inhibitor DY-807f in Healthy Volunteers

IntroductionSince Vitamin K antagonists are associated with various limitations such as narrow therapeutic window, slow onset and offset of effect, and numerous interactions with food and drugs, new oral anticoagulants targeted to inhibit thrombin or factor Xa (FXa) have been developed. DY-807f is a highly selective, reversible and orally bioavailable FXa inhibitor. ObjectivesThis article describes a first-in-human study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of single ascending oral doses of the novel direct FXa inhibitor DY-807f in healthy males. Methodsa placebo-controlled, single-blinded, randomized, single ascending dose study with 84 subjects (10, 30, 60, 120, 240, and 360mg). Effects of food and formulation (tablet vs solution) on bioavailability of 60mg were also assessed as a crossover design. ResultsDY-807f doses were safe and well-tolerated with no dose-dependent increase in adverse events up to 360mg. Pharmacokinetics profiles were consistent across doses with rapid absorption, biphasic elimination, and terminal elimination half-life of 10.5 to 12.4hours. Coagulation parameters (Activated Partial Thromboplastin Time (aPTT) and Prothrombin Time (PT)) were linearly correlated with plasma DY-807 (free base of DY-807f) concentrations (correlation coefficient: 0.786 for aPTT, 0.945 for PT). ConclusionsSingle doses of DY-807f are safe and well-tolerated up to 360mg with predictable pharmacokinetic and pharmacodynamic profiles.

A Subcutaneously Administered RNAi Therapeutic (ALN-AT3) Targeting Antithrombin for Treatment of Hemophilia: Interim Phase 1 Study Results in Healthy Volunteers and Patients with Hemophilia a or B

Introduction: Hemophilia A and B are congenital bleeding disorders caused by insufficient thrombin generation due to deficiency in factor VIII or IX, respectively. In the presence of normal levels of endogenous anticoagulants, deficiency of factor VIII or IX results in an imbalance of the hemostatic system toward a bleeding phenotype. ALN-AT3 is a subcutaneously administered investigational RNAi therapeutic aimed at reducing the levels of antithrombin (AT) with the purpose of increasing thrombin generation and thereby restoring hemostatic balance in hemophilia.Material and methods: Preclinical studies in hemophilia mouse models were used to investigate the ability of ALN-AT3 to reduce AT, increase thrombin generation, restore thrombus formation after microvascular laser injury, and control traumatic bleeding after saphenous vein transection. A study in an induced hemophilia A model in non-human primates was used to investigate the ability of ALN-AT3 to enhance thrombin generation in the setting of inhibitors to factor VIII.A Phase 1 clinical study in healthy volunteers and severe/moderate hemophilia A or B is ongoing. Part A, a single ascending dose study in healthy volunteers, has been completed and Part B, a multiple ascending dose study in hemophilia patients, is currently ongoing. Primary endpoints are safety and tolerability. Secondary endpoints are pharmacokinetics, relative reduction in levels of AT and change in thrombin generation as measured by Calibrated Automated Thrombin (CAT) generation.Results: ALN-AT3 treatment resulting in residual AT levels of 20-40% in hemophilia A and B mouse models increased thrombin generation, restored real-time localized thrombus formation in the laser-injury model comparable to treatment with full-length recombinant factor VIII. ALN-AT3 controlled traumatic bleeding in the saphenous vein model with an increase in number of hemostatic events equivalent to that achieved with infusion of 25 IU/kg full-length recombinant factor VIII. ALN-AT3 treatment targeting 20% residual AT levels normalized thrombin generation in non-human primates with induced high titer inhibitor hemophilia A.In Part A of the phase 1 study, a total of 4 human volunteer subjects were randomized to receive a single subcutaneous dose of ALN-AT3 0.03 mg/kg or placebo (3:1) and were followed for at least 70 days. No serious adverse events (SAEs) were observed. A total of 5 mild AEs were recorded. Four out of 5 mild AEs were considered unlikely/not related to study drug. One mild AE of temporary self-limiting headache was considered possibly related to study drug. In Part A, per protocol, the maximum allowable level of AT relative reduction was set at 40%. Results in healthy volunteers show that a single, low subcutaneous dose of ALN-AT3 at 0.03 mg/kg resulted in an up to 28-32% knockdown of AT activity at nadir, and the treatment effect was statistically significant relative to placebo (p < 0.01 by ANOVA). This led to a statistically significant (p < 0.01) increase in peak thrombin generation, that was temporally associated and consistent with the degree of AT knockdown. The AT reduction was stable and durable for up to 70 days post single dose. In the ongoing Part B, cohorts of 3 hemophilia patients will receive 3 weekly doses of ALN-AT3, with dosing commenced at 0.015 mg/kg. Up-to-date results from Part B will be presented.Conclusion: Collectively, these data suggest that the use of a novel RNAi therapeutic targeting AT is a promising approach for restoring hemostatic balance in hemophilia, and potentially, other bleeding disorders. Further, the subcutaneous route of administration, infrequent dosing, and applicability to persons with hemophilia who have inhibitors, make this a particularly encouraging potential therapy. DisclosuresSorensen:Alnylam Pharmaceuticals: Employment, Equity Ownership. Off Label Use: ALN-AT3 is an investigational drug for potential treatment of hemophilia. The data represent phase 1/2 data. Mant:Quintiles phase 1 unit, London: Employment. Akinc:Alnylam Pharmaceuticals: Employment. Simon:Alnylam Pharmaceuticals: Employment, Equity Ownership. Melton:Alnylam Pharmaceuticals: Employment, Equity Ownership. Lynam:Alnylam Pharmaceuticals: Employment. Strahs:Alnylam Pharmaceuticals: Employment, Equity Ownership. Sehgal:Alnylam Pharmaceuticals: Employment, Equity Ownership. Hutabarat:Alnylam Pharmaceuticals: Employment, Equity Ownership. Chaturvedi:Alnylam Pharmaceuticals: Employment, Equity Ownership. Barros:Alnylam Pharmaceuticals: Employment, Equity Ownership. Vaishnaw:Alnylam Pharmaceuticals: Employment, Equity Ownership. Investigators:Alnylam Pharmaceuticals: Clinical investigators in phase 1/2 study Other, Consultancy.

Phase I Single (SAD) and Multiple Ascending Dose (MAD) Studies of the Safety, Tolerability, Pharmacokinetics (PK) and Pharmacodynamics (PD) of AG-348, a First-in-Class Allosteric Activator of Pyruvate Kinase-R, in Healthy Subjects

INTRODUCTION: Pyruvate kinase deficiency (PKD) is an inborn error of metabolism affecting children and adults that results in lifelong hemolytic anemia and is associated with serious long-term comorbidities such as poor growth and development in children and chronic iron overload in adults. PKD is caused by a functional deficiency of the R-isoform of pyruvate kinase (PK-R) caused most often by a missense mutation. As a result of deficiency of this terminal enzyme in glycolysis, blood 2,3-DPG levels are elevated and ATP levels are low. AG-348 is a novel, first-in-class, small molecule allosteric activator of PK-R that directly targets the underlying metabolic defect in PKD. Preclinical studies demonstrated that AG-348 increases the activity of both wild type and various mutated PK-R enzymes. The key objectives of these first-in-human, Phase I, randomized, double-blind, placebo-controlled single (SAD) and multiple ascending dose (MAD) studies are to identify a safe and pharmacodynamically-active dose and schedule for AG-348 to be used in subsequent clinical studies in subjects with PKD [NCT02108106; NCT202149966].METHODS: In the SAD, healthymen and women (non-childbearing potential) aged 18-60 years were randomized to receive a single oral dose of AG-348 or placebo (P). Six cohorts were evaluated, each containing 8 subjects (6 AG-348, 2 P), starting with 30 mg in cohort 1 followed by 120, 360, 700, 1400 and 2500 mg in cohorts 2-6, respectively. In the ongoing MAD, 2 cohorts (120 mg bid and 360 mg bid) of 8 subjects each (6 AG-348, 2 P) have completed 14 days of dosing and 2 weeks of follow-up. In both studies, safety assessments included adverse events (AEs), vital signs, ECG and clinical laboratory parameters. Serial blood samples are drawn for assessment of PK and PD parameters (2,3-DPG and ATP) pre-dose and at regular intervals thereafter at multiple doses in both the SAD and MAD studies. Preliminary results are reported here; final results will be available at the time of presentation.RESULTS: In the SAD, all 48 subjects enrolled completed the study (47 males and 1 female; mean age 40 years). A preliminary analysis of safety data indicated that 19/48 (39%) subjects receiving AG-348 or placebo under fasted and/or fed conditions experienced at least 1 treatment-emergent AE during the study. All AEs were mild or moderate (Grade 1 and 2) in severity, and the most common were nausea (n=5; 10%) and headache (n=7; 14%). In the 2 completed MAD cohorts (13 males; 3 females; mean age 44 years), 8/16 (50%) of subjects receiving AG-348 or P experienced 11 AEs. All AEs were mild (n=10) or moderate (n=1) and the most frequent were venipuncture bruises. Frequency of AEs by treatment group will be presented. There were no serious AEs, discontinuations due to AEs, or dose-limiting toxicities in either study. Maximum tolerated dose was not reached in the SAD and dose escalation continues in the MAD. In SAD cohorts 1-6, exposure to single doses of AG-348 increased in a dose-proportional manner (mean plasma Cmax, AUC0-12hr and AUC0-72hr) (Figure 1 SAD study). Absorption was rapid, with a median Tmax of 0.75–4.0 h. Expected changes in pharmacodynamic markers including decrease in 2,3-DPG concentration (SAD [Figure 2] and MAD studies) and increase in ATP concentration (MAD study) were observed and will be presented in greater detail.CONCLUSION: AG-348 had a favorable safety profile and was well tolerated in healthy subjects based on preliminary analysis of subjects receiving a single dose up to 2500 mg or multiple bid doses up to 360 mg for up to 14 days. AG-348 also demonstrated a desirable PK profile, with rapid absorption, low PK variability and dose-proportional exposure with PD effect as demonstrated on 2,3-DPG (Figure 2) and ATP. [Display omitted] [Display omitted] DisclosuresYang:Agios Pharmaceuticals: Employment, Stockholder Other. Merica:Agios Pharmaceuticals: Employment, Stockholder Other. Chen:Agios Pharmaceuticals: Employment, Stockholder Other. Cohen:Agios Pharmaceuticals: Consultancy. Goldwater:PAREXEL International: Employment. Hill:Agios Pharmaceuticals: Employment, Stockholder Other. Kim:Agios Pharmaceuticals: Employment, Stockholder Other. Kosinski:Agios Pharmaceuticals: Employment, Stockholder Other. Kung:Agios Pharmaceuticals: Employment, Stockholder Other. Silver:Agios Pharmaceuticals: Consultancy. Utley:Agios Pharmaceuticals: Employment, Stockholder Other. Agresta:Agios Pharmaceuticals: Employment, Stockholder Other.

Pharmacodynamics, Pharmacokinetics, Safety, and Tolerability of Encenicline, a Selective α7 Nicotinic Receptor Partial Agonist, in Single Ascending-dose and Bioavailability Studies

PurposeEncenicline (EVP-6124) is a selective α7 nicotinic acetylcholine receptor partial agonist being developed for cognitive impairment in Alzheimer’s disease and schizophrenia. We report on 2 single-dose studies to assess the relative bioavailability, pharmacokinetic profile, tolerability, and cognitive effects of encenicline in healthy volunteers. MethodsA single ascending-dose study assessed the safety, tolerability, pharmacokinetic, and pharmacodynamic profiles of encenicline in healthy male volunteers. Subjects received a single 1-, 3.5-, 7-, 20-, 60-, or 180-mg oral solution dose of encenicline or placebo. A second single-dose, randomized, open-label, 3-period, crossover study in healthy male and female subjects compared the relative bioavailability of a 1-mg oral capsule versus a 1-mg oral solution dose of encenicline and evaluated the effects of food and sex on encenicline pharmacokinetic profile. FindingsIn the first study, encenicline was well tolerated and dose-proportional increases in Cmax (mean range 0.59−100 ng/mL) and AUC0−∞ (mean range 45.6−8890 ng·h/mL) were observed over a 1- to 180-mg dose range. Procognitive effects on the Digit Symbol Substitution Test were maximal at the 20-mg dose. In the second study, encenicline 1-mg oral capsules and oral solution were bioequivalent and there was no observed food effect on encenicline pharmacokinetic profile with the 90% confidence intervals of the treatment ratios for both comparisons (ie, capsule to solution and fed to fasted) for Cmax and AUC being within 80% to 125%. A 30% to 40% higher encenicline exposure in female subjects than respective values in male subjects was consistent with a 33% higher weight of the male subjects. No clinically relevant safety profile or tolerability effects of encenicline were observed. ImplicationsEncenicline was well tolerated at single doses up to 180 mg, and doses as low as 1 mg had dose- and time-dependent pharmacodynamic effects on the central nervous system. Oral capsule and solution were bioequivalent and were not affected by food. Although a sex effect on pharmacokinetic profile was observed, it was attributable to weight differences. Clinical Trial Registration at EudraCT: 2006-005623-42 and EudracT: 2008-000029-20.

Discovery of 5-chloro-4-((1-(5-chloropyrimidin-2-yl)piperidin-4-yl)oxy)-1-(2-fluoro-4-(methylsulfonyl)phenyl)pyridin-2(1H)-one (BMS-903452), an antidiabetic clinical candidate targeting GPR119.

G-protein-coupled receptor 119 (GPR119) is expressed predominantly in pancreatic β-cells and in enteroendocrine cells in the gastrointestinal tract. GPR119 agonists have been shown to stimulate glucose-dependent insulin release by direct action in the pancreas and to promote secretion of the incretin GLP-1 by action in the gastrointestinal tract. This dual mechanism of action has generated significant interest in the discovery of small molecule GPR119 agonists as a potential new treatment for type 2 diabetes. Herein, we describe the discovery and optimization of a new class of pyridone containing GPR119 agonists. The potent and selective BMS-903452 (42) was efficacious in both acute and chronic in vivo rodent models of diabetes. Dosing of 42 in a single ascending dose study in normal healthy humans showed a dose dependent increase in exposure and a trend toward increased total GLP-1 plasma levels.

G.O.18: Results of a phase 2 study of ISIS-SMNRx in children with spinal muscular atrophy

This open-label, multiple ascending-dose study was conducted to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of ISIS-SMNRx (ISIS 396443) in children with Types 2 and 3 SMA. ISIS-SMNRx is an antisense oligonucleotide designed to alter splicing of SMN2 mRNA to increase the amount of functional SMN protein. Results from SMA mouse models indicate ISIS-SMNRx had a significant effect on functional and histological measures of neuromuscular health when delivered to the CNS. A Phase 1 single ascending-dose study in children with SMA had previously been completed, showing acceptable safety/tolerability. Multiple doses of ISIS-SMNRx (3 dose levels) were delivered by intrathecal injection to medically stable SMA patients 2–15 years of age (n = 25). Subjects were dosed 2–3 times over 3 months and then followed for 6 months post-dosing and monitored for drug safety and tolerability, CSF and plasma pharmacokinetics, CSF SMN protein levels, and clinical outcome measures. Overall, no safety or tolerability concerns related to ISIS-SMNRx were identified; the majority of adverse events were mild or moderate in severity and none were related to dose level of ISIS-SMNRx. No drug-related changes in neurological exams, laboratory assessments (including CSF safety), or systemic evaluations were reported. Repeated intrathecal injections were well tolerated in SMA children. CSF and plasma drug levels were dose-dependent predictable, and consistent with expected levels. HFMSE scores indicated an improvement in motor function at all doses levels, with a time and dose dependency. 6MWT and ULM functional tests also indicated improvement, although with limited data. Measurement of SMN protein levels in CSF indicated a significant increase at the highest dose (p = 0.004), indicating biological activity of ISIS-SMNRx in SMA patients. Results from this study support continued development and further examination of ISIS-SMNRx in a Phase 2/3 controlled study.

Addressing matrix effects in ligand-binding assays through the use of new reagents and technology.

Ligand-binding assays (LBAs) used in the quantification of biotherapeutics for pharmacokinetic determinations rely on interactions between reagents (antibodies or target molecule) and the biotherapeutic. Most LBAs do not employ an analyte extraction procedure and are susceptible to matrix interference. Here, we present a case study on the development of a LBA for the quantification of a PEGylated domain antibody where matrix interference was observed. The assay used to support the single ascending dose study was a plate-based electrochemiluminescent assay with a lower limit of quantification of 80 ng/mL. To meet sensitivity requirements of future studies, new reagents and the Gyrolab™ Workstation were evaluated. Assay sensitivity improved nearly threefold in the final method utilizing new antibody reagents, a buffer containing blockers to human anti-animal antibodies, and the Gyrolab Workstation. Experimental data indicate that all factors changed played a role in overcoming matrix effects.

Radiation Safety Considerations for the Use of 223RaCl2 DE in Men with Castration-resistant Prostate Cancer

The majority of patients with late stage castration-resistant prostate cancer (CRPC) develop bone metastases that often result in significant bone pain. Therapeutic palliation strategies can delay or prevent skeletal complications and may prolong survival. An alpha-particle based therapy, radium-223 dichloride (²²³RaCl₂), has been developed that delivers highly localized effects in target areas and likely reduces toxicity to adjacent healthy tissue, particularly bone marrow. Radiation safety aspects were evaluated for a single comprehensive cancer center clinical phase 1, open-label, single ascending-dose study for three cohorts at 50, 100, or 200 kBq kg⁻¹ body weight. Ten patients received administrations, and six patients completed the study with 1 y follow-up. Dose rates from patients administered ²²³Ra dichloride were typically less than 2 μSv h⁻¹ MBq⁻¹ on contact and averaged 0.02 μSv h⁻¹ MBq⁻¹ at 1 m immediately following administration. Removal was primarily by fecal excretion, and whole body effective half-lives were highly dependent upon fecal compartment transfer, ranging from 2.5-11.4 d. Radium-223 is safe and straightforward to administer using conventional nuclear medicine equipment. For this clinical study, few radiation protection limitations were recommended post-therapy based on facility evaluations. Specific precautions are dependent on local regulatory authority guidance. Subsequent studies have demonstrated significantly improved overall survival and very low toxicity, suggesting that ²²³Ra may provide a new standard of care for patients with CRPC and bone metastases.

Journal of Diabetes News

Journal of Diabetes News

Pharmacokinetics of Mirabegron, a β3-Adrenoceptor Agonist for Treatment of Overactive Bladder, in Healthy Japanese Male Subjects: Results from Single- and Multiple-Dose Studies

BackgroundMirabegron is a human β3-adrenoceptor agonist for the treatment of overactive bladder. The pharmacokinetic profile of mirabegron has been extensively characterized in healthy Caucasian subjects.ObjectiveThe objective of this study was to evaluate the pharmacokinetics, dose-proportionality, and tolerability of mirabegron following single and multiple oral doses in healthy Japanese male subjects. The results were compared with those reported in non-Japanese (primarily Caucasian) subjects.MethodsTwo studies were conducted. In a single-blind, randomized, placebo-controlled, parallel-group, single- and multiple-ascending dose study (Study 1), mirabegron oral controlled absorption system (OCAS) tablets were administered at single doses of 50, 100, 200, 300, and 400 mg, with eight subjects (six active, two placebo) per dose group (Part I), and once daily for 7 days at 100 and 200 mg with 12 subjects (eight active, four placebo) per group (Part II). In an open-label, three-period, single-ascending dose study (Study 2), mirabegron OCAS was administered to 12 subjects at 25, 50, and 100 mg in an intra-subject dose-escalation design. Plasma and/or urine samples were collected up to 72 h after the first and last dose and analyzed for mirabegron. Pharmacokinetic parameters were determined using non-compartmental methods. Tolerability assessments included physical examinations, vital signs, 12-lead electrocardiogram, clinical laboratory tests (biochemistry, hematology, and urinalysis), and adverse event (AE) monitoring.ResultsForty and 24 young male subjects completed Part I and II, respectively, of Study 1. Twelve young males completed Study 2. After single oral doses (25–400 mg), maximum plasma concentrations (C max) were reached at approximately 2.8–4.0 h postdose. Plasma exposure (C max and area under the plasma concentration–time curve) of mirabegron increased more than dose proportionally at single doses of 25–100 mg and approximately dose proportionally at high doses of 300 and 400 mg. A more than dose proportional increase in plasma exposure was noted in the body of the same individual. Mirabegron accumulated twofold upon once-daily dosing relative to single-dose data. Steady state was reached within 7 days. Mirabegron was generally well-tolerated at single doses up to 400 mg and multiple doses up to 200 mg. The AE with the highest incidence was increased pulse rate at 400 mg in Study 1.ConclusionsMirabegron OCAS exhibits similar single- and multiple-dose pharmacokinetic characteristics and deviations from dose proportionality in healthy Japanese male subjects compared with those observed in non-Japanese (primarily Caucasian) subjects in previous studies.

Lipid lowering in healthy volunteers treated with multiple doses of MGL-3196, a liver-targeted thyroid hormone receptor-β agonist

MGL-3196 is an oral, liver-targeted selective agonist for the thyroid hormone receptor-β (THR-β) that is being developed for the treatment of dyslipidemia. The safety profile and tolerability of THR-β agonist MGL-3196 was assessed in first-in humans studies, including a single ascending dose study (NCT01367873) in which MGL-3196 appeared safe at all doses tested. A two-week multiple dose study was conducted at doses of 5, 20, 50, 80, 100, and 200 mg per day in healthy subjects with mildly elevated low density lipoprotein (LDL) cholesterol (>110 mg/dL) (NCT01519531). MGL-3196 was well-tolerated at all doses with no dose-related adverse events or liver enzyme, ECG or vital-sign changes. At the highest dose, there was a reversible reduction of ∼20% in the level of pro-hormone, free thyroxine (free T4) that was significantly different from placebo (p < 0.0001) that may be explained by increased hepatic metabolism of T4. There was no change in thyrotropin (TSH) or triiodothyronine (free T3) or other evidence of central thyroid axis dysfunction at any dose. Doses ranging from 50 to 200 mg demonstrated highly statistically significant reductions relative to placebo of up to: 30% for LDL cholesterol (range, p = 0.05–<0.0001); 28% for non- high density lipoprotein (HDL) cholesterol (range, p = 0.027–0.0001); 24% for Apolipoprotein B (range, p = 0.008–0.0004), and statistical trends of up to 60% reduction in triglycerides (TG) (range, p = 0.13–0.016). The near maximal lipid effects were observed at a dose of 80 mg daily. In summary, in a two-week study in healthy volunteers with mild LDL cholesterol elevation, MGL-3196 appeared safe, was well-tolerated and showed a beneficial effect on lipid parameters.

Pharmacokinetics and pharmacodynamics of single subcutaneous doses of tocilizumab administered with or without rHuPH20

To investigate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of tocilizumab with and without rHuPH20 (a recombinant human hyaluronidase) in healthy volunteers. This was an open-label, single ascending dose study. Subjects were assigned to tocilizumab 162 mg or tocilizumab 162, 324, or 648 mg plus rHuPH20. PK and PD samples were collected after dosing and were estimated with non-compartmental methods. Geometric mean ratio (GMR) for area under the plasma concentration-time curve from zero to infinity (AUC0-∞) and (maximum serum concentration) Cmax with and without rHuPH20 was estimated using one-way analysis of variance. Safety and tolerability were monitored throughout the study. 48 subjects (12/cohort) received a single dose of tocilizumab with or without rHuPH20. For tocilizumab 162 mg, tocilizumab 162 mg/rHuPH20, tocilizumab 324 mg/rHuPH20, and tocilizumab 648 mg/rHuPH20, mean ± SD tocilizumab PK parameters were 2,510 ± 1,060, 2,860 ± 468, 10,800 ± 3,220, and 29,900 ± 5,280 μg×h/ml for AUC0-∞; 11.5 ± 3.7, 16.2 ± 2.8, 43.8 ± 12.4, and 77.8 ± 14.5 μg/ml for Cmax; and 89.1 ± 41.1, 54.0 ± 19.5, 66.0 ± 26.8, and 86.1 ± 50.6 h for tmax, respectively. Coadministration of tocilizumab 162 mg with rHuPH20 resulted in slightly increased exposure: GMR (90% confidence interval) for AUC0-∞, 1.20 (1.00 - 1.44) and Cmax, 1.45 (1.24 - 1.70). Increasing tocilizumab doses resulted in significant deviation from dose proportionality for tocilizumab Cmax (p = 0.0057) and AUC0-∞ (p < 0.0001). Changes in interleukin-6, soluble interleukin- 6 receptor, and C-reactive protein were also dose dependent and similar with and without rHuPH20. Tocilizumab in combination with rHuPH20 resulted in slightly increased tocilizumab exposure compared with tocilizumab alone, whereas PD markers were comparable. Subcutaneous administration of tocilizumab with rHuPH20 was well tolerated.

A single ascending-dose study of BIIB037 in people with mild-to-moderate Alzheimer's disease

A single ascending-dose study of BIIB037 in people with mild-to-moderate Alzheimer's disease