Administration In Healthy Subjects Research Articles

Pharmacokinetics of Cefozopran by Single and Multiple Intravenous Infusions in Healthy Chinese Volunteers

Background and ObjectivesCefozopran is a parenteral cephalosporin with a broad spectrum of activity against Gram-positive and Gram-negative bacteria. The objective of this study was to evaluate the pharmacokinetics of cefozopran after single- and multiple-dose intravenous administration in healthy subjects, to provide clinical guidance in its application.MethodsThis was a single-center, open-label, randomized, two-phase study conducted in 12 subjects. In the single-dose phase, subjects were randomly assigned to receive single doses of 0.5, 1.0 and 2.0 g of injected cefozopran hydrochloride in a three-way crossover design with a 5-day washout period between administrations. In the multiple-dose phase, subjects received 2.0 g every 12 h for 4 days. Plasma and urine pharmacokinetic samples were assayed by a validated high-performance liquid chromatography–tandem mass spectrometry method. Pharmacokinetic parameters were calculated and analyzed statistically. Safety assessments were conducted throughout the study.ResultsTwelve healthy volunteers (six males and six females) were enrolled and completed the study. Following a single 1-h intravenous infusion of 0.5, 1.0 or 2.0 g cefozopran, maximum plasma concentration (C max) and area under the plasma concentration–time curve from time zero to the time of the last measurable concentration (AUClast) increased in a dose-proportional manner. The mean half-life in plasma (t ½) was in the range of 1.20–2.80 h. Cefozopran was mainly excreted in its unchanged form, with no tendency for accumulation, via the kidney, and varied from 65.99 to 73.33 %. No appreciable accumulation of either drug occurred with multiple intravenous doses of cefozopran, and pharmacokinetic parameters for cefozopran were similar on days 1 and 4. No serious adverse events were reported. Adverse events were generally mild.ConclusionCefozopran was safe and well tolerated in the volunteers and displayed linear increases in the C max and AUClast values.

The neuropsychological hypothesis of antidepressant drug action revisited.

Depression is one of the most debilitating disorders of our times. Antidepressant medication, one of the most common (and often first-line) treatments to date, aim to alleviate symptoms, but finding which type of drug benefits which patient remains a daunting task. The underlying mechanism that translates neurochemical effects to symptom improvement is still far from precise. In this review we summarized the evidence on the effects of antidepressants on brain systems and cognitive functioning, and examined the possible value of these correlates as predictors of response. Studies using acute (or sub-chronic) antidepressant administrations in healthy subjects showed effects on affective cognition. In depressed patients, neuroimaging studies examining the effects of antidepressants in pre-post designs have shown changes in the activation of the anterior cingulate cortex and the limbic system after treatment. Increasing evidence shows that baseline anterior cingulate cortex activation could be a possibly critical biomarker of treatment response. The few studies performed to date also indicate potentially different pathways for antidepressants targeting the serotonergic neurotransmitter system versus those targeting the noradrenergic one, but findings are not always consistent. More studies are necessary to establish whether early cognitive effects of drugs are predictive of long-term efficacy in depressed patients. Considering the heterogeneity of depression and in order to approach a more personalized treatment, future studies should also elucidate the effects of antidepressants on different cognitive systems and subsequently on different symptom profiles.

SAT0447 Safety, Tolerability and Pharmacokinetics of Abt-981, an IL-1A and IL-1β Dual Target Biologic Drug in Development for Osteoarthritis, following Single Dose Administration in Healthy Subjects

BackgroundInterleukin-1 (IL-1) plays an important role in the development and progression of osteoarthritis (OA) through stimulating inflammatory mediators, increasing cartilage degradation processes, as well as inhibiting chondrocyte repair of degraded...

Effects of Short-Term Dexamethasone Administration on Corticospinal Excitability

The short-term administration of glucocorticoids increases maximal voluntary force in healthy humans, but the underlying mechanisms remain poorly understood. The present study investigated the glucocorticoid effects on spinal and corticospinal pathways and on electromechanical properties of the tibialis anterior muscle in response to nerve stimulation. Twelve healthy men participated in a single-blind randomized study to receive either dexamethasone (8 mg · d(-1), n = 8 subjects) or placebo (n = 4 subjects) for 7 d. Group Ia afferent and corticospinal pathways were assessed, respectively, by recording the amplitude of the Hoffmann (H) reflex and motor-evoked potential (MEP) by transcranial magnetic stimulation. The ankle dorsiflexor torque and EMG activity during a maximal voluntary contraction (MVC) and muscle twitch evoked by electrical stimulation were also assessed before and after the intervention. The MVC torque (+14%) and the associated tibialis anterior EMG (+16%) increased after glucocorticoid treatment (P < 0.05), whereas muscle twitch parameters did not change (P > 0.05). The H-reflex amplitude did not change (P = 0.58), but the MEP threshold was significantly (P = 0.008) reduced after treatment. Moreover, the slope of the MEP input-output relation and the silent period/MEP ratio increased (P = 0.049) and decreased (P = 0.029), respectively, after treatment. The amount of change in MEP amplitude and MVC torque were positively associated (r(2) = 0.59) for the dexamethasone group. This is the first study indicating that short-term glucocorticoid administration in healthy subjects increased corticospinal excitability that contributed to enhance MVC torque.

Randomized, double-blind, placebo-controlled, multiple-dose study of the safety, tolerability and pharmacokinetics of benvitimod, a candidate drug for the treatment of psoriasis

Benvitimod is a newly synthesized non-steroidal small molecule, aimed at the treatment for psoriasis. Several trials have demonstrated that benvitimod improves plaque psoriasis. However, its maximum tolerated dose and pharmacokinetic characteristics have not been reported on. The goals of this study were to evaluate the safety, tolerability and pharmacokinetics of benvitimod after topical administration in healthy subjects. This phase I trial in healthy subjects was designed as a randomized, double-blind, placebo-controlled, ascending-dose study. After screening and randomization, 56 volunteers received benvitimod (0·5-2·0%) or placebo cream once or twice daily. Doses were escalated from 5 to 30mg daily in six cohorts. Safety and tolerability were appraised by monitoring adverse events and laboratory parameters. Benvitimod concentrations were measured using liquid chromatography-tandem-mass spectrometry. Exposure to benvitimod did not result in electrocardiographic or clinical laboratory changes. Doses up to 30mg were well tolerated. All adverse events were mild. Adverse effects at the application site were observed in subjects randomized to benvitimod 5mg q.d and b.i.d, but there were no observable dose effects in the dose-range evaluated. Benvitimod was detected in fewer than 5% of the plasma samples. Benvitimod cream, at single doses of up to 30mg, is well tolerated by healthy subjects. Following topical application, systemic absorption was negligible.

Opicapone: a short lived and very long acting novel catechol-O-methyltransferase inhibitor following multiple dose administration in healthy subjects.

The aim of this study was to assess the tolerability, pharmacokinetics and inhibitory effect on erythrocyte soluble catechol-O-methyltransferase (S-COMT) activity following repeated doses of opicapone. This randomized, placebo-controlled, double-blind study enrolled healthy male subjects who received either once daily placebo or opicapone 5, 10, 20 or 30 mg for 8 days. Opicapone was well tolerated. Its systemic exposure increased in an approximately dose-proportional manner with an apparent terminal half-life of 1.0 to 1.4 h. Sulphation was the main metabolic pathway. Opicapone metabolites recovered in urine accounted for less than 3% of the amount of opicapone administered suggesting that bile is likely the main route of excretion. Maximum S-COMT inhibition (Emax ) ranged from 69.9% to 98.0% following the last dose of opicapone. The opicapone-induced S-COMT inhibition showed a half-life in excess of 100 h, which was dose-independent and much longer than plasma drug exposure. Such a half-life translates into a putative underlying rate constant that is comparable with the estimated dissociation rate constant of the COMT-opicapone complex. Despite its short elimination half-life, opicapone markedly and sustainably inhibited erythrocyte S-COMT activity making it suitable for a once daily regimen.

Bioequivalence of Canakinumab Liquid Pre-Filled Syringe and Reconstituted Lyophilized Formulations Following 150 mg Subcutaneous Administration: A Randomized Study In Healthy Subjects

Canakinumab is a human anti-interleukin-1beta antibody approved for the treatment of cryopyrin associated periodic syndrome currently formulated as a lyophilized powder requiring reconstitution. A new formulation (solution for injection as pre-filled syringe) has been developed to avoid reconstitution. The objective of this study was to evaluate the bioequivalence of pre-filled syringe and reconstituted formulations following 150 mg administration in healthy subjects. This was an open-labeled, randomized, single dose, parallel-group study in 130 healthy subjects, followed for 120 days. Subjects received a single subcutaneous injection of 150 mg canakinumab after either reconstitution or in pre-filled syringe formulation, followed by pharmacokinetics/pharmacodynamics evaluations and safety assessments. The main outcome measure for the study was the pharmacokinetic bioequivalence of the two formulations, which was concluded if the 90% confidence intervals for the ratios of AUC(last) (area under the serum concentration-time curve from time zero to time of last measurable concentration) and C(max) (maximum serum concentration) were entirely contained within the interval, 0.80-1.25. The arithmetic mean values for the exposure parameters C(max) and AUC(last) were similar for the two formulations. The geometric mean ratio (pre-filled syringe vs. lyophilized form) of C(max) and AUC(last) were 0.99 and 1.01. The associated 90% confidence intervals were 0.90 to 1.08 and 0.94 to 1.09, respectively. Most common adverse events were headache and nasopharyngitis. Neutropenia occurred in 2 cases (reported as serious adverse events). No deaths occurred. The 150 mg liquid pre-filled syringe and lyophilized formulations of canakinumab are bioequivalent.

Pharmacokinetics and Pharmacodynamics of CHF5074 After Short-term Administration in Healthy Subjects

CHF5074 has been shown to inhibit brain β-amyloid deposition and attenuate memory deficits in different transgenic mice models of Alzheimer disease. We evaluated the safety, pharmacokinetics, and pharmacodynamics of 3 ascending dose regimens of CHF5074 (200, 400, and 600 mg/d for 14 d) in a double-blind, placebo-controlled, parallel group study involving 48 healthy subjects. Plasma, urine, and cerebrospinal fluid (CSF) samples were collected for measuring drug and main metabolite concentrations and potential biomarkers of pharmacodynamic activity (β-amyloid1-40, β-amyloid1-42, soluble CD40 ligand, and tumor necrosis factor-α). All subjects completed the study, and no serious or severe adverse events were reported. The maximum tolerated dose was close to 600 mg/d with mild diarrhea being the most frequent adverse event at this dose. CHF5074 reached peak plasma levels 2 to 3 hours after drug administration and then was slowly eliminated (t(1/2z)=30 h) in the urine as glucoronide. Systemic exposure to the drug appeared to be dose-proportional with a 2-fold accumulation ratio at steady state. Metabolite plasma levels peaked at 4 to 5 hours and accounted for about 25% of the parent compound. Drug levels in the CSF were dose-proportional. The drug dose-dependently lowered the levels of the soluble CD40 ligand, a marker of microglia activation, in both plasma and CSF samples.

Endoscopic Vascular Targeted Photodynamic Therapy with the Photosensitizer WST11 for Benign Prostatic Hyperplasia in the Preclinical Dog Model

Vascular targeted photodynamic therapy with WST11 (TOOKAD® Soluble) is in phase III clinical trials of an interstitial transperineal approach for focal therapy of prostate cancer. We investigated the safety and efficacy of the endourethral route in the context of benign prostatic hyperplasia in the dog model. An optical laser fiber was positioned in the prostatic urethra of 34 dogs, including 4 controls. It was connected to a 753 nm diode laser at 200 mW/cm fluence, delivering 200 to 300 J. WST11 (5 to 15 mg/kg) was infused intravenously in 2 modes, including continuous, starting 5 to 15 minutes before and during illumination, or a bolus 5 to 10 minutes before illumination. Prostate ultrasound, cystourethrogram, urodynamics and histopathology were performed. Followup was 1 week to 1 year. Endourethral WST11 vascular targeted photodynamic therapy was uneventful in all except 1 dog, which experienced urinary retention but reached the 1-week end point. All prostates except those in controls showed hemorrhagic lesions. They consisted of 2 levels of concentric alterations, including periurethral necrosis with endothelial layer destruction and adjacent inflammation/atrophy with normal blood vessels. Prostatic urethral width increased as early as 6 weeks after treatment, while prostatic volume decreased, reaching 25% by 18 to 26 weeks. A parallel decrease in urethral pressure at 6 weeks lasted up to 1 year. We confirmed the vascular effect of endourethral WST11 vascular targeted photodynamic therapy. To our knowledge we report for the first time that the resulting periurethral necrosis led to significant, sustained widening of the prostatic urethra, accompanied by long-term improvement in urodynamic parameters. These findings support future clinical applications of this minimally invasive approach to benign prostatic hyperplasia.

Diagnosing malabsorption with systemic lipid profiling: pharmacokinetics of pentadecanoic acid and triheptadecanoic acid following oral administration in healthy subjects and subjects with cystic fibrosis

Objective: A Malabsorption Blood Test (MBT) is proposed as an alternative method to the 72-hour stool and dietary collection for assessing the degree of fat malabsorption in people with pancreatic insufficiency. The MBT consists of a simultaneous oral dose of pentadecanoic acid (PA), a free fatty acid, and triheptadecanoic acid (THA), a triglyceride with three heptadecanoic (HA) saturated fatty acids requiring hydrolysis by pancreatic lipase before HA can be intestinally absorbed. The aim of this study is to demonstrate the ability of MBT to detect fat malabsorption in healthy adult subjects using the pancreatic lipase (PL) inhibitor Orlistat (Xenical®), and in subjects with CF and PI while on and off routine pancreatic enzyme doses. Materials and methods: The MBT with the PA and THA were delivered in a breakfast test meal (2.5 g PA and either 5 g or 8 g THA) to healthy adult subjects (ages 18 – 50 years, BMI 21 – 30) and to subjects with CF (> 12 years, FEV1% predicted > 40%), after a 12-hour fast and 24 hours without dairy foods. Serum levels of PA and HA were assessed by gas-liquid chromatography, from blood samples drawn prior to MBT and then hourly for 8 hours. For healthy subjects, the MBT was administered before and after Orlistat treatment, and in subjects with CF, both with subjects receiving routine pancreatic lipase treatment (“on enzyme”) and also “off enzyme” treatment. Treatment groups were compared for baseline (C0) and maximum (Cmax) plasma concentrations of PA and HA over 8 hours: area under the curve (AUC) was calculated using linear trapezoid method. The ratio of HA to PA Cmax and AUC was also calculated and compared. Results: For the healthy subjects (n = 15, 60% female, ages 21 – 49 years), absorption of HA was reduced 71% for Cmax (p < 0.001) and 65% for AUC (p = 0.001) after Orlistat treatment, and absorption of PA was unchanged. For subjects with CF (n = 6, 50% female, ages 13 – 19 years), absorption of HA was minimal with subjects “off enzymes” and increased significantly with subjects “on enzymes” while absorption of PA did not differ between groups. Enzyme administration resulted in increased Cmax HA/PA ratios from 0.02 to 0.92 and from 0.05 to 0.73 in subjects with CF receiving 5.0 g and 8.0 g of THA, respectively. AUC HA/PA ratios showed similar increases. Conclusions: In this pilot and feasibility proof-of-concept study, the MBT, utilizing the relative absorption of HA to PA, two odd-chained fatty acids, responds to changes in fat absorption in healthy subjects using a lipase inhibitor and in subjects with CF while on or off enzyme therapy. The MBT holds promise to provide a more accurate, specific and acceptable alternative to the 72-hour stool collection to quantify pancreatic-based fat malabsorption in a variety of clinical and research contexts.

Pharmacokinetics, Pharmacodynamics and Safety of JES9501 after Single and Multiple Oral Administration in Healthy Subjects

=Abstract= Pharmacokinetics, Pharmacodynamics and Safety of JES9501 after Single and Multiple Oral Administration in Healthy Subjects AnHye Kim, Bo-Hyung Kim, Dongseong Shin, Joo-Youn Cho, Kyung-Sang Yu, In-Jin Jang, Jae-Yong Chung Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Korea, Department of Clinical Pharmacology and Therapeutics, Kyung Hee University Hospital, Seoul, Republic of Korea , Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Bundang Hospital, Seongnam, Korea

Pharmacokinetics and Pharmacodynamics of IPI-145, a Potent Inhibitor of Phosphoinositide-3-Kinase-δ,γ, Following Single- and Multiple-Dose Administration in Healthy Subjects and Patients with Advanced Hematologic Malignancies

AbstractAbstract 4853 Introduction:Phosphoinositide-3-kinases (PI3Ks) play pivotal roles in cell signaling and regulate a variety of cellular functions. PI3K-δ and PI3K-γ isoforms are necessary for adaptive and innate immunity and contribute to the development and maintenance of inflammatory and autoimmune diseases and hematologic malignancies. IPI-145 is a potent inhibitor of PI3K- δ,γ isoforms (Ki = 23 pM and 243 pM, respectively) in clinical development for patients with advanced hematologic malignancies and inflammatory/autoimmune disorders. The pharmacokinetics (PK) and pharmacodynamics (PD) of IPI-145 were evaluated in a Phase 1 clinical study in healthy subjects and are being characterized in patients with advanced hematologic malignancies. Methods:In a healthy subject study, IPI-145 was administered orally as a single dose and as multiple doses once daily (QD) or twice daily (BID) for 14 days. In a Phase 1 oncology study, IPI-145 was administered orally starting at a dose of 8 mg BID. PK and PD markers were evaluated after the first dose and at steady state. PD activity (PI3K inhibition) in whole blood was evaluated using a basophil activation assay which measured reduction in CD63 expression on the surface of basophils following ex vivo stimulation. Results:IPI-145 was well tolerated in healthy subjects at single doses up to 30 mg (highest dose tested) and up to 10 mg total daily dose (highest dose tested; 5 mg BID or 10 mg QD) for 14 days. In healthy subjects, the PK profile of IPI-145 is characterized by rapid absorption (peak plasma concentrations reached within 0.5–1 hour), moderately rapid elimination (half-life 3.5 to 9.5 hours following a single dose and 6.5 to 11.7 hours following repeat dosing) and dose proportional increases in systemic exposure (Cmax and AUC). Minimal accumulation was observed after multiple dose administration (accumulation ratio 1.65–1.83 for BID dosing and 1.54 for QD dosing). Following single oral dose administration, clearance ranged from 6.7 L/h to 11.1 L/h and the volume of distribution ranged from 38.8 L to 147 L. Excretion of unchanged IPI-145 in urine was <2% of the administered dose, indicating minimal renal elimination of parent drug. CD63 expression on the surface of activated CCR3+ basophils was reduced in a dose-dependent manner at all single and multiple dose levels, with a maximum reduction at 1 hour post dose, corresponding to the time of maximum IPI-145 plasma concentrations. Inhibition of basophil activation mirrored the IPI-145 concentration-time profile, with CD63 expression returning to baseline levels as plasma concentrations declined. Administration of 5 mg BID maintained PI3K-δ inhibition (EC50 = 48 ng/mL) throughout the 12 hour dosing interval. Concomitant administration of a high-fat, high-calorie meal decreased Cmax approximately 10%, shifted median Tmaxfrom 1 to 3 hours, and increased overall exposure (AUC) approximately 8–9%. These data suggest IPI-145 may be administered without regard to meals. Emerging data from a Phase 1, dose escalation study in subjects with hematologic malignancies demonstrate rapid drug absorption and dose-proportional PK. As in healthy subjects, maximum inhibition of basophil activation was observed 1 hour post dose. Prior to dose administration at the beginning of Cycle 2 (i.e. after 28 days of BID dosing), CD63 expression was reduced 45% or more relative to the start of treatment. Mean steady-state trough concentrations were maintained above levels sufficient for PI3K-δ inhibition following doses ≥15 mg BID. Early signs of clinical response have been observed. Conclusions:Across both Phase 1 studies, IPI-145 drug absorption was rapid and exposure was proportional to dose. CD63 expression on the surface of activated basophils was reduced in the presence of IPI-145 in both healthy and oncology subjects, an observation consistent with PI3K-δ inhibition. An exposure-response relationship was evident, suggesting a concentration-dependent pharmacological response to IPI-145. Preliminary PK/PD data from the oncology study demonstrate inhibition of PI3K-δ activity and suggest higher doses may increasingly suppress PI3K-γ activity. Dose escalation and PK/PD monitoring are ongoing. Collectively, the data available support the clinical development of IPI-145 as a potential therapeutic in hematologic malignancies and inflammatory diseases. Disclosures:Dunbar:Infinity Pharmaceuticals, Inc.: Employment. Nevejans:Infinity Pharmaceuticals, Inc.: Employment. McKee:Infinity Pharmaceuticals, Inc.: Employment. Faia:Infinity Pharmaceuticals, Inc.: Employment. Zhao:ApoCell: Employment. Kahl:Infinity Pharmaceuticals, Inc.: Research Funding. Horwitz:Seattle Genetics: Consultancy, Research Funding; Allos: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy; Genzyme: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy; Johnson & Johnson: Consultancy; Infinity Pharmaceuticals, Inc.: Research Funding. Patel:Infinity Pharmaceuticals, Inc.: Research Funding. Younes:Novartis: Honoraria, Research Funding; Celgene: Honoraria; Seattle Genetics: Honoraria, Research Funding; Sanofi-Aventis: Honoraria, Research Funding; MIllenium: Honoraria; Incyte: Honoraria; Genentech: Research Funding; Infinity Pharmaceuticals, Inc.: Research Funding; Gilead: Research Funding. Flinn:Infinity Pharmaceuticals, Inc.: Research Funding.

P1‐229: Population pharmacokinetic modeling of the novel BACE inhibitor MK‐8931 following single and multiple dose administration in healthy subjects

P1‐229: Population pharmacokinetic modeling of the novel BACE inhibitor MK‐8931 following single and multiple dose administration in healthy subjects

A Double-Blind, Placebo-Controlled, and Multiple Dose Escalation Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Ono-7746 in Healthy Subjects

Abstract 4828 Background:ONO-7746 is a potent orally administered thrombopoietin receptor (c-Mpl) agonist and can elevate platelet counts after a single dose in healthy subjects. Therefore, it could be potentially used for the treatment of thrombocytopenia associated with a variety of etiologies. Objectives:This study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of ONO-7746 after multiple dose administration in healthy subjects. Methods:A total of 60 subjects were randomly assigned to 5 groups of 12 subjects each to receive active ONO-7746 (9 subjects) or placebo (3 subjects) once daily for 14 days at doses of 1, 2, 4, 6, and 10 mg per day. Dose selection was adjusted based on data from earlier cohorts according to the dose-escalation procedures, i.e. Dose escalation was only permitted if adequate safety and tolerability were demonstrated and the results did not meet the stopping rule criteria at the previous dose level as described in the single-dose study. Subjects returned on Day 42 for follow-up assessments. ONO-7746 was administered once daily under fasted conditions at the dose of 1 mg to 10 mg for 14 days. Subjects were admitted to the clinical study site on Day –1 and remained at the site until discharge on Day 32. Intensive safety, tolerability, PK, and PD assessments were made throughout the study. Safety assessments included 12-lead ECGs, vital signs, serum chemistry, hematology, urinalysis and adverse event (AE) reporting. Plasma samples for ONO-7746 concentration-time analysis were collected at several time points. PD parameters included platelet count, platelet activation, and aggregation. Results:Maximum platelet count and change from Baseline values increased with ascending ONO-7746 dose level. The mean platelet counts in the ONO-7746 cohorts increased from Baseline beginning on Days 3 or 4, peaked between Days 12 and 17, decreased from Days 22 to 32, and returned to baseline levels by Day 42. The largest mean percent change from Baseline in average platelet count (145.9%) was observed in the 10-mg cohort, compared with 17.4% in the placebo cohort. Platelet function as measured by the exploratory platelet aggregation and activation tests was not affected by administration of ONO-7746. In general, endogenous TPO values and CD34+ cell counts seemed not to be affected by the administration of ONO-7746. The PK profiles of ONO-7746 showed that Cmax and AUC24h increased with dose and T1/2 after the last dose was similar to that after a single dose. The plasma trough concentration of ONO-7746 reached steady state by Day 10. The PK of ONO-7746 was not affected by multiple-dose administration. Six subjects in the 10-mg cohort had an adverse event of special interest (AESI) of increased platelet count > 500 × 109/L. No treatment- or dose-related trends were observed in AEs, clinical laboratory results, influence on other blood cell counts, physical examination findings, vital sign measurements, 12-lead ECG and telemetry results, or slit lamp examination results. There were no deaths, serious AEs, severe AEs, or AEs that led to study discontinuation. Conclusion:ONO-7746 is safe and well-tolerated at all tested dose levels. The PK, PD, and safety profile demonstrated in this study supports further clinical studies in thrombocytopenic patients.Observed Platelet Count by Study Day [Display omitted] Disclosures:Hunt:ONO Pharma USA: Research Funding. Lu:ONO Pharma USA: Employment. Kawasaki:Ono Pharmaceutical Co., Ltd.: Employment. Hall:ONO Pharma USA: Employment. Komaba:Ono Pharmaceutical Co., Ltd.: Employment. Takeuchi:Ono Pharmaceutical Co., Ltd.: Employment. Imamura:ONO Pharma USA: Employment. Kuter:ONO Pharma USA: Consultancy.

Short-term metabolic effects of prednisone administration in healthy subjects

Supraphysiologic glucocorticoid activity is well established to cause impaired glucose tolerance and insulin resistance, yet no study has evaluated dose-dependent effects of low-dose prednisone during short-term oral administration. The objective of this study was to quantify the effects of daily 10 or 25 mg prednisone administration for one week on insulin sensitivity by employing a two-step hyperinsulinemic euglycemic glucose clamp (Step 1: insulin infusion = 20 mU/m²/min; Step 2: insulin infusion = 80 mU/m²/min) in healthy, lean males. The amount of glucose infused at steady-state to maintain stable blood glucose [90 mg/dl (4.95 mmol/l)] was used to calculate several indices of insulin sensitivity. During Step 1 of the clamp, whole body glucose disposal (M) was reduced by 35% (p = 0.003) and M/I was reduced by 29% (p = 0.025) for 25 mg prednisone compared to placebo. No appreciable effect of 10 mg prednisone was observed. During Step 2, M was reduced by 33% (p = 0.001) and 15% (p = 0.006) for 25 and 10 mg prednisone compared to placebo; and M/I ratio was reduced by 31% (p < 0.001) and 13% (p = 0.026), respectively. The insulin sensitivity index, Si, calculated as the quotient of augmentation of M/I between Step 1 and 2, was reduced by 35.3% (p < 0.01) and 23.5% (p < 0.05) for 25 and 10 mg prednisone, respectively. Administration of relatively low pharmacological doses of prednisone for one week impaired insulin sensitivity in a dose-dependent manner in healthy males. These observed changes in insulin sensitivity are likely to be clinically relevant, especially in individuals predisposed to develop glucose intolerance.

A randomized, placebo‐controlled study investigating the effects of moxaverine on ocular blood flow after oral administration in healthy subjects

AbstractPurpose We know that several eye diseases such as glaucoma, diabetic retinopathy and AMD are associated with ocular perfusion abnormalities. In recent studies we have shown that intravenous administration of moxaverine is capable of increasing ocular blood flow in healthy subjects compared to placebo as well as in elderly people with healthy eyes and in patients with eye diseases associated with hypoperfusion. In the present study we hypothesized that oral moxaverine may increase ocular blood flow.Methods In this placebo‐controlled, two‐way crossover study 16 healthy subjects received 900 mg moxaverine‐hydrochloride, administrated per os in 3 equal doses, and placebo. Outcome variables were measured at BL and 5 hours after first drug administration. Choroidal and optic nerve head blood flow (ONHBF) were assessed with laser Doppler flowmetry and blood velocities in the retrobulbar vessels were measured with color Doppler imaging.Results No parameter showed any difference between moxaverine and placebo. The p‐values of ANOVA testing between moxaverine and placebo were as follows: Choroidal blood flow (p=0.52), ONHBF (p=0.54), peak systolic velocity (PSV) in the ophthalmic artery (p=0.33), end diastolic velocity (EDV) in the ophthalmic artery (p=0.58), PSV in the posterior ciliary arteries (p=0.38), EDV in the posterior ciliary arteries (p=0.26), PSV in the central retinal artery (p=0.35), EDV in the central retinal artery (p=0.51).Conclusion Our results indicate that oral moxaverine, in contrast to systemic moxaverine, does not increase ocular blood flow. This may be related to the relatively low bioavailability of moxaverine after oral administration.

Ascorbic acid prevents vascular dysfunction induced by oral glucose load in healthy subjects

Objectives To examine the effects of oral glucose load on forearm circulatory regulation before and after ascorbic acid administration in healthy subjects. Design Microcirculation study with laser Doppler was performed at the hand in basal conditions, after ischemia and after acetylcholine and nitroprusside; strain gauge plethysmography was performed at basal and after ischemia. The tests were repeated in the same sequence 2 hour after oral administration of glucose (75 g). The subjects were randomised for administration of ascorbic acid (1 g bid) or placebo (sodium bicarbonate 1 g bid) for 10 days. After that, the tests were repeated before and after a new oral glucose load. Blood pressure and heart rate were monitored. Results Macrocirculatory flux, pressure values and heart rate were unvaried throughout the study. The glucose load caused a reduction in the hyperemic peak flow with laser Doppler and plethysmography; it reduced flux recovery time and hyperemic curve area after ischemia; acetylcholine elicited a minor increase in flux with laser Doppler. The response to nitroprusside was unvaried after glucose load as compared to basal conditions. Treatment with ascorbic acid prevented the decrease in hyperemia after glucose, detected with laser Doppler and plethysmography. Ascorbic acid prevented the decreased response to acetylcholine after glucose, the response to nitroprusside was unaffected by ascorbic acid. Results after placebo were unvaried. Conclusions Oral glucose load impairs endothelium dependent dilation and hyperaemia at microcirculation, probably via oxidative stress; ascorbic acid can prevent it.

Effects of strong CYP2D6 and 3A4 inhibitors, paroxetine and ketoconazole, on the pharmacokinetics and cardiovascular safety of tamsulosin.

Tamsulosin metabolism involves both CYP2D6 and 3A4. However, data on potential drug-drug interactions between tamsulosin and inhibitors of CYP2D6 and 3A4 are limited and information on potential pharmacodynamic consequences of such pharmacokinetic interactions is missing. This study provides information on the drug-drug interactions of tamsulosin with strong CYP2D6 and strong CYP3A4 inhibitors after single dose administration in healthy subjects. To determine the effect of the strong CYP2D6 inhibitor paroxetine and strong CYP3A4 inhibitor ketoconazole on the pharmacokinetics and safety (orthostatic challenge) of tamsulosin. Two open-label, randomized, two-way crossover studies were conducted in healthy male volunteers (extensive CYP2D6 metabolizers). Co-administration of multiple oral doses of 20 mg paroxetine once daily with a single oral dose of the 0.4 mg tamsulosin HCl capsule increased the adjusted geometric mean (gMean) values of C(max) and AUC(0,∞) of tamsulosin by factors of 1.34 (90% CI 1.21, 1.49) and 1.64 (90% CI 1.44, 1.85), respectively, and increased the terminal half-life (t(1/2) ) of tamsulosin HCl from 11.4 h to 15.3 h. Co-administration of multiple oral doses of 400 mg ketoconazole once daily with a single oral dose of the 0.4 mg tamsulosin increased the gMean values of C(max) and AUC(0,∞) of tamsulosin by a factor of 2.20 (90% CI 1.96, 2.45) and 2.80 (90% CI 2.56, 3.07), respectively. The terminal half-life was slightly increased from 10.5 h to 11.8 h. These pharmacokinetic changes were not accompanied by clinically significant alterations of haemodynamic responses during orthostatic stress testing. The exposure to tamsulosin is increased upon co-administration of strong CYP2D6 inhibitors and even more so of strong 3A4 inhibitors, but neither PK alteration was accompanied by clinically significant haemodynamic changes during orthostatic stress testing.

First-in-Human Study of the Novel Acid Pump Antagonist, RQ-00000004, Demonstrated a Rapid Elevation of Gastric pH Following Single Oral Administration in Healthy Subjects

First-in-Human Study of the Novel Acid Pump Antagonist, RQ-00000004, Demonstrated a Rapid Elevation of Gastric pH Following Single Oral Administration in Healthy Subjects

Pharmacodynamics-Mediated Drug Disposition (PDMDD) and Precursor Pool Lifespan Model for Single Dose of Romiplostim in Healthy Subjects

The objective of this study was to characterize the pharmacokinetics and pharmacodynamics (PK-PD) of romiplostim after single-dose administration in healthy subjects. The mean serum romiplostim concentrations (PK data) and mean platelet counts (PD data) collected from 32 subjects receiving a single intravenous (0.3, 1 and 10 μg/kg) or subcutaneous (0.1, 0.3, 1, and 2 μg/kg) dose were fitted simultaneously to a mechanistic PK-PD model based on pharmacodynamics-mediated drug disposition (PDMDD) and a precursor pool lifespan concept. The two-compartment PK model incorporated receptor-mediated endocytosis and linear mechanisms as parallel elimination pathways. The maximal concentration of receptors (assumed to be proportional to the platelet count), the equilibrium dissociation constant, and the first-order internalization rate constant for endocytosis of the drug-receptor complex were 0.022 fg/platelet, 0.131 ng/mL, and 0.173 h⁻¹, respectively. Romiplostim concentration stimulates the production of platelet precursors via the Hill function, where the SC₅₀ was 0.052 ng/mL and S (max) was 11.2. The estimated precursor cell and platelet lifespans were 5.9 and 10.5 days, respectively. Model-based simulations revealed that the romiplostim exposure and the platelet response are both dependent on the dose administered and the baseline platelet counts. Also, weekly dosing produced a sustained PD response while dosing intervals ≥2 weeks resulted in fluctuating platelet counts. Thus, the mechanistic PK-PD model was suitable for describing the romiplostim PK-PD interplay (PDMDD), the dose-dependent platelet stimulation, and the lifespans of thrombopoietic cell populations.