Single Ascending Dose Study Research Articles

Effects of a selective glucocorticoid receptor modulator (AZD9567) versus prednisolone in healthy volunteers: two phase 1, single-blind, randomised controlled trials.

Glucocorticoids are highly effective and widely used anti-inflammatory drugs, but their use is limited by serious side-effects, including glucocorticoid-induced hyperglycaemia and diabetes. AZD9567 is a non-steroidal, selective glucocorticoid receptor modulator that aims to reduce side-effects. We aimed to assess the safety, tolerability, and pharmacokinetics of AZD9567 in healthy volunteers. Two phase 1 clinical studies were done. First, a randomised, placebo-controlled, single-blind, single-ascending dose study was done in healthy men who received single oral doses of AZD9567 2 mg, 10 mg, 20 mg, 40 mg, 80 mg, 100 mg, 125 mg, or 155 mg, or prednisolone 60 mg (n=8 per dose group, randomly assigned [6:2] to receive active drug or placebo). Second, a randomised, active-controlled, single-blind, multiple-ascending dose study was done, in which men and women received oral AZD9567 or prednisolone once daily for 5 days. One cohort of volunteers with prediabetes received AZD9567 10 mg (n=7) or prednisolone 20 mg (n=2). All other cohorts comprised healthy volunteers, receiving AZD9567 20 mg, 40 mg, 80 mg, or 125 mg (n=7 per dose group), or prednisolone 5 mg (n=13), 20 mg (n=16), or 40 mg (n=13). Participants and study centre staff were masked to treatment assignment for each cohort, although data were unmasked for safety review between cohorts. The primary outcome of the single-ascending dose study was the safety, tolerability, and pharmacokinetics of single ascending doses of AZD9567; for the multiple-ascending dose study it was the safety and tolerability of AZD9567 following multiple ascending doses. As a secondary outcome, effects on glycaemic control were ascertained with oral glucose tolerance tests (OGTTs) done at baseline and on day 1 of the single-ascending dose study, and at baseline and on day 4 of the multiple-ascending dose study. These trials are registered at ClinicalTrials.gov, NCT02512575 and NCT02760316. In the single-ascending dose study, between Nov 18, 2015, and Sept 26, 2016, 72 healthy white men were enrolled, and all completed the study. In the multiple-ascending dose study, between May 2, 2016, and Sept 13, 2017, 77 predominantly white male volunteers (including nine individuals with prediabetes and eight women) were enrolled and 75 completed the study. All doses of AZD9567 and prednisolone were well tolerated, with no serious adverse events or events suggesting adrenal insufficiency. In the single-ascending dose study, nine adverse events of mild intensity were reported (five with AZD9567 and four with placebo); no adverse event was reported by more than one person. In the multiple-ascending dose study, 44 adverse events of mild or moderate intensity were reported (18 with AZD9567 and 26 with prednisolone). The most common were headache and micturition. Apparent clearance, volume of distribution, and half-life of AZD9567 were consistent across doses and for single versus repeated dosing. In the multiple-ascending dose study, OGTTs showed no significant difference with AZD9567 doses up to 80 mg compared with prednisolone 5 mg in glucose area under the curve from 0 h to 4 h post-OGTT (AUC0-4h) from baseline to day 4; the increase in glucose AUC0-4h from baseline to day 4 was significantly lower with all AZD9567 doses versus prednisolone 20 mg (AZD9567 20 mg p<0·0001, 40 mg p=0·0001, 80 mg p=0·0001, and 125 mg p=0·0237). AZD9567 appears to be safe and well tolerated in healthy, predominantly white male volunteers and shows promising initial evidence for improved post-prandial glucose control. Studies of longer duration, with a greater proportion of women and other ethnic groups, and in patients requiring anti-inflammatory treatment are needed to characterise the clinical efficacy and safety profile of AZD9567. AstraZeneca.

A Phase 1 single ascending dose study of a novel orexin 2 receptor agonist, TAK-925, in healthy volunteers (HV) and subjects with narcolepsy type 1 (NT1) to assess safety, tolerability, pharmacokinetics, and pharmacodynamic outcomes

A Phase 1 single ascending dose study of a novel orexin 2 receptor agonist, TAK-925, in healthy volunteers (HV) and subjects with narcolepsy type 1 (NT1) to assess safety, tolerability, pharmacokinetics, and pharmacodynamic outcomes

P.165 Double-blind, placebo-controlled phase 1 single ascending dose study of sage-718

P.165 Double-blind, placebo-controlled phase 1 single ascending dose study of sage-718

A Double‐Blind, Phase I, Single Ascending Dose Study to Assess the Safety, Pharmacokinetics, and Pharmacodynamics of BOS161721 in Healthy Subjects

The purpose of this study was to assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and immunogenicity of BOS161721, a humanized immunoglobulin G1 triple mutation (M252Y/S254T/T256E) monoclonal antibody that inhibits interleukin‐21 (IL‐21) bioactivity. This randomized, single‐center, double‐blind, placebo‐controlled study randomized healthy volunteers 3:1 to single ascending intravenous and subcutaneous doses of BOS161721 (range 1–240 mg) or placebo. BOS161721 and placebo groups had similar rates of adverse events, mostly mild; none led to study discontinuation. There were no clinically significant findings in physical examination, vital signs, or laboratory assessment. In the pooled BOS161721 population, four subjects (8.5%) tested antidrug antibody‐positive predose, and seven (14.9%) postdose. Absolute CD4+ lymphocyte count remained normal throughout follow‐up. BOS161721 administered subcutaneously was absorbed slowly, with a median time to maximum concentration (Tmax) of 144 hours across doses (range 1–15 days) and a mean apparent terminal elimination half‐life of 80–87 days for doses ≥ 30 mg. Area under the concentration‐time curve from time zero to infinity (AUC0‐inf) and maximum observed concentration (Cmax) were linear across doses > 10 mg. Subcutaneous bioavailability was 64%. Phosphorylated signal transducer and activator of transcription 3 (pSTAT3) decreased dose‐dependently with threshold characteristics at doses of ≥ 10 mg. Downregulation in BATF, IL6, LAG3, and SOCS3 genes caused by IL‐21 stimulation was reversed dose‐dependently. BOS161721 was well‐tolerated across doses, suppressed IL‐21‐induced pSTAT3 dose‐dependently, and reversed downregulation of genes critical to tolerance induction and T‐cell exhaustion induced by IL‐21. Further clinical studies are ongoing in patients with systemic lupus erythematosus, in which IL‐21 has a pathogenetic role.

Randomized, double-blind, placebo-controlled phase I dose escalation study of Dan Qi Tong Mai tablet in healthy volunteers

BackgroundThis study aims to assess the tolerability and safety of DQTM tablet, which contains a complex mixture of Salvia miltiorrhiza salvianolic acids and Panax notoginseng saponins.MethodsA double-blind, randomized, placebo-controlled phase I dose escalation study was conducted in 84 healthy volunteers. In a single ascending dose study, active ingredients were administered in various doses (90, 270, 540, 1080, 1800, 2880, 4320 or 5760 mg) to 60 subjects in cohorts 1–8. In a multiple ascending dose study, active ingredients were administered at doses of 360, 720 or 2160 mg twice daily to 24 subjects in cohorts 9–11 for 14 consecutive days. Safety was evaluated based on clinical symptoms, vital signs, physical examinations, electrocardiography, laboratory tests and adverse events.ResultsNo serious adverse events or clinically significant changes in vital signs or electrocardiography were observed. One subject experienced mildly elevated levels of alanine aminotransferase and aspartate transaminase but recovered spontaneously. Five subjects experienced a small increase in the number of daily stools.ConclusionsDQTM tablet was well tolerated at single doses of up to 5760 mg and twice-daily doses of up to 2160 mg for 14 consecutive days. The most frequent adverse event was an increase in the number of daily stools.

Phase 1 Single (SAD) and Multiple Ascending Dose (MAD) Studies of the Safety, Tolerability, Pharmacokinetics (PK) and Pharmacodynamics (PD) of FT-4202, an Allosteric Activator of Pyruvate Kinase-R, in Healthy and Sickle Cell Disease Subjects

Phase 1 Single (SAD) and Multiple Ascending Dose (MAD) Studies of the Safety, Tolerability, Pharmacokinetics (PK) and Pharmacodynamics (PD) of FT-4202, an Allosteric Activator of Pyruvate Kinase-R, in Healthy and Sickle Cell Disease Subjects

A Phase I Study to Investigate the Safety, Tolerability, and Pharmacokinetics/Pharmacodynamics of Tripegfilgrastim (Dulastin®) after Single Administration in Pediatric Patients

Introduction: Chemotherapy-induced neutropenia (CIN) is one of main complications following systemic chemotherapy, which can cause many kinds of opportunistic infections. To overcome CIN, granulocyte colony stimulating factor (G-CSF) is usually administered to reduce neutropenic period. Tripegfilgrastim (Dulastin®) is one of pegfilgrastim drugs, which was approved for adult CIN by Korea Ministry of Food and Drug Safety in 2014. Methods: We have conducted a phase I, open-label, single ascending dose study to investigate the pharmacokinetics, safety, tolerability and pharmacodynamics of Tripegfilgrastim in pediatric patients with lymphoma or solid tumors. The patients were divided by dose of Tripegfilgrastim (60 μg/kg [lower dose, LD] and 100 μg/kg [higher dose, HD]) and age (6≤ and &amp;lt;12 years versus 12≤ and &amp;lt;19 years). Total planned number of patients was 32; 8 patients in each groups. Tripegfilgrastim was injected subcutaneously at 24 hours after the end of chemotherapy, and serial pharmacokinetic/pharmacodynamics blood samplings and safety monitoring were conducted. The trial was registered at ClinicalTrials.gov, NCT02963389. This study was supported by Dong-A ST Co., Ltd., Seoul, Republic of Korea. Results: Twenty-seven patients enrolled on this study, including 4 in LD and younger age group, 7 in LD and older age group, 8 in HD and younger age group, and 8 in HD and older age group. Six malignant germ cell tumors, 5 non-rhabdomyosarcoma soft tissue sarcomas, 4 osteosarcomas, 3 rhabdomyosarcomas, 3 neuroblastomas, 2 medulloblastomas, and 4 others were included. All enrolled patients had previously received the same-regimen chemotherapy, which had induced grade 4 neutropenia. Due to insufficient pharmacodynamics by interim analysis in some patients of LD groups, these were early closed and subsequent enrolled patients received HD of Tripegfilgrastim. The maximum concentration (Cmax) and area under the curve until 312 hours (AUC0-312h) were 89.57 ± 40.97 μg/L and 8371.99 ± 4773.29 μg∙h/L in LD group, and 130.15 ± 72.04 μg/L, 11977.40 ± 7572.29 μg∙h/L in HD group, respectively. The peak concentration was achieved at 24 hours after injection, and the Cmax and AUC0-312h of HD group were increased by 45% compared with LD group. The half-life, clearance, and volume of distribution were 47.22 hours, 0.45 L/h, 28.1 L in LD group, 40.78 hours, 0.52 L/h, 28.78 L in HD group, respectively. When these pharmacokinetics parameters were compared with our previous results of healthy adult volunteers, Cmax of LD group was similar to adult 3.6 mg injection, while Cmax and AUC0-312h of HD group were 36% and 50% of those of adult 6.0 mg injection. To investigate the pharmacodynamics, days when the absolute neutrophil count (ANC) is above 1,000/μL (T above ANC 1000), and days when ANC is below 500/μL (T below ANC 500) were evaluated. The mean T above ANC 1000 (range, days) were 7.1 days (1.6-13.6) in LD group, and 9.3 days (3.4-13.7) in HD group, respectively. Furthermore, the mean T below ANC 500 (range, days) were 4.4 days (0-10.8) in LD group, and 2.5 days (0-10.1) in HD group, respectively, which showed better pharmacodynamics in HD group. However, high inter-patient variability was observed. There was no significant difference between younger and older age groups in each LD and HD groups. There were 2 adverse drug reactions (7.4%) related to Tripegfilgrastim, which were grade 1 back pain and grade 2 arthralgia. Three severe adverse events occurred (2 bacteremia and 1 skin lesion), which resolved with further treatments. Conclusions: Tripegfilgrastim have shown safety and tolerability in pediatric patients between 6 to 19 years old with solid tumors. The pharmacokinetics parameters, Cmax and AUC0-312h of HD group were increased by 45% compared with LD group, which translates into the better pharmacodynamics parameters of HD group without increasing toxicity. Our results suggests that Tripegfilgrastim 100 μg/kg once injection could be feasible to reduce CIN in pediatric patients. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: Tripegfilgrastim to investigate the safety, tolerability, and pharmacokinetics/pharmacodynamics

Study of Single Ascending Doses of PF-07081532 in Healthy Adult Participants

Study of Single Ascending Doses of PF-07081532 in Healthy Adult Participants

Clinical pharmacology of the dual orexin receptor antagonist ACT-541468 in elderly subjects: Exploration of pharmacokinetics, pharmacodynamics and tolerability following single-dose morning and repeated-dose evening administration.

The dual orexin receptor antagonist ACT-541468 showed sedative pharmacodynamic effects during initial clinical testing in adult subjects. The present study explored pharmacokinetics, pharmacodynamics and tolerability in healthy elderly subjects. Double-blind, placebo-controlled, randomised, single-ascending dose study in 24 male/female elderly (65-80 years, 5, 15 and 25 mg in the morning, 6/2 active/placebo per group). Additionally, 10 subjects (8/2 active/placebo) received 25 mg for 7 days in the evening. Pharmacokinetics, pharmacodynamics (saccadic peak velocity, adaptive tracking, body sway, visual analogue scales according to Bowdle and Bond and Lader, Karolinska Sleepiness Scale) and tolerability were assessed. In particular, pharmacodynamics results are to be interpreted exploratorily. Absorption was quick with a median time to maximum concentration of ∼ 1.0 h. The mean elimination half-life was 8.5-9.8 h, the area under the curve and the maximum plasma concentration increased proportionally with dose. Following repeated evening administration of 25 mg, minimal accumulation was observed. There were no pharmacodynamic effects at 5 mg. At 15 mg, saccadic peak velocity (degree/s; SD) was reduced (69; 38), while other variables showed no effects. At 25 mg, effects on all objective pharmacodynamic parameters were observed. At 8-12 h post-dose, there were no differences to placebo and no next-day effects on pharmacodynamic variables after evening administration. Elderly subjects reported fewer adverse events compared to adults in previous studies. ACT-541468 in elderly subjects was well tolerated and pharmacokinetics and pharmacodynamics are compatible with a drug for the treatment of insomnia. Clinicaltrials.gov: NCT02571855.

Single Ascending Dose Study to Investigate the Safety and Pharmacokinetics of XC101-D13H in Healthy Adult Subjects

Single Ascending Dose Study to Investigate the Safety and Pharmacokinetics of XC101-D13H in Healthy Adult Subjects

A Study of Single Ascending Doses of STAR-101 in Healthy Participants

A Study of Single Ascending Doses of STAR-101 in Healthy Participants

A Single and Multiple Ascending Dose Study of BMS-986318 in Healthy Participants

A Single and Multiple Ascending Dose Study of BMS-986318 in Healthy Participants

Single Ascending Dose Study to Assess the Safety, Tolerability, PK and PD of ONO-4685 in Japanese and Caucasian Healthy Adult Male Subjects

Single Ascending Dose Study to Assess the Safety, Tolerability, PK and PD of ONO-4685 in Japanese and Caucasian Healthy Adult Male Subjects

Single Ascending Dose Study to Assess Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of HM15912 in Healthy Korean Subjects

Single Ascending Dose Study to Assess Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of HM15912 in Healthy Korean Subjects

A Study of Single and Multiple Ascending Doses of KBL697 in Healthy Subjects

A Study of Single and Multiple Ascending Doses of KBL697 in Healthy Subjects

Single Ascending Dose Study Investigating the Safety, Tolerability, and PK of XC130-A10H in Healthy Adult Subjects

Single Ascending Dose Study Investigating the Safety, Tolerability, and PK of XC130-A10H in Healthy Adult Subjects

Effect of Cefiderocol, a Siderophore Cephalosporin, on QT/QTc Interval in Healthy Adult Subjects

PurposeCefiderocol is a novel siderophore cephalosporin with potent activity against gram-negative bacteria, including multidrug-resistant strains. This Phase I study was conducted to assess the tolerability of single-ascending doses of cefiderocol (part 1) and the effect of cefiderocol on cardiac repolarization, assessed using the electrocardiographic corrected QT interval (QTcF) and other ECG parameters (part 2), in healthy adult subjects. MethodsPart 1 was a randomized, double-blind, placebo-controlled, single-ascending dose study in healthy adult male and female subjects. Part 2 was a 4-period crossover study in which subjects received a single 2-g dose of cefiderocol (therapeutic dose), a single 4-g dose of cefiderocol (supratherapeutic dose), or saline (placebo), each infused over 3 hours, and a single oral 400-mg dose of moxifloxacin. In each treatment period, continuous cardiac monitoring was used to assess the effects of cefiderocol on ECG parameters. The QT interval corrected using the Fridericia formula (QTcF) was the primary ECG parameter; the time-matched placebo- and baseline-adjusted (dd)-QTcF interval was the primary end point. The plasma pharmacokinetic properties of cefiderocol were calculated on the basis of concentration–time profiles in all evaluable subjects. FindingsAll point estimates for the ddQTcF interval were <5 ms and the upper bound of the 90% CIs were <10 ms at each timepoint after the initiation of the cefiderocol 3-hour infusion. Concentration-effect modeling showed a slightly negative slope and predicted modestly negative values of the ddQTcF interval at the Cmax of cefiderocol. Both doses of cefiderocol were well tolerated. All adverse events were mild in severity, with no deaths or serious adverse events reported. ImplicationsOverall, therapeutic and supratherapeutic doses of cefiderocol had no apparent clinically significant effect on the QTcF.

Single Ascending Dose Study for Evaluation of Safety, Tolerability and Pharmacokinetics of L606

Single Ascending Dose Study for Evaluation of Safety, Tolerability and Pharmacokinetics of L606

A Single Ascending Dose Study to Investigate the Safety, Tolerability, Immunogenicity and Pharmacokinetics of Intravenously Administered RO7126209 in Healthy Participants

A Single Ascending Dose Study to Investigate the Safety, Tolerability, Immunogenicity and Pharmacokinetics of Intravenously Administered RO7126209 in Healthy Participants

Single and Multiple Ascending Dose Study of JW1601 for Healthy Volunteers

Single and Multiple Ascending Dose Study of JW1601 for Healthy Volunteers