Pharmacokinetics, Safety, and Pharmacodynamics of Romiplostim in Chinese Subjects With Immune Thrombocytopenia: A Phase I/II Trial.
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ABSTRACT:
SUBMITTER: Qi J
PROVIDER: S-EPMC9299913 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Objective: Omadacycline is a new type of aminomethylcycline antibiotic, having a broad antibacterial spectrum. But the pharmacokinetic characteristics and safety profile of the Chinese population remain unknown. It is also unclear whether the US-approved treatment regimen is applicable for the Chinese population. Methods: In a randomized, double-blinded, placebo-controlled dose-escalated trial, the pharmacokinetics of omadacycline was evaluated by a non-compartmental and compartmental model. Monte Carlo simulations were performed using the pharmacokinetic data from the Chinese population to evaluate the probability of target attainment (PTA) and the cumulative fraction of response (CFR) of the US FDA-approved dose regimen. Results: The three-compartment model successfully described the rapid distribution and slow elimination of omadacycline after the intravenous infusion (i.v.). The double-peak concentration-time curve of the oral absorption (p.o.) was explained by the two-compartment model with two absorption compartments. The steady-state AUC of 100 mg omadacycline i.v. and 300 mg omadacycline p. o. were 12.1 and 19.4 mg h/L, respectively. Pharmacokinetics/pharmacodynamics (PK/PD) analysis showed that the omadacycline dosing regimen with a loading dose (200 mg i.v. q24 h, 100 mg i.v. q12 h, 450 mg p. o. q24 h × 2 days or 300 mg p. o. q12 h) and maintenance dose (100 mg i.v. q24 h or 300 mg p. o. q24 h) could cover the main pathogens of the indications acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP): Staphylococcus aureus and Streptococcus pneumoniae. Also, omadacycline had showed a good safety profile in the Chinese population. Conclusions: With the evidence provided, omadacycline could be a novel treatment option to Chinese patients with ABSSSI and CABP.
| S-EPMC9068897 | biostudies-literature
Project description:AimsTo evaluate the safety, pharmacokinetics and pharmacodynamics of BI 655064 in healthy Chinese and Japanese subjects after administration of single doses of 80-240 mg and multiple dosing of 240 mg once weekly over 4 weeks.MethodsTwo phase 1, double-blind, placebo-controlled studies were conducted (single-rising doses of BI 655064 in Chinese/Japanese male subjects [n = 12 per BI 655064 dose group] or repeated 240 mg BI 655064 in Chinese male subjects [n = 9]). Plasma samples were collected to investigate BI 655064 pharmacokinetics, pharmacodynamics (CD40 receptor occupancy [RO]) and immunogenicity, along with the safety and tolerability of BI 655064.ResultsBI 655064 showed good overall tolerability following single-dose administration of 80-240 mg and repeated administration of 240 mg BI 655064 over 4 weeks. More Chinese subjects reported adverse events compared with Japanese subjects following single-dose administration (59.4% vs 3.1%). BI 655064 exhibited nonlinear, saturable kinetics, with higher doses resulting in slower apparent clearance (0.514-0.713 mL min-1 ), and disproportionately higher total exposure (AUC0-inf ; 5610-7780 μg·h mL-1 ) and maximum plasma concentration (15 700-21 300 ng mL-1 ) with 240 mg BI 655064. Ninety percent inhibition of CD40 RO was achieved with doses ≥120 mg, and a direct relationship between BI 655064 plasma concentration and inhibition of CD40 RO was observed. Most subjects had a positive treatment-emergent antidrug antibody response.ConclusionsBI 655064 pharmacokinetic and safety profiles in East Asian male subjects were consistent with those observed in a Western population. No adjustments in the BI 655064 dosing recommendations are warranted for future clinical trials.
| S-EPMC8056730 | biostudies-literature
Project description:BACKGROUND: Preclinical studies have demonstrated that pharmacological mobilization and recruitment of endogenous bone marrow stem cells and immunoregulatory cells by a combination of plerixafor and low-dose tacrolimus (MRG-001) improves wound healing, promotes tissue regeneration and prevents allograft rejection. This first‐in‐human phase I dose‐escalation study evaluates the safety, tolerability, pharmacokinetics and pharmacodynamics of MRG-001, a novel fixed-dose combination drug. METHODS: In this Phase 1, double‐blind, randomized, placebo-controlled study, multiple ascending dose (MAD) cohorts are randomized to receive MRG-001 containing up to 0.02 mL/kg (plerixafor 24 mg/mL and tacrolimus 0.5 mg/mL) or saline placebo, subcutaneously every other day (SC, QAD) for 5 days (ClinicalTrials.gov: NCT04646603)The primary outcome is safety and tolerability. Safety and functional assessments are performed throughout the study. Blood samples are collected to evaluate systemic exposure. Fluorescence-activated cell sorting analysis and RNA expression of peripheral blood mononuclear cells (PBMCs) are used to evaluate the pharmacodynamics. RESULTS: Fourteen subjects received MRG-001 and 7 received a placebo. MRG-001 is safe and well-tolerated over the selected dose range. No deaths or severe adverse events are reported. There are no clinically significant laboratory changes after MRG-001 administration, apart from the predicted generalized leukocytosis. The intermediate dose group (0.01 mL/kg) showed the most significant white blood cell mobilization over time and increased by 2-4 fold from baseline and returned to baseline levels prior to the next injection. Circulating immune cells including FOXP3+ regulatory T cells and hematopoietic stem cells (CD45IntCD34+) increased significantly after MRG-001 injection. PBMC RNA sequencing and gene set enrichment analysis revealeds 31 down-regulated pathways in the intermediate dose MRG-001 group compared to no changes in the placebo group. CONCLUSION: MRG-001 is safe and well-tolerated across the full dose ranges tested. MRG-001 may be a clinically useful therapy for immunoregulation and tissue regeneration. A Phase II trial to treat severely and critically ill COVID-19 patients with MRG-001 has been initiated (NCT04646603) and a second phase II trial will explore the potential of MRG-001 to accelerate wound healing (NCT05844527),
2023-07-24 | GSE237965 | GEO
Project description:Objective: Pharmacokinetics (PK), pharmacodynamics (PD), safety and immunogenicity studies were conducted to evaluate the bioequivalence of CMAB807, a biosimilar to denosumab (Prolia®), which is the only approved RANKL inhibitor for the treatment of osteoporosis. Methods: In this randomized, double-blind, single-dose phase I study, 132 healthy Chinese male subjects received a subcutaneous injection of 60 mg of CMAB807 or denosumab at a 1:1 ratio. The PK, PD, safety and immunogenicity results were assessed prior to and up to 126 days after administration. Results: The PK profiles of CMAB807 and denosumab were similar. The geometric mean ratios of the maximum concentration (Cmax), AUC0-t and AUCo-∞ were 102.41, 104.15 and 103.89%, respectively, and the 90% confidence interval was observed to be within 80.00-125.00%, which indicated the bioequivalence of CMAB807 and denosumab. The PD profiles of the two groups were also comparable. The production of the C-terminal cross-linking telopeptide of type I collagen (CTX1) was inhibited by up to 85% for 10 days, and this inhibition was sustained for up to 126 days in both the CMAB807 and denosumab groups. No subjects in the CMAB807 group, three subjects in the denosumab group before administration, and two subjects in the denosumab group after administration were positive for anti-drug antibody (ADA). Adverse events (AEs) were observed in 98.5% of subjects in both groups. The most common AE recorded was increased parathyroid hormone (PTH) levels, with incidences of 92.4 and 95.5% in the CMAB807 and denosumab groups, respectively. No clinically meaningful differences were observed in safety and immunogenicity between CMAB807 and denosumab. Conclusion: CMAB807 represents a new potential treatment option for patients with osteoporosis. Clinical Trial Registration: https://clinicaltrials.gov (Registration No. NCT03925051), http://www.chinadrugtrial/org.cn/index.html (Registration No. CTR20190800).
| S-EPMC8819684 | biostudies-literature
Project description:Background: Ciprofol, a novel sedative-hypnotic drug, has been approved for its use in inducing and maintaining general anesthesia, as well as for providing sedation. Methods: In this phase I, single-center, parallel, controlled, open-label clinical trial, our objective was to analyze the pharmacokinetics (PK), pharmacodynamics (PD), and safety of ciprofol emulsion in 24 participants with mild and moderate renal impairment (n = 8 per group) and matched healthy participants (n = 8). An initial loading infusion of ciprofol was administered at 0.4 mg/kg for 1 min, followed by a maintenance infusion at a rate of 0.4 mg/kg/h for 30 min. We collected plasma and urine samples from the participants to assess the PK of ciprofol and its metabolite M4. The evaluation of PD involved using a modified observer's alertness/sedation scale (MOAA/S) in combination with bispectral index (BIS) monitoring. Safety assessments were conducted throughout the trial process. Results: The plasma concentration-time curve of ciprofol in participants with renal impairment was similar to that in participants with normal kidney function. The area under the curve (AUC) and maximum concentration (Cmax) of total and unbound ciprofol in plasma for participants with renal impairment were only slightly higher (0.7-1.2-fold) than those in participants with normal renal function. In contrast, for the metabolite M4, AUC values were 1.3- and 2.1-fold greater in participants with mild and moderate renal impairment, respectively, than in healthy controls. However, renal impairment had no significant impact on the PD parameters. The study found that ciprofol was well-tolerated, with all adverse events (AEs) reported being mild or moderate in severity. Conclusion: Based on these findings, we can conclude that no dosage adjustment of ciprofol is necessary for patients with mild-moderate renal impairment who receive the injection. Clinical Trial Registration: https://clinicaltrials.gov, identifier NCT04142970.
| S-EPMC10704090 | biostudies-literature
Project description:GLPG1690 is a novel autotaxin inhibitor in development for the treatment of idiopathic pulmonary fibrosis (IPF). We report phase 1 studies investigating the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of GLPG1690 in healthy subjects. We performed a first-in-human randomized, double-blind, placebo-controlled trial of single (20, 60, 150, 300, 600, 1000, 1500 mg) and multiple (14 days: 150 mg twice daily; 600 and 1000 mg once daily) ascending oral doses of GLPG1690 (NCT02179502), and a randomized, open-label, crossover relative bioavailability study to compare the PK of tablet and capsule formulations of GLPG1690 600 mg and to assess the effect of food on PK of the tablet formulation (NCT03143712). Forty and 13 subjects were randomized in the first-in-human and relative bioavailability studies, respectively. GLPG1690 was well tolerated, with no dose-limiting toxicity at all single and multiple doses. GLPG1690 was rapidly absorbed and eliminated, with a median tmax and mean t1/2 of approximately 2 and 5 hours, respectively. GLPG1690 exposure increased with increasing dose (mean Cmax , 0.09-19.01 µg/mL; mean AUC0-inf , 0.501-168 µg·h/mL, following single doses of GLPG1690 20-1500 mg). PD response, evidenced by rapid reduction in plasma lysophosphatidic acid (LPA) C18:2 levels, increased with increasing GLPG1690 plasma levels, plateauing at approximately 80% reduction in LPA C18:2 at around 0.6 µg/mL GLPG1690. Tablet and capsule formulations had similar PK profiles, and no clinically significant food effect was observed when comparing tablets taken in fed and fasted states. The safety, tolerability, and PK/PD profiles of GLPG1690 support continued clinical development for IPF.
| S-EPMC6767429 | biostudies-literature
Project description:This phase 1, open-label, single-center study evaluated the pharmacokinetics (PK), pharmacodynamics, safety, and tolerability of single-dose emicizumab in healthy Chinese males. Overall, 16 subjects received a single subcutaneous dose of 1-mg/kg emicizumab. Blood samples were obtained before dosing on day 1 and at regular intervals over 16 weeks after dosing for PK evaluation. A single 1-mg/kg subcutaneous dose of emicizumab was safe and well tolerated in healthy Chinese male subjects in the study. Mean (± standard deviation) area under the concentration-time curve from time 0 to infinity and maximum concentration were 287 ± 74.2 μg⋅d/mL and 7.11 ± 1.77 μg/mL, respectively, with a terminal half-life of 26.7 (±4.3) days. Emicizumab administration did not show significant impact on pharmacodynamic markers tested, which mostly remained stable throughout the study. One subject tested positive for antidrug antibody, with no impact on his PK or safety profile. Compared with results from healthy Japanese and Caucasian subjects receiving the same dose in previous clinical trials, the current results further indicated the absence of difference of emicizumab PK profile across Chinese, Japanese, and Caucasian subjects, validating the use of similar therapeutic doses in Asian and non-Asian populations.
| S-EPMC7818492 | biostudies-literature
Project description:Primary immune thrombocytopenia is an autoimmune disorder characterized by increased platelet destruction and insufficient platelet production without another identified underlying disorder. Splenectomy may alter responsiveness to treatment and/or increase the risk of thrombosis, infection, and pulmonary hypertension. The analysis herein evaluated the safety and efficacy of the thrombopoietin receptor agonist romiplostim in splenectomized and nonsplenectomized adults with primary immune thrombocytopenia. Data were pooled across 13 completed clinical studies in adults with immune thrombocytopenia from 2002-2014. Adverse event rates were adjusted for time of exposure. Results were considered different when 95% confidence intervals were non-overlapping. Safety was analyzed for 1111 patients (395 splenectomized; 716 nonsplenectomized) who received romiplostim or control (placebo or standard of care). At baseline, splenectomized patients had a longer median duration of immune thrombocytopenia and a lower median platelet count, as well as a higher proportion with >3 prior immune thrombocytopenia treatments versus nonsplenectomized patients. In each treatment group, splenectomized patients used rescue medications more often than nonsplenectomized patients. Platelet response rates (≥50×109/L) for romiplostim were 82% (310/376) for splenectomized and 91% (592/648) for nonsplenectomized patients (P<0.001 by Cochran-Mantel-Haenszel test). Platelet responses were stable over time in both subgroups. Exposure-adjusted adverse event rates were higher for control versus romiplostim for both splenectomized (1857 versus 1226 per 100 patient-years) and nonsplenectomized patients (1052 versus 852 per 100 patient-years). In conclusion, responses to romiplostim were seen in both splenectomized and nonsplenectomized patients, and romiplostim was not associated with an increase in the risk of adverse events in splenectomized patients. clinicaltrials.gov Identifier: 00111475(A)(B), 00117143, 00305435, 01143038, 00102323, 00102336, 00415532, 00603642, 00508820, 00907478, 00116688, and 00440037.
| S-EPMC5541869 | biostudies-literature
Project description:"Immune thrombocytopenia" (ITP) is an autoimmune disorder that leads to peripheral destruction, as well as a decreased production of platelets. ITP most commonly presents as mild mucocutaneous bleeding. Though it is rare, the leading cause of mortality in persons with ITP is intracranial hemorrhage and those that do not respond to therapy are at increased risk. Our understanding of the pathophysiology of ITP has evolved immensely, especially over the last 60 years. The discovery of the platelet-production stimulator, thrombopoietin (TPO), lent clarity to an earlier hypothesis that inhibition of platelet production at the level of the megakaryocyte, at least in part, accounts for thrombocytopenia in adults with ITP. This facilitated the development of TPO-based therapies to treat ITP. Thrombopoietin receptor agonists are one of the most recent treatments to enter the landscape. Original production of a recombinant human TPO was halted after clinical trials revealed the untoward effect of autoantibodies to the recombinant human TPO with cross-reactivity to endogenous TPO. Next-step development focused on stimulation of the TPO receptor with fewer immunogenic agents. Currently, two such thrombopoietin receptor agonists, romiplostim and eltrombopag, are licensed in the USA to treat thrombocytopenia in adults with persistent or chronic ITP. Ongoing research will assess their efficacy in other immune-mediated and nonimmune-mediated primary and secondary thrombocytopenias.
| S-EPMC4304598 | biostudies-other
Project description:Study objectiveTo investigate the pharmacodynamic and pharmacokinetic profiles of fluticasone furoate (FF)/vilanterol (VI) - a fixed-dose combination of an inhaled corticosteroid (ICS) and a long-acting β2 -agonist for the treatment of asthma and chronic obstructive pulmonary disease - after single and repeat administration in healthy Chinese subjects.DesignDouble-blind, placebo-controlled, single-site, randomized, four-way crossover study.SettingThe Clinical Pharmacological Research Centre at Peking Union Medical College Hospital [PUMCH]) in Beijing, China.SubjectsSixteen healthy, nonsmoking Chinese adults.InterventionSubjects were randomized to receive FF/VI 50/25, 100/25, or 200/25 μg, or placebo once/daily in the morning, delivered by the Ellipta dry powder inhaler, for 7 consecutive days. The subjects then received the other three treatments, with each treatment period separated by a 7-day washout period.Measurements and main resultsThe co-primary outcome measures reflected pharmacodynamic responses relating to recognized class effects of the two drug classes: reduced serum cortisol level (ICSs), and increased Fridericia's corrected QT interval (QTcF) and reduced serum potassium level (long-acting β2 -agonists). Co-primary pharmacodynamic endpoints were 0-24-hour weighted mean serum cortisol level on day 7 (cortisol0-24 hr, Day 7 ), and 0-4-hour weighted mean and maximum QTcF and weighted mean and minimum serum potassium level on days 1 and 7. Fluticasone furoate and VI plasma concentrations, derived pharmacokinetic parameters, and safety were also assessed. Of the 16 subjects randomized, 15 completed the study. Reductions in cortisol0-24 hour, Day 7 of 15% and 25% were observed with FF/VI 100/25 and 200/25 μg, respectively, versus placebo. Minor increases (< 10 msec) in maximum QTcF on day 7 were seen with FF/VI 50/25 and 100/25 μg but not with 200/25 μg. Slight decreases in serum potassium level were only observed in subjects receiving FF/VI 50/25 μg on day 1 and FF/VI 50/25 and 200/25 μg on day 7. Fluticasone furoate accumulation (day 7 vs day 1) for FF/VI 50/25-200/25 μg ranged from 38 to 54% for maximum observed concentration and 63-71% for area under the concentration-time curve from 0 to 4 hours. Fluticasone furoate pharmacokinetics were less than dose proportional. The VI pharmacokinetic profiles were similar for all three FF/VI doses. Adverse events were all mild in intensity and were reported by 13 (81%) of the 16 subjects.ConclusionIn healthy Chinese subjects, minimal and non-clinically relevant β-adrenergic pharmacodynamic effects were observed with FF/VI doses ranging from 50/25 to 200/25 μg. FF dose-dependent reductions in serum cortisol levels of 15-25% were seen after administration of FF/VI 100/25 and 200/25 μg. FF/VI was safe and well tolerated in these subjects at doses ranging from 50/25 to 200/25 μg.
| S-EPMC4744690 | biostudies-literature