Dataset Information

Open-Label Study To Evaluate the Single-Dose Pharmacokinetics, Safety, and Tolerability of Doripenem in Infants Less than 12 Weeks in Chronological Age.

ABSTRACT: Doripenem, a parenteral carbapenem with broad-spectrum activity against aerobic Gram-negative and Gram-positive and anaerobic pathogens, is currently approved for use in adults in the United States and European Union. Single-dose doripenem pharmacokinetics in 52 infants <12 weeks in chronological age were investigated in this phase 1 study. Hospitalized, medically stable infants <12 weeks in chronological age were stratified into 6 groups based on chronological and gestational age designed to reflect increasing renal maturation and decreasing volume of distribution (Vz) for ?-lactam antimicrobials during the first 3 months of life. Subjects received single-dose doripenem (5 mg/kg of body weight for <8 weeks and 8 mg/kg for ?8 weeks in chronological age) administered intravenously over 1 h. Plasma samples were obtained immediately before the end of the infusion and 1.5, 3, and 7 h after the start of the infusion. Urine was obtained by indwelling catheter during the 8 h following infusion. Doripenem showed linear pharmacokinetics across the 6 age groups. Neonates (<4 weeks in chronological age) had increased mean exposure (area under the plasma concentration-time curve from time zero to infinite time [AUC?], 45.7 versus 32.4 ?g · h/ml), longer elimination half-life (2.98 versus 1.79 h), and lower clearance (2.03 versus 3.03 ml/min/kg) compared with infants >4 weeks. Mean Vz was highest in subjects with the earliest gestational age (<32 weeks): 0.564 liter/kg for neonates and 0.548 liter/kg for infants. Single-dose pharmacokinetics of doripenem administered as a 1-hour infusion in term and preterm infants <12 weeks in chronological age were similar to what has been observed in neonates and very young infants with other carbapenems. Single-dose doripenem was generally safe and well tolerated. (This study has been registered with ClinicalTrials.gov under registration no. NCT01381848 and with EudraCT under registration no. 2009-014387-20.).

SUBMITTER: Cirillo I

PROVIDER: S-EPMC4505202 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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Open-Label Study To Evaluate the Single-Dose Pharmacokinetics, Safety, and Tolerability of Doripenem in Infants Less than 12 Weeks in Chronological Age.

Cirillo Iolanda I Vaccaro Nicole N Castaneda-Ruiz Bibiana B Redman Rebecca R Cossey Veerle V Bradley John S JS Allegaert Karel K

Antimicrobial agents and chemotherapy 20150526 8

Doripenem, a parenteral carbapenem with broad-spectrum activity against aerobic Gram-negative and Gram-positive and anaerobic pathogens, is currently approved for use in adults in the United States and European Union. Single-dose doripenem pharmacokinetics in 52 infants <12 weeks in chronological age were investigated in this phase 1 study. Hospitalized, medically stable infants <12 weeks in chronological age were stratified into 6 groups based on chronological and gestational age designed to re ...[more]

PMID: 26014957

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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),

Project description:BackgroundEvidence on the optimal time to initiation of complementary feeding in preterm infants is scarce. We examined the effect of initiation of complementary feeding at 4 months versus 6 months of corrected age on weight for age at 12 months corrected age in preterm infants less than 34 weeks of gestation.MethodsIn this open-label, randomised trial, we enrolled infants born at less than 34 weeks of gestation with no major malformation from three public health facilities in India. Eligible infants were tracked from birth and randomly assigned (1:1) at 4 months corrected age to receive complementary feeding at 4 months corrected age (4 month group), or continuation of milk feeding and initiation of complementary feeding at 6 months corrected age (6 month group), using computer generated randomisation schedule of variable block size, stratified by gestation (30 weeks or less, and 31-33 weeks). Iron supplementation was provided as standard. Participants and the implementation team could not be masked to group assignment, but outcome assessors were masked. Primary outcome was weight for age Z-score at 12 months corrected age (WAZ12) based on WHO Multicentre Growth Reference Study growth standards. Analyses were by intention to treat. The trial is registered with Clinical Trials Registry of India, number CTRI/2012/11/003149.FindingsBetween March 20, 2013, and April 24, 2015, 403 infants were randomly assigned: 206 to receive complementary feeding from 4 months and 197 to receive complementary feeding from 6 months. 22 infants in the 4 month group (four deaths, two withdrawals, 16 lost to follow-up) and eight infants in the 6 month group (two deaths, six lost to follow-up) were excluded from analysis of primary outcome. There was no difference in WAZ12 between two groups: -1·6 (SD 1·2) in the 4 month group versus -1·6 (SD 1·3) in the 6 month group (mean difference 0·005, 95% CI -0·24 to 0·25; p=0·965). There were more hospital admissions in the 4 month group compared with the 6 month group: 2·5 episodes per 100 infant-months in the 4 month group versus 1·4 episodes per 100 infant-months in the 6 month group (incidence rate ratio 1·8, 95% CI 1·0-3·1, p=0·03). 34 (18%) of 188 infants in the 4 month group required hospital admission, compared with 18 (9%) of 192 infants in the 6 month group.InterpretationAlthough there was no evidence of effect for the primary endpoint of WAZ12, the higher rate of hospital admission in the 4 month group suggests a recommendation to initiate complementary feeding at 6 months over 4 months of corrected age in infants less than 34 weeks of gestation.FundingIndian Council of Medical Research supported the study until Nov 14, 2015. Subsequently, Shuchita Gupta's salary was supported for 2 months by an institute fellowship from All India Institute Of Medical Sciences, and a grant by Wellcome Trust thereafter.

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Dataset Information

Open-Label Study To Evaluate the Single-Dose Pharmacokinetics, Safety, and Tolerability of Doripenem in Infants Less than 12 Weeks in Chronological Age.

Publications

Open-Label Study To Evaluate the Single-Dose Pharmacokinetics, Safety, and Tolerability of Doripenem in Infants Less than 12 Weeks in Chronological Age.

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