A novel oral formulation of BIO 300 confers prophylactic radioprotection from acute radiation syndrome in mice

Singh, Vijay K.; Fatanmi, Oluseyi O.; Wise, Stephen Y.; Carpenter, Alana D.; Nakamura-Peek, Sara; Serebrenik, Artur A.; Kaytor, Michael D.

doi:10.1080/09553002.2021.1981556

Cited by 17 publications

(17 citation statements)

References 39 publications

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“…The significant DEGs identified in the MSD cohort at 8 to 12 hours after the sixth dose are visualized in volcano plots relative to all other genes (>18 000 genes) (Figure 4C). The number of DEGs following the final dose in the MSD study highlights the importance of administering multiple doses for optimal radioprotection as observed in mouse studies 11 . Temporal changes in gene expression were analyzed by comparing the Log2 fold change (Log2FC) in expression relative to baseline of significantly DEGs at multiple timepoints in the MSD study.…”

Section: Resultsmentioning

confidence: 99%

“…Genistein functions as a selective estrogen receptor beta (ERβ) agonist and has a 2000‐fold higher selectivity for ERβ compared to ER‐alpha (ERα) 4 . Nonclinical studies in mice exposed to lethal total‐body irradiation (TBI) show that prophylactic treatment with genistein HME for 6 consecutive days significantly improves survival 11 . Additionally, studies with aqueous nanosuspensions of genistein formulated for oral or parental administration have demonstrated prophylactic efficacy for H‐ARS in mice 4,12,13 .…”

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confidence: 99%

“…4 Nonclinical studies in mice exposed to lethal total-body irradiation (TBI) show that prophylactic treatment with genistein HME for 6 consecutive days significantly improves survival. 11 Additionally, studies with aqueous nanosuspensions of genistein formulated for oral or parental administration have demonstrated prophylactic efficacy for H-ARS in mice. 4,12,13 The radioprotective effects of genistein are likely due to activation of ERβ which is known to regulate the cell cycle and inflammatory response.…”

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confidence: 99%

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Safety, Pharmacokinetics, and Biomarkers of an Amorphous Solid Dispersion of Genistein, a Radioprotectant, in Healthy Volunteers

Serebrenik

Verduyn

Kaytor

2022

Clinical Pharm in Drug Dev

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A pharmaceutical formulation of genistein, produced as an amorphous solid dispersion by hot melt extrusion (genistein HME), has been developed that can be administered prophylactically to improve outcomes and survival following radiation exposure. Here, genistein HME was evaluated in a phase 1, open‐label, single ascending dose (SAD) and multiple single dose (MSD) study enrolling 34 healthy volunteers. In the SAD study, participants were administered a single dose (500, 1000, 2000, or 3000 mg) and in the MSD study, participants were administered a single daily dose for six consecutive days (3000 mg/day). The overall adverse event profile and pharmacokinetics of genistein HME were determined. Additionally, biomarkers of genistein HME were evaluated by profiling whole blood for changes in gene expression by RNA sequencing. Genistein HME was found to be safe at doses up to 3000 mg. Most toxicities were mild to moderate gastrointestinal events, and no dose‐limiting toxicities were reported. The maximum tolerated dose was not determined and the no observable adverse effect level was 500 mg. Genistein HME bioavailability greatly increased between the 2000 mg and 3000 mg doses. RNA sequencing analysis revealed that the majority of drug‐related changes in gene expression occurred 8–12 hours after the sixth dose in the MSD study. Based on these results, the putative effective dose in humans is 3000 mg.

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Safety, Pharmacokinetics, and Biomarkers of an Amorphous Solid Dispersion of Genistein, a Radioprotectant, in Healthy Volunteers

Serebrenik

Verduyn

Kaytor

2022

Clinical Pharm in Drug Dev

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“…BIO 300 OP is a solid dosage, free-flowing dry powder, which is in contrast to previous BIO 300 formulations which are aqueous nanosuspensions. Our initial study using BIO 300 OP formulation has demonstrated that it has efficacy in a murine H-ARS model equivalent to that of BIO 300 OS 24 , 40 . The purpose of this study was to determine the pharmacokinetics (PK) of a single dose of BIO 300 OP and the associated metabolic changes in an NHP model.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic and metabolomic studies with a BIO 300 Oral Powder formulation in nonhuman primates

Girgis

Jayatilake

et al. 2022

Sci Rep

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BIO 300, a pharmaceutical formulation of genistein, is being developed as a radiation countermeasure to treat hematopoietic acute radiation syndrome (H-ARS) and the delayed effects of acute radiation exposure (DEARE). Several studies have affirmed its safety and efficacy in alleviating the damaging effects of ionizing radiation. However, dose optimization of any drug has always been an important area of research because unnecessarily high drug doses may result in serious complications. In this study, we assessed the pharmacokinetics (PK) and metabolic profiles of two different doses of a novel solid-dosage formulation of BIO 300 (BIO 300 Oral Powder; 100 mg/kg and 200 mg/kg), when administered orally to nonhuman primates (NHPs). While the Tmax values of both doses remained the same, the area under the curve at 48 h (AUC0-48) was tripled by doubling the dose. Additionally, we monitored serum samples for global metabolomic/lipidomic changes using high resolution mass spectrometry followed by functional pathway analysis prior to and at various time points up to 48 h post drug administration. Interestingly, the metabolomic profiles of sera from NHPs that received the lower dose demonstrated a transient perturbation in numerous metabolites between the 4 and 12 h time points. Eventually, the metabolite abundance reverted to near-normal by 48 h. These study results are consistent with our previous studies focused on the PK and metabolomic analysis for parenteral and oral aqueous nanosuspension formulations of BIO 300. This study affirms that administration of a single dose of up to 200 mg/kg of BIO 300 Oral Powder is safe in NHPs and conferred no metabolomic-mediated safety features.

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“…This oral formulation, BIO 300 Oral Powder (BIO 300 OP), is produced by hot-melt extrusion. Our initial study using BIO 300 OP formulation has demonstrated that it has e cacy in a murine H-ARS model equivalent to that of BIO 300 OS 24,39 . The purpose of this study was to determine the pharmacokinetics (PK) of a single dose of BIO 300 OP and the associated metabolic changes in an NHP model.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic and metabolomic studies with a BIO 300 Oral Powder formulation in nonhuman primates

Girgis

Jayatilake

et al. 2022

Preprint

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BIO 300, a nanosuspension of genistein, is a radiation countermeasure being developed to treat hematopoietic acute radiation syndrome (H-ARS) and the delayed effects of acute radiation exposure (DEARE). Several studies have affirmed its safety and efficacy in alleviating the damaging effects of ionizing radiation. However, dose optimization of any drug has always been an important area of research because unnecessarily high drug doses may result in serious complications. In this study, we assessed the pharmacokinetics (PK) and metabolic profiles of two different doses of BIO 300 Oral Powder (100 mg/kg and 200 mg/kg) when administered orally to nonhuman primates (NHPs). While the Tmax values of both doses remained the same, the area under the curve at 48 h (AUC0−48) was tripled by doubling the dose. Additionally, we monitored serum samples for global metabolomic/lipidomic changes using high resolution mass spectrometry followed by functional pathway analysis prior to and at various time points up to 48 h post drug administration. Interestingly, the metabolomic profiles of sera from NHPs that received the lower dose demonstrated a transient perturbation in numerous metabolites between the 4 and 12 h time points. Eventually, the metabolite abundance reverted to near-normal by 48 h. These study results are consistent with our previous studies focused on the PK and metabolomic analysis for parenteral and oral suspension formulations of BIO 300. This study affirms that administration of a single dose of up to 200 mg/kg of BIO 300 Oral Powder conferred no metabolomic-mediated safety features, suggesting the drug can be safely used to combat radiation injury.

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A novel oral formulation of BIO 300 confers prophylactic radioprotection from acute radiation syndrome in mice

Cited by 17 publications

References 39 publications

Safety, Pharmacokinetics, and Biomarkers of an Amorphous Solid Dispersion of Genistein, a Radioprotectant, in Healthy Volunteers

Safety, Pharmacokinetics, and Biomarkers of an Amorphous Solid Dispersion of Genistein, a Radioprotectant, in Healthy Volunteers

Pharmacokinetic and metabolomic studies with a BIO 300 Oral Powder formulation in nonhuman primates

Pharmacokinetic and metabolomic studies with a BIO 300 Oral Powder formulation in nonhuman primates

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