Ibrexafungerp (IBX) (formerly SCY-078) is a novel glucan synthase inhibitor whose oral availability is being evaluated for efficacy against vulvovaginal candidiasis (VVC). Bioavailability and in vitro activity are important efficacy indicators, but accepted susceptibility methods do not always accurately predict activity in an acidic environment, such as the vagina.
Abstract Background SCY-247 is an IV/oral second-generation triterpenoid anti-fungal for systemic fungal infections including multidrug resistant pathogens. Here we present translational data for nonclinical pharmacokinetics (PK) including dose-related tissue disposition in a murine C. glabrata model and correlation to reductions in fungal burden. Further, in vitro CYP450 interactions were evaluated to assess potential for clinical drug-drug interactions (DDIs). Methods The PK of SCY-247 was determined in rats and dogs. Plasma and tissue exposures were compared to reductions in kidney and lung fungal burden in a model of invasive C. glabrata. Neutropenic mice were infected IV with C. glabrata (∼108 yeast cells/mouse) and sacrificed on Day +7. Potential for inhibiting or inducing CYP450 isoforms was assessed in vitro using methods supportive of an FDA Investigational New Drug (IND) Application. Results SCY-247 has low clearance (∼10% liver blood flow) with half-life ≥15 hours following oral and IV administration to rat and dog consistent with once-daily administration in humans. Volume of distribution is ∼3 L/kg supportive of extensive tissue distribution. Exposure increased on repeat administration. Solubility of oral SCY-247 as a salt is >30 mg/mL at gastric pH consistent with rapid dissolution in the stomach and rapid absorption - as demonstrated by an early Tmax (0.5-2hr) following oral administration. In a murine model of C. glabrata infection, SCY-247 demonstrated dose-related increases in exposure and corresponding reduction in fungal burden (right figure panel) with higher distribution in kidney and lung tissue compared to plasma (left figure panel). In vitro, SCY-247 did not induce human CYP450s 1A2, 2B6 or 3A4. The IC50 values for inhibition of human 2C9, 2C19 and 3A isoforms were >20 μM ( >10-fold higher than the anticipated clinical Cmax) supportive of low risk of DDI’s for these isoforms. Conclusion SCY-247 has demonstrated dose- and tissue-related exposure reductions in fungal burden, PK consistent with once daily dosing to humans and low risk for CYP450-related DDIs. Disclosures Steve Wring, PhD, SCYNEXIS, Inc.: Advisor/Consultant Katyna Borroto-Esoda, MS, Scynexis Inc: Advisor/Consultant Nathan P. Wiederhold, PharmD, BioMerieux: Grant/Research Support|F2G: Advisor/Consultant|F2G: Grant/Research Support|Mycovia: Grant/Research Support|Scynexis: Grant/Research Support|Sfunga: Grant/Research Support David A. Angulo, MD, SCYNEXIS, Inc.: Board Member|SCYNEXIS, Inc.: SCYNEXIS, INC Officer and Board Member, SCYNEXIS Patents|SCYNEXIS, Inc.: Stocks/Bonds (Public Company)
Tenofovir disoproxil fumarate (TDF), the bisphosphonate ester prodrug of tenofovir (TFV), has poor bioavailability due to intestinal degradation and efflux transport. Reformulation using U.S. Food and Drug Administration–approved esterase and efflux inhibitors to increase oral bioavailability could provide lower dose alternatives and reduce costs for patients with HIV in resource-limited settings. Inhibition of mucosal and intracellular esterases was studied in human and rat intestinal extracts (S9), where TDF was protected by the carboxylesterase inhibitor bis-para-nitrophenylphosphate, the ester mix EM1, and the generally recognized-as-safe (GRAS) excipient propylparaben. Permeability studies using Madin-Darby canine kidney and Caco-2 cell monolayers demonstrated that TDF was a substrate for the permeability glycoprotein with permeability glycoprotein inhibitors reducing basolateral to apical transport of TDF. These studies also showed that transport was increased by esterase inhibitors. TDF, TFV, and tenofovir monophosphonate ester transport across Caco-2 monolayers with esterase and efflux inhibitors revealed a maximum 38.7-fold increase in apical to basolateral TDF transport with the potent non-GRAS combination of EM1 and GF120918. Transport was increased 22.8-fold by the GRAS excipients, propylparaben, and d-a-tocopheryl polyethylene glycol 1000 succinate (a vitamin E derivative). TFV pharmacokinetics in rats following oral administration of TDF and GRAS esterase and efflux inhibitors confirmed enhanced bioavailability. Area under the curve increased 1.5- to 2.1-fold with various combinations of parabens and d-a-tocopheryl polyethylene glycol 1000 succinate. This significant inhibition of TDF hydrolysis and efflux in vivo exhibits the potential to safely increase TDF bioavailability in humans.
ABSTRACT Tenofovir disoproxil fumarate (TDF), a prodrug of tenofovir, has oral bioavailability (25%) limited by intestinal transport (P-glycoprotein), and intestinal degradation (carboxylesterase). However, the influence of luminal pancreatic enzymes is not fully understood. Physiologically based pharmacokinetic (PBPK) modeling has utility for estimating drug exposure from in vitro data. This study aimed to develop a PBPK model that included luminal enzyme activity to inform dose reduction strategies. TDF and tenofovir stability in porcine pancrelipase concentrations was assessed (0, 0.48, 4.8, 48, and 480 U/ml of lipase; 1 mM TDF; 37°C; 0 to 30 min). Samples were analyzed using mass spectrometry. TDF stability and permeation data allowed calculation of absorption rates within a human PBPK model to predict plasma exposure following 6 days of once-daily dosing with 300 mg of TDF. Regional absorption of drug was simulated across gut segments. TDF was degraded by pancrelipase (half-lives of 0.07 and 0.62 h using 480 and 48 U/ml, respectively). Previously reported maximum concentration ( C max ; 335 ng/ml), time to C max ( T max ; 2.4 h), area under the concentration-time curve from 0 to 24 h (AUC 0–24 ; 3,045 ng · h/ml), and concentration at 24 h ( C 24 ; 48.3 ng/ml) were all within a 0.5-fold difference from the simulated C max (238 ng/ml), T max (3 h), AUC 0–24 (3,036 ng · h/ml), and C 24 (42.7 ng/ml). Simulated TDF absorption was higher in duodenum and jejunum than in ileum (p<0.05). These data support that TDF absorption is limited by the action of intestinal lipases. Our results suggest that bioavailability may be improved by protection of drug from intestinal transporters and enzymes, for example, by coadministration of enzyme-inhibiting agents or nanoformulation strategies.
Background: Rodatristat ethyl (RE) targets peripheral serotonin (5HT) biosynthesis and is in Phase IIb development (ELEVATE 2) for pulmonary arterial hypertension (PAH). Upregulated 5HT signaling in lung drives pulmonary artery smooth muscle cell proliferation and vascular remodeling in PAH. Here, in healthy subjects, we characterize the magnitude and time to maximal reductions in peripheral 5HT biosynthesis to levels associated with efficacy in nonclinical PAH models, and the reversibility following RE withdrawal. Methods: Healthy subjects (n=79) received 100-800 mg BID of RE over 14-16 days. 5HT reductions were assessed via plasma and urine 5-HIAA (biomarker of 5HT levels) at baseline, last day of treatment and 7 days later. Results: Maximal 5-HIAA reductions in plasma and urine were achieved by 7 days of RE treatment. Reductions in plasma and urine 5-HIAA were correlated (Pearson R=0.5514; p<0.05). RE ≤ 300 mg BID led to a dose proportional decrease in plasma and urine 5-HIAA (-46% plasma; -47% urine at 300 mg BID). Doses >300 mg BID yielded only a further ~10% reduction in 5-HIAA (-54% plasma; -59%, urine at 800 mg BID). Doses of ≥300 mg BID achieved ~40% reduction in urine 5-HIAA associated with efficacy in rat monocrotaline and SUGEN hypoxia PAH models. Inhibition of 5HT biosynthesis was reversible as 5-HIAA returned to near baseline values by 7 days post dosing. Conclusions: RE achieved dose-dependent reductions in serotonin synthesis in healthy subjects. A target ~40% reduction associated with efficacy in rat PAH models was achieved by day 7 for RE doses ≥300mg BID. Inhibition of 5HT biosynthesis was reversible.
Abstract Background There are limited treatment options for invasive fungal infections (IFIs) with broad-spectrums of activity that can be delivered both orally and intravenously. SCY-247 is a second-generation novel triterpenoid antifungal in development. It has broad-spectrum activity covering yeasts, molds and dimorphic fungi, including azole- and echinocandin-resistant strains and can be given orally or intravenously. Recent in vivo murine efficacy studies were performed with SCY-247 and results from 3 studies demonstrating activity against Candida and Mucorales are presented.Table 1:Study Methodology Details Methods The in vivo activity of SCY-247 was assessed in murine models of invasive candidiasis (IC) caused by C. albicans and C. glabrata and a murine model of pulmonary mucormycosis (PM) caused by R. delemar. In each model, SCY-247 was administered by oral gavage, twice daily (BID), for seven days with doses ranging from 5 to 48 mg/kg. Efficacy endpoints included changes in tissue fungal burden (CFU) and/or survival. Details are shown in Table 1. Results SCY-247 demonstrated potent in vivo activity in all three murine IFI models. In each dose-dependent responses based on the primary endpoints of fungal burden and/or survival were observed. Significant reductions in kidney fungal burden vs placebo (P < 0.01) were observed at doses ≥10 mg/kg against C. albicans and at doses ≥16 mg/kg against C. glabrata; significant reductions in lung fungal burden (P < 0.01) were also observed in the C. glabrata model at doses ≥32 mg/kg. Bioanalysis demonstrated SCY-247 preferentially distributed to kidney and lung tissues versus plasma and reductions in C. glabrata fungal burden correlated with dose and exposure. Against pulmonary mucormycosis, treatment with SCY-247 at doses ≥32 mg/kg resulted in prolonged survival (P < 0.05) and reductions in both lung and brain fungal burden vs placebo (P < 0.05). Conclusion SCY-247 demonstrated significant in vivo activity in murine models of invasive candidiasis and pulmonary mucormycosis, and the antifungal responses correlated with dose and exposure. Disclosures Steve Wring, PhD, SCYNEXIS, Inc.: Advisor/Consultant Katyna Borroto-Esoda, MS, Scynexis Inc: Advisor/Consultant Nathan P. Wiederhold, PharmD, BioMerieux: Grant/Research Support|F2G: Advisor/Consultant|F2G: Grant/Research Support|Mycovia: Grant/Research Support|Scynexis: Grant/Research Support|Sfunga: Grant/Research Support Ashraf S. Ibrahim, PhD, SCYNEXIS, Inc.: Advisor/Consultant|SCYNEXIS, Inc.: Grant/Research Support David A. Angulo, MD, SCYNEXIS, Inc.: Board Member|SCYNEXIS, Inc.: SCYNEXIS, INC Officer and Board Member, SCYNEXIS Patents|SCYNEXIS, Inc.: Stocks/Bonds (Public Company)
Background: Rodatristat ethyl (RE) is a prodrug for rodatristat (R), a peripheral inhibitor of tryptophan hydroxylase (TPH). TPH isoform 1 is over expressed in lungs of pulmonary arterial hypertension (PAH) patients resulting in enhanced serotonin production and pulmonary arterial remodeling. R did not reduce brain 5HT in healthy nor PAH model rats. Here we predict potential for RE to reduce CNS 5HT in humans and report incidence of mood changes in healthy human subjects. Methods: Maximal exposure (Cmax) of pharmacologically active unbound R (Ru) in human brain was predicted from PK and QWBA data in rat, in vitro tissue binding, and PK in healthy human subjects. Cumulative mood-related safety data including nervous system, psychiatric disorders, and Columbia-Suicide Severity Rating Scale assessments were collated from Phase 1 studies in healthy adults administered repeat 100mg-800mg BID doses (14-16 days). Results: Predicted steady-state Ru Cmax in human brain was 0.22/0.34ng/mL (300mg/600mg BID) reflecting sub-pharmacological levels of only 4.4% and 6.8% of the CNS TPH isoform 2 IC50 (5ng/mL). In 89 healthy subjects, incidence of total nervous system disorder AEs was 19.1% (dizziness or headache) for RE, and 20.0% (dizziness, headache, somnolence) for placebo. Psychiatric disorders were limited to anxiety in 2 (2.2%) RE-treated subjects. No RE treated subjects (0/53) reported suicidal ideation, suicidal behavior, or self-injurious behavior without suicidal intent. Conclusion: RE is predicted to have low risk for impacting brain 5HT consistent with no changes in mood or suicidal ideation in healthy subjects.
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