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P0115 Absorption, Distribution, and Excretion of [14C ... · Absorption, Distribution, and...
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Absorption, Distribution, and Excretion of [ 14 C]Rezafungin after Single-Dose Intravenous (IV) Administration in Rats and Monkeys V. Ong 1 , S. Flanagan 1 , D. Watson 2 , A. Sadeque 2 1 Cidara Therapeutics, San Diego, CA, USA; 2 QPS, Newark, DE , USA Rezafungin (RZF) is a novel echinocandin antifungal in development for the treatment as well as prevention (prophylaxis) of invasive fungal infections. RZF is differentiated from previous echinocandins by greater stability and efficacy-enhancing, front-loaded pharmacokinetics (PK) with once-weekly dosing. Distribution of RZF into the lung epithelial lining fluid (ELF) in the mouse was high with lung ELF-to-plasma free-drug exposure ratio of 100 1 . Indeed, results from mouse infection models have demonstrated the efficacy of RZF for prophylaxis against candidiasis, aspergillosis, and Pneumocystis pneumonia 2 . PK/PD analysis indicated that clinical dosing with a front-loading 400 mg dose followed by 200 mg once weekly will likely be effective in preventing these 3 common classes of fungal infections 3 . The aim of these current studies is to further characterize the extent of distribution as well as the excretion profile of of [ 14 C]-radiolabeled RZF. In the intact SD rat, mean cumulative recovery of [ 14 C]RZF radioactivity in rats was 95% of the dose. The primary route of elimination was in feces, which accounted for 70% of the dose (predominantly parent drug) after 2 weeks. An average of 14% and 3% of the administered dose was recovered in the urine and cage residues, respectively, with 8% remaining in the carcass. In the LE rat, [ 14 C]RZF radioactivity was extensively distributed throughout the body within 1 hour following a single IV dose. In the monkey, a similar pattern of elimination to that in the rat was observed but at a lower excretion rate, with 74% cumulative recovery after 30 days. As in the rat, the primary route of elimination was in feces (60%) with 10% and 4% recovered in urine and cage residue, respectively. As [ 14 C]RZF is extensively distributed throughout the entire body and is cleared slowly primarily via excretion in feces (predominantly as parent drug), RZF has the potential to be used as treatment and prophylaxis against invasive fungal infections. P0115 Voon Ong, Ph.D. Cidara Therapeutics, Inc. 6310 Nancy Ridge Dr., Suite 101 San Diego, CA 92121 USA [email protected] METHODS (con’t) INTRODUCTION AND PURPOSE RESULTS (con’t) RESULTS (con’t) RESULTS (con’t) 1. V. Ong, et al., “CD101 Lung Epithelial Lining Fluid (ELF) Concentrations Substantiate Its Use For Prophylaxis Treatment As Evident In Mouse Disseminated and Pulmonary Aspergillosis Models”, 8th Advances Against Aspergillosis, 2018. 2. V. Ong, et al., “Antifungal Prophylaxis with CD101 in Immunosuppressed Mouse Models of Candidiasis, Aspergillosis, and Pneumocystis Pneumonia (PCP)” 22nd Congress of the European Hematology Association, 2017 3. E. Lakota, et al., “Pharmacokinetic-Pharmacodynamic Analyses to Provide Rezafungin Prophylaxis Dose Selection for Prevention of Invasive Fungal Infections for Bone Marrow Transplant Patients”, American Society of Hematology, 2018. REFERENCES METHODS Male Sprague-Dawley (SD) albino (intact and bile duct– cannulated) as well as Long-Evans (LE) pigmented rats were administered a single IV bolus dose of [ 14 C]RZF. Urine and feces samples were collected for up to 14 days post-dose. Blood/plasma and bile samples were collected up to 5 days post-dose. Male cynomolgus monkeys were administered a single IV infusion dose of [ 14 C]RZF. Urine and feces samples were collected for up to 30 days post-dose. Blood/plasma samples were collected up to 60 days post-dose. Blood, plasma, bile, and excreta samples were analyzed for radioactivity by liquid scintillation counting. Tissue distribution was assessed by quantitative whole-body autoradiography (QWBA). 1 hr 10 days CONCLUSIONS QWBA images below show the long residence times in most tissues of the monkey following a single IV dose. RESULTS Low-level oxidative metabolites (2-, 3-, 4-hydroxylpentyl CD101, and despentyl-CD101) were observed during metabolite profiling at later (≥4 hr) timepoints, with greater levels detected in rat than in monkey plasma/excreta. Also similar to the rat, exposure in most tissues was higher than in blood through 60 days after a single dose. A pertinent selection of tissue conc-time profiles in the monkey are plotted below. Exposure (AUC) in most tissues was higher than in blood and sustained; quantifiable concentrations were present in 50 of 54 tissues through 36 days after a single dose. Tissue concentration versus time profiles in rats showed that elimination/tissue release of radioactivity from most tissues was slower with t 1/2 values of >200 hours compared with a t 1/2 of 186 hours in blood. Similar radioactivity distribution trends and exposures were observed in pigmented LE and non-pigmented SD skin indicating that [ 14 C]RZF was not specifically associated with melanin. In bile duct–cannulated rats, 35% of the dose was recovered in feces suggesting intestinal secretion of RZF, while 17%, 14%, 30%, and 1% was recovered in the bile, urine, carcass, and cage residues, respectively, for a cumulative recovery of 97%. Plasma, urine, bile, and fecal samples were analyzed using liquid chromatography tandem mass spectrometry coupled with a radio flow-through detector for metabolite profiling and identification. 4 hrs 24 hrs 10 days
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Absorption, Distribution, and Excretion of [14C]Rezafungin after Single-Dose Intravenous (IV) Administration in Rats and Monkeys
V. Ong1, S. Flanagan1, D. Watson2, A. Sadeque2
1Cidara Therapeutics, San Diego, CA, USA; 2QPS, Newark, DE , USA
Rezafungin (RZF) is a novel echinocandin antifungal in development for the treatment as well as prevention (prophylaxis) of invasive fungal infections. RZF is differentiated from previous echinocandins by greater stability and efficacy-enhancing, front-loaded pharmacokinetics (PK) with once-weekly dosing. Distribution of RZF into the lung epithelial lining fluid (ELF) in the mouse was high with lung ELF-to-plasma free-drug exposure ratio of 1001. Indeed, results from mouse infection models have demonstrated the efficacy of RZF for prophylaxis against candidiasis, aspergillosis, and Pneumocystis pneumonia2. PK/PD analysis indicated that clinical dosing with a front-loading 400 mg dose followed by 200 mg once weekly will likely be effective in preventing these 3 common classes of fungal infections3.The aim of these current studies is to further characterize the extent of distribution as well as the excretion profile of of [14C]-radiolabeled RZF.
In the intact SD rat, mean cumulative recovery of [14C]RZF radioactivity in rats was 95% of the dose. The primary route of elimination was in feces, which accounted for 70% of the dose (predominantly parent drug) after 2 weeks. An average of 14% and 3% of the administered dose was recovered in the urine and cage residues, respectively, with 8% remaining in the carcass.
In the LE rat, [14C]RZF radioactivity was extensively distributed throughout the body within 1 hour following a single IV dose.
In the monkey, a similar pattern of elimination to that in the rat was observed but at a lower excretion rate, with 74% cumulative recovery after 30 days. As in the rat, the primary route of elimination was in feces (60%) with 10% and 4% recovered in urine and cage residue, respectively.
As [14C]RZF is extensively distributed throughout the entire body and is cleared slowly primarily via excretion in feces (predominantly as parent drug), RZF has the potential to be used as treatment and prophylaxis against invasive fungal infections.
P0115Voon Ong, Ph.D.Cidara Therapeutics, Inc.6310 Nancy Ridge Dr., Suite 101San Diego, CA 92121 [email protected]
METHODS (con’t)INTRODUCTION AND PURPOSE RESULTS (con’t) RESULTS (con’t) RESULTS (con’t)
1. V. Ong, et al., “CD101 Lung Epithelial Lining Fluid (ELF) Concentrations Substantiate Its Use For Prophylaxis Treatment As Evident In Mouse Disseminated and Pulmonary Aspergillosis Models”, 8th Advances Against Aspergillosis, 2018.
2. V. Ong, et al., “Antifungal Prophylaxis with CD101 in Immunosuppressed Mouse Models of Candidiasis, Aspergillosis, and Pneumocystis Pneumonia (PCP)” 22nd Congress of the European Hematology Association, 2017
3. E. Lakota, et al., “Pharmacokinetic-Pharmacodynamic Analyses to Provide Rezafungin Prophylaxis Dose Selection for Prevention of Invasive Fungal Infections for Bone Marrow Transplant Patients”, American Society of Hematology, 2018.
REFERENCES
METHODS
Male Sprague-Dawley (SD) albino (intact and bile duct–cannulated) as well as Long-Evans (LE) pigmented rats were administered a single IV bolus dose of [14C]RZF. Urine and feces samples were collected for up to 14 days post-dose. Blood/plasma and bile samples were collected up to 5 days post-dose.
Male cynomolgus monkeys were administered a single IV infusion dose of [14C]RZF. Urine and feces samples were collected for up to 30 days post-dose. Blood/plasma samples were collected up to 60 days post-dose.
Blood, plasma, bile, and excreta samples were analyzed for radioactivity by liquid scintillation counting. Tissue distribution was assessed by quantitative whole-body autoradiography (QWBA).
1 hr
10 days
CONCLUSIONS
QWBA images below show the long residence times in most tissues of the monkey following a single IV dose.
RESULTS
Low-level oxidative metabolites (2-, 3-, 4-hydroxylpentyl CD101, and despentyl-CD101) were observed during metabolite profiling at later (≥4 hr) timepoints, with greater levels detected in rat than in monkey plasma/excreta.
Also similar to the rat, exposure in most tissues was higher than in blood through 60 days after a single dose. A pertinent selection of tissue conc-time profiles in the monkey are plotted below.
Exposure (AUC) in most tissues was higher than in blood and sustained; quantifiable concentrations were present in 50 of 54 tissues through 36 days after a single dose. Tissue concentration versus time profiles in rats showed that elimination/tissue release of radioactivity from most tissues was slower with t1/2 values of >200 hours compared with a t1/2 of 186 hours in blood.
Similar radioactivity distribution trends and exposures were observed in pigmented LE and non-pigmented SD skin indicating that [14C]RZF was not specifically associated with melanin.
In bile duct–cannulated rats, 35% of the dose was recovered in feces suggesting intestinal secretion of RZF, while 17%, 14%, 30%, and 1% was recovered in the bile, urine, carcass, and cage residues, respectively, for a cumulative recovery of 97%.
Plasma, urine, bile, and fecal samples were analyzed using liquid chromatography tandem mass spectrometry coupled with a radio flow-through detector for metabolite profiling and identification.
4 hrs 24 hrs 10 days
