Brown Px dose rationale EBMT encore of TCT19 PSTR-FINAL
1
www.ebmt.org #EBMT19 J. Brown 1 , E.A. Lakota 2 , S. Flanagan 3 , T. Sandison 3 , V. Ong 3 , C.M. Rubino 2 1 Stanford University Medical Center, Stanford, CA, USA; 2 Institute for Clinical Pharmacodynamics, Schenectady, NY, USA; 3 Cidara Therapeutics, San Diego, CA, USA • Rezafungin (RZF) is a novel echinocandin antifungal being developed for single-agent prophylaxis against invasive fungal disease caused by Candida, Aspergillus, and Pneumocystis species in patients at high risk of infection, such as blood and marrow transplant (BMT) recipients. • The long half-life of RZF (~133 h) in human enables administration of once-weekly dosing regimens. 1 Prophylactic efficacy in a mouse Pneumocystis model is achieved at a human equivalent dose of <50 mg once-weekly. 2 A dose of 400 mg followed by 200 mg once weekly achieved >90% target attainment for treatment of Candida. 3 • Pharmacokinetic-pharmacodynamic (PK-PD) simulations were performed using the rezafungin dosing regimen for treatment of Candida to evaluate the appropriateness for prophylaxis against A. fumigatus among BMT patients. INTRODUCTION METHODS • These data support a weekly RZF dosing regimen for prevention of A. fumigatus infections in BMT patients. • No clinically significant covariates were identified in infected patients, indicating consistent exposure across a wide range of subject factors. • The effectiveness of antifungal prophylactic regimens are often limited due to pill burden, adherence, safety, tolerability, and DDIs. • In addition to the excellent safety, tolerability, and lack of drug interactions exhibited by echinocandins, the favorable PK profile of RZF presents the opportunity to mitigate the typical challenges faced when administering antifungal prophylaxis in BMT patients. CONCLUSIONS 1. Sandison T, et al. Antimicrob Agents Chemother 2016;6:e01627-16. 2. Ong V, Abstract 9645. 22 nd Congress of the European Hematology Association. Madrid, ES. June 22-25, 2017. REFERENCES Presenter Information: Voon Ong, PhD | Cidara Therapeutics, Inc. | San Diego, CA 92121 USA | [email protected] PK-PD Analyses of Dose Selection for Rezafungin Prophylaxis Against Invasive Fungal Infections in Blood and Marrow Transplantation Population Pharmacokinetic (PopPK) Model • A previously developed PopPK model 3 was updated with data from an additional Phase 1 trial and the Phase 2 STRIVE trial in patients with candidemia and/or invasive candidiasis. The PopPK model was refined using NONMEM Version 7.2. • The ability of covariates (eg, body size, age, sex, albumin, creatinine clearance, and infection status) to explain interindividual variability on select PK parameters was explored (stepwise forward selection [α = 0.01] and stepwise backward elimination [α = 0.001]). Monte Carlo Simulations • Baseline demographic data from 100 BMT recipients at Stanford Med Ctr and the PopPK model were used for Monte Carlo simulation (n=2,000) of expected RZF concentration-time profiles in BMT patients following RZF IV 400 mg on Week 1 and then 200 mg weekly x11. • Free-drug concentration-time profiles (plasma protein binding estimate of 97.4%) 4 were evaluated relative to the max observed minimal effective concentration to inhibit 100% of isolates tested (MEC 100 , 0.03 mg/L) (Table 1). A. fumigatus (60) # of occurrences by MEC (mg/L) (cumulative % inhibited) a MEC 50 MEC 90 MEC 100 ≤0.008 0.015 0.03 25 (41.7) 29 (90.0) 6 (100) 0.015 0.015 0.03 a. Based on clinical isolates from the SENTRY Antifungal Surveillance Program (2017). 5 Table 1. RZF MEC distributions and cutoff values for A. fumigatus RESULTS • Final PopPK model: linear, 4-compartment model with zero-order IV input; provided precise and unbiased fits to the observed data. • Albumin, sex, infection status, and body surface area were found to be significant covariates. Differences in predicted median AUC across a wide range of covariates were modest (Figure 1). • Monte Carlo simulations: Across simulated patients (Table 2), exposures were highest during Week 1 (Figure 2). 3. Lakota EA, et al. Antimicrob Agents Chemother 2018; 62:e02603-17. 4. Flanagan S, et al. Biol Blood Marrow Transplant 2018;24:S389–S390. 5. Pfaller MA, et al. Open Forum Infect Dis 2018;5(suppl_1):S716-S717. Variable Median (Range) N (%) Age (years) 58 (19 – 75) — Weight (kg) 73.7 (41.6 – 133) — Height (cm) 169 (142 – 193) — BSA (m 2 ) 1.84 (1.27 – 2.61) — BMI (kg/m 2 ) 26.4 (17.1 – 48.5) — Albumin (g/dL) 3.35 (1.80 – 4.43) — Female — 39 (39%) Allograft Transplant — 87 (87%) Table 2. Summary of patient demographics • The percent of simulated patients with free-drug plasma concentrations above the MEC 100 and MEC 90 values for the entire dosing interval (one week) was 100% and 98.0% at Week 1, 99.9% and 92.0% at Week 4, and 90.2% and 99.8% at Week 12. B214 Figure 2. Rezafungin free-drug plasma concentration–time profiles by week relative to A. fumigatus MEC 100 (0.03 mg/L, marked in red) Figure 1. Covariate effects on rezafungin Week 1 plasma AUC
Transcript of Brown Px dose rationale EBMT encore of TCT19 PSTR-FINAL
www.ebmt.org #EBMT19
J. Brown1, E.A. Lakota2, S. Flanagan3, T. Sandison3, V. Ong3, C.M. Rubino2
1Stanford University Medical Center, Stanford, CA, USA; 2Institute for Clinical Pharmacodynamics, Schenectady, NY, USA; 3Cidara Therapeutics, San Diego, CA, USA
• Rezafungin (RZF) is a novel echinocandin antifungal being developed for single-agent prophylaxis against invasive fungal disease caused byCandida, Aspergillus, and Pneumocystis species in patients at high risk of infection, such as blood and marrow transplant (BMT) recipients.
• The long half-life of RZF (~133 h) in human enables administration of once-weekly dosing regimens.1 Prophylactic efficacy in a mouse Pneumocystis model is achieved at a human equivalent dose of <50 mg once-weekly.2 A dose of 400 mg followed by 200 mg once weekly achieved >90% target attainment for treatment of Candida.3
• Pharmacokinetic-pharmacodynamic (PK-PD) simulations were performed using the rezafungin dosing regimen for treatment of Candida to evaluate the appropriateness for prophylaxis against A. fumigatus among BMT patients.
INTRODUCTION
METHODS
• These data support a weekly RZF dosing regimen for prevention of A. fumigatus infections in BMT patients. • No clinically significant covariates were identified in infected patients, indicating consistent exposure across a wide range of subject
factors.• The effectiveness of antifungal prophylactic regimens are often limited due to pill burden, adherence, safety, tolerability, and DDIs. • In addition to the excellent safety, tolerability, and lack of drug interactions exhibited by echinocandins, the favorable PK profile of
RZF presents the opportunity to mitigate the typical challenges faced when administering antifungal prophylaxis in BMT patients.
CONCLUSIONS
1. Sandison T, et al. Antimicrob Agents Chemother 2016;6:e01627-16.2. Ong V, Abstract 9645. 22nd Congress of the European Hematology
Association. Madrid, ES. June 22-25, 2017.
REFERENCES
Presenter Information: Voon Ong, PhD | Cidara Therapeutics, Inc. | San Diego, CA 92121 USA | [email protected]
PK-PD Analyses of Dose Selection for Rezafungin Prophylaxis Against
Invasive Fungal Infections in Blood and Marrow Transplantation
Population Pharmacokinetic (PopPK) Model• A previously developed PopPK model3 was updated with data from an additional Phase 1 trial and the Phase 2 STRIVE trial in patients with
candidemia and/or invasive candidiasis. The PopPK model was refined using NONMEM Version 7.2. • The ability of covariates (eg, body size, age, sex, albumin, creatinine clearance, and infection status) to explain interindividual variability on
select PK parameters was explored (stepwise forward selection [α = 0.01] and stepwise backward elimination [α = 0.001]).
Monte Carlo Simulations• Baseline demographic data from 100 BMT recipients at Stanford
Med Ctr and the PopPK model were used for Monte Carlo simulation (n=2,000) of expected RZF concentration-time profiles in BMT patients following RZF IV 400 mg on Week 1 and then 200 mg weekly x11.
• Free-drug concentration-time profiles (plasma protein binding estimate of 97.4%)4 were evaluated relative to the max observed minimal effective concentration to inhibit 100% of isolates tested (MEC100, 0.03 mg/L) (Table 1).
A. fumigatus(60)
# of occurrences by MEC (mg/L)(cumulative % inhibited)a
MEC50 MEC90 MEC100≤0.008 0.015 0.0325 (41.7) 29 (90.0) 6 (100) 0.015 0.015 0.03
a. Based on clinical isolates from the SENTRY Antifungal Surveillance Program (2017).5
Table 1. RZF MEC distributions and cutoff values for A. fumigatus
RESULTS
• Final PopPK model: linear, 4-compartment model with zero-order IV input; provided precise and unbiased fits to the observed data.
• Albumin, sex, infection status, and body surface area were found to be significant covariates. Differences in predicted median AUC across a wide range of covariates were modest (Figure 1).
• Monte Carlo simulations: Across simulated patients (Table 2), exposures were highest during Week 1 (Figure 2).
3. Lakota EA, et al. Antimicrob Agents Chemother 2018; 62:e02603-17.4. Flanagan S, et al. Biol Blood Marrow Transplant 2018;24:S389–S390. 5. Pfaller MA, et al. Open Forum Infect Dis 2018;5(suppl_1):S716-S717.
Variable Median (Range) N (%)Age (years) 58 (19 – 75) —
Weight (kg) 73.7 (41.6 – 133) —
Height (cm) 169 (142 – 193) —
BSA (m2) 1.84 (1.27 – 2.61) —
BMI (kg/m2) 26.4 (17.1 – 48.5) —
Albumin (g/dL) 3.35 (1.80 – 4.43) —
Female — 39 (39%)
Allograft Transplant — 87 (87%)
Table 2. Summary of patient demographics
• The percent of simulated patients with free-drug plasma concentrations above the MEC100 and MEC90 values for the entire dosing interval (one week) was 100% and 98.0% at Week 1, 99.9% and 92.0% at Week 4, and 90.2% and 99.8% at Week 12.
B214
Figure 2. Rezafungin free-drug plasma concentration–time profiles by week relative to A. fumigatus MEC100 (0.03 mg/L, marked in red)
Figure 1. Covariate effects on rezafungin Week 1 plasma AUC
