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Elizabeth A. Lakota, Pharm.D., M.S.Institute for Clinical Pharmacodynamics, Inc.242 BroadwaySchenectady, NY 12305Telephone: (518) 631-8100Fax: (518) 631-8199E-mail: [email protected]
Pharmacokinetic-Pharmacodynamic Target Attainment Analyses to Support Rezafungin Dose Selection in the Treatment of Candida Infections
CONCLUSIONS
RESULTS
IDWeek 2018, San Francisco, CA. October 3-7, 2018
RESULTS
REFERENCES
INTRODUCTION
Poster No. 1390
E.A. Lakota1, H. Ganesan1, S. Flanagan2, V. Ong2, T. Sandison2, S.M. Bhavnani1, C.M. Rubino1, P.G. Ambrose1
1Institute for Clinical Pharmacodynamics, Inc., Schenectady, NY, USA; 2Cidara Therapeutics, San Diego, CA, USA
METHODS
• A population PK model describing rezafungin PK in healthy subjects and patients with candidemia and/or invasive candidiasis was successfully developed.
• Rezafungin dosing regimens evaluated demonstrated high percent probabilities of PK-PD target attainment against C. albicans and C. glabrata in simulated patients with demographics similar to those observed in the Phase 2 STRIVE trial.o Percent probabilities of PK-PD target attainment ≥95.1% were achieved up to the MIC100
regardless of the pathogen, fungal reduction endpoint, period of assessment, or dosing regimen evaluated.
• These data support selection of either the 400 mg once-weekly or the 400 mg on Week 1, then 200 mg once-weekly regimen for the treatment of patients with candidemia or invasive candidiasis.
1. Lakota EA, Ong V, Flanagan S, Rubino CM. 2018. Population Pharmacokinetic Analyses for Rezafungin (CD101) Efficacy Using Phase 1 Data. AntimicrobAgents Chemother e02603-17.
2. Lepak AJ, Zhao M, VanScoy BA, Ambrose PG, Andes DR. 2018. Pharmacodynamics of a long-acting echinocandin, CD101, in a neutropenic invasive-candidiasis murine model using an extended-interval dosing design. Antimicrob Agents Chemother 62:e02154-17.
3. Bader JC, Lakota EA, Flanagan S, Ong V, Sandison T, Rubino CM, Bhavnani SM, Ambrose PG. 2018. Overcoming the Resistance Hurdle: PK-PD Target Attainment Analyses of Rezafungin (CD101) for Candida albicans and Candida glabrata. Antimicrob Agents Chemother 62(6) e02614-17.
4. Pfaller MA, Messer SA, Rhomberg PR, Castanheira M. 2017. CD101, a long-acting echinocandin, and comparator antifungal agents tested against a global collection of invasive fungal isolates in the SENTRY 2015 Antifungal Surveillance Program. Int J Antimicrob Agents 50:352-358.
5. Flanagan S, Sandison T, Locke JB, Ong V, Ye G, Bartizal K, Daruwala P. 2018. CD101 prophylactic dose rationale for prevention of Aspergillus, Candida, and Pneumocystis Infections. Biol Blood Marrow Transplant 24: S389–S390.
• Rezafungin is a novel antifungal of the echinocandin class with distinctive pharmacokinetics (PK) that support weekly dosing intervals.
• Rezafungin has activity against Pneumocystis, Aspergillus, and Candida species, including azole- and echinocandin-resistant isolates and is being developed for the treatment of candidemia and invasive candidiasis and the prevention of invasive fungal infections.
• A population PK model based on Phase 1 intravenous (IV) data was previously developed [1] and pharmacokinetic-pharmacodynamic (PK-PD) target attainment analyses were conducted using this model and nonclinical PK-PD targets for efficacy [2, 3].
• A Phase 2 trial (STRIVE, NCT02734862) was recently conducted in patients with candidemia and/or invasive candidiasis.
• Rezafungin dose selection analyses were updated using PK data from the above-described Phase 2 patients infected with candidemia and/or invasive candidiasis.
OBJECTIVES• To refine the previously-developed population PK model using IV data from
additional Phase 1 and Phase 2 (STRIVE) trials.• To assess PK-PD target attainment for different rezafungin dosing regimens using
Monte Carlo simulations based on the refined population PK model and nonclinical PK-PD targets for Candida albicans or Candida glabrata efficacy.
Population Pharmacokinetic Model• Data from the two Phase 1 trials used previously to develop the model were pooled
with data from an additional Phase 1 trial and the Phase 2 STRIVE trial data in patients with candidemia and/or invasive candidiasis. o CD101.IV.1.01: evaluated single IV doses ranging from 50 – 400 mgo CD101.IV.1.02: evaluated multiple weekly IV doses ranging from 100 – 400 mgo CD101.IV.1.06: evaluated single IV doses ranging from 600 – 1400 mgo CD101.IV.2.03 (STRIVE):
§ Treatment Arm 1: 400 mg once-weekly x 2 weeks, optional additional weekly doses§ Treatment Arm 2: 400 mg once-weekly x 1 week followed by 200 mg once-weekly x 1 week, optional
additional weekly doses doses
• The population PK model was refined using NONMEM Version 7.2. • The ability of covariates such as body size, age, sex, albumin, markers of hepatic
and renal function, and infection status to explain a portion of the interindividual variability on select PK parameters was explored using stepwise forward selection (α = 0.01) and backward elimination (α = 0.001).
Nonclinical Pharmacokinetic-Pharmacodynamic Targets for Efficacy• PK-PD targets for efficacy were determined using neutropenic murine (CD-1 mice)
disseminated candidiasis models [2].o Median free-drug ratio of the area under the concentration-time curve from time 0 to 168
hours to the minimum inhibitory concentration (AUC0-168:MIC ratio) targets associated with net fungal stasis and 1-log10 colony forming unit (CFU) reduction from baseline were 20.46 and 37.24, respectively, for C. albicans and 0.50 and 2.94, respectively, for C. glabrata.
Rezafungin In Vitro Activity• Rezafungin MIC distributions for C. albicans and C. glabrata isolates collected
worldwide as part of the JMI 2015 SENTRY Antifungal Surveillance Program [4] were used to interpret the PK-PD target attainment results and calculate overall percent probabilities of PK-PD target attainment (Table 1).
METHODS
Population Pharmacokinetic Model• The final population PK model was a linear, four-compartment model with zero
order IV input. • The model provided precise and unbiased fits to the observed data (Figure 1).• Albumin was the most important predictor of the interindividual variability in
rezafungin PK as significant relationships were found between serum albumin concentration and clearance, volume of the central compartment, volume of peripheral compartment 1, and volume of peripheral compartment 2. o Additional relationships were found between PK parameters and sex, body weight, and
infection status. o Mean parameter estimates for a 75 kg male subject with an albumin concentration of 4.2
g/dL: CL = 0.263 L/h, Vc = 12.7 L, CLd1 – 21.3 L/h, Vp1 = 14 L, CLd2 = 0.748 L/h, Vp2 = 10.2 L
Pharmacokinetic-Pharmacodynamic Target Attainment Analyses• Week 1 and Week 4 percent probabilities of PK-PD target attainment by MIC for
C. albicans and C. glabrata are shown in Figure 2 and Figure 3, respectively, and Table 2.
• Regardless of fungal reduction endpoint or dosing regimen:o At the MIC90 for C. albicans and C. glabrata (0.06 and 0.12 mg/L, respectively), percent
probabilities of PK-PD target attainment of 100% were achieved through Week 4. o Percent probabilities of PK-PD target attainment of >90% were achieved at or above the
MIC100 values for C. albicans and C. glabrata (0.25 and 2 mg/L, respectively) through Week 4.
o Percent probabilities of PK-PD target attainment determined using randomly assigned MIC values were 100% through Week 4.
Pharmacokinetic-Pharmacodynamic Target Attainment Analyses• Using the above-described population PK model, free-drug plasma concentration-
time profiles were generated for 2,000 simulated subjects following administration of rezafungin 400 mg once-weekly or 400 mg on Week 1, then 200 mg once-weekly thereafter.o Each patient’s albumin, sex, and weight were randomly selected from the STRIVE trial
database using a bootstrap technique.o A protein binding estimate for rezafungin for humans of 97.4% was used [5].
• Weekly free-drug plasma AUC values were calculated for each subject following administration of the rezafungin dosing regimens.
• The free-drug plasma AUC0-168 values were then divided by MIC values ranging from 0.008 to 2 mg/L. In a second analysis, MIC values were randomly assigned based on the rezafungin MIC distributions for C. albicans and C. glabrata shown in Table 1.
• Percent probabilities of PK-PD target attainment by week were calculated for each pathogen, dosing regimen, and PK-PD endpoint combination.
Table 1. Rezafungin MIC distributions for C. albicans and C. glabrata based on isolates collected in the international SENTRY Antifungal Surveillance Program
Pathogen (N)
No. of occurrences by MIC (mg/L)(cumulative % inhibited)a
≤0.008 0.015 0.03 0.06 0.12 0.25 0.5 1 2 MIC50 MIC90
C. albicans (304) 56 (18.4) 81 (45.1) 125 (86.2) 33 (97.0) 8 (99.7) 1 (100) - - - 0.03 0.06
C. glabrata (121) - 3 (2.50) 69 (59.5) 22 (77.7) 25 (98.3) 1 (99.2) 0 (99.2) 1 (100) - 0.03 0.12
a. Based on data for clinical C. albicans and C. glabrata isolates described in reference 4. Shaded cells represent the MIC values up to and including the MIC90.
Figure 1. Goodness-of-fit plots for final population PK model
Figure 3. Week 4 percent probabilities of PK-PD target attainment by MIC following administration of 400 mg once-weekly (left) or 400 mg on Week 1 then 200 mg once-weekly (right)
Figure 2. Week 1 percent probabilities of PK-PD target attainment by MIC following administration of rezafungin 400 mg
Table 2. Percent probabilities of PK-PD target attainment by MIC and for simulatedpatients randomly assigned MIC values based on nonclinical AUC0-168:MIC ratio targetsassociated with net fungal stasis and a 1-log10 CFU reduction from baseline
Fungal reduction endpoint
MIC(mg/L)
Percent probabilities of PK-PD target attainment by rezafungin regimens and weeka
C. albicans C. glabrata
400 mg x 1 weekly400 mg x 1 week
followed by 200 mg Weekly
400 mg x 1 weekly400 mg x 1 week
followed by 200 mg weekly
Week 1 Week 4 Week 1 Week 4 Week 1 Week 4 Week 1 Week 4
Net fungal stasis
0.008 100 100 100 100 100 100 100 100
0.015 100 100 100 100 100 100 100 100
0.03 100 100 100 100 100 100 100 100
0.06 100 100 100 100 100 100 100 100
0.12 100 100 100 100 100 100 100 100
0.25 100 100 100 100 100 100 100 100
0.5 98.8 100 98.8 90.55 100 100 100 100
1 35.1 88.3 35.1 15 100 100 100 100
2 0.05 10.75 0.05 0 100 100 100 100
4 0 0 0 0 100 100 100 100
8 0 0 0 0 100 100 100 100
16 0 0 0 0 100 100 100 98.65
Overallb 100 100 100 100 100 100 100 100
1-log10 CFU reduction from
baseline
0.008 100 100 100 100 100 100 100 100
0.015 100 100 100 100 100 100 100 100
0.03 100 100 100 100 100 100 100 100
0.06 100 100 100 100 100 100 100 100
0.12 100 100 100 100 100 100 100 100
0.25 99.6 100 99.6 95.1 100 100 100 100
0.5 47.25 93.65 47.25 23.95 100 100 100 100
1 0.2 19 0.2 0.15 100 100 100 100
2 0 0 0 0 100 100 100 99.95
4 0 0 0 0 95.95 99.95 95.95 77.85
8 0 0 0 0 18.5 73.7 18.5 6.65
16 0 0 0 0 0 3.55 0 0
Overallb 100 100 100 100 100 100 100 100a. Shaded cells indicate PK-PD target attainment values ≥90%. b. Simulated patients were randomly assigned MIC values based on the C. albicans and C. glabrata in vitro surveillance data presented in Table 1.