Elizabeth A. Lakota, Pharm.D., M.S.Institute for Clinical Pharmacodynamics, Inc.242 BroadwaySchenectady, NY 12305Telephone: (518) 631-8100Fax: (518) 631-8199E-mail: ELakota@icpd.com

Pharmacokinetic-Pharmacodynamic Target Attainment Analyses to Support the Selection of Extended-Interval CD101 Dosing Regimens

CONCLUSIONS

OBJECTIVES

RESULTS RESULTS

REFERENCES

Background: CD101 is a novel, long-acting echinocandin with activity against Candida albicans and other clinically relevant Candida species. Given CD101’s half-life of up to 150 h in humans and that efficacy for this class is associated with area under the concentration-time curve (AUC), CD101 is an excellent candidate for extended-interval dosing. PK-PD target attainment analyses were conducted to evaluate single and weekly dosing of CD101 to provide dose selection decision support. Methods: A population PK model was developed in S-ADAPT using data from two Phase 1 studies in healthy volunteers evaluating single and multiple weekly IV doses of CD101 up to 400 mg. Monte Carlo simulation (n= 2000) was performed using this population PK model. Three CD101 dosing regimens were evaluated: a single 400 mg dose, 400 mg weekly for 3 weeks, and 400 mg for Week 1 followed by 200 mg weekly for 2 weeks. Individual free-drug plasma AUC values from time zero to 168 h (AUC0-168) were calculated. Simulated patients were assigned a CD101 MIC value based on an MIC distribution for C. albicans (MIC50 and MIC90 were 0.03 and 0.06 mg/L, respectively) [ICAAC 2015 Abstract M-849]. A free-drug plasma AUC0-168:MIC ratio target associated with a 2-log10 CFU reduction from baseline for C. albicans of 10, derived from a neutropenic murine disseminated candidiasis model, was used. Percent probabilities of PK-PD target attainment were computed for each CD101 dosing regimen.Results: CD101 PK data were best described using a four-compartment model with zero-order drug input and first-order, linear elimination with all parameters scaled to body weight. This model fit the observed data with very little bias and excellent precision (all parameters had %CV <18%). Figure 1 shows boxplots of AUC0-168:MIC ratio following administration of the three CD101 dosing regimens. Percent probabilities of PK-PD target attainment for both weekly CD101 dosing regimens were 100% from Weeks 1 to 4; for the single CD101 400 mg dose, percent probabilities were >99% during Weeks 1 to 3 and >95% at Week 4. Conclusion: Results of these analyses provide support for each CD101 dosing regimen evaluated. Single and once-weekly CD101 dosing presents the opportunity to deliver drug exposures in a PK-PD-optimized manner, improve compliance, and reduce resources required for therapeutic drug monitoring.

ABSTRACT

Poster No. 1994

INTRODUCTION

E.A. Lakota1, J.C. Bader1, D. Thye2, K. Bartizal2, V. Ong2, S.M. Bhavnani1, P.G. Ambrose1, C.M. Rubino1

1Institute for Clinical Pharmacodynamics, Inc., Schenectady, NY, USA; 2Cidara Therapeutics, San Diego, CA, USA

• To develop a population PK model to describe the disposition of CD101.

• To assess PK-PD target attainment for different CD101 dosing regimens using Monte Carlo simulations based on the developed population PK model and a non-clinical PK-PD target.

METHODSPopulation PK Model

• The data were best described using a four-compartment model with zero-order drug input and first-order, linear elimination.

• All parameters in the model were scaled to subject body weight using standard allometric coefficients (a power of 0.75 and 1 for the clearance and volume terms, respectively).

• All model parameters were estimated with excellent precision (%SEM < 20) as shown in Table 2.

• Excellent fits to the data were obtained, as evidenced by the overall r2 of 0.982 based on observed versus individual predicted plasma concentrations (Figure 1A), and the model fit with minimal bias, as indicated by the slope and intercept terms (Figures 1A and 1B).o Both individual weighted residuals and conditional weighted residuals demonstrated an

even and constant spread across the population predicted concentrations (Figure 1C and 1D), again indicating minimal bias.

PK-PD Target Attainment Analyses

• Percent probabilities of PK-PD target attainment based on free-drug AUC0-168:MIC ratios determined using randomly assigned MIC values and the MIC90 were 100% from Weeks 1 to 4 for both weekly CD101 dosing regimens (Figure 2).

• When evaluated based on free-drug AUC0-168:MIC ratios determined using randomly assigned MIC values, percent probabilities of PK-PD target attainment were >99% during Weeks 1 to 3 and >95% at Week 4 for the single CD101 400 mg dose (Figure 2A). When evaluated based on free-drug AUC0-168:MIC ratios determined using MIC90, percent probabilities of PK-PD target attainment were 100, 100, 72.8 and 10.2% at Weeks 1, 2, 3 and 4, respectively (Figure 2D).

• Results of these analyses provide support for each of the CD101 dosing regimens evaluated.

• Single and once-weekly CD101 dosing presents the opportunity to deliver drug exposures in a PK-PD-optimized manner, improve compliance, and reduce resources required for therapeutic drug monitoring.

• CD101 is a novel echinocandin antifungal agent with activity against Aspergillusand Candida species, including azole- and echinocandin-resistant isolates.

• CD101 is a structural analog of anidulafungin, resulting in the following different physical and biological properties:o Reduced hepatotoxicity relative to anidulafungin.o Longer half-life (up to 150 hours) relative to anidulafungin (~25 hours).

• The ratio of the area under the concentration-time curve to the minimum inhibitory concentration (AUC:MIC ratio) is the pharmacokinetic-pharmacodynamic (PK-PD) index associated with CD101 efficacy [1].

• Given CD101’s long half-life and the above-described PK-PD index associated with efficacy, CD101 is an excellent candidate for extended-interval dosing [2].o To test this hypothesis, a PK-PD target attainment analysis was undertaken to evaluate single

and weekly dosing of CD101.

1. Rubino CM, Ong V, Thye D, Ambrose PG. Pharmacokinetics Pharmacodynamics (PKPD) of a Novel Echinocandin, CD101, in a Neutropenic Murine Disseminated Candidiasis Model. [Abstract # A-1292]. ICAAC, San Diego CA. September 17-21, 2015.

2. Ambrose PG, Drusano GL, Craig WA. In Vivo Activity of Oritavancin in Animal Infection Models and Rationale for a New Dosing Regimen in Humans. Clin Infect Dis 2012; Apr; 54 (S3):S220-8.

3. Bauer RJ. S-ADAPT/MCPEM User's Guide: Software for Pharmacokinetic, Pharmacodynamic and Population Data Analysis. Berkley, CA: 2006.4. Lakota EA, Rubino CM, Ong V, Bartizal K, Miesel L, Bhavnani SM, Ambrose PG. Pharmacological Basis of CD101 Efficacy:

Exposure Shape Matters .[SUNDAY-505, PW-046]. American Society of Microbiology Microbe 2016, Boston, MA June 16-20, 2016.5. Castanheira M, Messer SA, Rhomberg PR, Dietrich RR, Pfaller MA. Activity of a Long-Acting Echinocandin(CD101) and Comparator Antifungal Agents Tested against

Contemporary Invasive Fungal Isolates. [Abstract # M-849]. ICAAC, San Diego CA. September 17-21, 2015.6. Data on file, Cidara Therapeutics

Population PK Model

• Data for the population PK model analyses were obtained from two Phase 1 studies in healthy subjects (Studies CD101.IV.1.01 and CD101.IV.1.02).

o Study CD101.IV.1.01 was a single ascending dose study, with CD101 IV doses ranging from 50 to 400 mg.

o Study CD101.IV.1.02 was a multiple ascending dose study, with CD101 IV doses ranging from 100 mg to 400 mg once-weekly for 2 to 3 doses.

• Candidate population PK models were fit to the pooled data using Monte Carlo parametric expectation maximization (MCPEM) as implemented in the open-source software program S-ADAPT version 1.5.6 [3].

Non-Clinical PK-PD Target for Efficacy

• The non-clinical free-drug AUC0-168:MIC target for efficacy of 10 was used for this analysis. This value was associated with a 2-log10 CFU reduction from baseline for C. albicans in a neutropenic murine disseminated candidiasis model [4].

CD101 In Vitro Activity

• The CD101 MIC distribution for C. albicans based on 251 isolates collected worldwide that were used for the PK-PD target attainment analysis are summarized in Table 1.

PK-PD Target Attainment Analyses

• Using the above-described population PK model, free-drug plasma concentration-time profiles over 4 weeks were generated for 2,000 simulated subjects following administration of each of the following CD101 regimens: single 400 mg IV dose, 400 mg IV weekly for 3 weeks, and 400 mg IV for Week 1 followed by 200 mg IV weekly for 2 weeks.

o Each subject’s weight was randomly selected from a distribution of weight values collected from pneumonia patients.

o A protein binding estimate for CD101 for humans of 99.1% was used [6].

• Weekly free-drug plasma AUC values (AUC0-168) were calculated over 4 weeks for each subject following administration of the CD101 dosing regimens.

• The free-drug plasma AUC0-168:MIC ratio was then calculated for each simulated subject using both a randomly assigned MIC value and the MIC90 value, both of which were based on the CD101 MIC distribution for C. albicans shown in Table 1.

• The percent probability of PK-PD target attainment by week was calculated for each CD101 dosing regimen.

Table 1. CD101 MIC distributions for C. albicansa

Pathogen(no. of isolates

tested)

No. of occurrences by MIC (mg/L)(cumulative % inhibited)b

≤0.008 0.015 0.03 0.06 0.12 0.25 0.5 1 MIC50 MIC90

C. albicans(n=251)

17(6.8)

107(49.4)

91(85.7)

28(96.8)

8(100) 0.06 0.12

a. Based on data from reference 5.b. Shaded cells represent the MIC values up to and including the MIC90 value.

Table 2. Final population PK model parameter estimates

ParameterPopulation mean

(Centered on 75 kg)Mean value for study subjects

Interindividual variability(%CV)

Final estimate %SEM Final value Final estimate %SEMCL (L/h) 0.187 1.46 0.188 13.0 14.6Vc (L) 8.88 3.22 8.94 28.0 15.6Q2 (L/h) 24.3 5.42 24.4 45.2 17.1V2 (L) 12.5 1.04 12.6 8.81 17.0Q3 (L/h) 0.908 10.0 0.912 84.3 17.0V3 (L) 8.70 2.35 8.75 19.6 15.9Q4 (L/h) 0.0736 5.29 0.0739 44.7 16.3V4 (L) 27.7 9.70 27.9 81.3 18.0SDin 0.01 — — — —SDsl 0.0624 4.72 — — —

Minimum value of the objective function = 2636

Figure 1. Goodness-of-fit plots for final population PK model

Figure 2. Distributions of free-drug AUC0-168:MIC ratios based on randomly assigned MIC values (A, B and C) and the MIC90 (D, E and F) for C. albicans isolates collected worldwide

D

A BC

EF

A B

C D

IDWeek 2016, New Orleans, LA. October 26-30, 2016Poster No. 1994