1994. PK-PD Target Attainment Analyses to Support the Selection of Extended Interval CD101 Dosing Regimens
Session: Poster Abstract Session: Antimicrobial Pharmacokinetics and Pharmacodynamics
Saturday, October 29, 2016
Room: Poster Hall
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.

Elizabeth A. Lakota, Pharm.D., M.S.1, Justin C. Bader, Pharm.D., MBA1, Dirk Thye, M.D.2, Ken Bartizal, Ph.D.2, Voon Ong, PhD2, Sujata Bhavnani, Pharm.D., M.S.1, Paul G. Ambrose, Pharm.D., FIDSA1 and Christopher M. Rubino, Pharm.D.1, (1)Institute for Clinical Pharmacodynamics, Schenectady, NY, (2)Cidara Therapeutics, San Diego, CA

Disclosures:

E. A. Lakota, Cidara Therapeutics: Research Contractor , Research support

J. C. Bader, Cidara Therapeutics: Research Contractor , Research support

D. Thye, Cidara Therapeutics: Employee and Shareholder , Salary

K. Bartizal, Cidara Therapeutics: Employee and Shareholder , Salary

V. Ong, Cidara Therapeutics: Employee and Shareholder , Salary

S. Bhavnani, Cidara Therapeutics: Research Contractor , Research support

P. G. Ambrose, Cidara Therapeutics: Research Contractor , Research support

C. M. Rubino, Cidara Therapeutics: Research Contractor , Research support

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