Pharmacokinetics, Safety, and Target Attainment of Single and Multiple Doses of CD101 IV

Introduction: CD101 is a novel, long-acting echinocandin with activity against Candida and Aspergillus spp. in development for prevention and treatment of serious fungal infections. CD101 has shown robust efficacy in neutropenic mouse infection models of disseminated candidiasis as well as aspergillosis and an excellent nonclinical safety/toxicology profile. Two randomized, double-blind, placebo-controlled, phase 1, dose-escalation trials were conducted to establish the safety and pharmacokinetics (PK) of single and multiple weekly dosing of CD101 administered intravenously. PK-pharmacodynamic (PD) analyses of these data were conducted to evaluate the probability of achieving therapeutic targets against Candida.

Methods: Sequential cohorts of 8 healthy subjects (n=6, CD101; n=2, placebo) received a single dose of CD101 (50, 100, 200, 400 mg) or multiple weekly doses (100 mg x2, 200 mg x2, 400 mg x3) infused intravenously over 1 hour. PK was assessed using plasma and urine samples collected over 21 days. Safety and tolerability were assessed by adverse events (AEs), vital signs, physical exams, electrocardiograms, and safety laboratory values up to 21 days after dosing. Data from these clinical trials were used to develop a population PK model and perform Monte Carlo simulation (n=2000) evaluating a single dose of 400 mg and multiple weekly doses (400 mg x3 or 400 mg x1 followed by 200 mg x2) chosen for an upcoming Phase 2, dose-ranging trial in candidemia. For each dosing regimen, percent probabilities of PK-PD target attainment against Candida albicans (R303, human blood isolate) were calculated.

Results: CD101 and placebo groups had similar incidences of AEs. The majority were mild, and all resolved completely. Slightly higher incidences of AEs and mild transient infusion reactions were seen in the group that received CD101 400 mg x 3 weekly doses. There were no clinically significant safety issues in observed or laboratory assessments, and no deaths, serious AEs, severe AEs, or withdrawals due to an AE. CD101 IV demonstrated dose-proportional plasma exposures, low apparent clearance (<0.3 L/h), long half-life (t_1/2 >80 h), minimal urinary excretion (<1%), and minor accumulation (30% to 55%, multiple-dose study). The percent probability of therapeutic target attainment against C. albicans was 100% for both weekly dosing regimens of CD101 (Figure) and >99% for the single dose of CD101 400 mg.

Conclusion: CD101 IV was safe and well tolerated as single and multiple doses up to 400 mg once weekly for up to 3 weeks. Target attainment analyses support the dosing regimens evaluated and suggest these regimens will effectively cover the vast majority of Candida likely to be encountered clinically. The high plasma exposures achieved with CD101 IV may improve treatment outcomes compared to other echinocandins, and its long t_1/2 enables weekly dosing. These findings support the continued development of CD101 IV dosed once-weekly as treatment or prophylaxis for invasive fungal infections, delivering PK-PD optimized drug exposures while reducing the resources required for therapeutic drug monitoring.

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