Elizabeth A. Lakota

Pharmacological Basis of CD101 Efficacy: Exposure Shape Matters

ABSTRACT CD101 is a novel echinocandin with concentration-dependent fungicidal activity in vitro and a long half-life (∼133 h in humans, ∼70 to 80 h in mice). Given these characteristics, it is likely that the shape of the CD101 exposure (i.e., the time course of CD101 concentrations) influences efficacy. To test this hypothesis, doses which produce the same total area under the concentration-time curve (AUC) were administered to groups of neutropenic ICR mice infected with Candida albicans R303 using three different schedules. A total CD101 dose of 2 mg/kg was administered as a single intravenous (i.v.) dose or in equal divided doses of either 1 mg/kg twice weekly or 0.29 mg/kg/day over 7 days. The studies were performed using a murine disseminated candidiasis model. Animals were euthanized at 168 h following the start of treatment. Fungi grew well in the no-treatment control group and showed variable changes in fungal density in the treatment groups. When the CD101 AUC from 0 to 168 h (AUC0–168) was administered as a single dose, a >2 log10 CFU reduction from the baseline at 168 h was observed. When twice-weekly and daily regimens with similar AUC values were administered, net fungal stasis and a >1 log10 CFU increase from the baseline were observed, respectively. These data support the hypothesis that the shape of the CD101 AUC influences efficacy. Thus, CD101 administered once per week demonstrated a greater degree of fungal killing than the same dose divided into twice-weekly or daily regimens.

Pharmacokinetic-Pharmacodynamic Evaluation of Gepotidacin Against Gram-Positive Organisms Using Data From Murine Infection Models

ABSTRACT Gepotidacin (formerly called GSK2140944) is a novel triazaacenaphthylene bacterial topoisomerase inhibitor with in vitro activity against conventional and biothreat pathogens, including Staphylococcus aureus and Streptococcus pneumoniae. Using neutropenic murine thigh and lung infection models, the pharmacokinetics-pharmacodynamics (PK-PD) of gepotidacin against S. aureus and S. pneumoniae were characterized. Candidate models were fit to single-dose PK data from uninfected mice (for doses of 16 to 128 mg/kg of body weight given subcutaneously [s.c.]). Dose fractionation studies (1 isolate/organism; 2 to 512 mg/kg/day) and dose-ranging studies (5 isolates/organism; 2 to 2,048 mg/kg/day; MIC ranges of 0.5 to 2 mg/liter for S. aureus and 0.125 to 1 mg/liter for S. pneumoniae) were conducted. The presence of an in vivo postantibiotic effect (PAE) was also evaluated. Relationships between the change from baseline in log10 CFU at 24 h and the ratio of the free-drug plasma area under the concentration-time curve (AUC) to the MIC (AUC/MIC ratio), the ratio of the maximum concentration of drug in plasma (Cmax) to the MIC (Cmax/MIC ratio), and the percentage of a 24-h period that the drug concentration exceeded the MIC (%T>MIC) were evaluated using Hill-type models. Plasma and epithelial lining fluid (ELF) PK data were best fit by a four-compartment model with linear distributional clearances, a capacity-limited clearance, and a first-order absorption rate. The ELF penetration ratio in uninfected mice was 0.65. Since the growth of both organisms was poor in the murine lung infection model, lung efficacy data were not reported. As determined using the murine thigh infection model, the free-drug plasma AUC/MIC ratio was the PK-PD index most closely associated with efficacy (r2 = 0.936 and 0.897 for S. aureus and S. pneumoniae, respectively). Median free-drug plasma AUC/MIC ratios of 13.4 and 58.9 for S. aureus, and 7.86 and 16.9 for S. pneumoniae, were associated with net bacterial stasis and a 1-log10 CFU reduction from baseline, respectively. Dose-independent PAE durations of 3.07 to 12.5 h and 5.25 to 8.46 h were demonstrated for S. aureus and S. pneumoniae, respectively.

Ensuring quality pharmacokinetic analyses in antimicrobial drug development programs

Pharmacokinetic studies and analyses can be expensive, time consuming, and labor intensive. However, it is crucial to understand that much of what happens in antimicrobial drug development, such as dose-selection and clinical study design, can be optimized with a strong understanding of the underlying pharmacokinetics of an agent. In this way, pharmacokinetics forms the bedrock of a pharmacometric approach to antimicrobial development. Thus, pharmacokinetic analyses must be considered an integral part of a drugs development strategy and studies must be planned and designed accordingly. This paper provides a brief overview of pharmacokinetic analysis methods, including best practices and their use in the context of a drug development program. In addition we will conclude with an overview of proper design and conduct of pharmacokinetic studies to optimize their use in evaluating clinical study data.

Overcoming the Resistance Hurdle: PK-PD Target Attainment Analyses of Rezafungin (CD101) for Candida albicans and Candida glabrata

ABSTRACT Rezafungin (CD101) is a novel echinocandin antifungal agent with activity against Aspergillus and Candida species, including azole- and echinocandin-resistant isolates. The objective of these analyses was to conduct pharmacokinetic (PK)-pharmacodynamic (PD) target attainment analyses to evaluate single and once-weekly rezafungin dosing to provide dose selection support for future clinical studies. Using a previously developed rezafungin population PK model, Monte Carlo simulations were conducted utilizing the following three intravenous rezafungin regimens: (i) a single 400 mg dose, (ii) 400 mg for week 1 followed by 200 mg weekly for 5 weeks, and (iii) 400 mg weekly for 6 weeks. Percent probabilities of achieving the nonclinical PK-PD targets associated with net fungal stasis and 1-log10 CFU reductions from baseline for Candida albicans and Candida glabrata were calculated for each rezafungin regimen. At the MIC90 for C. albicans and C. glabrata, a single 400 mg dose of rezafungin achieved probabilities of PK-PD target attainment of ≥90% through week 3 of therapy for all PK-PD targets evaluated. When evaluating the multiple-dose (i.e., weekly) regimens under these conditions, percent probabilities of PK-PD target attainment of 100% were achieved through week 6. Moreover, high (>90%) probabilities of PK-PD target attainment were achieved through week 6 following administration of the weekly regimens at or above the MIC100 values for C. albicans and C. glabrata based on contemporary in vitro surveillance data. These analyses support the use of single and once-weekly rezafungin regimens for the treatment of patients with candidemia and/or candidiasis due to C. albicans or C. glabrata.

Pharmacokinetic-Pharmacodynamic Target Attainment Analysis to Support VL-2397 Dose Selection for a Phase 2 Trial in Patients with Invasive Aspergillosis

Abstract Background VL-2397 is a novel antifungal agent in clinical development for treatment of invasive aspergillosis (IA). The analysis objectives were to: 1) develop a population PK model using data from a Phase 1 trial in healthy adult volunteers, 2) define the PK-PD driver of efficacy in a mouse model of IA, and 3) conduct PK-PD target attainment analyses to aid in Phase 2 dose selection for patients with IA. Methods Data from two studies were used: a dose fractionation study in a mouse model of IA and a Phase 1 study in healthy adult volunteers receiving single- and multiple-ascending doses of intravenous (IV) VL-2397 ranging from 3 mg to 1200 mg daily. Mouse lung fungal burden (LFB) measured on Day 4 after infection with Aspergillus fumigatus FP1305 (MIC of 1 µg/mL) was used to assess the predictive value of three measures of VL-2397 exposure: total-drug AUC0-24:MIC (tAUC0-24:MIC), total-drug Cmax:MIC, and total-drug %T>MIC; total drug was used because serum protein binding is similar in mice and humans. A population PK model for VL-2397 in humans was developed in NONMEM v7.1.2 and formed the basis of Monte Carlo simulations. The model was also fit to mouse PK data to estimate the VL-2397 exposure in mice. Results VL-2397 concentration-time data in humans revealed nonlinear PK behavior consistent with highly-bound compounds. A robust fit to the data was obtained using a two-compartment model with linear elimination and concentration-dependent binding in both central and peripheral compartments. The results of the dose fractionation study suggested that tAUC0-24:MIC was the most predictive (r2 = 0.713) driver of efficacy, with a value of 21.8 on Day 1 associated with a 2-log reduction in LFB on Day 4. Comparisons of the simulated VL-2397 tAUC0-24:MIC on Day 1 in humans receiving daily dosing regimens of 300 mg, 600 mg, and 900 mg of VL-2397 to the 2-log target (figure) suggested that a dose of 600 mg Q24 would provide robust (99.9%) PK-PD target attainment up to an A. fumigatus MIC of 2 µg/mL. Conclusion The PK-PD driver of efficacy for VL-2397 was tAUC0-24:MIC and a value of 21.8 was associated with a 2-log reduction in LFB in a mouse model of IA. PK-PD target attainment assessments indicate that a VL-2397 dose of 600 mg IV Q24 will provide adequate target attainment up to an MIC of 2 µg/mL. Disclosures C. M. Rubino, Vical Incorporated: Consultant, Consulting fee; L. R. Smith, Vical Incorporated: Employee, Salary and Stock Options; M. P. Mammen, Vical Incorporated: Employee, Salary and Stock Options; A. M. Hopkins, Vical Incorporated: Employee, Salary and Stock Options; E. A. Lakota, Vical Incorporated: Consultant, Consulting fee; S. M. Sullivan, Vical Incorporated: Employee, Salary and Stock Options

Traditional PK-PD Indices for Efficacy – Can We Do Better?

Abstract Background The relationship between antimicrobial activity and exposure relative to MIC is typically evaluated using one of three PK-PD indices, AUC:MIC ratio, Cmax:MIC ratio, and %T>MIC. However, under certain circumstances, none of these PK-PD indices may be the most optimal. These include when the fitted Hill functions for each of the PK-PD indices do not allow for sufficient discrimination, the variability about the fitted functions is wide, and/or the pattern of dose fractionation data is non-informative. Relationships fit using the traditional PK-PD indices may be suboptimal for drugs which exhibit extreme PK characteristics such as abnormally short or long half-lives. As described herein, we explored the use of a fourth PK-PD index for such instances, AUC/τ:MIC ratio (τ = dosing interval). Methods Previously-described ceftolozane dose-fractionation data from a study using a neutropenic murine thigh-infection model were evaluated [AAC 2013; 57(4):1577–82]. In this prior study, mice were infected with E. coli ATCC 25922 (MIC = 0.5 mg/L) or K. pneumoniae ATCC 43816 (MIC = 1.4 mg/L). Ceftolozane doses ranged from 1.56 to 1600 mg/kg/24h given q3h, q6h, q12h, or q24h. Relationships between log10 colony forming units (CFU) at 24 hours and AUC:MIC ratio, Cmax:MIC ratio, %T>MIC, and AUC/τ:MIC ratio were evaluated by pathogen and pooled using Hill-type models and non-linear least squares regression. Results For evaluations of data by pathogen, AUC/τ:MIC ratio best described changes in log10 CFU at 24 hours. The coefficients of determination (r2) for these pathogens were improved by 0.20 and 0.11, respectively, relative to the highest r2 achieved using any of the traditional PK-PD indices. Similar results were observed when the data were evaluated using a pooled approach (Figure 1). Conclusion AUC/τ:MIC ratio may be useful to evaluate drugs demonstrating the extremes of PK. Accordingly, this PK-PD index best described ceftolozane PK-PD, an agent with a very short murine plasma half-life (<15 minutes). The use of the PK-PD index that allows for the best fit of the data to the Hill function and reduced variability about the fitted function will not only improve the characterization of PK-PD but will also improve the accuracy of future dose selection analyses. Disclosures All authors: No reported disclosures.