Challenges of Psychiatry Drug Development and the Role of Human Pharmacology Models in Early Development—A Drug Developer's Perspective

Psychiatric diseases have the lowest probability of success in clinical drug development. This presents not only an issue to address the unmet medical needs of patients, but also a hurdle for pharmaceutical and biotech industry to continue R&D in this disease area. Fundamental pharmacokinetic and pharmacodynamic principles provide an understanding of the drug exposure, target binding and pharmacological activity at the target site of action for a new drug candidate. Collectively, these principles determine the likelihood of testing the mechanism of action and enhancing the likelihood of candidate survival in Phase 2 clinical development, therefore, they are termed as the “three pillars of survival.” Human Phase 1 pharmacokinetic and pharmacodynamic studies provide evidence of the three pillars. Electroencephalogram (EEG) assessments and cognitive function tests in schizophrenia patients can provide proof of pharmacology and ensure that a pharmacological active regimen will be tested in Phase 2 proof of concept (POC) studies for the treatment of cognitive impairment associated with schizophrenia (CIAS).

Differences in the Pharmacokinetics of Gentamicin between Oncology and Nononcology Pediatric Patients

ABSTRACT Dosing gentamicin in pediatric patients can be difficult due to its narrow therapeutic index. A significantly higher percentage of fat mass has been observed in children receiving oncology treatment than in those who are not. Differences in the pharmacokinetics of gentamicin between oncology and nononcology pediatric patients and individual dosage requirements were evaluated in this study, using normal fat mass (NFM) as a body size descriptor. Data from 423 oncology and 115 nononcology patients were analyzed. Differences in drug disposition were observed between the oncology and nononcology patients, with oncology patients having a 15% lower central volume of distribution and 32% lower intercompartmental clearance. Simulations based on the population pharmacokinetic model demonstrated low exposure target attainment in all individuals at the current clinical recommended starting dose of 7.5 mg/kg of body weight once daily, with 57.4% of oncology and 35.7% of nononcology subjects achieving a peak concentration (Cmax) of ≥25 mg/liter and 64.3% of oncology and 65.6% of nononcology subjects achieving an area under the concentration-time curve at 24 h postdose (AUC24) of ≥70 mg · h/liter after the first dose. Based on simulations, the extent of the impact of differences in drug disposition between the two cohorts appeared to be dependent on the exposure target under examination. Greater differences in achieving a Cmax target of >25 mg/liter than an AUC24 target of ≥70 mg · h/liter between the cohorts was observed. Further investigation into whether differences in the pharmacokinetics of gentamicin between oncology and nononcology patients are a consequence of changes in body composition is required.

711. Exebacase (Lysin CF-301) Activity Against Staphylococcus aureus (S. aureus) Isolates From Bacteremic Patients Enrolled in a Phase 2 Study (CF-301-102)

Background Exebacase (CF-301) is a novel, recombinantly-produced, bacteriophage-derived lysin (cell wall hydrolase) which is the first lysin to report Phase 2 (Ph2) results which demonstrated 42.8% higher clinical responder rates with a single dose of exebacase used in addition to standard of care antibiotics (SOC) vs. SOC alone for the treatment of methicillin-resistant S. aureus (MRSA) bacteremia including endocarditis. We examined exebacase activity by broth microdilution (BMD) against baseline methicillin-sensitive S. aureus (MSSA) and MRSA isolates from each of the 116 participants in the recently complete exebacase”first in-patient’ Ph2 study (NCT03163446). Methods Patients with complicated bacteremia or endocarditis caused by S. aureus were enrolled into Study CF-301-102 at study centers in the United States, EU, Latin America, Israel, and Russia from 2017 and 2018. Baseline isolates from blood cultures were collected prior to administration of exebacase. Exebacase MICs against 117 isolates of MSSA (n = 74) and MRSA (n = 43) were determined at a central laboratory using a modified BMD approved by the CLSI for exebacase AST. Results The exebacase MICs of baseline patient isolates from the Ph2 study ranged from 0.125 – 2 µg/mL and the MIC50/90 values for all MSSA and MRSA isolates were 0.5/1 µg/mL. Exebacase MICs reported in a recent surveillance study were similar, with MIC50/90 values of 0.5/1 µg/mL. Of the 6 total subjects with EXE MICs of 2, 3 were clinical responders, 2 were indeterminate (not available for assessment), and 1 was a clinical nonresponder at Day 14. Conclusion Exebacase was highly active against all baseline S. aureus isolates from blood cultures obtained from bacteremic patients enrolled in the Ph2 study. Based on data from previously presented exposure target attainment animal studies, PK/PD modeling and preliminary nonclinical breakpoint assessments, we expected that strains with MIC values of ≤2 µg/mL will have been susceptible to the Ph2 clinical exebacase dose determined based on target attainment studies under study in Ph2. Disclosures All authors: No reported disclosures.

Pharmacokinetics of Levofloxacin in Children Treated for Exposure to Drug-Resistant Tuberculosis

ABSTRACT Levofloxacin is used to treat and prevent drug-resistant tuberculosis in children. We assessed levofloxacin serum drug concentrations in 24 children aged 2 to 10 years who received levofloxacin-based tuberculosis preventive therapy in Karachi, Pakistan. Only 9 children (37.5%) achieved adequate drug exposure. Target serum drug concentration was met in 4 (26.7%) of 15 children dosed consistently with World Health Organization recommendations and 4 (80.0%) of 5 who received higher-than-recommended doses. Levofloxacin dosing recommendations may require reevaluation.

Is One Sample Enough? β-Lactam Target Attainment and Penetration into Epithelial Lining Fluid Based on Multiple Bronchoalveolar Lavage Sampling Time Points in a Swine Pneumonia Model

ABSTRACTDescribing the disposition of antimicrobial agents at the site of infection is crucial to guide optimal dosing for investigational agents. For antibiotics in development for the treatment of nosocomial pneumonia, concentrations in the epithelial lining fluid (ELF) of the lung are frequently determined from a bronchoscopy at a single time point. The influence of profiles constructed from a single ELF concentration point for each subject has never been reported. This study compares the pharmacokinetics of two β-lactams, ceftolozane and piperacillin, among different ELF sampling approaches using simulated human regimens in a swine pneumonia model. Plasma and ELF concentration-time profiles were characterized in two-compartment models by the use of robustly sampled ELF concentrations and by the random selection of one or two ELF concentrations from each swine. A 5,000-subject Monte Carlo simulation was performed for each model to define the ELF penetration, as described by the ratio of the area under the concentration curve (AUC) for ELF to the AUC for free drug in plasma (AUCELF/fAUCplasma) and the probability of target attainment (PTA). Given the intersubject variability of the ELF penetrations observed, differences between the models developed using robust numbers of ELF samples versus one or two ELF samples per swine were minimal for both drugs (maximum dispersion < 20%). Using a threshold exposure target of 60% of the time that the free drug concentration remains above the MIC target, the ceftolozane and piperacillin regimens achieved PTAs of ≥90% at MICs of up to 4 and 1 μg/ml, respectively, among the different ELF sampling strategies. These models suggest that the ELF models constructed with concentrations from sparse ELF sampling time points result in exposure estimates similar to those constructed from robustly sampled ELF profiles.

Pharmacokinetic-Pharmacodynamic Target Attainment Analyses To Determine Optimal Dosing of Ceftazidime-Avibactam for the Treatment of Acute Pulmonary Exacerbations in Patients with Cystic Fibrosis

ABSTRACT Acute pulmonary exacerbations (APE) involving Pseudomonas aeruginosa are associated with increased morbidity and mortality in cystic fibrosis (CF) patients. Drug resistance is a significant challenge to treatment. Ceftazidime-avibactam (CZA) demonstrates excellent in vitro activity against isolates recovered from CF patients, including drug-resistant strains. Altered pharmacokinetics (PK) of several beta-lactam antibiotics have been reported in CF patients. Therefore, this study sought to characterize the PK of CZA and perform target attainment analyses to determine the optimal treatment regimen. The PK of CZA in 12 adult CF patients administered 3 intravenous doses of 2.5 g every 8 h infused over 2 h were determined. Population modeling utilized the maximum likelihood expectation method. Monte Carlo simulations determined the probability of target attainment (PTA). An exposure target consisting of the cumulative percentage of a 24-h period that the free drug concentration exceeds the MIC under steady-state pharmacokinetic conditions (fT >MIC) was evaluated for ceftazidime (CAZ), and an exposure target consisting of the cumulative percentage of a 24-h period that the free drug concentration exceeds a 1-mg/liter threshold concentration (fT >1 mg/liter) was evaluated for avibactam (AVI). Published CAZ and CZA MIC distributions were incorporated to evaluate cumulative response probabilities. CAZ and AVI were best described by one-compartment models. The values of total body clearance (CL; CAZ CL, 7.53 ± 1.28 liters/h; AVI CL, 12.30 ± 1.96 liters/h) and volume of distribution (V; CAZ V, 18.80 ± 6.54 liters; AVI V, 25.30 ± 4.43 liters) were broadly similar to published values for healthy adults. CZA achieved a PTA (fT >MIC, 50%) of >0.9 for MICs of ≤16 mg/liter. The overall likelihood of a treatment response was 0.82 for CZA, whereas it was 0.42 for CAZ. These data demonstrate improved pharmacodynamics of CZA in comparison with those of CAZ and provide guidance on the optimal dosing of CZA for future studies. (This study has been registered at ClinicalTrials.gov under registration no. NCT02504827.)

Phase 1b Study of New Posaconazole Tablet for Prevention of Invasive Fungal Infections in High-Risk Patients with Neutropenia

ABSTRACTPosaconazole tablets, a new oral formulation of posaconazole, can be effective when given as antifungal prophylaxis to neutropenic patients at high risk for invasive fungal infection (e.g., those with acute myelogenous leukemia or myelodysplastic syndrome). Such effectiveness might be specifically important to patients with poor oral intake because of nausea, vomiting, or chemotherapy-associated mucositis. This was a prospective, global study in high-risk patients to characterize the pharmacokinetics and safety profile of posaconazole tablets and to identify the dose of posaconazole tablets that would provide exposure within a predefined range of exposures (steady-state average concentration [area under the concentration-time curve/24 h] of ≥500 ng/ml and ≤2,500 ng/ml in >90% of patients). The study evaluated two sequential dosing cohorts: 200 mg posaconazole once daily (n= 20) and 300 mg posaconazole once daily (n= 34) (both cohorts had a twice-daily loading dose on day 1) taken without regard to food intake during the neutropenic period for ≤28 days. The exposure target was reached (day 8) in 15 of 19 (79%) pharmacokinetic-evaluable patients taking 200 mg posaconazole once daily and in 31 of 32 (97%) patients taking 300 mg posaconazole once daily; 300 mg posaconazole once daily achieved the desired exposure target. Posaconazole tablets were generally well tolerated in high-risk neutropenic patients. (This study has been registered atClinicalTrials.govunder registration no. NCT01777763.)