Generating Robust and Informative Nonclinical In Vitro and In Vivo Bacterial Infection Model Efficacy Data To Support Translation to Humans

Abstract

In June 2017, the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, organized a workshop entitled “Pharmacokinetics-Pharmacodynamics (PK/PD) for Development of Therapeutics against Bacterial Pathogens.” The aims were to discuss details of various PK/PD models and identify sound practices for deriving and utilizing PK/PD relationships to design optimal dosage regimens for patients. Workshop participants encompassed individuals from academia, industry, and government, including the United States Food and Drug Administration. This and the accompanying review on clinical PK/PD summarize the workshop discussions and recommendations. Nonclinical PK/PD models play a critical role in designing human dosage regimens and are essential tools for drug development. These includein vitroandin vivoefficacy models that provide valuable and complementary information for dose selection and translation from the laboratory to human. It is crucial that studies be designed, conducted, and interpreted appropriately. For antibacterial PK/PD, extensive published data and expertise are available. These have been leveraged to develop recommendations, identify common pitfalls, and describe the applications, strengths, and limitations of various nonclinical infection models and translational approaches. Despite these robust tools and published guidance, characterizing nonclinical PK/PD relationships may not be straightforward, especially for a new drug or new class. Antimicrobial PK/PD is an evolving discipline that needs to adapt to future research and development needs. Open communication between academia, pharmaceutical industry, government, and regulatory bodies is essential to share perspectives and collectively solve future challenges.

Pharmacokinetics and Dialytic Clearance of Apixaban During In Vitro Continuous Renal Replacement Therapy

“…As recognized by the FDA, NIH, and NIAID, non-clinical PK/PD models play a critical role in designing human dosage regimens and are essential tools for drug development and dose optimization in special populations [42]. This study thoroughly explored the PK and dialytic clearance of apixaban during CRRT during tightly controlled in vitro experimentation.…”

“…As such, in vitro CRRT models are useful for generating precise assessments of sieving/saturation coe cients (SC/SA) across different modes, ow rates, lter types, and points of dilution while eliminating the variability introduced by the patient. As recognized by the U.S Food and Drug Administration (FDA), National Institutes of Health (NIH), and National Institute of Allergy and Infectious Diseases (NIAID), these models can be used to guide dosing in the absence of, or when combined with, in vivo data and have been shown to accurately predict in vivo total body clearance (CL T ) [41], allowing for data derived from in vitro investigations to be utilized in estimating clinical dosing regimens [42].…”

Pharmacodynamics of Tebipenem: New Options for Oral Treatment of Multidrug-Resistant Gram-Negative Infections

“…There have been significant advances in the use of PK-PD to develop new antibacterial and antifungal drugs. The European Medicines Agency (EMA) and FDA each have recommendations for preclinical data that should be considered to progress to human clinical trials, and this topic has also been considered in a recent publication sponsored by NIH/NIAID (14). A deep understanding of dose-exposure-response relationships substantially derisks development programs (15).…”

“…For murine studies, these include stasis and various orders of logarithmic killing. Stasis has generally been considered suitable for dose identification in patients with cUTI, whereas orders of logarithmic killing are used for more serious high-burden infections, such as hospital-acquired pneumonia and ventilator-associated pneumonia (14). Importantly, however, there are some additional subtleties.…”

Pharmacokinetic-Pharmacodynamic Characterization of Omadacycline against Haemophilus influenzae Using a One-Compartment In Vitro Infection Model

“…In the current era of drug development for antimicrobial agents, PK-PD assessments are carried out during all stages of drug development [27,33,34,35,36,37]. Evaluation of PK-PD targets for efficacy from non-clinical infection models, together with Phase 1 PK data and Monte Carlo simulation, prior to execution of clinical trials in patients ensures that efficacious dosing regimens are selected for study in infected patients and serves to de-risk the drug development program.…”