Applications of pharmacometrics in the clinical development and pharmacotherapy of anti-infectives

Abstract

With the increased emergence of anti-infective resistance in recent years, much focus has recently been drawn to the development of new anti-infectives and the optimization of treatment regimens and combination therapies for established antimicrobials. In this context, the field of pharmacometrics using quantitative numerical modeling and simulation techniques has in recent years emerged as an invaluable tool in the pharmaceutical industry, academia and regulatory agencies to facilitate the integration of preclinical and clinical development data and to provide a scientifically based framework for rationale dosage regimen design and treatment optimization. This review highlights the usefulness of pharmacometric analyses in anti-infective drug development and applied pharmacotherapy with select examples.

Parameter estimation for sigmoid Emax models in exposure-response relationship

“…The approximate values of the T max (the time at which the maximum concentration was observed) for single-and multiple-dose study were 3.15 and 2.78 h, respectively and the half-life was around 13.9 h. The blood sampling time points for dense sampling schedules were 0 (predose), 0.25, 0.5, 0.75, 1,2,3,4,5,6,8,12,24, and 48 h after drug administration. The samples at 24 and 48 h were not included for multiple-dose scenarios.…”

“…[1] PK/PD modeling and simulation is also used for individualized pharmacotherapy based on relevant demographic factors including race, age, sex, weight, height and genotype. [4,5] Pharmacometric analysis usually relies on non-linear mixed effect models to explain and quantify time-varying PK/PD parameters, disease progression, and their relationships based on population data. Pharmacokinetic models describe the change of drug concentration over time and pharmacodynamic models quantify the relationship between concentration and effect.…”

Translational PK/PD of anti-infective therapeutics

“…For decades, the PK/PD relationships of antibiotics have been categorized with three different PK/PD indices, which rely on a summary measurement of in vivo drug exposure relative to the MIC, determined in vitro using serial dilution steps [6]. Usually, only free rather than total drug concentrations are considered as only free drug which is not bound to plasma proteins exerts the pharmacological activity.…”

Multiscale Modeling in the Clinic: Drug Design and Development

“…While systems pharmacology models are starting to be applied in the context of clinical data analysis and simulation, the application of pharmacometrics techniques has been occurring for longer. However, the therapeutic areas and applications where systems pharmacology results have been published are multiple: infectious diseases 11 , cancer 12 , cardiovascular disease 13–15 and neurosciences 16 among others. Future challenges 17 include continuing to augment the biological realism of multiscale models used in drug development, as well as continue to improve integration between bioanalytical and laboratory sciences and model development experts.…”