Semi-mechanistic population pharmacokinetic modeling of DZIF-10c, a neutralizing antibody against SARS-Cov-2: predicting systemic and lung exposure following inhaled and intravenous administration.

Publication date: Dec 05, 2024

DZIF-10c (BI 767551) is a recombinant human monoclonal antibody of the IgG1 kappa isotype. It acts as a SARS-CoV-2 neutralizing antibody. DZIF-10c has been developed for both systemic exposure by intravenous infusion as well as for specific exposure to the respiratory tract by application as an inhaled aerosol generated by a nebulizer. An integrated preclinical/clinical semi-mechanistic population pharmacokinetic model was developed to characterize the exposure profile of DZIF-10c in the systemic circulation and lungs. To inform and reduce uncertainty around exposure in the lungs following different methods of dosing, preclinical cynomolgus monkey data was combined with human data using allometric scaling principles. Human serum concentrations of DZIF-10c from two clinical trials were combined with serum/plasma and lung epithelial lining fluid (ELF) concentrations from three preclinical studies to characterize the relationship between dosing, serum/plasma, and lung exposure. The final model was used to predict exposure in the lungs following different routes of administration. Simulations showed that inhalation provides immediate and relevant exposure in the lung ELF at a much lower dose compared with an infusion. Combining inhalation with intravenous therapy results in high and sustained DZIF-10c exposure in the lungs and systemic circulation, thereby combining the benefits of both routes of administration. By combining preclinical data with clinical data (via allometric scaling principles), the developed population pharmacokinetic model reduced uncertainty around exposure in the lungs allowing evaluation of alternative dosing strategies to achieve the desired concentrations of DZIF-10c in human lungs.

Concepts Keywords
10c Administration, Inhalation
Lungs Administration, Intravenous
Monkey Allometric scaling
Pharmacokinetic Animals
Antibodies, Monoclonal
Antibodies, Monoclonal
Antibodies, Neutralizing
Antibodies, Neutralizing
COVID-19
COVID-19 Drug Treatment
Humans
Inhaled administration
Lung
Macaca fascicularis
Male
Models, Biological
Monoclonal antibodies
Pharmacokinetic model
Population pharmacokinetics
SARS-CoV-2
Semi-mechanistic

Semantics

Type Source Name
disease MESH uncertainty
disease MESH COVID-19

Original Article

(Visited 2 times, 1 visits today)