(T-038) The PK-PD model of dexamethasone for fetal lung maturation and developmental neurotoxicity: A dose optimization study

Dongyang Liu, N/A – Professor, Peking University Third Hospital; Ling Song, N/A – Assistant investigator, Peking University Third Hospital; Hui Wang, N/A – Professor, Wuhan University

Objective: Dexamethasone (DEX) is an essential medication for preventing infant respiratory distress syndrome (IRDS) in developing countries. However, its long-term neurotoxicity requires optimizing the dosage. Animal studies combined with model-informed precision dosing can provide crucial support.

Method: In pharmacodynamic part, pregnant rats (n=18) were equally divided into three groups, and intramuscularly administered DEX bid at gestational day (GD) 18-19, respectively. Fetal lungs were collected at GD 20, and qPCR and ELISA methods were used to measure the concentrations of surfactant protein A and B (SP-A/B) and related mRNA. A physiologically based pharmacokinetic (PBPK-PD) model was established by MATLAB to describe the quantitative relationship between DEX concentrations and SP-A/B by borrow some parameters from literature. In developmental neurotoxicity part, a total of 54 pregnant rats were administered with the same dosing groups as mentioned earlier, and allowed to give birth naturally. The offspring underwent an open field test on postnatal day 84, and the correlation between drug exposure and offspring behavior was analyzed. The therapeutic window of DEX was determined by balance of PBPK-PD model simulation results and neurotoxicity results. Then we recommend the better dosing regimen using predicted pregnant pharmacokinetic characteristics simulated from published population pharmacokinetic (PPK) model of DEX by assuming same therapeutic concentration window between rats and humans.

Results: The mechanistic based PBPK-PD model profiled the quantitative characteristics. Validation results showed no systematic error in our model. The estimated PK parameters were K_a (0.76 1/h), CL_h,int (437.65 mL/h) and CL_int,P-gp (64.4 mL/(h*mL placenta)). Model simulation indicated that the minimal efficacy plasma concentration of DEX in pregnant rats is 4 ng/mL. Systematic analysis showed that plasma DEX concentrations exceeding 26 ng/mL in pregnant rats can lead to behavioral differences. PPK model simulation indicated that for intramuscular administration of DEX, 2.5 mg per dose, administered every 12 hours for 4 doses could reach the therapeutic window.

Conclusion: We firstly constructed mechanism based PBPK-PD model of DEX involving placental P-gp transporter, revealing that toxic effect can also occur with clinical administration for 2 days. We established quantitative relationships of dose-efficacy and dose-safety. Based on the obtained therapeutic window and pregnancy PPK simulation, the recommended optimal dosage is: 2.5 mg per dose, administered every 12 hours for 4 doses.

Citations: [1] Du R, Zhao X, Song L, Wang H, Liu D, Wang Q. A physiologically based toxicokinetic model of P-glycoprotein transporter-mediated placenta perfusion of dexamethasone in the pregnant rat. Food Chem Toxicol Int J Publ Br Ind Biol Res Assoc. 2024;183:114213. doi:10.1016/j.fct.2023.114213