AUTHOR=Zhang Zhiwei , Fu Shuang , Wang Furun , Yang Chunmiao , Wang Lingchao , Yang Meiyan , Zhang Wenpeng , Zhong Wu , Zhuang Xiaomei 

TITLE=A PBPK Model of Ternary Cyclodextrin Complex of ST-246 Was Built to Achieve a Reasonable IV Infusion Regimen for the Treatment of Human Severe Smallpox

JOURNAL=Frontiers in Pharmacology

VOLUME=Volume 13 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.836356

DOI=10.3389/fphar.2022.836356

ISSN=1663-9812

ABSTRACT=ST-246 is an oral drug against pathogenic orthopoxvirus infections. An intravenous formulation is required for some critical patients. A ternary complex of ST-246/Meglumine/hydroxypropyl-β-cyclodextrin with well-improved solubility was successfully developed in our institute. The aim of this study is to achieve a reasonable intravenous infusion regimen of this novel formulation by a robust PBPK model based on preclinical pharmacokinetic studies. The pharmacokinetics of ST-246 after intravenous injection at doses of 2, 5, 20 mg/kg in rats, 1, 2.5, 10 mg/kg in dogs, and 3mg/kg in monkeys were conducted to obtain clearances. Clearance of humans was generated by the allometric scaling approach. Tissue distribution of ST-246 was conducted in rats to obtain tissue partition coefficients (Kp). PBPK model of the rat was first built using in vivo clearance and Kp combined with in vitro physicochemical properties, unbound fraction, and cyclodextrin effect parameters of ST-246. Then, the PBPK model was transferred to a dog and monkey and validated simultaneously. Finally, pharmacokinetic profiles after IV infusion at different dosages utilizing the human PBPK model were compared to the observed oral PK profile of ST-246 at therapeutic dosage (600 mg). Mechanistic PBPK model well described the animal PK behaviors of ST-246 via intravenous injection and infusion with fold errors within 1.2. It appeared that 6h-IV infusion at 5 mg/kg BID produced similar Cmax and AUC as oral administration at 600 mg. A PBPK model of ST-246 was built to achieve a reasonable regimen of IV infusion for the treatment of severe smallpox, which will facilitate the clinical translation of this novel formulation.