Quantitative pulmonary pharmacokinetics of tetrandrine for SARS-CoV-2 repurposing: a physiologically based pharmacokinetic modeling approach

Abstract

Tetrandrine (TET) has been traditionally used in China as a medication to treat silicosis and has recently demonstrated anti-SARS-CoV-2 potential in vitro. By recognizing the disparity between in vitro findings and in vivo performance, we aimed to estimate the free lung concentration of TET using a physiologically based pharmacokinetic (PBPK) model to link in vitro activity with in vivo efficacy. Comparative pharmacokinetic studies of TET were performed in rats and dogs to elucidate the pharmacokinetic mechanisms as well as discern interspecies variations. These insights facilitated the creation of an animal-specific PBPK model, which was subsequently translated to a human model following thorough validation. Following validation of the pharmacokinetic profile from a literature report on single oral dosing of TET in humans, the plasma and lung concentrations were predicted after TET administration at approved dosage levels. Finally, the antiviral efficacy of TET in humans was assessed from the free drug concentration in the lungs. Both in vivo and in vitro experiments thus confirmed that the systemic clearance of TET was primarily through hepatic metabolism. Additionally, the lysosomal capture of basic TET was identified as a pivotal factor in its vast distribution volume and heterogeneous tissue distribution, which could modulate the absorption dynamics of TET in the gastrointestinal tract. Notably, the PBPK-model-based unbound lung concentration of TET (1.67-1.74 μg/mL) at the recommended clinical dosage surpassed the in vitro threshold for anti-SARS-CoV-2 activity (EC₉₀ = 1.52 μg/mL). Thus, a PBPK model was successfully developed to bridge the in vitro activity and in vivo target exposure of TET to facilitate its repurposing.

Keywords: drug repurpose; lysosomal trapping; physiologically based pharmacokinetic (PBPK); pulmonary exposure; tetrandrine.

FIGURE 1

Chemical structure of tetrandrine (TET).

FIGURE 2

Schematic of the whole-body PBPK model depicting the disposition of TET.

FIGURE 3

Comparison of NADPH-depended depletion profiles of TET in the liver microsomes of different species (n = 3).

FIGURE 4

Representative observed (symbols) and PBPK model fitted (lines) pharmacokinetic profiles of TET in the plasma of rats following (A) a single i.v. bolus administration of 5 mg/kg of TET and (B–D) single oral administration of 15–45 mg/kg of TET .

FIGURE 5

Temporal concentrations of TET in different tissues of rats following single oral administration of 30 mg/kg of TET. The symbols represent the observed values, while the lines represent the PBPK model predicted profiles.

FIGURE 6

Representative observed (symbols) and PBPK model fitted (lines) pharmacokinetic profiles of TET in the plasma of dogs following (A) a single i.v. bolus administration of 5 mg/kg of TET and (B, C) single oral administrations of 10 and 15 mg/kg of TET.

FIGURE 7

Predicted (lines) and observed (symbols) TET exposure profiles from the plasma and lung of a typical Chinese after (A) a single oral dose of 100 mg and (B) repeated oral doses of 100 mg per session thrice a day for 6 consecutive days according to the recommended dosing regimen for treating silicosis. The clinical data were obtained from literature.