TABLE 3

Physiologic, experimental, and final calculated parameters for humanized liver mouse and human PBPK models for atomoxetine, 4-hydroxyatomoxetine, and N-desmethylatomoxetine

ParameterAbbreviation (Unit)Humanized Liver MouseHuman
Fraction absorbed × intestinal availabilityFa·Fg(1)1
Absorption rate constantka (1/h)(5.93 ± 0.02)4.41
Volume of systemic circulation for atomoxetineV1_substrate (L)0.0961 ± 0.0030a278
Hepatic intrinsic clearance for atomoxetineCLh,int_substrate (l/h)0.671 ± 0.015a,b671c
Hepatic clearance for atomoxetineCLh,_substrate (l/h)0.063550.4
Renal clearance for atomoxetineCLr_substrate (l/h)0.00010.0252
Volume of systemic circulation for 4-hydroxyatomoxetineV1_4-hydroxyatomoxetine (L)0.0233 ± 0.0025a75.6
Volume of systemic circulation for N-desmethylatomoxetineV1_ N-desmethylatomoxetine (L)0.756 ± 0.014a2130
Hepatic intrinsic clearance for 4-hydroxyatomoxetineCLh,int_4-hydroxyatomoxetine (l/h)0.00923 ± 0.00091a9.23
Hepatic intrinsic clearance for N-desmethylatomoxetineCLh,int_N-desmethylatomoxetine (l/h)0.527 ± 0.014a527
Hepatic clearance for 4-hydroxyatomoxetineCLh_4-hydroxyatomoxetine (l/h)0.006636.46
Hepatic clearance for N-desmethylatomoxetineCLh_N-desmethylatomoxetine (l/h)0.062349.6
Renal clearance for 4-hydroxyatomoxetineCLr_4-hydroxyatomoxetine (l/h)0.001550.307
Renal clearance for N-desmethylatomoxetineCLr_N-desmethylatomoxetine (l/h)0.00010.0248
  • aData are presented as mean ± standard deviation.

  • bA decreased hepatic intrinsic clearance for atomoxetine (0.309 l/h) was used to model the presence of coadministered P450 2D6 inactivator paroxetine, resulting in suppression of plasma Cmax (24%) and AUC (52%) values of atomoxetine and fraction metabolized by P450 2D6 (0.9) and the unchanged part (0.671 × 0.9 × 0.4 + 0.671 × 0.1).

  • cA decreased hepatic intrinsic clearance for atomoxetine (309 l/h) was used to model the presence of paroxetine.

  • The original metabolic ratio of 4-hydroxyatomoxetine and N-desmethylatomoxetine (0.95 and 0.05) from atomoxetine by hepatic clearance was also modified to 0.70 and 0.30 in the presence of paroxetine.

  • A set of differential equations was solved for the concentrations in mice: Embedded Image Embedded Image Embedded Image where Ch, Cr, Cb, and Ri.v. are the hepatic, renal, and blood substrate concentrations and the rate of administration, respectively (Kamiya et al., 2022). Vh, Vr, and Qh/Qr are the liver (0.85 ml) and kidney (0.34 ml) volumes and the blood flow rates of the systemic circulation to the hepatic/renal compartments (0.16 l/h) in mice (25 g body weight), respectively.

  • A set of differential equations was also solved for concentrations in humans: Embedded Image Embedded Image Embedded Image Embedded Image where Xg is the amount of drug in the gut. Vh, Vr, and Qh/Qr are the liver (1.5 L) and kidney (0.28 L) volumes and the blood flow rates of the systemic circulation to the hepatic/renal compartments (96.6 l/h) in adult humans (70 kg body weights) (Kamiya et al., 2022). A multiplicative factor of 0.744 was applied to the virtual absorption rate constant (the number in parenthesis) in humanized liver mice to generate the human absorption rate constant (Kamiya et al., 2022).