Table 3.

Pharmacokinetic variables from mouse and human pharmacokinetic studies and from PBPK model simulations

MouseTissueλ-t1/2* (h)AUC0→24 (h·μmol/L)CL (L/h)t1/2 ratioAUC0→24 ratio
20 mg/kgPlasmaActual8.619.30.024
Simulated7.319.90.0231.180.97
LiverActual6.194.00.0048
Simulated6.281.20.00550.981.16
IntestineActual5.9158.80.0028
Simulated7.1103.50.00420.831.53
KidneyActual5.0145.70.0031
Simulated9.3134.40.00300.541.08
5 mg/kgPlasmaActual4.5
Simulated7.30.61
LiverActual4.7
Simulated6.60.71
IntestineActual3.2
Simulated6.90.46
KidneyActual5.2
Simulated9.20.57
Human
Tissue
α-t1/2 (min)
β-t1/2 (h)
γ-t1/2 (h)
λ-t1/2 (h)
AUC0→24 (h·μmol/L)
CL (L/h)
30 mg/m2PlasmaActual§7.4 ± 2.91.4 ± 0.327.5 ± 5.51.02 ± 0.3976.1 ± 54.5
Simulated7.2 ± 3.61.1 ± 0.521.0 ± 10.90.96 ± 0.5683.3 ± 47.9
36 mg/m2PlasmaActual7.4 ± 2.22.1 ± 1.421.9 ± 7.70.95 ± 0.3087.6 ± 21.8
Simulated9.3 ± 6.51.1 ± 0.417.3 ± 0.50.66 ± 0.03118.7 ± 9.8
100 mg/m2PlasmaActual**8.2 ± 5.02.94 ± 1.6277.2 ± 73.3
Simulated††12.23.1564.5
  • NOTE: Pharmacokinetic variables were calculated using noncompartmental analysis. Plasma pharmacokinetic variables for mouse 20 mg/kg and human 30 and 36 mg/m2 doses were calculated using a three-compartment model. Data represent the mean ± SD from six or three patient data sets for 30 and 36 mg/m2 doses, respectively.

    Abbreviation: CL, clearance.

  • * λ-t1/2 is the estimated terminal t1/2 for drug elimination from plasma or tissue as estimated from linear regression of the terminal elimination phase.

  • AUC0→24 represents the AUC calculated from time 0 to 24 h.

  • Ratio of the value generated for that variable from the measured versus the simulated data sets.

  • § Human time course data were provided by Drs. Gail Eckhart and Cindy O'Bryant (University of Colorado Health Sciences Center, Denver, CO) and have been previously published (35).

  • Simulated time course data were generated using our PBPK model with actual patient weight, dose (30 or 36 mg/m2 multiplied by body surface area), and infusion time set in the model.

  • Pharmacokinetic variables were calculated using noncompartmental analysis.

  • ** Human time course data were estimated from previously published data (35).

  • †† Simulated time course data were generated using our PBPK model with an estimated patient weight of 70 kg, dose of 100 mg/m2, and body surface area of 1.75m2.