Table 4

Comparison of in vivo pharmacokinetic data with values predicted from in vitro liver microsomal intrinsic clearance data

RatGuinea PigDogMonkeyHuman
CL′int(ml/min/mg microsomal protein)4-a 0.2480.3890.0212.540.0077
CL′int(ml/min/kg)4-b 4467003036586.9
fu(blood) 4-c 0.00830.00870.00820.00490.044
fu(microsomes) 4-d 0.0310.0400.0100.0270.033
CLh (predicted, ml/min/kg)4-e
 Well Stirred Model:
  fu(microsomes) included444814416.3
 Parallel Tube Model:
CLbl (actual, ml/min/kg)4-f 451072539<84-g
Fh (predicted, %)4-e
 Well Stirred Model:
 Parallel Tube Model:
F (actual, %)4-f 15<0.2282.1≈604-g
  • 4-a  In vitro intrinsic clearance data from Table1.

  • 4-b  Calculated using standard values of 45 mg of microsomal protein/g liver for all species and the following values for g liver/kg body weight: rat, 40; guinea pig, 40; dog, 32; monkey, 32; and human, 20.

  • 4-c  Calculated from protein binding and blood-to-plasma ratios from Reed-Hagen et al., (2000).

  • 4-d  Determined using equilibrium dialysis at microsomal protein concentrations used in substrate saturation experiments and ezlopitant concentrations atKMapp, by the method described in Obach (1997).

  • 4-e  Values calculated using the following equations: Well Stirred Model; fu(microsomes) included:Embedded Image Well Stirred Model; fu(microsomes) disregarded:Embedded Image Parallel Tube Model; fu(microsomes) included:Embedded Image Parallel Tube Model: fu(microsomes) disregarded:Embedded Image

  • 4-f  Data from Reed-Hagen et al., (2000).

  • 4-g  Intravenous data for human is unavailable. Clearance calculated after oral administration is approximately 8 ml/min/kg, and as such represents an upper limit for intravenous clearance in the case that ezlopitant is completely absorbed after oral administration. Estimation of 60% oral bioavailability is based on F = 1 − (CL/Q). As such, this value would represent an upper estimate assuming complete oral absorption.