TABLE 1

Key system parameters and drug-specific parameters used in construction of the customized semi–physiologically based pharmacokinetic model for maribavir in cynomolgus monkeys

For a full list of parameters, refer to Supplemental Table 5. “Drug” refers to maribavir.

Parameter in SimBiologyDescriptionValueNotes
Key System Parameters
k_T_StomachRate of transit from stomach to duodenum2.0 h−1From fasted state, gastric emptying time of 30 min
SITTSmall intestine transit time2.7 hIkegami et al., 2003
k_T_ColonColon transit rate0.042 h−1Peters et al., 2012
Key Drug-Specific Parameters from In Vitro Data or In Vivo BDC Group Data
Drug_PeffEffective permeability in jejunum1.3 × 10−4 cm/sCalculated from Caco-2 cell data; see Supplemental Methods
Drug_ka_JejunumFirst-order absorption rate in jejunum2.3 h−1Calculations in Supplemental Methods
Drug_ka_ColonFirst-order absorption rate in colon0.056 h−1Calculations in Supplemental Methods
Drug_fm_glucFraction metabolized by the direct glucuronidation pathway0.73 or 0.850.728 from in vivo data in BDC group (Table 5); 0.853 from in vitro hepatocyte data
Gluc_k_hydrolysisRate of hydrolysis of maribavir glucuronides3.1 h−1Calculations in Supplemental Methods
Drug_CL_RenalRenal clearance of parent from central compartment0.013 l/hFrom BDC mean systemic CL × %dose in urine: 5.72 l/h × 0.224% (Tables 3 and 4)
Drug_CL_BiliaryBiliary clearance of parent from central compartment0.072 l/hFrom BDC systemic CL × %dose in bile: 5.72 l/h × 1.26% (Tables 3 and 4)
Drug-Specific Parameters from Fitting the Model to the Observed Plasma Concentration Time Course in BDC Animals
Drug_Q12Central-to-peripheral transfer CL0.66 l/hS.E. 0.0049
Drug_Liver_CLDrug clearance from the liver compartment16 l/hS.E. 0.24
Drug_Vc_RefVolume of the central compartment6.3 lS.E. 0.085
Drug_Vp_RefVolume of peripheral compartment2.8 lS.E. 0.046
  • CL, clearance.