TABLE 1.
Physicochemical properties, absorption, distribution, and elimination characteristsics used for oseltamivir PBPK model development
| Parameter | Oseltamivir | Reference |
|---|---|---|
| Physicochemical properties | ||
| Molecular weight (g/mol) | 312.4 | |
| LogD at pH 7.4 | 0.36 | (Parrott et al., 2011) |
| pKa | 7.75 | |
| Fraction unbound | 0.58 | (Hu et al., 2014) |
| Blood-to-plasma ratio | 1.42 | (Instiaty et al., 2013) |
| Absorption | ||
| Absorption model | ADAM model | |
| Cell permeability (10−4 cm/s) | 0.8 | Simcyp (fitted) |
| Distribution | ||
| Distribution model | Minimal PBPK model | |
| Vss (l/kg) | 3.4 | Simcyp (fitted) |
| Elimination | ||
| Clearance type | Whole-organ metabolic clearance | |
| CLint in S9 fraction, adults (µl/min/mg protein) | 67 | (Nishimuta et al., 2014) |
| CLrenal, adults (L/h) | 29 | US FDA (http://www.accessdata.fda.gov/drugsatfda_docs/nda/99/21087_Tamiflu_bior.pdf) |
| Ontogeny equationa |  |
|
| CES1 ontogeny parametersb | Fbirth, Adultmax, Age50, and n: 0.20, 1, 1.10, and 0.56, respectivelyb | Present study |
The observed differences between the pediatric and adult CLint are assumed to be due to the differences in Vmax, which are extrapolated from the obtained CES abundance data in pediatric subjects. ADAM, advanced dissolution, absorption, and metabolism; CLrenal, renal clearance; FDA, Food and Drug Administration; Vss, volume at steady state.
Equation terms: Adultmax, maximum average relative protein abundance; Age, age in years of the subject at the time of sample collection; Age50, age in years at which half-maximum adult protein abundance is obtained; F, fractional protein abundance in adult samples; Fbirth, fractional protein abundance (of adult) at birth; n, exponential factor.
Since CES1 is functionally active in both microsomal and cytosolic fractions, the ontogeny equation was derived based on the total microsomal plus cytosolic abundance of CES1 per gram of liver tissue. To do so, reported values of milligram of microsomal and cytosolic proteins per gram liver tissue (39.8 and 80.7 mg/ml, respectively) were used to first obtain microsomal and cytosolic CES1 abundance per gram of liver tissue. Then, the total microsomal plus cytosolic abundance of CES1 per gram of liver tissue was derived by adding the two values. Finally, the adult normalized fractional values were derived by considering Adultmax to be equal to 1.