TABLE 1

Physicochemical properties, absorption, distribution, and elimination characteristsics used for oseltamivir PBPK model development

ParameterOseltamivirReference
Physicochemical properties
 Molecular weight (g/mol)312.4
 LogD at pH 7.40.36(Parrott et al., 2011)
 pKa7.75
 Fraction unbound0.58(Hu et al., 2014)
 Blood-to-plasma ratio1.42(Instiaty et al., 2013)
Absorption
 Absorption modelADAM model
 Cell permeability (10−4 cm/s)0.8Simcyp (fitted)
Distribution
 Distribution modelMinimal PBPK model
 Vss (l/kg)3.4Simcyp (fitted)
Elimination
 Clearance typeWhole-organ metabolic clearance
 CLint in S9 fraction, adults (µl/min/mg protein)67(Nishimuta et al., 2014)
 CLrenal, adults (L/h)29US FDA (http://www.accessdata.fda.gov/drugsatfda_docs/nda/99/21087_Tamiflu_bior.pdf)
 Ontogeny equationaEmbedded Image
 CES1 ontogeny parametersbFbirth, Adultmax, Age50, and n: 0.20, 1, 1.10, and 0.56, respectivelybPresent 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.

  • a 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.

  • b 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.