TABLE 2

Summary of drug-specific parameters used in the simulations at term (week 40)

ParameterDrug XDrug Y
Molecular weight236.23a325.8i
logP0.05b3.13i
B/P ratio1.17c0.66i
Vss (l/kg)0.7d1.1i
fu,plasma0.99e0.032i
Fa1.0f0.88i
ka (h−1)1.5g4.0j
Fg0.78f0.58i
CLr (l/h)18.1d0.085i
CLiv (l/h)45.6d43.0i
CLPD (l/h)1.80h22.7k
fm and fefm = 61%, fe = 39%dfm,3A = 92%, fe ≈ 0%i
CLf0 (l/h)0.9h0m
  • The above values for drug X and drug Y at term (week 40) were based on the reported didanosine and midazolam PK parameters in the literature, respectively. B/P, blood/plasma concentration ratio; CLiv, intravenous clearance; CLr, renal clearance; fe, fraction renally eliminated; fm, fraction metabolized; fu,plasma, unbound fraction in the plasma

  • a Extracted from didanosine product monograph (http://monographs.iarc.fr/ENG/Monographs/vol76/mono76-9.pdf).

  • b Literature value (Tuntland et al., 1999).

  • c Calculated from the reported blood/plasma didanosine AUC ratio (Barry et al., 1993).

  • d Predicted by Simcyp (version 14) based on literature value (Knupp et al., 1991). Vss increased slightly from 0.68 l/kg at week 20 to 0.71 l/kg to week 40.

  • e Reported plasma binding of didanosine is <5%. Minimal binding of 1% was assumed for ease of data interpretation.

  • f Reported average didanosine absolute bioavailability is 23.5% [range 14–33% (77)] (Knupp et al., 1991). Animal studies indicate that didanosine is rapidly and completely absorbed. Therefore, Fa was assumed to be 1. The reported intravenous nonrenal clearance (∼30 l/h) (Knupp et al., 1991) does not fully explain the first pass effect. Fg of 0.78 was used to recover oral PK.

  • g Literature value (Velasque et al., 2007).

  • h Irreversible human fetal drug X clearance at term was calculated as the product of fetal didanosine clearance in the macaque fetus (dam weight normalized) (Tuntland et al., 1999) and the average term body weight of 85 kg in human pregnant women (Abduljalil et al., 2012). The reported steady-state fetal/dam didanosine plasma concentration ratio is ∼0.5 (Tuntland et al., 1999). Therefore, placental passive diffusion clearance was estimated as 1.8 l/h (Supplemental eq. 2), assuming that the same F/M AUC ratio holds true for drug X in human maternal-fetal pairs.

  • i Reported values of midazolam pregnancy PBPK model (Ke et al., 2012).

  • j Estimated from midazolam oral data from term pregnant women (Kanto et al., 1983).

  • k Estimated from the reported midazolam umbilical venous plasma concentrations (Kanto et al., 1983; Zhang and Unadkat, 2017).

  • m Assumed.