Summary of midazolam, theophylline, and zidovudine drug-dependent parameters

ParameterMidazolam ValueMethods/ ReferenceTheophylline ValueMethods/ ReferenceZidovudine ValueMethods/Reference
Molecular weight325.8Librarya180.2Librarya267.2Librarya
Log Po:w3.13Optimizedb−0.02Librarya0.05Librarya
B/P ratio0.66Librarya0.82Librarya0.91Librarya
Fa0.88Librarya0.97Librarya0.83Predicted by ADAM model
ka (h−1)4.0Optimizedc1.0Reportede4.05Reportedf
Vss (L/Kg)1.1Reportedd0.39Reportedd1.10Optimizedh
CLiv (L/h)23.0Librarya3.0Reportedd91.0Reportedi
CLr (L/h)0.085Librarya0.45Reportedd15.5Libraryj
CLhep,int,u (L/h)1672.3Librarya4.60Reportedd30.9Calculatedk
fm and fefm,3A = 92%,Reporteddfm,1A2 = 68%,Reporteddfm,UGT2B7 = 67%,Reportedl
fe ≈ 0%fm,3A = 7%,fe = 17%
fm,2E1 = 10%,
fe = 15%
  • * Midazolam is a weak base (Andersin, 1991), whereas zidovudine is a weak acid (Gallicano, 2000). In contrast, theophylline is neutral (Hardman, 1962).

  • a Refers to the SimCYP Simulator compound library (version 14).

  • b Previously optimized and validated to match the predicted volume of distribution at steady state (Vss) to the reported Vss value of 1.10 L/kg in the literature (Ke et al., 2012).

  • c Optimized based on sensitivity analysis to match reported absorption in pregnant subjects (Kanto et al., 1983).

  • d Validated literature value used in our pregnancy PBPK model (Ke et al., 2012, 2013).

  • e Phoenix estimate from reported oral absorption data in healthy volunteers (Aslaksen et al., 1981).

  • f Phoenix estimate from reported oral absorption data in nonpregnant subjects (Klecker et al., 1987).

  • g No report on zidovudine Fg is available. Zidovudine Fg was assumed 1 because human intestinal microsomes showed negligible UGT2B7 activity measured by two UGT2B7 probes (diclofenac and gemfibrozil) (Furukawa et al., 2014).

  • h The reported average zidovudine Vss is 1.4 ± 0.4 L/kg (Collins and Unadkat, 1989). This Vss was optimized through manual sensitivity analysis in the range of 0.8–1.6 L/kg to match the predicted peak plasma concentration (Cmax) to the reported Cmax following i.v. infusion in nonpregnant population (Klecker et al., 1987; Cload, 1989).

  • i Calculated based on the reported average i.v. clearance of 1.3 L/h/kg assuming 70 kg body weight.

  • j Reported zidovudine fraction excreted in the urine (fe) ranges from 14% to 20%. The SimCYP Simulator compound library value of 15.5L/h (fe = 17%) was used.

  • k Back calculation from well-stirred liver model using hepatic blood flow of 90 L/h assuming hepatic clearance of 20.7 L/h.

  • l Estimated from urinary data (Cload, 1989; Stagg et al., 1992).