TABLE 1

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

Parameter	Midazolam Value	Methods/ Reference	Theophylline Value	Methods/ Reference	Zidovudine Value	Methods/Reference
Molecular weight	325.8	Library^{^a}	180.2	Library^{^a}	267.2	Library^{^a}
Log P_o:w	3.13	Optimized^{^b}	−0.02	Library^{^a}	0.05	Library^{^a}
pKa	10.95,6.2	Library^{^a}	8.8,0.99	Library^{^a}	9.70	Library^{^a}
B/P ratio	0.66	Library^{^a}	0.82	Library^{^a}	0.91	Library^{^a}
f_u,_p^*	0.032	Library^{^a}	0.58	Library^{^a}	0.80	Library^{^a}
F_a	0.88	Library^{^a}	0.97	Library^{^a}	0.83	Predicted by ADAM model
k_a (h⁻¹)	4.0	Optimized^{^c}	1.0	Reported^{^e}	4.05	Reported^{^f}
F_g	0.58	Library^{^a}	1.0	Reported^{^d}	1	Assumed^{^g}
V_ss (L/Kg)	1.1	Reported^{^d}	0.39	Reported^{^d}	1.10	Optimized^{^h}
CL_iv (L/h)	23.0	Library^{^a}	3.0	Reported^{^d}	91.0	Reported^ⁱ
CL_r (L/h)	0.085	Library^{^a}	0.45	Reported^{^d}	15.5	Library^{^j}
CL_hep,int,u (L/h)	1672.3	Library^{^a}	4.60	Reported^{^d}	30.9	Calculated^{^k}
f_m and f_e	f_m,3A = 92%,	Reported^{^d}	f_m,1A2 = 68%,	Reported^{^d}	f_m,UGT2B7 = 67%,	Reported^{^l}
	f_e ≈ 0%		f_m,3A = 7%,		f_e = 17%
			f_m,2E1 = 10%,
			f_e = 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 (V_ss) to the reported V_ss 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 F_g is available. Zidovudine F_g 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 V_ss is 1.4 ± 0.4 L/kg (Collins and Unadkat, 1989). This V_ss was optimized through manual sensitivity analysis in the range of 0.8–1.6 L/kg to match the predicted peak plasma concentration (C_max) to the reported C_max 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 (f_e) ranges from 14% to 20%. The SimCYP Simulator compound library value of 15.5L/h (f_e = 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).