Population Pharmacokinetics of Clozapine: A Systematic Review

Table 3

Model variability, error, and validation.

Study	Interindividual variability		Error	Residual		Model evaluation
	Clozapine	Norclozapine		Clozapine	Norclozapine
Daily et al. [18]	IIV Cl = 27.1%; IIV Vd = 22.5%	NA	Pro	CV = 33.3%	NA	NA
Doude van Troostwijk et al. [19]	SD Vd = 1.01 L/kg; SD F = 0.09; SD Ka = 0.01 h^−1; SD Cl = 6.31 L/h; SD Ke = 0.037 h^−1	NA	NA	NA	NA	NA
Ng et al. [20]	IIV Cl = 60.8%; IIV Vd = 131.5%	IIV Cl = 60.25%	Add + Pro	CV = 11.5%	CV = 9.5%	Basic internal (Goodness of fit)
Qiu et al. [21]	IIV Cl = 42.2%; IIV Vd = 10%	NA	Add + Pro	SD = 45.8 ng/mL; CV = 26.4%	NA	Advanced internal (Jack-knife) and external (validation group)
Ismail et al. [22]	IIV Cl = 44.5% IIV Vd = 93.2%	IIV Cl = 44.5%	Add + Pro	SD = 178.4 ng/mL	SD = 101.4 ng/mL	Basic internal (LLP)
Li et al. [23]	IIV Cl = 42.9%; IIV Vd = 65.7%	IIV Cl = 42.1%; IIV Vd = 75.6%	Add + Pro	SD = 52.9 ng/mL; CV = 26.6%	SD = 36.6 ng/mL; CV = 16.9%	Advanced internal (NPDE)
Shang et al. [24]	IIV Cl = 45.1%; IIV Vc = 32.7%; IIV Vp = 90.3%; IIV	NA	Add + Pro	CV = 28.4%	NA	Basic and advanced internal (goodness of fit + NPDE)
Li et al. [25]	IIV Ke = 15.2%	NA	Add	SD = 0.149 h^−1	NA	Advanced internal (bootstrap + VPC)
Olmos et al. [26]	IIV Cl = 43.3%	IIV Cl = 49.9%	Pro	CV = 9.54%	CV = 15.3%	Advanced internal (NPC + NPDE + bootstrap)

IIV: interindividual variability; CV: coefficient of variation; SD: standard deviation; Cl: clearance; Vd: volume of distribution; V_c: volume of distribution of the central compartment; V_p: volume of distribution of the peripheral compartment; K_a: absorption rate constant; K_e: elimination rate constant; F: bioavailability; Add: additive error; Pro: proportional error; LLP: log-likelihood profiling; NPC: numerical predictive check; NPDE: normalized prediction distribution error; VPC: visual predictive check; NA: not available. Fixed value from the literature.