Population Pharmacokinetics of Clozapine: A Systematic Review

Table 2

Model structure, pharmacokinetic parameters, and tested and retained covariates.

Study	Assay	Software	Structure model	Pharmacokinetic parameters		Covariates tested	Retained covariates in the final model
				Clozapine	Norclozapine
Choc et al. [15]	HPLC	NONLIN	Two-compartment model with first-order absorption	Cl = 44.8 L/h; Vd = 363 L; F = 0.94	NA	NA	NA
Jerling et al. [16]	GC	NPML	One-compartment with first-order absorption and elimination	Cl = 45.2 L/h; Vd = 666 L; Ka = 0.096 h^−1	NA	Age, sex, and, CYP1A2 activity	Lower Cl in females; Lower Vd in females
Guitton et al. [17]	HPLC	NA	Two-compartment model	Cl = 44.7 L/h; Vc = 7 L/kg; K10 = 0.087 h^−1; K20 = 0.156 h^−1; K12 = 1.25 h^−1	NA	NA	NA
Daily et al. [18]	HPLC	NONMEM	One-compartment model	Cl = 32.3 L/h; Vd = 272 L	NA	Age, body weight, height, CYP1A2 activity, and daily dose	Higher Cl with higher CYP1A2 activity
Doude van Troostwijk et al. [19]	HPLC	MWPharm	One-compartment with first-order absorption and elimination	Vd = 4.3 L/kg; F = 0.42; Ka = 0.98 h^−1; Cl = 14.4 L/h; Ke = 0.037 h^−1	NA	CYP1A2 activity	Higher Cl with higher CYP1A2 activity
Ng et al. [20]	HPLC	NONMEM	One-compartment with first-order absorption and elimination	Cl = 18 L/h Vd = 7 L/kg Ka = 0.14 h^−1	Cl = 39 L/h	Age, sex, weight, smoking status, and dosage formulation	Higher Cl in smokers Lower Cl in females
Qiu et al. [21]	HPLC	NONMEM	One-compartment with first-order absorption	Cl = 28.5 L/h Vd = 1290 L Ka = 2.26 h^−1	NA	Demographic index, coadministration of other drugs and CYP1A2 genotypes	Higher Cl in smokers
Ismail et al. [22]	HPLC	NONMEM	One-compartment with first-order absorption and elimination	Cl = 33.9 L/h; Vd = 950 L	Cl = 58.9 L/h	Age, sex, height, weight, and dosage formulation	Cl decreased with increased age; Lower Cl in females
Li et al. [23]	HPLC	NONMEM	One-compartment with first-order absorption	Cl = 21.9 L/h; Vd = 526 L	Cl = 32.7 L/h; Vd = 624 L	Age, weight, sex, and smoking status	Higher Cl in smokers; Lower Cl in females
Shang et al. [24]	HPLC	NONMEM	Two-compartment model with first-order absorption	Cl = 29 L/h; Vc = 314 L; Vp = 272 L	NA	Smoking, sex, age, and weight	Lower Cl in females; Higher Cl in smokers
Li et al. [25]	HPLC	NONMEM	One-compartment with first-order absorption and elimination	Cl = 21.9 L/h; Vd = 526 L; Ka = 1.3 h^−1; Ke = 0.0258 h^−1	NA	Sex, hemoperfusion, age, toxic dosage, ratio of norclozapine to clozapine, trough concentration, and the time of gastric lavage	Lower Ke with higher reported intoxication dosage
Olmos et al. [26]	HPLC	NONMEM	One-compartment model	Vd = 750 L; Ka = 1.24 h^−1; Cl = 32.1 L/h	Vd = 1860 L; Cl = 53.6 L/h	Smoking, age, sex, caffeine consumption, and coadministration of other drugs	Higher Cl in smokers

HPLC: high-performance liquid chromatography; GC: gas chromatography; NONMEM: nonlinear mixed-effects modeling; NONLIN: nonlinear regression; NPML: nonparametric maximum likelihood; 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; k₁₀: elimination rate constants from compartment 1; k₂₀: elimination rate constants from compartment 2; k₁₂: rate of metabolism; F: bioavailability; CYP: cytochrome P450; NA: not available. Fixed value from the literature.