Influence of dose, gender, and cigarette smoking on clozapine plasma concentrations

Figures & data

Table 1 Factors influencing clozapine plasma concentration (PC) in studies

Reference, number of patients	Influence of dose	Influence of gender	Influence of age	Influence of body weight	Influence of smoking	Influence of caffeine	Influence of comedication	PC outside proposed RR
Rajkumar et al^Citation12 (N=101)	Dose and PC correlation (p<0.001)	NA	NA	NA	NA	Caffeine intake associated with PC (p=0.04)	Valproate associated with PC (p=0.005)	NA
Gaertner et al^Citation11 (N=233)	Dose and PC correlation (p<0.0001)	No significant influence	No significant influence	NA	Smoking influences PC (p<0.0001); 35% lower PC in S	NA	Fluv (p<0.0001); depends on dose; clo PC 82% higher in patients taking fluv	NA
Lane et al^Citation13 (N=162)	Every 1 mg of clozapine can increase PC by 0.31%	PC 34.9% higher in women	Each additional year of age increased PC by 1.1%	No significant influence	NA	NA	NA	NA
Jann et al^Citation14 (N=40)	NA	PC decreased in men	NA	NA	NA	NA	NA	NA
Ulrich et al^Citation15 (N=86; BS=404)	NA	PC increased in women	PC increased in aged patients	NA	PC increased in NS	NA	NA	NA
Rostami-Hodjegan et al^Citation16 (N=3,782; BS=9,894)	NA	PC +17% in women	PC ±4% for every 5 years (reference 40 years)	±5% for every 10 kg BW (reference 80 kg)	PC +48% in NS	NA	NA	PC below RR in 50% samples
Tang et al^Citation10 (N=193)	NA	PC higher in women (p<0.001)	No significant difference in PC between patients ≤40 and >40 years old	NA	No significant difference in PC between male S and NS, despite higher clo dosage for S	NA	NA	Large interindividual variability, up to eightfold at a given dose (400 mg, N=18)
Bowskill et al^Citation17 (N=778; BS=1930)	NA	No significant difference (dose higher in men, more men smokers)	Higher PC after the age of 65, despite dose reduction (N=196)	NA	NA	NA	NA	32% PC under RR, 37% above
Tsuda et al^Citation18 – MA of 4 studies, (N=120 S; 76 NS)	NA	NA	NA	NA	PC/dose ratio lower in S (p<0.00001); to have the same PC, NS needs 100 mg and S 200 mg	NA	NA	NA
Seppälä et al^Citation19 (N=44)	NA	No significant difference	NA	NA	PC 40% lower in S; no significant influence of number of cigarettes	NA	NA	NA
Ng et al^Citation20 (N=197; BS=519)	NA	Lower PC in men (higher oral clearance)	NA	NA	Lower PC in S (higher oral clearance)	NA	NA	NA
Hägg et al^Citation21 (N=12 healthy volunteers)	NA	NA	NA	NA	NA	19% increase in the mean clo AUC during caffeine intake (p=0.05) (mean caffeine daily dose 550 mg)	NA	NA
Raaska et al^Citation22 (N=12)	NA	NA	NA	NA	NA	Trough PC 20% higher during the caffeine phase	NA	NA

Abbreviations: AUC, area under curve; BS, number of blood samples; BW, body weight; clo, clozapine; fluv, fluvoxamine; MA, meta-analysis; NA, not available; NS, nonsmokers; RR, reference range; S, smokers.

Figure 1 Correlation of clozapine daily dose and PC.

Notes: Number of patients: 98. Horizontal red lines = reference range.
Abbreviation: PC, plasma concentrations.

Table 2 Comparison of patient characteristics according to smoking status

Characteristics	Nonsmokers (N=52)a	Smokers (N=46)a	p-valueb
Men	30 (57.7%)	38 (82.6%)	0.009
Education (years)	13 (9; 19)	12 (9; 16)	0.410
Employment	9 (17.3%)	10 (21.7%)	0.617
Relationship	4 (7.7%)	12 (26.1%)	0.026
Weight (kg)	78 (54; 108)	89 (63; 122)	0.050
BMI	26 (19; 36)	27 (19; 38)	0.133
Diagnosis F25	7 (13.5%)	15 (32.6%)	0.030
Clozapine dose (mg/day)	300 (200; 600)	300 (200; 600)	0.058
Clozapine PC (ng/mL)	460 (140; 1,490)	300 (120; 730)	<0.001
Age (years)	34 (17; 55)	35 (20; 55)	0.743
Length of disease (months)	102 (4; 420)	125 (3; 426)	0.317
Length of disease >1 year	43 (82.7%)	39 (84.8%)	1.000
Length of clozapine usage (months)	0.3 (0.3; 180.0)	14.0 (0.3; 72.0)	0.287
Length of clozapine usage >1 month	23 (44.2%)	28 (60.9%)	0.110
CGI-S	6 (4; 7)	5 (3; 6)	<0.001
CGI-S >4	48 (92.3%)	33 (71.7%)	0.014
CGI-S >5	37 (71.2%)	15 (32.6%)	<0.001

Notes:

a Median supplemented by 5th–95th percentile range for continuous data, absolute and relative frequencies for categorical data.

b Mann–Whitney U-test for continuous data, Fisher’s exact test for categorical data. Significant p-values (p≤0.05) are shown in bold.

Abbreviations: BMI, body mass index; CGI-S, Clinical Global Impression – Severity Scale; F25, schizoaffective disorder; N, number of patients; PC, plasma concentration.

Table 3 Comparison of patients’ characteristics according to gender

Characteristics	Women (N=30)a	Men (N=68)a	p-valueb
Education (years)	12 (9; 19)	13 (9; 18)	0.904
Employment	5 (16.7%)	14 (20.6%)	0.785
Relationship	6 (20.0%)	10 (14.7%)	0.559
Smoking	8 (26.7%)	38 (55.9%)	0.009
Weight (kg)	76 (53; 122)	88 (63; 115)	0.030
BMI	27 (19; 43)	27 (19; 35)	0.734
Diagnosis F25	4 (13.3%)	18 (26.5%)	0.194
Clozapine dose (mg/day)	300 (150; 500)	300 (200; 600)	0.004
Clozapine PC (ng/mL)	390 (120; 1,370)	370 (140; 950)	0.331
Age (years)	36 (20; 56)	33 (18; 55)	0.159
Length of disease (months)	142 (3; 420)	119 (4; 426)	0.627
Length of disease >1 year	26 (86.7%)	56 (82.4%)	0.770
Length of clozapine usage (months)	0.3 (0.3; 132.0)	5.0 (0.3; 154.0)	0.259
Length of clozapine usage >1 month	13 (43.3%)	38 (55.9%)	0.279
CGI-S	6 (5; 7)	5 (3; 7)	0.002
CGI-S >4	30 (100.0%)	51 (75.0%)	0.001
CGI-S >5	23 (76.7%)	29 (42.6%)	0.002

Notes:

a Median supplemented by 5th–95th percentile range for continuous data, absolute and relative frequencies for categorical data.

b Mann–Whitney U-test for continuous data, Fisher’s exact test for categorical data. Significant p-values (p<0.05) are shown in bold.

Abbreviations: BMI, body mass index; CGI-S, Clinical Global Impression – Severity Scale; F25, schizoaffective disorder; N, number of patients; PC, plasma concentration.

Table 4 Predictors associated with clozapine plasma concentration in linear regression model

Predictora	Univariate model		Multivariate model
	Beta (95% CI)	p-value	Beta (95% CI)	p-value
Men	−0.114 (−0.445; 0.122)	0.262
Education (years)	0.042 (−0.525; 0.799)	0.683
Employment	−0.023 (−0.371; 0.296)	0.823
Relationship	0.019 (−0.323; 0.389)	0.854
Smoking	−0.400 (−0.764; −0.280)	<0.001	−0.432 (−0.802; −0.323)	<0.001
Weight (kg)	0.121 (−0.251; 1.010)	0.235
BMI	0.126 (−0.227; 0.988)	0.217
Diagnosis F25	0.034 (−0.263; 0.369)	0.740
Clozapine dose (mg/day)	0.341 (0.270; 0.954)	<0.001	0.405 (0.423; 1.033)	<0.001
Age (years)	0.023 (−0.010; 0.012)	0.819
Length of disease (months)	0.114 (−0.052; 0.186)	0.264
Length of disease >1 year	0.133 (−0.119; 0.588)	0.191
Length of clozapine usage >1 month	−0.092 (−0.382; 0.143)	0.370
CGI-S	0.195 (−0.002; 0.218)	0.054
CGI-S >4	0.069 (−0.229; 0.465)	0.500
CGI-S >5	0.226 (0.038; 0.552)	0.025	0.071 (−0.144; 0.330)	0.439

Notes:

a All continuous predictors with the exception of age were log transformed prior to regression analysis; the evaluated variable clozapine PC was also log transformed. Significant p-values (p<0.05) are shown in bold.

Abbreviations: BMI, body mass index; CGI-S, Clinical Global Impression – Severity Scale; F25, schizoaffective disorder.

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