The Effect of Liver and Kidney Disease on the Pharmacokinetics of Clozapine and Sildenafil: A Physiologically Based Pharmacokinetic Modeling

Figures & data

Table 1 Parameter Values Used for Clozapine and Sildenafil Simulation

Parameters	Value
	Clozapine	Sildenafil
Physical chemistry and blood binding molecular weight (g/mol)	326.8	474.5
Log P	3.5	2.9
Compound type	Monoprotic base	Monoprotic base
PKa	7.7	6.5
Blood/plasma ratio	0.8	0.6
Fraction unbound in plasma (Fu plasma)	0.055	0.036
Absorption model used	ADAM	M-ADAM
Predicted Peff, man(x 10^−4 cm/sec)	6.8	-
Predicted Ptrans(x 10^−6 cm/sec)		411.7
Distribution model	Full PBPK	Full PBPK
Vss(L/kg)	4.7	1.2
Elimination model	Enzyme kinetics	Enzyme kinetics
rCYP1A2 Vmax (pmol/min/pmol)	13.1	–
rCYP1A2 Km (µM)	14.2	–
rCYP2D6 Vmax(pmol/min/pmol)	4.5	–
rCYP2D6 Km (µM)	19.5	–
rCYP3A4 Vmax (pmol/min/pmol)	11.6	–
rCYP3A4 Km (µM)	91.6
rCYP3A4 Clint (L/h)	–	2.2
rCYP2C9 Clint (L/h)	–	0.49

Table 2 Comparison Between Predicted and Observed Pharmacokinetic Parameters

Parameter	Clozapine (100 mg, Twice Daily)			Sildenafil (100 mg, Once Daily)
	Predicted	^aObserved	Predicted/Observed	Predicted	^bObserved	Predicted/Observed
Tmax (h)	1.9 (1.4–3.1)	2.0 (0–5.4)	0.9	0.5 (03–0.8)	0.7 (0.50–3.00)	0.7
Cmax(ng/mL)	455.3 (36)	455.5 (50)	0.9	764.2 ± 304.9	645.3 ±281.83	1.1
AUC0-t(ng/mL.h)	4434.1(40)	3443 (55)	1.2	1910.6 ±957.2	1,971.1 ±978.16	0.9

Notes: For sildenafil, values are meanv ± standard deviation, except for T_max median (range). For clozapine, alues are mean with percent coefficient of variation in parenthesis, T_max median (range). ^aObserved data were retrieved from the clinical study by Golden and Honigfeld. ^bObserved data were retrieved from the clinical study by Radicioni et al.

Abbreviations: T_max, time-to-maximum concentration; C_max, maximum concentration; AUC_0-t, area under the time–concentration curve during dosing interval.

Table 3 Comparison of Clozapine Pharmacokinetic Parameters for Young Adults According to Different Conditions

Populations	Parameters						CLpo, ss(L/h)	Fold Change
	Tmax (h)	Fold Change	Cmax(ng/mL)	Fold Change	AUC0–72h(ng/mL.h)	Fold Change
HV	1.9 (1.4–3.1)		455.3 ± 166.0		4434.1 ± 1779.6		28.1 ± 17.1
HI-A	2.2 (1.8–2.5)	1.1	665.2 ± 238.4	1.4	7002.1 ± 2743.0	1.5	17.2 ± 8.5	0.6
HI-B	2.5 (1.8–3.6)	1.3	976.8 ± 303.5	2.1	10,888.3 ± 3547.0	2.4	10.3 ± 4.4	0.3
HI-C	2.7 (2.1–4.1)	1.4	1169.0 ± 326.7	2.5	13,392.7 ± 3828.1	3.0	8.1 ± 2.5	0.2
RI-GFR 30_60	2.3 (1.6–3.5)	1.2	651.9 ± 262.6	1.4	6881.8 ± 3057.1	1.5	18.0 ± 9.4	0.6
RI-GFR_30	1.9 (1.4–3.1)	1.0	938.1 ± 403.8	2.0	7563.5 ± 4141.9	1.7	18.0 ± 11.2	0.6

Notes: Values are mean ± standard deviation, except for T_max median (range). Parameters were predicted at the steady state (72 h) by the simulation of multiple administration of clozapine (100 mg every 12 h) for all populations, age of 20–45 years. Fold change is calculated by dividing pharmacokinetic parameters of the special population by the same parameter of HV.

Abbreviations: HV, healthy volunteers; HI, hepatic impairment; RI, renal impairment; T_max, time-to-maximum concentration; C_max, maximum concentration; AUC_0-t, area under the time–concentration curve during dosing interval; CL_{po, ss}, apparent oral clearance at the steady state.

Table 4 Comparison of Clozapine Pharmacokinetic Parameters for Elderlypopulationaccording to Different Conditions

Populations	Parameters						CLpo, ss (L/h)	Fold Change
	Tmax (h)	Fold Change	Cmax(ng/mL)	Fold Change	AUC0–72h(ng/mL.h)	Fold Change
Elderly	1.6 (1.4–2.1)		699.5 ± 288.7		4955.8 ± 2607.0		27.5 ± 19.4
HI-A	2.2 (1.8–3.1)	1.3	774.2 ± 273.8	1.1	8313.0 ± 3168.8	1.6	14.1 ± 7.0	0.5
HI-B	2.6 (1.7–3.4)	1.6	1103.8 ± 332.3	1.6	12,444.7 ± 3886.3	2.5	8.9 ± 3.2	0.3
HI-C	2.8 (1.9–6.0)	1.7	1272.4 ± 352.4	1.8	14,673.3 ± 4128.1	2.9	7.3 ± 2.1	0.2
RI-GFR 30_60	2.4 (1.7–3.8)	1.5	807.4 ± 318.7	1.1	8734.4 ± 3670.4	1.7	14.2 ± 8.5	0.5
RI-GFR_30	2.5 (1.8–4.2)	1.5	739.6 ± 283.3	1.0	8018.1 ± 3266.7	1.6	15.1 ± 8.1	0.5

Notes: Values are mean ± standard deviation, except for T_max median (range). Parameters were predicted at the steady state (72 h) by the simulation of multiple administration of clozapine (100 mg every 12 h) for all populations, age of 65–85 years. Fold change is calculated by dividing Pharmacokinetic parameter of the special population by the same parameter of the elderly volunteers.

Abbreviations: HI, hepatic impairment; RI, renal impairment; T_max, time-to-maximum concentration; C_max, maximum concentration; AUC_0–t, area under the time–concentration curve during dosing interval; CL_{po, ss,} apparent oral clearance at the steady state.

Figure 1 Comparison of simulated mean clozapine concentrations for young adults according to (A) hepatic function and (B) renal function after multiple administration of clozapine 100 mg every 12 h.

Figure 2 Comparison of simulated mean clozapine concentrations for elderly population according to (A) hepatic function and (B) renal function after multiple administration of clozapine 100 mg every 12 h.

Table 5 Comparison of Sildenafil Pharmacokinetic Parameters for Young Adults According to Different Conditions

Populations	Parameters						CLpo, ss(L/h)	Fold Change
	Tmax (h)	Fold Change	Cmax(ng/mL)	Fold Change	AUC0–24h(ng/mL.h)	Fold Change
HV	0.5 (03–0.8)		764.2 ± 304.9		1910.6 ±957.2		72.52± 35.3
HI-A	0.5 (0.3–0.7)	1.0	780.7 ± 260.9	1.0	2721.7 ± 1389.6	1.4	47.8 ± 27.7	0.7
HI-B	0.6 (0.3–0.9)	1.2	955.5 ± 267.2	1.2	5311.6 ± 2226.0	2.7	22.6 ± 10.7	0.3
HI-C	0.6 (0.3–1.0)	1.2	993.7 ± 261.6	1.3	6882.0 ± 2593.4	3.6	16.8 ± 7.1	0.2
RI-GFR 30_60	0.5 (0.3–1.0)	1.0	778.6 ± 311.6	1.0	2931.5 ± 1867.1	1.5	46.5 ± 28.5	0.7
RI-GFR_30	0.6 (0.4–0.9)	1.2	645.5 ± 260.8	0.8	2687.4 ± 1659.7	1.4	51.5 ± 34.0	0.8

Notes: Values are mean ± standard deviation, except for T_max median (range). Parameters were predicted after 24 h by the simulation of single-dose administration of sildenafil 100 mg for all populations, age of 20–45 years. Fold change is calculated by dividing PK parameter of the special population by the same parameter of HV.

Abbreviations: HV, healthy volunteers; HI, hepatic impairment; RI, renal impairment; T_max, time-to-maximum concentration; C_max, maximum concentration; AUC_0–t, area under the time–concentration curve during dosing interval; CL_{po, ss,} apparent oral clearance at the steady state.

Table 6 Comparison of Sildenafil Pharmacokinetic Parameters for Elderly According to Different Conditions

Populations	Parameters						CLpo, ss(L/h)	Fold Change
	Tmax (h)	Fold Change	Cmax(ng/mL)	Fold Change	AUC0–24h(ng/mL.h)	Fold Change
Elderly	0.4 (0.3–0.7)		749.7 ± 318.0		1963.7 ± 1266.2		71.8 ± 48.2
HI-A	0.5 (0.3–1.3)	1.2	902.1 ± 315.2	1.2	3546.2 ± 1739.2	1.8	35.7 ± 18.2	0.5
HI-B	0.6 (0.3–1.9)	1.5	1065.2 ± 313.0	1.4	6574.9 ± 2707.7	3.3	18.0 ± 7.6	0.3
HI-C	0.6 (0.3–1.7)	1.5	1083.8 ± 300.5	1.4	7937.1 ± 2901.1	4.0	14.4 ± 5.5	0.2
RI-GFR 30_60	0.5 (0.3–1.0)	1.2	855.6 ± 323.4	1.1	3556.9 ± 2009.9	1.8	38.0 ± 21.8	0.5
RI-GFR_30	0.6 (0.3–1.2)	1.5	709.2 ± 260.2	0.9	3266.7 ± 1755.7	1.6	41.3 ± 23.1	0.6

Notes: Values are mean ± standard deviation, except for T_max median (range). Parameters were predicted after 24 h by the simulation of single dose administration of sildenafil (100 mg) for all populations, age of 65–80 years.

Abbreviations: HI, hepatic impairment; RI, renal impairment; T_max, time-to-maximum concentration; C_max, maximum concentration; AUC_0–t, area under the time–concentration curve during dosing interval; CL_{po, ss}, apparent oral clearance at the steady state.

Figure 3 Comparison of simulated mean clozapine sildenafil for young adults according to (A) hepatic function and (B) renal function after single-dose administration of sildenafil 100 mg.

Figure 4 Comparison of simulated mean sildenafil concentrations for elderly population according to (A) hepatic function and (B) renal function after single-dose administration of sildenafil 100 mg.