TABLE 1.

Summary of published population pharmacokinetic studies of VPA in children with epilepsy.

Study (publication year)	Country (single/multiple sites)	Number of patients (male/female)	Total samples	VPA assay	Structural model	PK parameters and formula		BSV (%)	Residual error
Serrano et al. (1999)	Spain (single)	255 (128/127)	770	FPIA	1CMT	CL/F	0.012 × WT0.715 × (DDW)0.306 × (1.359, if concomitant CBZ)	21.4	15.6 mg/L
						V/F	0.24 × WT	/
						Ka	1.9 (fixed)	/
Desoky et al. (2004)	Egyptian (single)	81 (52/29)	81	FPIA	1CMT	CL/F	0.105 + 0.000248 × DD + 0.0968 × AGE/20 + (0.151, if concomitant CBZ) + (0.0803, if uncontrolled epilepsy)	23.6	5.24 mg/L
						V/F	11.5 (fixed)	—
						Ka	4 for syrup, 1 for EC-tablet (fixed)	—
Jiang et al. (2007)	China (multiple)	317 (195/122)	624	FPIA	1CMT	CL/F	0.106(0.98 × CO) + 0.0157 × AGE	25.1	13.2 mg/L
							CO = 1 when co-medication exists
						V/F	2.88 + 0.157 × WT	49.1
						Ka	0.251 + 2.24 (1 − HS), HS = 1 for SR-tablet, otherwise HS = 0	11.0
Correa et al. (2008)	Mexico (single)	110 (63/47)	119	CEDIA	1CMT	CL/F	(0.0466 + 0.00363 × WT + 0.000282 × DD) × (1.236, if concomitant PB)	14.1	17.3 mg/L
						V/F	0.24 × WT	—
						Ka	1.2 (fixed)	—
Williams et al. (2012)	United States (multiple)	52 (36/16)	231	FPIA	2CMT	CL/F	0.854 × (WT/70)0.75	35.9 a	34.8%
						Vc/F	10.3 × (WT/70) × (AGE/8.5) −0.267	19.6 a
						Vp/F	4.08 × (WT/70)	101.5 a
						Q/F	5.34 × (WT/70)0.75	—
						Ka	2.0 for capsule, 1.2 for sprinkle, 4.1 for tablet (fixed)	—
						Tlag	1.0 for sprinkle, 2.0 for tablet (fixed)	—
Ogusu et al. (2014)	Japan (single)	237 (137/100)	827	EMIT	1CMT	CL/F	0.559 × (DD/1000)0.596 × (0.917, if female) × (1.19, if concomitant CBZ) × (1.12, if concomitant PB) × (1.43, if concomitant PHT) × (0.906, if concomitant CLB)	24.2	24.8%
						V/F	21.4 × (DD/1000)1.52	0.043
						Ka	0.109	0.088
						Tlag	3.00	—
Ding et al. (2015)	China (multiple)	902 (547/355)	1107	FPIA	1CMT	CL/F	$0.3\times \left(1.43,\text{if\hspace{0.17em}concomitant\hspace{0.17em}CBZ}\right)\times {\left(\frac{\text{WT}}{70}\right)}^{0.791-\frac{0.096\times {\text{AGE}}^{8.63}}{{0.802}^{8.63}+{\text{AGE}}^{8.63}}}$	19.5	13.3 mg/L
							$\times \left(1+\frac{2.8\times {\text{DDW}}^{1.68}}{{37.4}^{1.68}+{\text{DDW}}^{1.68}}\right)$
						V/F	22.2 × (WT/70)	/
						Ka	2.64, 1.57, 0.46 for syrup, conventional tablet and SR tablet, respectively (fixed)	/
Rodrigues et al. (2018)	France (multiple)	98 (50/48)	325	FPIA	1CMT	CL/F	0.624 × (WT/70)0.75	33.9	15.4%
						V/F	13.0 × (WT/70)	/
						Ka	0.274	/
Gu et al. (2021)	China (single)	313 (209/104)	375	GC	1CMT	CL/F	$10.4\times \left(1.25,\text{if\hspace{0.17em}concomitant\hspace{0.17em}LGT}\right)\times {\left(\frac{\text{WT}}{70}\right)}^{0.75}$ $\times \left(\frac{{\text{PMA}}^{4.17}}{{33.7}^{4.17}+{\text{PMA}}^{4.17}}\right)$	43.0	2.5%
						V/F	1680.1 × (WT/70)	92.8
						Ka	2.64, 1.57, 0.46 for syrup, conventional tablet and SR tablet, respectively (fixed)	/
Teixeira-da-Silva et al. (2022)	Spain (single)	836 (451/385)	1751	FPIA	1CMT	CL/F	0.646 × (WT/70)0.75 × (AGE/15.0)−0.0154 × (1.640, if concomitant PHT) × (1.386, if concomitant PB) ×(1.521, if concomitant CBZ)	26.8	57.7%
						V/F	14.0 × (WT/70)	—
						Ka	2.64, 0.78, 0.38 for syrup, EC tablet and SR tablet, respectively (fixed)	—

BSV, between subject variability; CBZ, carbamazepine; CEDIA, cloned enzyme donor immunoassay; CLB, clobazam; CL/F, apparent clearance (L h⁻¹); CMT, compartment; CO, co-medication; DD, daily dose in mg day⁻¹; DDW, daily dose in mg kg⁻¹.day⁻¹; EC, enteric coated; EMIT, enzyme multiplied immunoassay technique; FPIA, fluorescence polarization immunoassay; GC, gas chromatography; k ₀, zero order rate constant (h⁻¹); K _a , absorption rate constant (h⁻¹); LGT, lamotrigine; PB, phenobarbital; PHT, phenytoin; PK, pharmacokinetics; PMA, post-menstrual age; Q, intercompartmental clearance (L h⁻¹); SR, sustained release; T _lag , lag time (h); V _c /F, apparent volume of distribution of central compartment (L); V/F, apparent volume of distribution (L); VPA, valproic acid; V _p /F, apparent volume of distribution of peripheral compartment (L); WT, weight.

^a Correlations are CL/F ∼ V_c: 0.0397; CL/F ∼ V_p: 0.0777; V_c ∼ V_p: 0.144.