Table 4 Input parameters for lamotrigine GastroPlus PBPK model.

	Parameters		Values/models
Physiochemical and blood binding properties	Molecular weight (g/mol)		256.1^a
	LogP		1.19^b
	pK_a		5.5^b
	Solubility (mg/mL) (pH = 7)		0.17^a
	B:P		1^b
	fu_p		0.45^c
Absorption	Absorption model		ACAT^d
	P_eff (10⁻⁴ cm/sec)		7.761^c
	Diffusion coefficient (10⁻⁵ cm²/sec)		0.92^d
	Dissolution model		Johnson^d
	Particle size distribution		Log-normal^d
	Particle radius (µm)		25^d
	Particle density (g/mL)		1.2^d
	Dose volume (mL)		250^d
	Precipitation model		First order^d
	Precipitation time (sec)		900^d
	Paracellular model		Zhimin^d
Distribution	Distribution model		Full PBPK-Poulin & Theil (homogeneous)^d
Distribution	V_ss (L/kg)		1.16^c,e
Elimination	CL_IV (L/h)		2^c
	f_CL,renal (CL_R in L/h)		0.10 (0.2)^a
	f_CL,hepatic (CL_H in L/h)		0.90 (1.8)^a
Metabolic clearance	CLu_int,H in L/h		4.09^a
	f_m,UGT (CLu_int,UGT in L/h)		0.86 (3.91)^a
	f_m,CYP (CLu_int,CYP in L/h)		0.04 (0.18)^a
Extrapolation factor	ISEF		1^d
Fraction unbound	fu_mic		1^d
Adult enzyme expression (mg enzyme/g tissue)	UGT1A3		0.016^d
Adult enzyme expression (mg enzyme/g tissue)	UGT1A4		0.017^d
DME _j	f _m,UGT (% contribution of DME _j )	K _m (µM)	V _max (pmol/min/pmol DME _j ) ^f	\({{\rm{C}}{\rm{L}}{\rm{u}}}_{{{\rm{i}}{\rm{n}}{\rm{t}}{\mathtt{,}}{\mathtt{\text{DME}}}}_{{\mathtt{j}}}}\) (L/h) ^g
UGT1A3	0.086 (10)^h	70^h	0.96	0.39
UGT1A4	0.774 (90)^h	550^h	65.54	3.52

Abbreviations: LogP, partition coefficient; pK_a, dissociation constant; B:P, blood to plasma concentration ratio; fu_p, unbound fraction in the plasma; ACAT, advanced compartmental absorption and transit; P_eff, effective permeability; V_ss, volume of distribution at steady state; CL_IV, intravenous plasma clearance; f_CL,renal, fraction of drug cleared unchanged renally; CL_R, renal plasma clearance; f_CL,hepatic, fraction of drug cleared through hepatic metabolism; CL_H, hepatic plasma clearance; CLu_int,_H, unbound hepatic intrinsic clearance; f_m,DME, fraction of drug metabolized by a specific drug metabolizing enzyme isoform (DME_j); ISEF, inter-system extrapolation factor; fu_mic, unbound fraction in the microsomes; K_m, concentration of substrate at which half-maximal enzymatic activity (V_max) is reached, and CLu_int, unbound intrinsic clearance for a particular metabolic pathway. For method/references, details are as follows: ^a⁵⁴, ^b⁴⁹, ^c⁶⁵, ^dDefault value in GastroPlus, ^eOptimized according to literature reported⁶⁵ value in adult by adjusting LogP value (1.629) with Poulin & Theil (homogeneous) method. Similar approach was used for V_ss calculation in paediatrics and HI populations, ^fCalculated using Equation 19, ^gCalculated using Equation 17, and ^h⁴⁶.

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