Table 2.

Population PK/PD Parameter Estimates

Description	Parameter (Unit)	Estimation (%CVa)	RSEb (%)	P Value
Fixed effects
Clearance	Cl (L/h)	2.67 (18)	3.6
Central distribution volume	V1 (L)	4.1 (15)	2.9
Intercompartmental exchange	Q (L/h)	0.626 (14)	3.5
Peripheral distribution volume	V2 (L)	6.89 (27)	7.5
Baseline platelet aggregation	Base_PPA (%)	79.8	1.6
ACT017 concentration required for 50% inhibition	IC50 (μg/mL)	0.924 (228)	27
Maximum inhibition	Imax (%)	72.9	1.9
Standard deviations
Clearance	ωCl	0.182	12
Central distribution volume	ωV1	0.148	13
Intercompartmental exchange	ωQ	0.144	20
Peripheral distribution volume	ωV2	0.265	22
ACT017 concentration required for 50% inhibition	ωIC50	1.35	15
Correlations
Intercompartmental exchange and clearance	rQ_Cl	0.796	14
Central volume and clearance	rV1_Cl	0.626	18
Central volume and intercompartmental exchange	rV1_Q	0.84	13
Covariate coefficients
Age on clearancec	βCl_tAGE	−0.304	29	.0005
BW on clearanced	βCl_tBW	1.09	18	2.4e‐08
CRE on clearancee	βCl_tCRE	−0.566	22	5.1e‐06
BW on central distribution volumef	βV1_tBW	0.694	22	6.1e‐06
Age on intercompartmental exchangeg	βQ_tAGE	−0.318	29	.00051
BW on intercompartmental exchangeh	βQ_tBW	0.812	23	1.5e‐05
Dose on inhibition potencyi	βIC50_tDOSE	−0.989	22	7.4e‐06
PLT on maximum inhibitionj	βImax_tPLT	0.17	35	.0038
Observational error
Constant PK error	a1 (μg/mL)	0.0869	16
Proportional coefficient of PK error model	b1 (‐)	0.0514	9.4
Constant PD error	a2 (‐)	0.778	3.7

BW indicates body weight; CRE, creatinine concentration; PD, pharmacodynamic; PK, pharmacokinetic; PLT, platelet count; RSE, relative standard error.

^a%CV computed as 100*sqrt(exp(SD^2)‐1.

^bStochastic approximation used for estimation of RSE.

^cCovariate effect: $C{l}_{pop}·{(\frac{AGE}{50})}^{{\beta }_{Cl\_tAGE}}$.

^dCovariate effect: $C{l}_{pop}·{(\frac{BW}{70})}^{{\beta }_{Cl\_tBW}}$.

^eCovariate effect: $C{l}_{pop}·{(\frac{CRE}{0.79})}^{{\beta }_{Cl\_tCRE}}$.

^fCovariate effect: $V{1}_{pop}·{(\frac{BW}{70})}^{{\beta }_{V1\_tBW}}$.

^gCovariate effect: $Q_{pop}·{(\frac{AGE}{50})}^{{\beta }_{Q\_tAGE}}$.

^hCovariate effect: $Q_{pop}·{(\frac{BW}{70})}^{{\beta }_{Q\_tBW}}$.

ⁱCovariate effect: $IC{50}_{pop}·{(\frac{DOSE}{500})}^{{\beta }_{IC50\_tDOSE}}$.

^jCovariate effect: $Ima{x}_{pop}·{(\frac{PLT}{220})}^{{\beta }_{Ima{x}_{tPLT}}}$.