. 2022 Jan 18;11(1):353–371. doi: 10.1007/s40120-021-00316-6

Table 2.

Final model parameter estimates

Theta/parameter		Estimate	ASE	% RSE	95% CI	Units	Shrinkage (%)^a
1	CL_MMF	13.5	0.422	3.1	(12.7–14.4)	L/h
2	Vc	30.4	0.386	1.3	(29.7–31.2)	L
3	Ka_MMF	5.04	0.126	2.5	(4.79–5.28)	h⁻¹
6	Ka_HES	3.24	0.0774	2.4	(3.09–3.40)	h⁻¹
7	CL_HES	1.49	0.0172	1.2	(1.46–1.53)	L/h
8	F4	0.6 FIXED
9	F1	0.162	0.00506	3.1	(0.152–0.172)
10	WT on Vc	0.878	0.0697	7.9	(0.742–1.01)
11	PM dosing on Ka_MMF	− 0.592 FIXED
12	LOW on Ka_MMF	− 0.368 FIXED
13	MED on Ka_MMF	− 0.512 FIXED
14	HI on Ka_MMF	− 0.666 FIXED
15	UNK on Ka_MMF	0.843	0.155	18.4	(0.539–1.15)
16	LOW on F1	− 0.296 FIXED
17	LOW on F1	–0.301 FIXED
18	HI on F1	− 0.131 FIXED
19	PM dosing on Ka_HES	− 0.267 FIXED
20	LOW on Ka_HES	− 0.335 FIXED
21	MED on Ka_HES	− 0.492 FIXED
22	HI on Ka_HES	− 0.621 FIXED
23	UNK on Ka_HES	0.399	0.0964	24.1	(0.210–0.588)
24	HES ALAG4 PM dosing	1.96 FIXED				h
25	HES ALAG4 LOW	0.421 FIXED				h
26	eGFR on CL_HES	0.547	0.0323	5.9	(0.484–0.611)
27	eGFR on CL_HES	0.831	0.0984	11.8	(0.638–1.02)
28	WT on CL_HES	0.335	0.0601	18.0	(0.217–0.453)
35	PTST on CL_MMF	− 0.284	0.0405	14.2	(− 0.363 to − 0.204)
36	PTST on CL_HES	− 0.122	0.0296	24.1	(− 0.180 to − 0.0642)
Residual variability
4	RE MMF (AM dose, fasted)	89.5	1.59	1.8	(86.4–92.6)	%
5	RE HES (AM dose, fasted)	25.2	0.335	1.3	(24.5–25.9)	%
29	RE MMF (AM dose, fed)^b	103	2.08	2.0	(98.6–107)	%
30	RE MMF (PM dose, fasted)	112	3.77	3.4	(105–120)	%
31	RE MMF (UNK)	102	3.37	3.3	(95.4–109)	%
32	RE HES (AM dose, fed)^b	46.8	0.744	1.6	(45.4–48.3)	%
33	RE HES (PM dose, fasted)	18.4	0.407	2.2	(17.6–19.2)	%
34	RE HES (UNK)	37.2	1.09	2.9	(35.1–39.4)	%
IIV
1	ETA1–CL_MMF	23.7			(20.3–26.7)	%CV	30.0
2	ETA2–Vc	19.8			(17.3–22.0)	%CV	19.4
4	ETA4–CL_HES	18.0			(16.4–19.6)	%CV	14.4
5	ETA4–CL_HES	37.0			(33.3–40.4)	%CV	15.0
8	ETA8–Ka_HES	42.4			(39.1–45.5)	%CV	4.3
OFV		− 3227.48

ALAG4 lag time for HES absorption with a low-fat meal, AM morning dose, ASE asymptotic standard error, CI confidence interval, CL_HES clearance of HES, CL_MMF clearance of MMF, %CV percentage coefficient of variation, eGFR estimated glomerular filtration rate, F1 bioavailability of MMF, F4 bioavailability of HES, HES 2-hydroxyethyl succinimide, HI administration with high-fat meal, IIV interindividual variability, Ka_HES absorption rate constant of HES, Ka_MMF absorption rate constant of MMF, LOW administration with low-fat meal, MED administration with medium-fat meal, MMF monomethyl fumarate, OFV objective function value, PM evening dose, PTST patient status, RE residual error, RSE relative standard error, UNK administration with or without meal of unknown fat content (only in patients), Vc central volume of distribution, WT body weight

Covariate parameters fixed to values estimated in the base model: low fat, medium fat, high fat, and PM dose on Ka_MMF; low fat, medium fat, high fat on F1; low fat, medium fat, high fat, and PM dose on Ka_HES; HES ALAG4 with PM dose; HES ALAG4 with low fat

Covariate parameters estimated in final model: UNK on Ka_MMF, UNK on Ka_HES, WT on CL_MMF, WT on CL_HES, WT on Vc, PTST on CL_MMF, PTST on CL_HES, eGFR on CL_HES

Model equations:

${CL}_{MMF, i} = 13.5 \cdot {(\frac{WT}{78})}^{0.831} \cdot (1 + PTST \cdot (- 0.284)) \cdot exp (η_{i}^{{CL}_{MMF}})$

${CL}_{HES, i} = 1.49 \cdot {(\frac{eGFR}{111.9})}^{0.547} \cdot {(\frac{WT}{78})}^{0.335} \cdot (1 + PTST \cdot (- 0.122)) \cdot exp (η_{i}^{{CL}_{HES}})$

$V c_{i} = 30.4 \cdot {(\frac{WT}{78})}^{0.878} \cdot exp (η_{i}^{Vc})$

${Ka}_{MMF} = 5.04 \cdot (1 + PM \cdot (- 0.592)) \cdot (1 + LOW \cdot (- 0.368)) \cdot (1 + MED \cdot (- 0.512)) \cdot (1 + HI \cdot (- 0.666)) \cdot (1 + UNK \cdot 0.843) \cdot exp (η_{i}^{{KA}_{MMF}})$

${Ka}_{HES, i} = 3.24 \cdot (1 + PM \cdot (- 0.267)) \cdot (1 + LOW \cdot (- 0.335)) \cdot (1 + MED \cdot (- 0.492)) \cdot (1 + HI \cdot (- 0.621)) \cdot (1 + UNK \cdot 0.399) \cdot exp (η_{i}^{{KA}_{HES}})$

$F 1 = 0.162 \cdot (1 + LOW \cdot (- 0.296)) \cdot (1 + MED \cdot (- 0.301)) \cdot (1 + HI \cdot (- 0.131))$

^aShrinkage estimate for epsilon was 5.6%

^bFed refers to drug administration with a meal of low, medium, or high fat content