Table 2.

Population pharmacokinetic models established using non-linear mixed-effect modeling

Study, year	References	No. of subjects	Age, years (range)	Body weight, kg (range)	Endogenous baselinea (%)	Sampling: sparse/richb	OSA/CSA	Endogenous baseline correctionc	Products	Software
Prophylactic standard half-life FVIII models
Bolon-Lager et al., 2007	[82]	33	7–77	21–120	0.1–19	Rich and sparse	OSA	NA	NA	NONMEM v5.1.1
Björkman et al., 2009	[48]	34	3–66	17–78	< 1–5	Sparse	CSA	No subtraction	Helixate, Kogenate, Octonativ-M, Immunate, Monoclate, Monoclate-P, Recombinate	NONMEM v6
Karafoulidou et al., 2009	[45]	28	18–70	54–104	< 1–17	Sparse	OSA/CSA	Multiplier	Refacto	NONMEM v6
Björkman et al., 2012	[14]	152	1.1–66	11–108	< 2	Rich and sparse	OSA	Proportion	Advate	SAS v9.13
Jiménez-Yuste et al., 2015	[50]	76	1–60	12.0–107	≤ 1	Rich	OSA	NA	NovoEight	NONMEM v7.1.2
Abrantes et al., 2017	[49]	754	0.0027–73	3–134	< 1–40	Rich and sparse	OSA/CSA	Estimated	Xyntha/Refacto AF	NONMEM v7.3
Garmann et al., 2017	[83]	183	1–61	11–124	< 1	Semi-sparse	CSA	NA	Kovaltry	NONMEM v7.2
Zhang et al., 2016	[84]	130	1–65	10–106	< 1	Rich and sparse	CSA	Estimated	Afstyla	NONMEM v7.2
Stass et al., 2006	[36]	19	4.3–18	21–96	< 1	Rich	OSA	Estimated	Kogenate-FS	NONMEM v5.1.1
Delavenne et al., 2019	[47]	95	2–67	13–140	< 1	Rich	OSA/CSA	NA	Nuwiq	MONOLIX v4.3.2
Shah et al., 2017	[85]	18	19–64	55–99	< 1	Rich	CSA	NA	Kovaltry	NONMEM v7.2
Abrantes et al., 2019	[86]	183	1–61	11.0–124	< 1	Rich	CSA	NA	Kovaltry	NONMEM v7.4.3
Chelle et al., 2019	[87]	92	1–72	9.68–119	< 1–17	Sparse	OSA	Subtraction	Fandhi and Alphanate	NONMEM v7.3
McEneny-King et al., 2019	[88]	310	1–67	10.6–132.5	< 1–5	Rich	OSA	Subtraction	Advate, Emoclot, Kogenate, Kovaltry, NovoEight, Octanate, Refacto AF	NONMEM v7.3
Allard et al., 2020	[89]	258	3–77	15.1–130	< 1	Rich and sparse	OSA	Estimated	Factane, Advate, Kogenate, Kovaltryd, Afstylad, Refacto, NovoEight, Eloctad	Monolix 2019R1 SAEM
Tiede et al., 2020	[90]	187	24 (7.88)e	71.8 (12.4)e	≤ 1	Sparse	OSA	NA	NovoEight	NONMEM v7.1
Prophylactic standard half-life FIX models
Björkman et al., 2012	[15]	26	16–65	47–115	< 2	Rich	OSA	Subtraction	Alphanine, Mononine, Preconativ, Nanotiv, Replenine-VF	NONMEM v6
Björkman et al., 2013	[61]	56	4–56	18–133	< 1–5	Rich	OSA	Subtraction	BeneFix	NONMEM v6
Brekkan et al., 2016	[62]	34	16.2–59g	40.1–93.1g	< 2	Rich and sparse	OSA	Estimated	Alphanine, Mononine, Preconativ, Nanotiv, Factor IX Grifols, Immunine, Octanine	NONMEM v7.3
Suzuki et al., 2016	[63]	201	0–69.2	1.3–172.5	1–2	Rich and sparse	OSA	Subtraction	BeneFix	NONMEM v7.2
Prophylactic extended half-life FVIII model
Nestorov et al., 2014	[52]	180	12– 65	42–127.4	< 1	Sparse	OSA	Residual decay	Eloctate	NONMEM v7.2
Shah et al., 2019	[53]	35	22–65	NA	< 1	Rich	OSA	NA	BAY 94-9027 and rFVIIIFc	NONMEM v7.4.1
Chelle et al., 2020	[54]	154	3.4–72.8	14.8–150	< 1 to NA	Sparse	OSA/CSA	Subtraction	Adynovate	NONMEM v7.3
Prophylactic extended half-life FIX models
Collins et al., 2012	[67]	15	21–55	NA	≤ 2	Sparse	OSA	Set to zero	Refixia	NONMEM v6.1.2
Diao et al., 2014	[68]	135	12.1–76.8	45–186.7	≤ 2	Rich and sparse	OSA	Residual decay	Alprolix	NONMEM v7.1
Zhang et al., 2016	[66]	104	1–61	11–132.3	< 2	Rich	OSA	Estimated	Idelvion	NONMEM v7.3
DDAVP model
Schütte et al., 2018	[59]	128	7–75	26–120	4–18f	Sparse	OSA	Estimated	DDAVP	NONMEM v7.1.2
Peri-operative standard half-life FVIII models
Hazendonk et al., 2016	[57]	119	0.2–78	5–111	≤ 5	Sparse	OSA	Subtraction	Kogenate FS, Helixate FS, Advate, Recombinate, Refacto AF, Aafact, Hemofil M	NONMEM v7.1.2
Peri-operative standard half-life FIX models
Preijers et al., 2018	[69]	118	0.2–90	5.3–132	< 1–5	Sparse	OSA	Subtraction	AlphaNine, Haemonine, Mononine, Replenine, Nonafact, BeneFix	NONMEM v7.3

CSA chromogenic substrate assay, DDAVP d-amino d-arginine vasopressin, FIX factor IX, FVIII factor VIII, NA not available, No. number, OSA one-stage assay, Ref. reference, v version

^aFor the endogenous baseline, 1% corresponds to 0.01 IU mL⁻¹

^bSparse and rich sampling were defined as having less than 10 or more than 9 samples, respectively; semi-sparse was defined as the application of both sparse and rich sampling frequencies

^cSubtraction: the endogenous measured baseline level was subtracted from the levels measured following dose administration; a proportional correction was defined as all measured levels were multiplied by 1 minus the factor of pre-infusion level divided by the highest measured level; the multiplier correction method consisted of the observed endogenous baseline that was multiplied by an estimated parameter value from the structural model; in residual decay correction, the corrected factor levels are used for modeling and calculated using the following equation: observed level − baseline level − (pre-dose level − baseline level) × exp(− lambda × time) in which lambda is the terminal first-order decay rate obtained from non-compartmental pharmacokinetics of the raw (uncorrected) observed levels [52]

^dTechnically, these are extended half-life FVIII products. However, most of the patients from this study used short half-life products

^eMedian (standard deviation)

^fInter-quartile range

^gBased on a 95% confidence interval, as calculated from the presented standard deviation