Randomized clinical trial: pharmacokinetics and safety of multimatrix mesalamine for treatment of pediatric ulcerative colitis

Figures & data

Table 1 Demographic data and baseline characteristics

	Multimatrix mesalamine
	30 mg/kg/day, n=21	60 mg/kg/day, n=22	100 mg/kg/day, n=9	All doses, N=52
Mean age (SD), years	14.0 (2.88)	13.9 (2.59)	10.6 (3.28)	13.3 (3.06)
Sex, n (%)
Male	7 (33.3)	11 (50.0)	4 (44.4)	22 (42.3)
Female	14 (66.7)	11 (50.0)	5 (55.6)	30 (57.7)
Ethnicity, n (%)
Not Hispanic or Latino	21 (100.0)	21 (95.5)	9 (100.0)	51 (98.1)
Hispanic or Latino	0	1 (4.5)	0	1 (1.9)
Race, n (%)
White	20 (95.2)	22 (100.0)	9 (100.0)	51 (98.1)
Asian	1 (4.8)	0	0	1 (1.9)
Mean BMI (SD),a kg/m^2	20.71 (3.365)	19.16 (3.123)	17.15 (2.330)	19.44 (3.308)
BMI category,b n (%)
Healthy weight	17 (81.0)	19 (86.4)	9 (100.0)	45 (86.5)
Obese	2 (9.5)	1 (4.5)	0	3 (5.8)
Overweight	2 (9.5)	0	0	2 (3.8)
Underweight	0	2 (9.1)	0	2 (3.8)
Median time since diagnosis of UC (range),c years	2.14 (0.3–9.4)	2.24 (0.2–9.6)	1.66 (0.3–8.2)	1.83 (0.2–9.6)

Notes:

a Calculated as screening weight (kg)/height (m²).

b Categories derived using the CDC BMI percentiles for children and adolescents: underweight=BMI <5th percentile; healthy weight = BMI 5th percentile to <85th percentile; overweight = BMI 85th percentile to <95th percentile; obese = BMI ≥95th percentile.

c Calculated as “date of diagnosis – date of first dose/365.25”.

Abbreviations: BMI, body mass index; CDC, Centers for Disease Control and Prevention; SD, standard deviation; UC, ulcerative colitis.

Figure 1 Subject flow diagram.

Note: ^aIncluded blood and urine collection.

Table 2 Summary of pharmacokinetic parameters of 5-ASA and Ac-5-ASA in children and adolescents

	Multimatrix mesalamine
	30 mg/kg/day, n=21	60 mg/kg/day, n=22	100 mg/kg/day, n=9
5-ASA
AUCss (µg×h/L), mean (SD)	21,411 (11,081)	46,173 (22,864)	49,213 (17,664)
Cmax,ss (µg/L), mean (SD)	1,884 (1,018)	3,825 (1,979)	4,314 (2,602)
tmax (h), median (min, max)	6.00 (0.00, 24.0)	8.98 (0.00, 24.0)	1.98 (0.00, 24.0)
Xu0–24h (mg), mean (SD)	162 (132)	298 (221)	235 (121)
CLR (L/h), mean (SD)	6.48 (2.99)	5.94 (2.95)	4.95 (2.07)
% dose absorbed, mean (SD)	29.4a (14.5)	27.0 (13.5)	22.1 (13.6)
Ac-5-ASA
AUCss (µg×h/L), mean (SD)	30,942 (13,743)	58,119 (22,729)	63,067 (21,752)
Cmax,ss (µg/L), mean (SD)	2,396 (1,217)	4,113 (1,641)	4,968 (2,911)
tmax (h), median (min, max)	9.00 (0.00, 24.0)	7.48 (0.00, 24.0)	1.98 (0.00, 24.0)
Xu0–24h (mg), mean (SD)	532 (411)	708 (341)	593 (251)
CLR (L/h), mean (SD)	16.2 (6.72)	12.2 (4.43)	10.0 (4.36)
MRAUCss, mean (SD)	1.56 (0.422)	1.34 (0.244)	1.31 (0.219)
MRCmax,ss, mean (SD)	1.37 (0.409)	1.15 (0.247)	1.18 (0.223)

Notes:

a n=20; exclusion of outlier from summary statistics.

Abbreviations: 5-ASA, 5-aminosalicylic acid; Ac-5-ASA, acetyl-5-aminosalicylic acid; AUC_ss, area under the curve for the defined interval between doses (tau = 24 h); SD, standard deviation; C_max,ss, maximum concentration occurring at t_max; t_max, time of maximum observed concentration sampled during a dosing interval; Xu_0–24h, cumulative amount recovered in urine in the time interval 0–24 hours; CL_R, clearance of a substance from the blood by the kidneys; MR_AUCss, metabolic ratio (Ac-5-ASA:5-ASA) calculated using the AUC_ss; MR_Cmax,ss, metabolic ratio (Ac-5-ASA:5-ASA) calculated using the C_max,ss; min, minimum; max, maximum.

Figure 2 Mean (SD) plasma concentration–time profiles for (A) 5-ASA and (B) Ac-5-ASA in children and adolescents by treatment group.

Abbreviations: 5-ASA, 5-aminosalicylic acid; Ac-5-ASA, acetyl-5-aminosalicylic acid; SD, standard deviation.

Figure 3 Box and whisker plots of simulated 5-ASA and Ac-5-ASA steady-state AUC in both child/adolescent and adult populations for low-dose (A [5-ASA] and C [Ac-5-ASA]) and high-dose exposures (B [5-ASA] and D [Ac-5-ASA]).

Abbreviations: 5-ASA, 5-aminosalicylic acid; Ac-5-ASA, acetyl-5-aminosalicylic acid; AUC_ss, area under the curve for the defined interval between doses.

Table 3 Treatment-emergent adverse events

TEAE	Multimatrix mesalamine, n (%)
	30 mg/kg/day, n=21	60 mg/kg/day, n=22	100 mg/kg/day, n=9	All doses, N=52
Subjects with ≥1 TEAE	4 (19.0)	4 (18.2)	2 (22.2)	10 (19.2)
Gastrointestinal disorders	2 (9.5)	2 (9.1)	0	4 (7.7)
Abdominal pain	1 (4.8)	1 (4.5)	0	2 (3.8)
Musculoskeletal and connective tissue disorders	1 (4.8)	1 (4.5)	0	2 (3.8)
Musculoskeletal pain	1 (4.8)	1 (4.5)	0	2 (3.8)
Nervous system disorders	2 (9.5)	1 (4.5)	0	3 (5.8)
Headache	1 (4.8)	1 (4.5)	0	2 (3.8)

Abbreviation: TEAE, treatment-emergent adverse event.

Figure S1 Schematic of final population pharmacokinetic structural model.

Notes: Numbers on the top left-hand corner of the boxes represent the compartment numbers for the population pharmacokinetic model in the NONMEM code. Hence, the two depot compartments were denoted as depot 1 and depot 3.
Abbreviations: ALAG₁, absorption lag time from depot 1; 5-ASA, 5-aminosalicylic acid; Ac-5-ASA, acetyl-5-aminosalicylic acid; Ka₁, absorption rate constant from depot 1; F₁, fraction of dose absorbed from depot 1; Ka₃, absorption rate constant from depot 3; ALAG₃, absorption lag time from depot 3 in addition to the lag time from depot 1; CLM, metabolic clearance of 5-ASA; CLNRM, non-renal clearance of Ac-5-ASA; CLR, renal clearance of 5-ASA; CLRM, renal clearance of Ac-5-ASA.

Figure S2 Goodness-of-fit and diagnostic plots for the final model in children and adolescents: plasma 5-ASA.

Notes: The dashed line represents the local regression (Loess) smoothing line. (A) Observed versus population predicted concentration; (B) observed versus individual predicted concentration; (C) conditional weighted residual versus population predicted concentration; (D) conditional weighted residual versus time.
Abbreviation: 5-ASA, 5-aminosalicylic acid.

Figure S3 Goodness-of-fit and diagnostic plots for the final model in children and adolescents: plasma Ac-5-ASA.

Notes: The dashed line represents the local regression (Loess) smoothing line. (A) Observed versus population predicted concentration; (B) observed versus individual predicted concentration; (C) conditional weighted residual versus population predicted concentration; (D) conditional weighted residual versus time.
Abbreviation: Ac-5-ASA, acetyl-5-aminosalicylic acid.

Table S1 Assay performance of 5-ASA and Ac-5-ASA bioanalytical quality control samples in human plasma and urine

	5-ASA and Ac-5-ASA nominal concentration in plasma
	Low QC (12.5 ng/mL)	Mid QC (2,500 ng/mL)	High QC (4,000 ng/mL)
5-ASA
CV, %	7.6	5.3	5.0
Bias, %	0.0	1.6	−0.8
Ac-5-ASA
CV, %	10.1	4.8	7.7
Bias, %	2.4	5.2	3.3
	5-ASA and Ac-5-ASA nominal concentration in urine
	Low QC (15.0 µg/mL)	Mid QC (400 µg/mL)	High QC (800 µg/mL)
5-ASA
CV, %	6.7	11.7	8.2
Bias, %	−1.3	−5.5	−4.0
Ac-5-ASA
CV, %	10.2	9.0	7.6
Bias, %	4.0	1.0	−1.4

Abbreviations: Ac-5-ASA, acetyl-5-aminosalicylic acid; 5-ASA, 5-aminosalicylic acid; QC, quality control; CV, coefficient of variation.

Table S2 Parameter estimates of final 5-ASA/Ac-5-ASA population pharmacokinetic modela

Parameterb	NONMEM estimates
	Point estimate	%RSE	95% CI	CV%
CLR/F (L/h)	1.15	45.9	1.01–1.32	NA
CLM/F (L/h)	85.6	1.38	75.9–96.5	NA
Vc/F (L)	109	4.78	70.1–169	NA
CLRM/F (L/h)	2.54	6.34	2.27–2.86	NA
CLNRM/F (L/h)	74.4	1.31	66.7–83.1	NA
VcM/F (L)	7.10	7.55	5.31–9.49	NA
Ka1 (h^−1)	0.0334	7.26	0.0207–0.0539	NA
Ka3 (h^−1)	0.273	19.5	0.165–0.448	NA
ALAG1 (h)	5.10	5.34	4.31–6.05	NA
ALAG3 (h)	15.0	1.23	14.0–16.1	NA
F1	0.734	22.3	0.413–1.06	NA
CLR/F~WT	0.75 FIX	NA	NA	NA
CLM/F~WT	0.75 FIX	NA	NA	NA
Vc/F~WT	1 FIX	NA	NA	NA
CLRM/F~WT	0.75 FIX	NA	NA	NA
CLNRM/F~WT	0.75 FIX	NA	NA	NA
VcM/F~WT	1 FIX	NA	NA	NA
Inter-individual variability
ω^Citation2CLR	0.181	22.8	0.100–0.262	42.5c
ω^Citation2CLM	0.115	25.4	0.0578–0.172	33.9c
ω^Citation2Vc	0.412	60.0	−0.0721–0.896	64.2c
ω^Citation2CLRM	0.133	21.6	0.0767–0.189	36.5c
ω^Citation2CLNRM	0.0823	27.0	0.0388–0.126	28.7c
ω^Citation2VcM	0.0225 FIX	NA	NA	15.0c
ω^Citation2Ka1	2.72	21.6	1.57–3.87	165c
ω^Citation2Ka3	1.87	27.3	0.868–2.87	137c
ω^Citation2ALAG1	0.256	23.0	0.141–0.371	50.6c
ω^Citation2ALAG3	0.0225 FIX	NA	NA	15.0c
ω^Citation2F1	0.662	32.8	0.237–1.09	81.4c
Residual variability
σ^Citation2prop, plasma 5-ASA	0.136	7.65	0.116–0.156	36.9d
σ^Citation2prop, urine 5-ASA	0.00360 FIX	NA	NA	6.00d
σ^Citation2prop, plasma Ac-5-ASA	0.0829	7.45	0.0708–0.0950	28.8d
σ^Citation2prop, urine Ac-5-ASA	0.00360 FIX	NA	NA	6.00d

Notes:

a The reference population for the pharmacokinetic parameters CLR/F, CLM/F, Vc/F, CLRM/F, CLNRM/F, and VcM/F is an individual weighing 70 kg.

b Estimates and 95% CI back-transformed from log_e scale.

c ${\text{CV}}_{T{V}_P}=\sqrt{{\mathrm{e}}^{{\omega }_P^2}-1}$, when ω²_P exceeds 0.15.

d CV of proportional error ($={\left[{\sigma }_{\text{prop}}^2\right]}^{0.5}\times 100$=[σ²).

Abbreviations: 5-ASA, 5-aminosalicylic acid; Ac-5-ASA, acetyl-5-aminosalicylic acid; ALAG₁, absorption lag time from depot 1; ALAG₃, absorption lag time from depot 3 in addition to the lag time from depot 1; CI, 95% confidence interval on the parameter; CLM/F, apparent metabolic clearance of 5-ASA; CLNRM/F, apparent non-renal clearance of Ac-5-ASA; CLR/F, apparent renal clearance of 5-ASA; CLRM/F, apparent renal clearance of Ac-5-ASA; CV, coefficient of variation; F₁, fraction of dose absorbed from depot 1; FIX, fixed; Ka₁, absorption rate constant from depot 1; Ka₃, absorption rate constant from depot 3; NA, not applicable; %RSE, percent relative standard error of the estimate = standard error/parameter estimate ×100; Vc/F, apparent volume of central compartment of 5-ASA; VcM/F, apparent volume of central compartment of Ac-5-ASA; WT, body weight; ω²_CLR, variance of random effect of CLR/F; ω²_CL, variance of random effect of CLM/F; ω²_Vc, variance of random effect of Vc/F; ω²_CLRM, variance of random effect of CLRM/F; ω²_CLNR, variance of random effect of CLNRM/F; ω²_VcM, variance of random effect of VcM/F; ω²_Ka1, variance of random effect of Ka₁; ω²_Ka3, variance of random effect of Ka₃; ω²_ALAG1, variance of random effect of ALAG₁; ω²_ALAG3, variance of random effect of ALAG₃; ω²_F1, variance of random effect of F₁; σ²_prop, proportionalcomponent of the residual error model.

Table S3 Simulated steady-state 5-ASA exposures by weight and dose group

Weight group	Statistic	AUC (ng×h/mL)
		Low dose	High dose
18–23 kg (n=555)	Dose (mg)	900	1,800
	Mean	24,100	47,000
	SD	12,200	23,500
	CV%	50.6	50.0
	Median (95% PI)a	22,100 (906–96,900)	43,100 (3,880–249,000)
24–35 kg (n=849)	Dose (mg)	1,200	2,400
	Mean	24,600	49,600
	SD	12,200	24,800
	CV%	49.7	50.0
	Median (95% PI)a	22,800 (652–171,000)	45,700 (676–218,000)
36–50 kg (n=962)	Dose (mg)	1,800	3,600
	Mean	27,000	54,000
	SD	13,100	26,500
	CV%	48.3	49.1
	Median (95% PI)a	25,000 (361–120,000)	50,000 (812–263,000)
51–90 kg (n=1,354)	Dose (mg)	2,400	4,800
	Mean	29,700	59,700
	SD	14,300	28,400
	CV%	48.2	47.5
	Median (95% PI)a	27,500 (620–125,000)	55,500 (1,030–363,000)
Adults (n=28 for 2,400 mg; n=81 for 4,800 mg)	Dose (mg)	2,400	4,800
	Mean	22,300	39,900
	SD	13,700	24,400
	CV%	61.4	61.2
	Median (95% PI)a	16,900 (7,160–57,800)	36,800 (1,030–103,000)

Note:

a Summarized as median (2.5th percentile, 97.5th percentile).

Abbreviations: 5-ASA, 5-aminosalicylic acid; AUC, area under the curve; SD, standard deviation; CV, coefficient of variation; PI, percentile.

Table S4 Simulated steady-state Ac-5-ASA pharmacokinetic parameters by dose and age group

Weight group	Statistic	AUC (ng×h/mL)
		Low dose	High dose
18–23 kg (n=555)	Dose (mg)	900	1,800
	Mean	33,000	66,500
	SD	13,900	28,400
	CV%	42.1	42.7
	Median (95% PI)a	30,800 (2,290–114,000)	63,100 (8,440–199,000)
24–35 kg (n=849)	Dose (mg)	1,200	2,400
	Mean	34,200	68,300
	SD	15,000	30,500
	CV%	43.9	44.6
	Median (95% PI)a	32,400 (1,510–229,000)	64,700 (1,330–432,000)
36–50 kg (n=962)	Dose (mg)	1,800	3,600
	Mean	37,800	75,200
	SD	16,000	31,800
	CV%	42.5	42.3
	Median (95% PI)a	35,700 (684–225,000)	71,600 (1,760–383,000)
51–90 kg (n=1,354)	Dose (mg)	2,400	4,800
	Mean	41,200	82,900
	SD	17,300	34,300
	CV%	41.8	41.4
	Median (95% PI)a	39,200 (800–182,000)	78,900 (2,850–343,000)
Adults (n=28 for 2,400 mg; n=81 for 4,800 mg)	Dose (mg)	2,400	4,800
	Mean	41,300	60,800
	SD	16,100	27,100
	CV%	39.0	44.7
	Median (95% PI)a	38,200 (16,400–75,400)	59,700 (5,330–123,000)

Note:

a Summarized as median (2.5th percentile, 97.5th percentile).

Abbreviations: Ac-5-ASA, acetyl-5-aminosalicylic acid; AUC, area under the curve; SD, standard deviation; CV, coefficient of variation; PI, percentile.

IrvineEJQuality of life of patients with ulcerative colitis: past, present, and futureInflamm Bowel Dis200814455456517973299

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