A minimal physiologically based pharmacokinetic model to characterize colon TNF suppression and treatment effects of an anti-TNF monoclonal antibody in a mouse inflammatory bowel disease model

Figures & data

Table 2. Parameter estimates of the mPBPK model.

Parameter	Unit	Definition	Estimate	RSE (%)
$V_s$^a	mL	Serum volume	0.85 (fixed)	-
$ISF$^a	mL	Volume of total interstitial space fluid	4.35 (fixed)	-
$V_{lymph}$^a	mL	Lymph volume	1.60 (fixed)	-
$L$^a	mL/hr	Total Lymph flow rate	0.12 (fixed)	-
${\sigma }_L$^a	-	Reflection coefficient for lymph	0.20 (fixed)	-
$V_{max,nonIBD}$	pmol/hr	Antibody elimination rate capacity in serum for non-IBD mice	3.39	13.5
$V_{max,IBD}$	pmol/hr	Antibody elimination rate capacity in serum for IBD mice	4.53	43.7
$K_m$	nM	Apparent affinity for antibody elimination	221	18.9
${\sigma }_{tight}$	-	Reflection coefficient for tight tissues	0.955	1.37
${\sigma }_{leaky}$	-	Reflection coefficient for leaky tissues	0.201	21.5
$k_a$	hr^−Citation1	First-order rate constant for i.p. absorption	0.104	71.8
${\sigma }_{colon,nonIBD}$	-	Reflection coefficient for colon in non-IBD mice	0.978	1.57
${\sigma }_{colon,IBD}$	-	Reflection coefficient for colon in IBD mice	0.391	16.9
$C{L}_{colon,nonIBD}$	mL/hr	Clearance of antibody from colon in non-IBD mice	0.000106	59.6
$C{L}_{colon,IBD}$	mL/hr	Clearance of antibody from colon in IBD mice	0.00217	20.1
$V_{colon,nonIBD}$^b	mL	ISF volume of colon in non-IBD mice	0.026 (fixed)	-
$V_{colon,IBD}$^b	mL	ISF volume of colon in IBD mice	0.039 (fixed)	-
$L_{colon,nonIBD}$^b	mL/hr	Lymph flow rate of colon in non-IBD mice	0.00137 (fixed)	-
$L_{colon,IBD}$^b	mL/hr	Lymph flow rate of colon in IBD mice	0.00205 (fixed)	-
$k_{deg}$	hr^−Citation1	Degradation/Turnover rate constant for TNF in serum	12.8	17.9
$k_{int}$	hr^−Citation1	Internalization (elimination) rate constant for CNTO5048−TNF complex in serum	0.866	0.554
$R_0$^c	pM	Baseline concentration of TNF in serum in IBD mice	2.22 (fixed)
$K_{ss}$	nM	Quasi-equilibrium binding constant for CNTO5048 and TNF in serum	1.88	34.1
$k_{deg,colon}$	hr^−Citation1	Degradation rate constant for TNF in colon ISF	1.17	33.1
$k_{int,colon}$	hr^−Citation1	Internalization rate constant for CNTO5048−TNF complex in colon ISF	0.0492	50.8
$R_{0,colon}$^c,d	pM	Baseline concentration of TNF in colon ISF in IBD mice	420 (fixed)
$K_{ss,colon}$	nM	Quasi-equilibrium binding constant for CNTO5048 and TNF in colon ISF	1.32	0.09

^aParameters values from the following references.^12,15,16

^bParameters from the following references.^16–19 Refer to the method section for the formula of calculation.

^cThe baseline concentration of TNFα in colon ISF was calculated from the concentration in colon tissue homogenate and in serum using the formulas: $\frac{1}{Rati{o}_{ISF}}\cdot \left(TN{F}_{colon}-Rati{o}_s\cdot TN{F}_s\right)$

Table 1. Study design showing treatment groups and dosing regimen.

Study Group	N	Treatment	Dosing Regimen
1	30	Non-IBD mice– CNTO 5048	1 × 10 mg/kg IV loading dose (day 21)
2	18	IBD mice – Isotype control CNTO 1322	1 × 10 mg/kg IV loading dose (day 21) + 9 × 0.3 mg/kg Q3D IP maintenance dose (days 24–48)
3	30	IBD mice – CNTO 5048	1 × 10 mg/kg IV loading dose (day 21)
4	22	IBD mice – CNTO 5048	1 × 10 mg/kg IV loading dose (day 21) + 9 × 0.3 mg/kg Q3D IP maintenance dose (days 24–48)
5	22	IBD mice – CNTO 5048	1 × 1.4 mg/kg IV dose (day 21) + 9 × 1.4 mg/kg Q3D IP maintenance dose (days 24–48)
6	22	IBD mice – CNTO 5048	1 × 0.3 mg/kg IV dose (day 21) + 9 × 0.3 mg/kg Q3D IP maintenance dose (days 24–48)

Figure 1. Summary of representative experimental observations: (a) percent change (mean ± standard error of the mean, SEM) in body weight (BW) from baseline (day 21); (b) full colon histopathology summed score (mean ± SEM), day 30 on the left and day 49 on the right for each group (i.e., 9 and 28 days after the first dose). G1: Non-IBD mice (without CD45RB^high T cell transfer), CNTO 5048 (10 mg/kg); G2: IBD mice (+ CD45RB^high T cell transfer), isotype control (1 × 10 + 9 × 0.3 mg/kg); G3: IBD mice, CNTO 5048 (1 × 10 mg/kg); G4: IBD mice, CNTO 5048 (1 × 10 + 9 × 0.3 mg/kg); G5: IBD mice, CNTO 5048 (10 × 1.4 mg/kg); G6: IBD mice, CNTO 5048 (10 × 0.3 mg/kg).

Figure 2. Observed percent (%) change (mean ± SD) from the mean TNF in the control group (G2) for serum (a) or colon free TNF in Groups 3–6 on Day 22, 30 and 49 (i.e., 1, 9, and 28 days after the first dose), and correlations between individual free TNF in serum (c) or colon (d) versus full colon histopathology summed score or neutrophil score on Day 30 and 49 (i.e., 9 and 28 days after the first dose). All BLQ TNF values were plotted at ½ of LLOQ.

Figure 3. Scheme of mPBPK/TE model for the CNTO 5048 interaction with TNF in serum and colon. (a) Basic second-generation minimal PBPK was used to characterize serum CNTO 5048 pharmacokinetics; (b) Colon compartments were incorporated into the basic mPBPK model to characterize colon CNTO 5048 distribution; (c) TMDD in the serum compartment was integrated into Model B to characterize the free TNF profile in serum; and (d) TMDD in the colon compartment was added to Model C to characterize the free TNF dynamics in colon.

Figure 4. Model fitting for (a) CNTO 5048 in serum; (b) CNTO 5048 in colon homogenate Symbols represent the observed data (mean±SD); solid black lines and blue dashed lines represent model fitting results. The LLOQ of CNTO 5048 in serum and colon tissue were 0.533 and 2.67 nM, respectively. LLOQ for colon shown in black dotted lines, while serum mean concentrations are above LLOQ for all groups and therefore the LLOQ for serum is not shown.

Figure 5. Model fitting for (a) free TNF in serum; (b) free TNF in colon homogenate. Symbols represent the observed data (mean±SD); lines represent model fitting results. The LLOQ of TNF in serum and colon tissue were 1.12 and 2.81 pM, respectively (shown in dotted lines).

Table

Antidrug antibodies	ADAs
Below the limit of quantification	BLQ
Body weight	BW
Collagen-induced arthritis	CIA
Crohn’s disease	CD
Electrochemiluminescent	ECL
Half-life	t1/2
Inflammatory bowel disease	IBD
Interstitial fluid	ISF
Intravenous	IV
Intraperitoneal	IP
Lower limit of quantification	LLOQ
Membrane TNF	mTNF
Minimal physiologically based PK	mPBPK
Model; monoclonal antibody	mAb
Pharmacokinetics	PK
Pharmacokinetic/pharmacodynamic	PK/PD
Standard deviation	SD
Target engagement	TE
Target-mediated drug disposition	TMDD
Tumor necrosis factor	TNF
Ulcerative colitis	UC

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