The minipig as an alternative non-rodent model for immunogenicity testing using the TNFα blockers adalimumab and infliximab

Figures & data

Table 1. Relative organ weights after adalimumab or infliximab treatment.

Compound	Dose (mg/kg)	Terminal body weight (kg)	Kidney	Thymus	Spleen	Liver	Lungs
Adalimumab	0.1	12.45 ± 1.9	3.64 ± 0.56	0.70 ± 0.32	1.35 ± 0.25	17.4 ± 0.2	6.03 ± 0.67
Adalimumab	1	12.73 ± 2.5	3.55 ± 0.57	0.60 ± 0.22	1.48 ± 0.22	16.8 ± 0.8	5.71 ± 0.39
Adalimumab	5	12.28 ± 2.1	3.97 ± 0.13	0.69 ± 0.14	1.60 ± 0.32	17.4 ± 2.1	5.73 ± 0.47
Infliximab	5	11.85 ± 1.8	4.14 ± 0.55	0.68 ± 0.34	1.37 ± 0.21	17.7 ± 1.2	5.65 ± 0.43

Organ weights are expressed in g/kg of the terminal body weight. Values shown are group means ± SD.

Statistical test ANOVA: *p < 0.05 versus low-dose (0.1 mg/kg) adalimumab group.

Figure 1. Adalimumab levels in the plasma of individual minipigs during time. Minipigs were treated SC every other week for 8 weeks with (a) 0.1, (b) 1.0, or (c) 5.0 mg adalimumab/kg.

Figure 2. Anti-adalimumab antibody (AAA) levels in serum of individual minipigs. Minipigs were treated SC every other week for 8 weeks with (a) 0.1, (b) 1.0, or (c) 5.0 mg adalimumab/kg. Anti-adalimumab levels were followed during time.

Figure 3. Infliximab levels in individual minipigs. Minipigs were treated SC every other week for 8 weeks with 5.0 mg infliximab/kg. Infliximab and anti-infliximab levels were followed over time. Arrows indicate treatment days. No anti-infliximab antibodies were observed during the study.

Figure 4. Plasma concentration vs time curves for individual minipigs receiving intramuscular dose of (a) 0.1, (b) 1.0, or (c) 5.0 mg adalimumab/kg after the first (Day 0) and final (Day 56) dose sessions. Sessions are indicated by arrows above the figure. Results presented here were used for PK analysis.

Table 2. Pharmacokinetic parameters for adalimumab and infliximab following SC dosing to female Göttingen minipigs every other week for 8 weeks (n = 4 per group).

	Adalimumab
Pharmacokinetic	Day 0			Day 56			Infliximab
parameter	0.1 mg/kg	1 mg/kg	5 mg/kg	0.1 mg/kg	1 mg/kg	5 mg/kg	Day 0	Day 56
Cmax (µg.ml)	1.2 ± 0.1	7.9 ± 1.6	42.5 ± 5.8	All plasma values < LLOQ	For n = 3,  all plasma values < LLOQ^a	For n = 3,  all plasma values < LLOQ^b	32.5 ± 7.9	57.4 ± 17.8
Tmax (days)	3.0 ± 1.0	7.5 ± 1.0	6.5 ± 1.0				2.5 ± 1.0	2.5 ± 1
Half-life (days)	0.7 ± 0.1	2.9 ± 3.6	0.7 ± 0.3				12.8 ± 4.1	19.6 ± 2.0
AUC(0–∞) (day*μg/ml)	8.5 ± 1.3	66.2 ± 25.9	357 ± 23				661 ± 129	1527 ± 472
Total clearance (L/kg*day)	0.012 ± 0.001	0.016 ± 0.007	0.014 ± 0.000				0.008 ± 0.002	0.004 ± 0.001
MRT (day)	4.9 ± 0.4	6.0 ± 1.1	6.0 ± 0.5				6.9 ± 0.2	11.8 ± 0.3

LLOQ, lower limit of quantification.

^aFor n = 3, all plasma values were < LOQ and no PK parameters could be calculated. For the remaining animal of this group, PK parameters were C_max = 18.8 µg/ml, T_max = 4 days, half-life = 6.2 days, AUC_(0-∞) = 295 day*μg/ml, total clearance = 0.003 L/kg*day, and MRT = 9.9 days.

^bFor n = 3, all plasma values were < LOQ and no PK parameters could be calculated. For the remaining animal of this group the PK parameters were C_max = 25.3 µg/ml, T_max = 2 days, half-life = 1.6 days, AUC_(0–∞) = 120 day*μg/ml, total clearance = 0.042 L/kg*day, and MRT = 4.1 days.