Adalimumab

Biological Activity

In vitro: Adalimumab blocks the interaction of TNF with the p55 and p75 cell surface TNF receptors, thereby neutralising the activity of this cytokine. Through its anti-TNF actions, adalimumab reduces concentrations of matrix metalloproteases (MMP-1 and -3) and other markers of cartilage and synovium turnover, reduces of matrix metalloproteases (MMP-1 and -3) and other markers of cartilage and synovium turnover, and reduces concentrations of acute phase reactants of inflammation (C-reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-1β mRNA, IL-1 receptor antagonist, IL-6).

In vivo: Adalimumab is safe and well tolerated. In healthy adults, the average absolute bioavailability of adalimumab 40 mg administered subcutaneously (s.c.) is 64%. Concentrations in the synovial fluid are 31-96% of those of the serum. Maximum plasma concentrations occur at 131 (± 56) h, and the mean half-life is ∼ 2 weeks (range, 10-20 days). Adalimumab treatment attenuates the Ovalbumin(OVA)-induced increase in serum IgE, TH2 and TH1 derived inflammatory cytokines (IL-4 and IFN-γ, respectively) in bronchoalveolar lavage (BAL) fluid, suppresses recruitment of inflammatory cells in BAL fluid and lung, and inhibits BAL fluid neutrophilia. It also ameliorates goblet cell metaplasia and bronchial fibrosis.

Protocol

Cell Experiment
Cell lines	Caco-2 BBE cells
Preparation method	T-84 and Caco-2 cells grown on transwell inserts were primed with IFN-γ (2.5 and 5 ng/ml, respectively) for 24 h followed by treatment with TNF-α (5 ng/ml), adalimumab (10 μg/ ml), or both.
Concentrations	10 μg/ ml
Incubation time	24 h

Animal Experiment
Animal models	CD1 mice
Formulation	PBS
Dosages	1 ml/100 g b.wt
Administration	i.p.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

Species	Mouse	Rat	Rabbit	Guinea pig	Hamster	Dog
Weight (kg)	0.02	0.15	1.8	0.4	0.08	10
Body Surface Area (m2)	0.007	0.025	0.15	0.05	0.02	0.5
Km factor	3	6	12	8	5	20

Animal A (mg/kg) = Animal B (mg/kg) multiplied by	Animal B Km
	Animal A Km

For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the K_m factor for a mouse and then divide by the K_m factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.

Chemical Information

References

[1] Jacks SM, et al. J Am Acad Dermatol. Rapid deterioration in a patient with primary aggressive cutaneous epidermotropic CD8+ cytotoxic T-cell ('Berti') lymphoma after administration of adalimumab.

[2] Fischer A, et al. Am J Physiol Gastrointest Liver Physiol. Adalimumab prevents barrier dysfunction and antagonizes distinct effects of TNF-α on tight junction proteins and signaling pathways in intestinal epithelial cells.