Tralokinumab is a fully human IgG4 monoclonal antibody that specifically binds to the type 2 cytokine interleukin-13 (IL-13) and inhibits its interaction with the IL-13 receptors. Tralokinumab neutralises the biological activity of IL-13 by blocking its interaction with the IL-13Rα1/IL-4Rα receptor complex. IL-13 is a major driver of human type 2 inflammatory disease, such as atopic dermatitis and inhibiting the IL-13 pathway with tralokinumab in patients decreases many of the mediators of type 2 inflammation.
In clinical trials, treatment with tralokinumab resulted in reduced levels of type 2 inflammation biomarkers in both lesional skin (CCL17, CCL18 and CCL26) and in blood (CCL17, periostin and IgE). In lesional skin, treatment with tralokinumab led also to reductions in epidermal thickness and to increase in marker of epithelial barrier integrity (loricrin). Skin colonization with Staphylococcus aureus was reduced more than 10-fold in patients treated with tralokinumab. Treatment with tralokinumab also resulted in a shift of the stratum corneum lipid profile from a lesional to that of non-lesional skin, indicating improvement of the skin barrier integrity.
After subcutaneous (SC) dose of tralokinumab median time to maximum concentration in serum (tmax) were 5-8 days. The absolute bioavailability of tralokinumab following SC dosing was estimated by population PK analysis to be 76%. In a phase 1 trial (10 subjects per arm), bioavailability was estimated to be 62% for the 150 mg dose and 60% for the 300 mg dose.
Steady-state concentrations were achieved by week 16 following a 600 mg starting dose and 300 mg every other week. Across clinical studies (ECZTRA 1, ECZTRA 2 and ECZTRA 3), the mean ±SD steady-state trough concentration ranged from 98.0±41.1 mcg/mL to 101.4±42.7 mcg/mL for 300 mg dose administered every other week.
A volume of distribution for tralokinumab of approximately 4.2 L was estimated by population PK analysis.
Specific metabolism studies were not conducted because tralokinumab is a protein. Tralokinumab is expected to degrade to small peptides and individual amino acids.
Tralokinumab is eliminated through a non-saturable proteolytic pathway. Half-life is 22 days, consistent with the typical estimate for human IgG4 monoclonal antibodies targeting soluble cytokines. In ECZTRA 1, ECZTRA 2, and ECZTRA 3, clearance was estimated by population PK analysis to be 0.149 L/day. In phase 1 trials with IV dosing, clearance was estimated to be between 0.179 and 0.211 L/day.
Exposure of tralokinumab increases proportionally to the dose of tralokinumab between 150-600 mg.
Gender was not found to be associated with any clinically meaningful impact on the systemic exposure of tralokinumab determined by population PK analysis.
Age was not found to be associated with clinically relevant impact of systemic exposure of tralokinumab determined by population PK analysis. 109 subjects above 65 years were included in the analysis.
Race was not found to be associated with any clinically meaningful impact on the systemic exposure of tralokinumab by population PK analysis.
Tralokinumab, as a monoclonal antibody, is not expected to undergo significant hepatic elimination. No clinical studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of tralokinumab. Mild hepatic impairment was not found to affect the PK of tralokinumab determined by population PK analysis. Very limited data are available in patients with moderate or severe hepatic impairment.
Tralokinumab, as a monoclonal antibody, is not expected to undergo significant renal elimination. No clinical studies have been conducted to evaluate the effect of renal impairment on the pharmacokinetics of tralokinumab. Population PK analysis did not identify mild or moderate renal impairment as having a clinically meaningful influence on the systemic exposure of tralokinumab. Very limited data are available in patients with severe renal impairment.
Tralokinumab exposure (AUC) was lower in subjects with higher body weight.
Area under the curve (AUC) by weight:
| Weight (kg) | 75 | 100 | 120 | 140 |
|---|---|---|---|---|
| AUC (mcg*day/mL) | 1532 | 1192 | 1017 | 889 |
| Ratio AUC 75 kg | 1 | 0.78 | 0.66 | 0.57 |
Calculated AUC at steady-state for the dosing interval for 300 mg Q2W for a subject of a certain weight based on the relation between Clearance and weight Clearance = 0.149 × (W/75)^0.873. AUC = F × Dose Clearance, where F = 0.761.
The pharmacokinetics of tralokinumab in paediatric patients below 12 years has not yet been studied. For adolescents 12 to 17 years of age with atopic dermatitis, the mean ±SD steady-state through concentration (at week 16) was 112.8±39.2 mcg/mL for 300 mg dose administered every other week.
Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity (including safety pharmacology endpoints) and toxicity to reproduction and development.
The mutagenic potential of tralokinumab has not been evaluated; however monoclonal antibodies are not expected to alter DNA or chromosomes.
Carcinogenicity studies have not been conducted with tralokinumab. An evaluation of the available evidence related to IL-13 inhibition and animal toxicology data with tralokinumab does not suggest an increased carcinogenic potential for tralokinumab.
Enhanced pre- and postnatal studies with tralokinumab in monkeys did not identify adverse effects in maternal animals or their offspring up to 6 months post-partum.
No effects on fertility parameters such as reproductive organs, menstrual cycle and sperm analysis were observed in sexually mature monkeys treated subcutaneously with tralokinumab up to 350 mg/animal (females) or 600 mg/animal (males) (AUC exposure up to 15-fold higher than in human patients receiving tralokinumab 300 mg every 2 weeks).
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