Dupilumab is a recombinant human IgG4 monoclonal antibody that inhibits interleukin-4 and interleukin-13 signaling. Dupilumab inhibits IL-4 signaling via the Type I receptor (IL-4Rα/γc), and both IL-4 and IL-13 signaling through the Type II receptor (IL-4Rα/IL-13Rα). IL-4 and IL-13 are major drivers of human type 2 inflammatory disease, such as atopic dermatitis, asthma, CRSwNP, PN, and EoE. Blocking the IL-4/IL-13 pathway with dupilumab in patients decreases many of the mediators of type 2 inflammation.
In atopic dermatitis clinical trials, treatment with dupilumab was associated with decreases from baseline in concentrations of type 2 immunity biomarkers, such as thymus and activation-regulated chemokine (TARC/CCL17), total serum IgE and allergen-specific IgE in serum. A reduction of lactate dehydrogenase (LDH), a biomarker associated with AD disease activity and severity, was observed with dupilumab treatment in adults and adolescents with atopic dermatitis.
In adult and adolescent patients with asthma, dupilumab treatment relative to placebo markedly decreased FeNO and circulating concentrations of eotaxin-3. total IgE, allergen specific IgE, TARC, and periostin, the type 2 biomarkers evaluated in clinical trials. These reductions in type 2 inflammatory biomarkers were comparable for the 200 mg Q2W and 300 mg Q2W regimens. In paediatric (6 to 11 years of age) patients with asthma, dupilumab treatment relative to placebo markedly decreased FeNO and circulating concentrations of total IgE, allergen specific IgE, and TARC, the type 2 biomarkers evaluated in clinical trials. These markers were near maximal suppression after 2 weeks of treatment, except for IgE which declined more slowly. These effects were sustained throughout treatment.
In COPD patients, dupilumab treatment decreased type 2 biomarkers including FeNO and total IgE compared to placebo. Decreases in FeNO were observed by Week 4. These effects on type 2 biomarkers were sustained throughout treatment with dupilumab.
The pharmacokinetics of dupilumab is similar in patients with atopic dermatitis, asthma, CRSwNP, PN EoE, and COPD.
After a single subcutaneous (SC) dose of 75-600 mg dupilumab to adults, median times to maximum concentration in serum (tmax) were 3-7 days. The absolute bioavailability of dupilumab following a SC dose is similar between AD, asthma, CRSwNP, EoE, and COPD patients, ranging between 61% and 64%, as determined by a population pharmacokinetics (PK) analysis.
Steady-state concentrations were achieved by week 16 following the administration of 600 mg starting dose and 300 mg dose every other week or 300 mg dose every other week without a loading dose. Across clinical trials, the mean ± SD steady-state trough concentrations ranged from 55.3 ± 34.3 mcg/mL to 81.5 ± 43.9 mcg/mL for 300 mg administered Q2W, from 172 ± 76.6 mcg/ml to 195 ± 71.7 mcg/ml for 300 mg administered weekly, and from 29.2 ± 18.7 to 36.5 ± 22.2 mcg/mL for 200 mg administered Q2W.
A volume of distribution for dupilumab of approximately 4.6 L was estimated by population PK analysis, indicating that dupilumab is distributed primarily in the vascular system.
Specific metabolism studies were not conducted because dupilumab is a protein. Dupilumab is expected to degrade to small peptides and individual amino acids.
Dupilumab elimination is mediated by parallel linear and nonlinear pathways. At higher concentrations, dupilumab elimination is primarily through a non-saturable proteolytic pathway, while at lower concentrations, the non-linear saturable IL-4R α target-mediated elimination predominates. After the last steady state dose of 300 mg QW, 300 mg Q2W, 200 mg Q2W, 300 mg Q4W, or 200 mg Q4W dupilumab, the median times to decrease below the lower limit of detection, estimated by population PK analysis, ranged from 9-13 weeks in adults and adolescents and are approximately 1.5 times and 2.5 times longer in paediatric patients 6 to 11 years of age and paediatric patients less than 6 years of age, respectively.
Due to nonlinear clearance, dupilumab exposure, as measured by area under the concentration-time curve, increases with dose in a greater than proportional manner following single SC doses from 75-600 mg.
Gender was not found to be associated with any clinically meaningful impact on the systemic exposure of dupilumab determined by population PK analysis.
Of the 1539 patients with atopic dermatitis, including patients with atopic hand and foot dermatitis exposed to dupilumab in a phase 2 dose-ranging study or phase 3 placebo-controlled studies, a total of 71 were 65 years or older. Although no differences in safety or efficacy were observed between older and younger adult atopic dermatitis patients, the number of patients aged 65 and over is not sufficient to determine whether they respond differently from younger patients.
Age was not found to be associated with any clinically meaningful impact on the systemic exposure of dupilumab determined by population PK analysis. However, there were only 61 patients over 65 years of age included in this analysis.
Of the 1,977 patients with asthma exposed to dupilumab, a total of 240 patients were 65 years or older and 39 patients were 75 years or older. Efficacy and safety in this age group were similar to the overall study population.
There were only 79 patients older than 65 years with CRSwNP exposed to dupilumab among them 11 patients were 75 years and older.
Of the 152 patients with PN exposed to dupilumab, a total of 37 were 65 years of age or older. A total of 8 patients were 75 years of age or older. Efficacy and safety in these age groups were similar to the overall study population.
There were only 2 patients older than 65 years with EoE exposed to dupilumab.
Of the 1872 patients with COPD exposed to dupilumab, a total of 1071 were 65 years of age and older including 244 patients 75 years of age and older. Efficacy and safety in this age group were similar to the overall study population.
Race was not found to be associated with any clinically meaningful impact on the systemic exposure of dupilumab by population PK analysis.
Dupilumab, 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 dupilumab.
Dupilumab, 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 dupilumab. Population PK analysis did not identify mild or moderate renal impairment as having a clinically meaningful influence on the systemic exposure of dupilumab. Very limited data are available in patients with severe renal impairment.
Dupilumab trough concentrations were lower in subjects with higher body weight with no meaningful impact on efficacy. There were only 6 patients exposed to dupilumab with body weight ≥130 kg in CRSwNP clinical studies.
Atopic dermatitis:
Based on population pharmacokinetic analysis, age did not affect dupilumab clearance in adults and in paediatric patients 6 to 17 years of age. In paediatric patients from 6 months to 5 years of age, clearance increased with age but is accommodated in the recommended dose regimen.
The pharmacokinetics of dupilumab in paediatric patients (<6 months of age) or body weight <5 kg with atopic dermatitis has not been studied.
For adolescents 12 to 17 years of age with atopic dermatitis receiving every other week dosing (Q2W) with either 200 mg (<60 kg) or 300 mg (≥60 kg), the mean ± SD steady state trough concentration of dupilumab was 54.5 ± 27.0 mcg/mL.
For children 6 to 11 years of age with atopic dermatitis receiving every four week dosing (Q4W) with 300 mg (≥15 kg) in AD-1652, the mean ± SD steady-state trough concentration was 76.3 ± 37.2 mcg/mL. At week 16 in AD-1434 in children 6 to 11 years of age who initiated every four week dosing (Q4W) with 300 mg (≥15 kg), and whose dose was increased to every other week dosing (Q2W) with 200 mg (≥15 to <60 kg) or 300 mg (≥60 kg), the mean ± SD steady-state trough concentration was 108 ± 53.8 mcg/mL. For children 6 to 11 years of age receiving 300 mg Q4W, initial doses of 300 mg on Days 1 and 15 produce similar steady-state exposure as an initial dose of 600 mg on Day 1, based on PK simulations.
For children 6 months to 5 years of age with atopic dermatitis receiving every four week dosing (Q4W) with 300 mg (≥15 to <30 kg) or 200 mg (≥5 to <15 kg) mean ± SD steady-state trough concentration was 110 ± 42.8 mcg/mL and 109 ± 50.8 mcg/mL, respectively.
Asthma:
The pharmacokinetics of dupilumab in paediatric patients (<6 years of age) with asthma has not been studied.
A total of 107 adolescents aged 12 to 17 years with asthma were enrolled in QUEST study. The mean ± SD steady-state trough concentrations of dupilumab were 107 ± 51.6 mcg/mL and 46.7 ± 26.9 mcg/mL, respectively, for 300 mg or 200 mg administered every other week. No age-related pharmacokinetic difference was observed in adolescent patients after correction for body weight.
In the VOYAGE study, dupilumab pharmacokinetics was investigated in 270 patients with moderate-to-severe asthma following subcutaneous administration of either 100 mg Q2W (for 91 children weighing <30 kg) or 200 mg Q2W (for 179 children weighing ≥30 kg). The volume of distribution for dupilumab of approximately 3.7 L was estimated by population PK analysis. Steady-state concentrations were achieved by week 12. The mean ± SD steady-state trough concentration was 58.4 ± 28.0 mcg/mL and 85.1 ± 44.9 mcg/mL, respectively. Simulation of a 300 mg Q4W subcutaneous dose in children aged 6 to 11 years with body weight of ≥15 kg to <30 kg and ≥30 kg to <60 kg resulted in predicted steady-state trough concentrations similar to the observed trough concentrations of 200 mg Q2W (≥30 kg) and 100 mg Q2W (<30 kg), respectively. In addition, simulation of a 300 mg Q4W subcutaneous dose in children aged 6 to 11 years with body weight of ≥15 kg to <60 kg resulted in predicted steady-state trough concentrations similar to those demonstrated to be efficacious in adults and adolescents. After the last steady state dose, the median time for dupilumab concentrations to decrease below the lower limit of detection, estimated by population PK analysis, was 14 to 18 weeks for 100 mg Q2W, 200 mg Q2W or 300 mg Q4W.
CRSwNP:
CRSwNP does not normally occur in children. The pharmacokinetics of dupilumab in paediatric patients (<18 years of age) with CRSwNP has not been studied.
PN:
The pharmacokinetics of dupilumab in paediatric patients (<18 years of age) with PN has not been studied.
Eosinophilic esophagitis:
A total of 35 adolescents aged 12 to 17 years with eosinophilic esophagitis weighing ≥40 kg were enrolled in TREET Parts A and B, receiving 300 mg every week dosing (QW). The mean ± SD steady-state trough concentration of dupilumab was 227 ± 95.3 mcg/mL.
COPD:
COPD does not normally occur in children. The pharmacokinetics of dupilumab have not been studied in paediatric patients (<18 years of age) with COPD.
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 dupilumab has not been evaluated; however monoclonal antibodies are not expected to alter DNA or chromosomes.
Carcinogenicity studies have not been conducted with dupilumab. An evaluation of the available evidence related to IL-4Rα inhibition and animal toxicology data with surrogate antibodies does not suggest an increased carcinogenic potential for dupilumab.
During a reproductive toxicology study conducted in monkeys, using a surrogate antibody specific to the monkey IL-4Rα, no fetal abnormalities were observed at doses that saturate the IL-4Rα.
An enhanced pre- and post-natal developmental study revealed no adverse effects in maternal animals or their offspring up to 6 months post-partum/post-birth.
Fertility studies conducted in male and female mice using a surrogate antibody against IL-4Rα showed no impairment of fertility.
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