International immunopharmacology · 2021
Dupilumab pharmacokinetics in Chinese healthy subjects and patients with atopic dermatitis: Results of two randomized, double-blind, placebo-controlled studies.
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Clot Pierre-François, Kamal Mohamed, Sun Jing, Xu Christine, Kong Fangyuan, Gu Yongzhen, Yang Na, Yin WeiHong, Chen Bing, Ming Jeffrey E, Yuan Yaozong
Аннотация
BACKGROUND: Dupilumab, a fully human monoclonal antibody targeting IL-4Rα, has demonstrated rapid and sustained improvements in clinical outcomes in patients with atopic dermatitis (AD), asthma, and chronic rhinosinusitis with nasal polyps.
METHODS: In a phase 1, double-blind, ascending-dose study, 30 healthy Chinese adults were randomized to single subcutaneous doses of dupilumab 200, 300, 600 mg, or placebo. In a phase 3, double-blind study, 165 Chinese adults with AD were randomized to dupilumab 300 mg or placebo every 2 weeks.
RESULTS: Following single doses of dupilumab 200, 300, and 600 mg in the phase 1 study, mean serum maximum concentrations (Cmax) were 25.4 ± 4.0, 37.2 ± 14.5, and 77.3 ± 19.0 mg/L, respectively. For a 1.5-fold increase in dupilumab dose, 1.31-, 1.73-, and 1.66-fold increases in Cmax, area under the curve to real time (AUClast), and extrapolated to infinity (AUC) were observed, respectively, while a 2-fold dose increase resulted in 2.17-, 2.81-, and 2.80-fold increases, respectively. In the phase 3 study, mean dupilumab trough concentrations were 78.8 ± 32.0 and 86.4 ± 33.6 mg/L at weeks 12 and 16, respectively.
CONCLUSIONS: Cmax increased approximately proportionally to dose, while AUC and AUClast increased greater than proportionally. Dupilumab pharmacokinetics were generally comparable between Chinese and non-Asian healthy subjects (single dose) and between Chinese and non-Asian AD patients (repeated doses), with differences accounted for by body weight. As differences in exposure by weight are unlikely to be clinically relevant based on late-stage study results, no dose adjustment by ethnic origin or weight is required.
METHODS: In a phase 1, double-blind, ascending-dose study, 30 healthy Chinese adults were randomized to single subcutaneous doses of dupilumab 200, 300, 600 mg, or placebo. In a phase 3, double-blind study, 165 Chinese adults with AD were randomized to dupilumab 300 mg or placebo every 2 weeks.
RESULTS: Following single doses of dupilumab 200, 300, and 600 mg in the phase 1 study, mean serum maximum concentrations (Cmax) were 25.4 ± 4.0, 37.2 ± 14.5, and 77.3 ± 19.0 mg/L, respectively. For a 1.5-fold increase in dupilumab dose, 1.31-, 1.73-, and 1.66-fold increases in Cmax, area under the curve to real time (AUClast), and extrapolated to infinity (AUC) were observed, respectively, while a 2-fold dose increase resulted in 2.17-, 2.81-, and 2.80-fold increases, respectively. In the phase 3 study, mean dupilumab trough concentrations were 78.8 ± 32.0 and 86.4 ± 33.6 mg/L at weeks 12 and 16, respectively.
CONCLUSIONS: Cmax increased approximately proportionally to dose, while AUC and AUClast increased greater than proportionally. Dupilumab pharmacokinetics were generally comparable between Chinese and non-Asian healthy subjects (single dose) and between Chinese and non-Asian AD patients (repeated doses), with differences accounted for by body weight. As differences in exposure by weight are unlikely to be clinically relevant based on late-stage study results, no dose adjustment by ethnic origin or weight is required.