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Population pharmacokinetics of brodalumab in healthy adults and adults with psoriasis from single and multiple dose studies
Author(s) -
Endres Christopher J.,
Salinger David H.,
Köck Kathleen,
Gastonguay Marc R.,
Martin David A.,
Klekotka Paul,
Nirula Ajay,
Gibbs Megan A.
Publication year - 2014
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/jcph.334
Subject(s) - psoriasis , medicine , pharmacokinetics , population , pharmacology , covariate , immunology , econometrics , environmental health , economics
Brodalumab, a human monoclonal IgG2‐antibody, acts as a potent antagonist at the interleukin‐17 receptor A, which is important in the pathogenesis of psoriasis. To characterize the pharmacokinetics of brodalumab and assess the effects of covariates, brodalumab concentrations from Phase 1a and Phase 2 clinical studies in healthy adults and subjects with psoriasis were used to construct a population PK model. The final two‐compartment model with parallel linear and non‐linear elimination pathways fit the data well. The population typical values for PK parameters CL, V, and V max were 0.223 L/day, 4.62 L, and 5.40 mg/day with between‐subject‐variability of 69.2, 69.6, and 25.9%CV, respectively. Body weight (BW) was an important covariate on CL (and Q), V (and V 2 ) and V max , with estimated effect exponents of 0.598, 0.849, and 1.12, respectively. Based on simulations from the final model, for doses between 140 and 210 mg, AUC was predicted to be greater than two fold higher in subjects weighing less than 75 kg compared to reference subjects. Age and diagnosis had smaller influence on exposure and was not clinically significant. These data suggest that BW is an important covariate explaining some of the variability in population PK observed in human clinical trials with brodalumab.