Abstract
A sequential pharmacokinetic (PK) and pharmacodynamic (PD) model was built with Nonlinear Mixed Effects Modelling based on data from a first-in-human trial of a novel biologic, MEDI7836. MEDI7836 is a human immunoglobulin G1 lambda (IgG1λ-YTE) monoclonal antibody, with an Fc modification to reduce metabolic clearance. MEDI7836 specifically binds to, and functionally neutralizes interleukin-13. Thirty-two healthy male adults were enrolled into a dose-escalation clinical trial. Four active doses were tested (30, 105, 300, and 600 mg) with 6 volunteers enrolled per cohort. Eight volunteers received placebo as control. Following single subcutaneous administration (SC), individual time courses of serum MEDI7836 concentrations, and the resulting serum IL13 modulation in vivo, were quantified. A binding pharmacokinetic-pharmacodynamic (PK-PD) indirect response model was built to characterize the exposure-driven modulation of the target over time by MEDI7836. While the validated bioanalytical assay specification quantified the level of free target (i.e., a free IL13 assay), emerging clinical data suggested dose-dependent increase in systemic IL13 concentration over time, indicative of a total IL13 assay. The target time course was modelled as a linear combination of free target and a percentage of the drug-target complex to fit the clinical data. This novel PK-PD modelling approach integrates independent knowledge about the assay characteristics to successfully elucidate apparently complex observations.
Highlights
Asthma is one of the major noncommunicable diseases, and was estimated to have affected more than 300 million people globally in 2016 [1]
The covariate analysis revealed that anti-drug antibodies (ADAs) positive post-baseline status was statistically associated with faster MEDI7836 monoclonal antibody (mAb) clearance (ADA CL increase, 71.7%, 49.4% RSE) (Table 2 and Figure 4)
PK-PD parameter estimates were all biologically plausible for a mAb directed against a soluble target
Summary
Asthma is one of the major noncommunicable diseases, and was estimated to have affected more than 300 million people globally in 2016 [1]. Asthma is characterized by hyperresponsiveness to specific and non-specific stimuli, chronic pulmonary eosinophilia, upregulated serum IgE, and excessive airway mucus production. Asthma is believed to be mediated by CD4+ T-lymphocytes, which produce type 2 cytokines including IL4 and IL5. IL13 has been implicated in development and expression of airway hyperresponsiveness, with IL13 alone shown to be sufficient to induce responses in murine models [2]. As IL13 is a validated target in driving the allergic asthma phenotype, IL13 neutralization had attractive therapeutic potential [3]. The standard of care for allergic asthma consists of inhaled corticosteroids and shortand long-acting bronchodilators, which control asthma symptoms in the majority of pa-
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