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Are you currently using Excel for PKTK analysis We will show how to leverage Phoenix WinNonlin to streamline all of the analyses and generate all of the output needed for noncompartmental analysis, TK, PK and PKPD studies from within a single, validatable environment.

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Moreover, a population PKPD analysis in this phase can lead to a better understanding of PKPD characteristics of WBP216.

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To optimize the dosage regimen for future clinical trials, pharmacokinetics (PK) and pharmacodynamics (PD) of WBP216 would be firstly characterized in Chinese rheumatoid arthritis (RA) patients.

PK, CRP and DAS28 data of WBP216 were collected from 26 RA patients in a single ascending dose study.

Non-linear mixed effects modeling was used for a population PKPD analysis.

A two-compartment model with a sequential zero-first order absorption and a first order elimination best described PK behavior of WBP216.

Apparent systemic clearance was 0.015 Lh, central volume was 8.04 L.

CRP as the fast-decreasing endpoint and DAS28 as the slow-reacting endpoint were both fitted well through an indirect response model.

The baseline of ALT and free IL-6 were found associated with PKPD parameters during covariates exploration.

Simulation results confirmed that a loading dose regimen either of administration at weeks 0, 2, and 6 or doubling the maintenance dose level, followed by maintenance dosing of 75150 mg every 8 weeks, was expected to provide a best riskbenefit ratio in future clinical studies.

We hope this first PKPD study of WBP216 in Chinese RA patients will help in the clinical development of WBP216 in future and provide a reference to the dosage optimization of similar antibodies with long half-life.

Clinical Trial Registration: CTR20170306 Introduction WBP216 is an IgG1 antibody that binds and neutralizes IL-6 and is designed as a biologic anti-rheumatic drug.

Rheumatoid arthritis (RA) is featured by progressive articular disability, systemic inflammation, and high morbidity, which stem from a complex interaction between various inflammatory cells and cytokines ( McInnes and Schett, 2011; Smolen et al., 2016 ).

Biological therapies are recommended for treating RA refractory to synthetic chemical drugs ( Newsome, 2002 ).

IL-6 is one of major pro-inflammatory cytokines involved in RA pathogenesis.

Inhibition of the IL-6 signaling pathway helps to reduce inflammation and pain in patients with RA ( Ohsugi and Kishimoto, 2008; Raimondo et al., 2017 ).

Tocilizumab, as an anti interleukin 6 receptor (IL-6R) monoclonal antibody, is launched in 2009 for the indication of RA, whose successful clinical use has proved the key role of IL-6 in RA pathogenesis ( Choy et al., 2002 ).

WBP216 is a fully humanized monoclonal antibody that has showed its significant efficacy in treatment of RA in phase trial.

WBP216 has a strong affinity for interleukin 6 (IL-6), with an affinity constant in the picomolar range.

WBP216 prevents the interaction of IL-6 and its receptor, thus reducing pro-inflammatory activity.

Unlike regular IgG1 antibodies, WBP216 includes YTE mutations in the fragment crystallization (Fc).

These mutations increase the ability of the Fc fragment to bind the neonatal Fc receptor (FcRn) ( Oganesyan et al., 2009 ), which protect WBP216 from intracellular degradation, and thereby extending its half-life to 40 days and bringing some different pharmacokinetic (PK) characters.

Thus, WBP216 has the potential to relieve RA effectively and for a sustained period.

Due to the blockade of IL-6 signaling, WBP216 can directly inhibit the hepatic production of C-reactive protein (CRP) directly ( Bastida et al., 2019 ) and the erythrocyte sedimentation rate (ESR).

According to the American College of Rheumatology (ACR) response criteria, the disease activity score based on 28 joint (DAS28) in its two versions employing ESR or CRP are most frequently used in clinical trials and also in clinical practice.

DAS28 includes assessment of swollentender counts for 28 joints and patientevaluator physician global assessment, and usually decreases slowly after RA treatments compared to CRP and ESR ( Smolen et al., 2003 ).

Hence, rapidly and slowly decreasing pharmacodynamic (PD) biomarkers should be assessed together to comprehensively evaluate RA medications.

We report here the population PKPD analysis of WBP216 PK and serum CRP and DAS28-ESR data in RA patients from phase a, and model-based simulation results.

The goal of this modeling and simulation is to optimize dose levels, dosing intervals and loading dose regimens for such a long half-life antibody in Phase bIIa, a multiple ascending dose (MAD) study, which will help to improve the drug development efficiency.

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