Minimal Physiologically-Based Pharmacokinetic (mPBPK) Metamodeling of Target Engagement in Skin Informs Anti-IL17A Drug Development in Psoriasis

• Published in: Frontiers in pharmacology Vol. 13; p. 862291
• Main Authors: Ayyar, Vivaswath S, Lee, Jong Bong, Wang, Weirong, Pryor, Meghan, Zhuang, Yanli, Wilde, Thomas, Vermeulen, An
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 25.04.2022
• Subjects: IL-17A; MBMA; mPBPK; Pharmacology; psoriasis; target engagement; translational medicine; ixekizumab; translational medicine; IL-17A; psoriasis; secukinumab; target engagement; MBMA; mPBPK
• ISSN: 1663-9812; 1663-9812
• DOI: 10.3389/fphar.2022.862291

The pharmacologic effect(s) of biotherapeutics directed against soluble targets are driven by the magnitude and duration of free target suppression at the tissue site(s) of action. Interleukin (IL)-17A is an inflammatory cytokine that plays a key role in the pathogenesis of psoriasis. In this work, clinical trial data from two monoclonal antibodies (mAbs) targeting IL-17A for treatment of psoriasis (secukinumab and ixekizumab) were analyzed simultaneously to quantitatively predict their target engagement (TE) profiles in psoriatic skin. First, a model-based meta-analysis (MBMA) for clinical responses was conducted separately for each drug based on dose. Next, a minimal physiologically-based pharmacokinetic (mPBPK) model was built to assess skin site IL-17A target engagement for ixekizumab and secukinumab simultaneously. The mPBPK model captured the observed drug PK, serum total IL-17A, and skin drug concentration-time profiles reasonably well across the different dosage regimens investigated. The developed mPBPK model was then used to predict the average TE (i.e., free IL-17A suppression) in skin achieved over a 12-weeks treatment period for each drug following their respective regimens and subsequently assess the TE-efficacy response relationship. It was predicted that secukinumab achieved 98.6% average TE in the skin at 300 mg q4w SC while ixekizumab achieved 99.9% average TE under 160 mg (loading) followed by 80 mg q2w SC. While direct quantification of free IL-17A levels at the site of action is technically challenging, integrated mPBPK-MBMA approaches offer quantitative predictions of free IL-17A levels at the site of action to facilitate future drug development via IL-17A suppression in psoriasis.