Population pharmacokinetic/pharmacodynamic analysis of AK111, an IL-17A monoclonal antibody, in subjects with moderate-to-severe plaque psoriasis

Qian Li; Ju Qiao; Hongzhong Jin; Benchao Chen; Zhimei He; Guoqin Wang; Xiang Ni; Max Wang; Michelle Xia; Baiyong Li; Rui Chen; Pei Hu

doi:10.3389/fphar.2022.966176

Population pharmacokinetic/pharmacodynamic analysis of AK111, an IL-17A monoclonal antibody, in subjects with moderate-to-severe plaque psoriasis

Front Pharmacol. 2022 Aug 16:13:966176. doi: 10.3389/fphar.2022.966176. eCollection 2022.

Authors

Qian Li¹, Ju Qiao², Hongzhong Jin², Benchao Chen³, Zhimei He³, Guoqin Wang³, Xiang Ni³, Max Wang³, Michelle Xia³, Baiyong Li³, Rui Chen¹, Pei Hu¹

Affiliations

¹ Clinical Pharmacology Research Center, Peking Union Medical College Hospital, State Key Laboratory of Complex Severe and Rare Diseases, NMPA Key Laboratory for Clinical Research and Evaluation of Drug, Beijing Key Laboratory of Clinical PK and PD Investigation for Innovative Drugs, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
² Department of Dermatology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, Beijing, China.
³ Akeso Biopharma, Inc, Zhongshan, China.

Abstract

AK111 is an innovative IL-17A antibody, presenting high affinity to IL-17A and showing similar pharmacokinetic (PK) characteristics to those of typical immunoglobulin (Ig) G1 antibodies. To optimize the dosage regimen for phase 2/3 clinical trials, PK and pharmacodynamics (PD) of AK111 were first characterized in Chinese moderate-to-severe plaque psoriasis patients in a phase 1b study. AK111 PK serum sample and Psoriasis Area and Severity Index (PASI) score data were collected from 48 moderate-to-severe psoriasis patients in this study. Non-linear mixed-effects modeling was used for the population PK/PD analysis. A one-compartment model with a first-order absorption and a first-order elimination best described the PK behavior of AK111. The apparent systemic clearance was 0.182 L/day, and the central volume was 6.65 L. The exposure-response relationship was characterized using an indirect response model. The pharmacological effect of AK111 was described in the form of inhibiting the formation of psoriatic plaque, whereas placebo was quantified in the form of promoting the degradation of psoriatic skin lesions. The maximum effect of drug effect (I_max) and placebo effect (PLB_max) was 1 and 0.429, respectively. The rate constant for psoriatic plaque production (K_in) was 0.474 PASI/day and psoriatic plaque loss (K_out) was 0.024 day^-1. The body surface area (BSA) affected by psoriasis was identified as a significant covariate on $K_{o u t}$ . The simulation results confirmed that all of the predicted PASI90 response rates at week 12 were higher than 60% at 150 and 300 mg dose levels with different regimens and could reach higher than 80% at week 24. We hope this first PK/PD study of AK111 in Chinese moderate-to-severe plaque psoriasis patients will be of help in the further clinical development of AK111 and provide a reference to the dosage optimization for similar antibodies with a long half-life.

Keywords: IL-17A; model; moderate-to-severe plaque psoriasis; monoclonal antibody; population pharmacodynamics; population pharmacokinetic; psoriasis area and severity index.