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


doi: 10.3389/fphar.2022.966176.


eCollection 2022.

Qian Li 
1
, Ju Qiao 
2
, Hongzhong Jin 
2
, Benchao Chen 
3
, Zhimei He 
3
, Guoqin Wang 
3
, Xiang Ni 
3
, Max Wang 
3
, Michelle Xia 
3
, Baiyong Li 
3
, Rui Chen 
1
, Pei Hu 
1

Affiliations

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Qian Li et al.


Front Pharmacol.


.

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 (Imax) and placebo effect (PLBmax) was 1 and 0.429, respectively. The rate constant for psoriatic plaque production (Kin) was 0.474 PASI/day and psoriatic plaque loss (Kout) 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.

Conflict of interest statement

BC, ZH, GW, XN, MW, MX, and BL were employed by Akeso Biopharma, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures


FIGURE 1



FIGURE 1

Schematic overview of the final population PK/PD model. SC: subcutaneous injection; Adepot: AK111 amounts in absorption depot; A1: AK111 amounts in central compartment; Ka: subcutaneous absorption rate constant; CL: clearance from the central compartment
Kin
: zero-order formation rate constant for the psoriatic plaques;
Kout
: first-order degradation rate constant for the psoriatic plaques; Imax: maximum inhibition effect on plaque forming rate constant; IC50: concentration at half-maximal inhibition;
PLBmax:
 maximum effect of placebo effect;
Kplb
: rate constant of the reduction from the maximum placebo effect.


FIGURE 2



FIGURE 2

Goodness-of-fit plots for the final population PK/PD model. Observed PASI score (DV) vs. Individual-predicted PASI score (IPRED).


FIGURE 3



FIGURE 3

Goodness-of-fit plots for the final population PK/PD model. Observed PASI score (DV) vs. Population-predicted PASI score (PRED).


FIGURE 4



FIGURE 4

Goodness-of-fit plots for the final population PK/PD model. The conditional weighted residuals (CWRES) vs. population-predicted PASI score (PRED).


FIGURE 5



FIGURE 5

Goodness-of-fit plots for the final population PK/PD model. CWRES vs. time after first dose.


FIGURE 6



FIGURE 6

Prediction-corrected visual predictive check (pcVPC) results for population PK and PK/PD models. pcVPC from the population PK model.


FIGURE 7



FIGURE 7

Prediction-corrected visual predictive check (pcVPC) results for population PK and PK/PD model. pcVPC from final population PK/PD model. Black circles represent prediction-corrected observation points. Red solid lines represent the 50th percentiles and blue solid lines represent the 5th and 95th percentiles of prediction-corrected observations; Red shadows around the curves represent 90% confidence intervals of the 50th percentiles of prediction-corrected prediction and blue shadows represent 90% confidence intervals of the 5th and 95th percentiles for prediction-corrected prediction.


FIGURE 8



FIGURE 8

Comparison of the observed time profiles of PASI75 and PASI90 response rates versus model-predicted time profiles stratified by dose. Observed and predicted PASI75 response rates stratified by dose.


FIGURE 9



FIGURE 9

Comparison of the observed time profiles of the PASI75 and PASI90 response rates versus model-predicted time profiles stratified by dose. Observed and predicted PASI90 response rates stratified by dose. Red circles represent observed response rates; black lines represent the 50th percentile of the predicted response rate; the two black-dotted lines represent a 95 % confidence interval for the predicted response rate.


FIGURE 10



FIGURE 10

Simulated median PASI75 and PASI90 response rates under different dose regimens using the final population PK/PD model. PASI75 response rate of 150 mg in the eight dosing regimens.


FIGURE 11



FIGURE 11

Simulated median PASI75 and PASI90 response rates under different dose regimens using the final population PK/PD model. The PASI90 response rate of 300 mg in eight dosing regimens. Different colors of lines represent the median response rate of different dosing regimens.


FIGURE 12



FIGURE 12

Simulated median PASI75 and PASI90 response rates under different dose regimens using the final population PK/PD model. The PASI75 response rate of 300 mg in eight dosing regimens.


FIGURE 13



FIGURE 13

Simulated median PASI75 and PASI90 response rates under different dose regimens using the final population PK/PD model PASI90 response rate of 150 mg in eight dosing regimens.

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