A pharmacokinetic comparison of anrukinzumab, an anti- IL-13 monoclonal antibody, among healthy volunteers, asthma and ulcerative colitis patients

Abstract

Aims: Anrukinzumab is an anti-IL13 monoclonal antibody. The goals of this study are to characterize the pharmacokinetics of anrukinzumab in healthy volunteers and different disease states and to identify covariates.

Methods: A population pharmacokinetic (PK) model was developed in NONMEM, using data from five clinical studies including healthy volunteers, asthma and ulcerative colitis (UC) patients. Different dosing regimens including different routes of administration were also included in the data.

Results: The PK of anrukinzumab were described by a two compartment model with first order absorption and elimination. The population estimates (relative standard error) of the volumes of distribution in the central (Vc ) and peripheral (Vp ) compartments were 3.8 (4.6%) and 2.2 l (8.7%), respectively. In non-UC patients, the population estimate of the systemic clearance (CL) and inter-compartmental CL was 0.00732 l h(-1) (4.9%) and 0.0224 l h(-1) (15.4%). For subcutaneous administration, the absorption rate constant was 0.012 h(-1) (6.6%) and bioavailability was nearly 100% in healthy and mild to moderate asthma patients. Both V and CL increased with body weight. CL (but not V) decreased with increasing baseline albumin concentrations. UC patients had an increased CL of 72.3% (10.5%), after correction for differences in body weight and albumin. Moderate to severe asthma patients had decreased bioavailability compared with other populations.

Conclusions: Anrukinzumab's PK behave like a typical antibody. UC patients were identified to have a faster CL of anrukinzumab than healthy volunteers and asthma patients. This finding suggests a higher dose level may be required for this population.

Keywords: IL13; IMA-638; NONMEM; anrukinzumab; asthma; healthy volunteers; monoclonal antibody; pharmacokinetics; population PK; ulcerative colitis.

Figure 1

Relationship between selected covariates and pharmacokinetic parameters in the base model (A) and the final model (B). The solid red line is a smooth curve fit of the data computed by loess. In the boxplots on the right, the thick line shows median, box shows the first and the third quartiles, and the bars show 1.5 *interquartile range. CL, clearance; V, total volume of distribution; BIL13, serum baseline IL-13 level; HV, healthy volunteers; mAsthma, mild to moderate asthma patients; sAsthma, moderate to severe asthma patients; UC, ulcerative colitis patients

Figure 2

Relationship between baseline Mayo score and CL for ulcerative colitis patients. In the boxplot, the thick line shows median, box shows the first and the third quartiles, and the bars show 1.5 *interquartile range.

Figure 3

Goodness-of-fit plots for the final model. A) Observed vs. population predicted serum anrukinzumab concentrations on a log scale. B) Observed vs. individual predicted serum anrukinzumab concentrations on log scale. C) Conditional weighted residual vs. population predicted serum anrukinzumab concentrations. D) Conditional weighted residual vs. time after dose (h). The broken blue line represents the line of identity in panels A and B and the zero line in panels C and D. The broken red line represents a smooth curve fit of the data. DV, observed concentration; PRED, predicted concentration; IPRED, individual predicted concentration; CWRES, conditional weighted residual

Figure 4

Visual predictive check for the final model stratified by dose. Examples included are A) 200 mg i.v. (study 5, UC patients), B) 400 mg i.v. (study 5, UC patients), C) 600 mg i.v. (study 5, UC patients), D) 0.6 mg kg^–1 s.c. (study 4, moderate to severe asthma patients), E) 3 mg kg^–1 i.v. (study 1, mild to moderate asthma patients) and F) 4 mg kg^–1 s.c. (studies 1 and 2, healthy volunteers and mild to moderate asthma patients). The circles show the observed data. The solid red lines represent the median of the observed data. The broken red lines represent the 5^th and 95^th percentiles of the observed data. The solid black lines represent the simulated median and the orange shaded area represents its 95% confidence interval. The broken black lines represent the 5^th and 95^th percentiles based on simulation and the blue shaded areas around the broken black lines represent their the 95% confidence interval, respectively

Figure 5

Concentration vs. time profiles of anrukinzumab given as multiple i.v. 200 mg doses to UC patients or non-UC subjects. The broken lines show median profiles and the shaded areas show 95% prediction interval. ,UC; ,non-UC