Journal of Pharmacokinetics and Pharmacodynamics

, Volume 31, Issue 6, pp 463–490

Population Pharmacokinetic Modeling of Subcutaneously Administered Etanercept in Patients with Psoriasis

Article

DOI: 10.1007/s10928-005-5912-0

Cite this article as:
Nestorov, I., Zitnik, R. & Ludden, T. J Pharmacokinet Pharmacodyn (2004) 31: 463. doi:10.1007/s10928-005-5912-0

Abstract

The objective of this paper is to present a population PK model which adequately describes the time–concentration profiles of different doses of etanercept (Enbrel®) administered subcutaneously to subjects with moderate-to-severe psoriasis and to simulate the time courses of concentrations following 50 mg once weekly (QW) dosing. Pharmacokinetic (PK) data from three clinical studies with doses 25 mg QW, 25 mg twice weekly (BIW) and 50 mg BIW, were used. A one-compartment model with gender, weight and time covariates on the apparent clearance and weight covariate on the apparent volume of distribution was developed. The population mean of the apparent steady state clearance in males was 0.129 l/h, compared to 0.148 l/h in females. The clearance varied with time being lower in the first 2 weeks of the therapy, increasing sharply during weeks 3–4, and converging gradually after that to its steady state level. The population mean of the apparent volume of distribution also varied with time and was 16.1 l during week 1, 20.0 l during weeks 2–4 and 22.5 l after week 4. The population PK model adequately described the observed concentration–time profiles in subjects with psoriasis. Despite a somewhat different covariate set, the parameter estimates of the population PK model for etanercept are very similar between the psoriasis and rheumatoid arthritis populations. The population PK model was used to simulate the pharmacokinetic profiles after a novel 50 mg QW dosing regimen. The simulations show good agreement with the observed data from 84 subjects participating in a fourth study (50 mg QW dose) used as an external validation set. The simulations of the 50 mg QW and the 25 mg BIW dosing regimens show that there is a significant overlap between the profiles yielding similar steady state exposures with both dosing regimens. The latter is an indication that the respective efficacy and safety profiles after those two dosing regimens are likely to be similar.

Keywords

etanerceptpsoriasispopulation pharmacokinetic modelsimulation

Glossary

ACR20

American College of Rheumatology response criteria of 20% improvement

AUC

area under the concentration curve

BIW

twice weekly

BMI

body mass index

BSA

body surface area formula=0.007184* (weight in kg)0.425* (height in cm)0.725

BQL

below quantification limit

CI

confidence interval

CL

clearance

CL/F

apparent clearance

CRF

case report form

CSR

clinical study report

CV

coefficient of variation

Cmax

maximum concentration

Cmin

minimum concentration

df

degrees of freedom

DOPD

duration of psoriasis disease

ELISA

enzyme-linked immunosorbent assay

F

bioavailability

FDA

food and Drug Administration

FO

first-order

FOCE

first-order conditional estimation

GAM

generalized additive model analysis

IV

intravenous

IIV

interindividual variability

IOV

interoccasion variability

IV

intravenous

Ka

absorption rate constant

LLOQ

lower limit of quantification

n

number of subjects

NC

not calculated

NCA

noncompartmental analysis

ND

no data

NSAIDs

nonsteroidal anti-inflammatory drugs

OFV

objective function value

OCC

occasion

PASB

PASI score at baseline

PASI

psoriasis area and severity index

PD

pharmacodynamic(s)

PK

pharmacokinetic(s)

PSPT

prior systemic or phototherapy

QOL

quality of life

QW

once weekly

RA

rheumatoid arthritis

SC

subcutaneous

SD

standard deviation

TAD

time since last administered dose

TNF

tumor necrosis factor, cachectin (previously known as TNFα)

TNFR

tumor necrosis factor receptor

V

volume of distribution

V/F

apparent volume of distribution

WTKG

weight in kilograms

Copyright information

© Springer Science+Business Media, Inc. 2005

Authors and Affiliations

  1. 1.ZymoGeneticsSeattleUSA
  2. 2.Amgen Inc.Thousand OaksUSA
  3. 3.GloboMax ICONHanover