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Population Pharmacokinetic Modeling of Subcutaneously Administered Etanercept in Patients with Psoriasis

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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.

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Abbreviations

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

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Authors and Affiliations

  1. ZymoGenetics, 1201 Eastlake Avenue East, Seattle, WA, 98102, USA

    Ivan Nestorov

  2. Amgen Inc., One Amgen Center Drive M.S. 30E-0-B, Thousand Oaks, CA, 91320-1799, USA

    Ralph Zitnik

  3. GloboMax ICON, 7250 Parkway Drive, Suite 430, 21076, Hanover, MD

    Thomas Ludden

Authors
  1. Ivan Nestorov
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  2. Ralph Zitnik
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  3. Thomas Ludden
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Correspondence to Ivan Nestorov.

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Nestorov, I., Zitnik, R. & Ludden, T. Population Pharmacokinetic Modeling of Subcutaneously Administered Etanercept in Patients with Psoriasis. J Pharmacokinet Pharmacodyn 31, 463–490 (2004). https://doi.org/10.1007/s10928-005-5912-0

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