Volume 62, Issue 4 p. 435-445
Open Access

Pharmacokinetics of subcutaneously administered etanercept in subjects with psoriasis

Ivan Nestorov

Ivan Nestorov

ZymoGenetics, Seattle, WA and

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Ralph Zitnik

Ralph Zitnik

Amgen Inc., Thousand Oaks, CA, USA

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Todd DeVries

Todd DeVries

ZymoGenetics, Seattle, WA and

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Arline M. Nakanishi

Arline M. Nakanishi

Amgen Inc., Thousand Oaks, CA, USA

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Andrea Wang

Andrea Wang

Amgen Inc., Thousand Oaks, CA, USA

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Christopher Banfield

Corresponding Author

Christopher Banfield

Amgen Inc., Thousand Oaks, CA, USA

Christopher Banfield PhD, Amgen Inc., One Amgen Center Drive, M.S. 38-3-A, Thousand Oaks, CA 91320–1799, USA.
Tel: + 1 805 447 0830
Fax: + 1 805 499 9495
E-mail:[email protected]Search for more papers by this author
First published: 14 February 2006
Citations: 39

This manuscript was prepared during the employment of both Drs Ivan Nestorov and Todd DeVries with Amgen Inc.

Abstract

Aims

To present the results of the pharmacokinetic analysis of the concentration–time profiles of etanercept, a soluble receptor tumour necrosis factor (TNF) antagonist, in more than 1300 subjects with psoriasis.

Methods

Pharmacokinetic samples were collected in one phase-2 and two phase-3 placebo-controlled, randomized clinical trials. Study 1 evaluated a 25-mg twice weekly (BIW) etanercept dosing regimen administered by subcutaneous (s.c.) injection for 24 weeks. Study 2 evaluated 25-mg BIW and 50-mg BIW s.c. doses for 12 weeks. Study 3 evaluated 25 mg once weekly (QW), 25 mg BIW and 50 mg BIW s.c. doses for 24 weeks.

Results

The mean ± SD steady-state predose serum concentrations of etanercept for the 25-mg BIW arm at 12 weeks in study 1 were 1590 ± 885 ng ml−1. In study 2, mean ± SD etanercept steady-state concentrations at 12 weeks were 1900 ± 1110 ng ml−1 in the 25-mg BIW group and 3830 ± 1870 ng ml−1 in the 50-mg BIW group. The mean ± SD steady-state predose serum concentrations of etanercept at 12 weeks in study 3 were 768 ± 475 ng ml−1 for the 25-mg QW regimen, 1990 ± 1030 ng ml−1 for the 25-mg BIW regimen and 4020 ± 2100 ng ml−1 for the 50-mg BIW regimen.

Conclusions

Pharmacokinetic results were highly consistent across clinical trials. The concentration–time profiles displayed dose proportionality. Etanercept concentrations in subjects with psoriasis are similar to the concentrations in subjects with rheumatoid arthritis.

Introduction

Psoriasis, a chronic inflammatory disorder affecting approximately 2% of the world’s population [1], is characterized by infiltration of the skin with activated T cells and by abnormal keratinocyte proliferation. Dysregulation of T cell-antigen presenting cell interactions and over-expression of proinflammatory cytokines play a central role in the pathogenesis of psoriatic skin lesions [2]. As a result of overproduction by T cells and keratinocytes, tumour necrosis factor (TNF) concentrations are increased in psoriatic lesions compared with concentrations in uninvolved skin in subjects and in normal individuals. Serum and lesional TNF concentrations decrease after effective psoriasis therapy, correlating with clinical improvement in the disease [3]. These observations suggest that interfering with the proinflammatory effects of TNF may reduce the characteristic inflammation seen in psoriatic lesions.

Etanercept is a dimeric fusion protein consisting of the extracellular ligand-binding protein of the human 75 kilodalton (p75) tumour necrosis factor receptor (TNFR) linked to the Fc portion of a human IgG1 [4]. Etanercept competitively inhibits the interaction of TNF with cell-surface receptors, preventing TNF-mediated cellular responses and modulating the activity of other proinflammatory cytokines that are regulated by TNF.

The safety and efficacy of etanercept has been demonstrated in subjects with rheumatoid arthritis (RA) [5, 6]. To most adult RA subjects, etanercept is administered at a dose of 25 mg twice weekly (BIW) as a subcutaneous (s.c.) injection, 72–96 h apart. A 50-mg once weekly (QW) s.c. dosing regimen has also been approved for RA, juvenile RA, ankylosing spondylitis (AS) and psoriatic arthritis.

It has been demonstrated that in subjects with psoriatic arthritis, etanercept also improved psoriatic skin lesions [7, 8]. This clinical observation led to the initiation of a development programme, evaluating the efficacy of three dosing regimens (25 mg QW, 25 mg BIW and 50 mg BIW) of etanercept in the treatment of chronic plaque psoriasis. In all studies of this programme, etanercept treatment of subjects with psoriasis led to dose-dependent improvement in disease severity [9–11]. The latter is an indication that exposure, and hence etanercept pharmacokinetics (PK), is a determinant of the observed efficacy of the drug in psoriasis.

The majority of the available information on the PK of etanercept originates from studies with either healthy volunteers or RA subjects. The concentration–time profiles after subcutaneously administered etanercept in healthy volunteers were best described by a one-compartment model [12]. Etanercept is slowly absorbed from the site of injection with an absorption rate (± SD) of 0.0396 ± 0.025 h−1. After a single s.c. administration, the mean peak concentration is 1460 ± 720 ng ml−1, achieved at a mean time of 51 ± 14 h. The elimination of etanercept in healthy subjects has a mean half-life of 68 ± 19 h; the apparent mean serum clearance (CL/F) is 0.132 ± 0.085 l h−1. The area under the curve to infinity AUC0–∞ after a single 25-mg s.c. dose is 235 ± 98 mg h l−1 and the apparent volume of distribution (V/F) is 12 ± 6 l. Etanercept is well absorbed after s.c. injection, and the absolute bioavailability (F), estimated after single intravenous (i.v.) and s.c. doses in six healthy subjects, is approximately 58%[13].

After a single 25-mg s.c. injection of etanercept to RA subjects (N = 25), the mean ± SD elimination half-life was 102 ± 30 h, the mean maximum concentration was 1100 ± 600 ng ml−1, observed at a mean time of 69 ± 34 h, and the estimated apparent clearance was 0.16 ± 0.08 l h−1[4]. After 6 months of twice-weekly 25 mg dosing, the mean maximum concentration increased to 2400 ± 1000 ng ml−1 (N = 23). An extensive analysis was performed to estimate the population PK/pharmacodynamic (PD) parameters of etanercept and their variability in RA subjects [14] and AS subjects [15]. For RA, the typical population value of the CL/F was 0.117 l h−1 for white females and 0.138 l h−1 for white males; the typical population value of the V/F was 16.1 l; the first order absorption rate constant was 0.0332 h−1; and half-life was 95.4 h for women and 80.9 h for men.

The PK of etanercept in psoriatic subjects has not previously been reported. In order to characterize the concentration–time profiles of etanercept after s.c. administration to subjects with psoriasis, multiple serum samples were taken during the clinical studies of the psoriasis development programme. The purpose of the current report is to present the results from the PK analysis of the generated concentration–time data of etanercept exposure in subjects with psoriasis.

Methods

Study design

The etanercept in the psoriasis clinical development programme consisted of a proof-of-concept phase-2 study (study 1) and two phase-3 studies (study 2 and study 3). Details of the particular studies are published elsewhere [9–11]. The Institutional Review Board of the participating medical centres approved the protocols.

Study 1 was a double-blind, randomized phase 2 study to evaluate the efficacy and safety of etanercept in subjects with chronic plaque psoriasis in the USA [9]. One hundred and twelve subjects were randomized and treated with blinded etanercept 25 mg BIW or placebo for 24 weeks. The primary efficacy endpoint was a ≥ 75% improvement from baseline in the psoriasis area and severity index (PASI 75) at 12 weeks [9].

Study 2 was a phase 3, randomized, double-blind, multicentre study in subjects with psoriasis [11]. This multinational study was conducted in the USA, Canada, the UK, Germany, France and the Netherlands. The study consisted of two periods: a double-blind treatment period (12 weeks), followed by an open-label treatment period. Only the PK data from the blinded period were included in the current analysis. During the first 12 weeks of the study, subjects were randomized to receive etanercept 50 mg BIW, etanercept 25 mg BIW, or placebo s.c. treatment. After week 12, all subjects began receiving open-label etanercept at a dose of 25 mg BIW. A total of 583 subjects received at least one dose of blinded-study medication. PASI 75 responses at weeks 12 and 24 have been previously reported [11].

Study 3 was a two-part study conducted in the USA to evaluate three s.c. dosing regimens of etanercept (50 mg BIW, 25 mg BIW, 25 mg QW) vs. placebo [10]. Only PK data from the first part of the study were included in the current analysis. The first part was a 24-week double-blind treatment period. After the 12-week visit, subjects in the placebo group began receiving etanercept 25 mg BIW in a blinded fashion. A total of 652 subjects received at least one dose of blinded-study drug and were analysed for safety and efficacy. PASI 75 responses at weeks 12 and 24 have been previously reported [10].

The demographic characteristics of the subjects from all three studies are presented in Table 1.

Table 1.
Demographic characteristics of the subjects participating in the three psoriasis studies
Study 1 2 3
Dose Placebo 25 mg BIW Placebo 25 mg BIW 50 mg BIW Placebo 25 mg QW 25 mg BIW 50 mg BIW
No of subjects 55 57 193 196 194 166 160 162 164
Sex, n (%)
 Men  37 (67)  33 (58) 124 (64) 128 (65) 130 (67) 104 (63) 119 (74) 109 (67) 106 (65)
 Women  18 (33)  24 (42)  69 (36)  68 (35)  64 (33)  62 (37)  41 (26)  53 (33)  58 (35)
Race, n (%)
 White  52 (95)  51 (89) 175 (91) 180 (92) 173 (89) 150 (90) 136 (85) 138 (85) 143 (87)
 Non-white   3 (5)   6 (11)  18 (9)  16 (8)  21 (11)  16 (10)  24 (15)  24 (15)  21 (13)
Age (years)
 Mean  46.5  48.2  44.8  45.4  45.2  45.6  44.4  45.4   44.8
 (SD) (13.2) (13.3)  (11.3) (12.0) (12.4) (12.9) (12.0) (13.1)  (10.8)
Weight (kg)
 Mean  90.7  91.8  90.7   87.6  85.6  95.8  94.9  93.0   94.8
 (SD) (21.0) (20.5) (21.6) (19.8) (18.9) (23.0) (21.9) (23.6)  (23.1)
Psoriasis duration (years)
 Mean  20.0  22.5  19.4  22.2  19.9  18.4  19.3   18.5   18.6
 (SD) (12.2) (12.1)  (11.3) (11.5) (11.2) (11.6) (11.0) (11.2) (11.2)
Baseline PASI
 Mean  19.5  17.8  18.6  19.1  19.5  18.3   18.2   18.5   18.5
 (SD)  (9.4)  (8.5)  (8.6)  (8.2)  (8.8)   (7.5)   (8.6)  (8.6)   (8.4)
  • PASI, Psoriasis area and severity index.

Drug concentration measurements

In study 1 (doses: placebo and 25 mg BIW), serum samples (1 cm3 serum) for PK analysis were obtained from all subjects before the first dose, at weeks 12 and 24, and at the 30-day follow-up visit for subjects who discontinued early.

In study 2 (doses: placebo, 25 mg BIW and 50 mg BIW), serum samples for PK analysis were obtained from all subjects before the first dose, and at weeks 2, 4, 8 and 12 during the double-blind period.

In the double-blind period of study 3 (doses: placebo, 25 mg QW, 25 mg BIW or 50 mg BIW), all subjects had serum PK samples (1 cm3 serum) obtained at baseline, weeks 2, 4, 8, 12 and 24. A number of subjects (N = 41) were designated as a ‘PK subset’ and had additional serum samples collected for PK analysis at the following nominal times: week 1 – at days 2, 3, 4 and 7; week 12 – at days 77, 78, 80 and 82; and week 24 – at days 161, 162, 164, 165 and 167.

Determination of etanercept concentrations in serum

Serum concentrations of etanercept were measured by a validated enzyme-linked immunosorbent assay (ELISA) method. This ELISA method utilized a sandwich format to measure etanercept.

A mouse anti-TNFR monoclonal antibody was bound to the ELISA plate and used to capture etanercept in the standards, controls or unknown samples. Experiments performed using variously mutated etanercept–avidin constructs revealed that this monoclonal antibody binds to an epitope corresponding to amino acids 190–249 of etanercept. A polyclonal goat anti-TNFR antibody was added to complete the sandwich. A horseradish peroxidase (HRP)-conjugated donkey antigoat antibody was then used to detect the bound goat antibody. Trimethylbenzidine-hydrogen peroxide substrate for HRP was added to generate a colorimetric reaction to quantify etanercept. The reaction was stopped with the addition of a stopping solution. The intensity of the colour in each well was proportional to the quantity of etanercept in the assay system. The quantity of etanercept in an unknown sample was determined by calculating the response of the sample against the calibration curve regressed using a four-parameter regression model.

The lower limit of quantification (LLOQ) was 0.625 ng ml−1, except for study 1 where the LLOQ was 0.3 ng ml−1 based on a 1 : 5 sample dilution developed by Immunex Corporation [16]. The assays were conducted at Amgen Inc., Seattle, WA (study 1), Covance Laboratories, Inc., Madison, WI (study 2) and MDS-Pharma, Toronto, Canada (study 3). The accuracy and precision characteristics of the assays have been previously reported [17]. Briefly, the accuracy of the assay in study 1 ranged from 1.3% to − 24.9% and its precision ranged from 9.8% to 13.8%. The accuracy of the assay in study 2 ranged from 13% to − 13.6%, while the precision ranged from 6.5% to 14%. The ranges of the accuracy (6% to − 21%) and precision (9% to 14%) of the assay in study 3 were similar to those of study 2.

Data handling and pharmacokinetic analysis

Missing concentration values were not considered in the analysis.

The PK parameters for the subjects participating in the PK subset of study 3 were calculated by noncompartmental analysis (NCA) of the serum concentration–time data using the Steady State Option of the WinNonlin NCA analysis tool [18]. The following PK parameters were estimated:

  • The maximum concentration (Cmax) and the time it occurred (Tmax) after dosing were recorded as observed.

  • The minimum concentration (Cmin) after dosing was recorded as observed.

  • The calculated average concentration (Cavg) within one dosing period (1 week).

  • The area under the serum concentration–time curve within one dosing period (week), AUCweek, was estimated using the linear trapezoidal method.

  • Fluctuation in percentage, characterizing the fluctuation of the concentration–time profile around the average concentration in steady state.

The formulae used for the calculation of the PK parameters during NCA analysis can be found in the WinNonlin Reference Guide [18]. For the calculation of the NCA parameters, the actual sampling times were used.

Results

Table 2 shows the results from the statistical analysis of the PK data for the subjects in the active arm (etanercept 25 mg BIW) during the 24 weeks of study 1.

Table 2.
Summary statistics of the concentration–time profiles for the active dosing arm during the blinded period in study 1
Etanercept concentration (ng ml−1)
Baseline Week 12 Week 24
N 57   52   49
Mean  0.05 1590 1630
Median  0.00 1660 1510
SD  0.20  885 1140

Table 3 shows the results from the statistical analysis of the PK data for the subjects in the active arms (etanercept 25 mg BIW and 50 mg BIW) during the blinded period of study 2. The mean (± SD) profiles for both dosing arms are presented in Figure 1. The trough concentration–time profiles display dose proportionality, with the concentrations in the 50-mg BIW arm being approximately twice as high as the values measured in the 25-mg BIW arm.

Table 3.
Summary statistics of the concentration–time profiles for the active dosing arms during the blinded period in study 2
Etanercept concentration (ng ml−1)
Baseline Week 2 Week 4 Week 8 Week 12
25 mg BIW
N 188  184  178  184  186
Mean   0.20 2170 1440 1790 1900
Median   0.00 2070 1180 1450 1800
SD   0.88 1120 1160 1200 1110
50 mg BIW
N 189  188  188  187  186
Mean   0.67 4420 3020 3470 3830
Median   0.00 4340 2680 3340 3640
SD   5.38 1840 1860 1790 1870
Details are in the caption following the image


Mean (± SD) etanercept serum trough concentration–time profiles for the active dosing arms during the blinded period of study 2. 25 mg BIW (□), 50 mg BIW (◆)

Table 4 shows summary statistics for the PK data for the subjects in all arms during the blinded period of study 3. The mean (± SD) profiles for all dosing arms are presented in Figure 2. The trough concentration–time profiles of the active arms again display dose proportionality, with the concentrations in the 50-mg BIW arm approximately twice as high as the values measured in the 25-mg BIW arm and almost four times higher than the concentrations obtained after the 25-mg QW dose. In study 3, the placebo group crossed over to receive 25 mg BIW for the second 12 weeks of the study. It is notable that the etanercept concentration at week 24 in this group was similar to that achieved at week 12 by the original group receiving 25 mg BIW.

Table 4.
Summary statistics of the concentration–time profiles for the active dosing arms during the blinded period in study 3
Etanercept concentration (ng ml−1)
Baseline Week 2 Week 4 Week 8 Week 12 Week 24
Placebo/25 mg BIW  a
N 161  145  150  150  131  133
Mean   0.05    0.03    0.08    0    0.04 1820
Median   0    0    0    0    0 1640
SD   0.37    0.17    0.56    0    0.3 1100
25 mg QW
N 155  140   133  138  133  126
Mean   0.07  926   545  586  768  846
Median   0  853   376  510  654  742
SD   0.34  466   472  351  475  571
25 mg BIW
N 155  136  138  143  143  131
Mean   0.05 2150 1390 1710 1990 2110
Median   0 2000 1140 1580 1990 1990
SD   0.26  975 1000  974 1030 1000
50 mg BIW
N 152  141  148  153  143  143
Mean   0.08 4220 2870 3390 4020 3940
Median   0 3990 2340 2950 3800 3450
SD   0.46 1940 2020 1760 2100 2440
  • a Week 24 after receiving active 25-mg BIW treatment for 12 weeks.
Details are in the caption following the image


Mean (± SD) etanercept serum trough concentration–time profiles for all dosing arms during the blinded period of study 3. 1Week 24 after receiving active 25 mg BIW for 12 weeks

Figure 3 compares the mean (± SD) concentration–time profiles of the four dosing arms at week 1 (Figure 3a), week 12 (Figure 3b) and week 24 (Figure 3c) for the subjects of the PK subset of study 3 (N = 41), who were sampled more frequently. Patients who received placebo during the first 12 weeks of the study (Figure 3b) subsequently received etanercept 25 mg BIW from weeks 13 to 24. The weekly concentration–time profiles for the active arms of the PK subset display dose proportionality both after the first dose and at weeks 12 and 24. Within each dosing arm the concentrations measured at week 12 and week 24 are similar, suggesting that steady state had already been reached by these time points.

Details are in the caption following the image


Mean (± SD) etanercept serum concentration–time profiles at week 1 (a), week 12 (b) and week 24 (c) of the subjects from the PK subset of study 3. 1Week 24 after receiving active 25 mg BIW for 12 weeks

The results from the NCA of the individual concentration–time profiles of the PK subset of study 3 are summarized in Table 5. The dose proportionality in the concentration–time profiles was also observed in the calculated PK parameters. As described earlier, for the placebo subjects in the blinded period of study 3, the week 24 concentration–time profiles, corresponding to week 12 of active dosing, were very similar to the profiles observed with the 25-mg BIW group at week 12. These profiles were consistent with the NCA-derived PK parameters presented in Table 5.

Table 5.
Summary statistics of the noncompartmental analysis results for the subjects from the PK subset of study 3
T max (h) C max (ng ml−1) AUCweek1 (mg h l−1)
Week 1
25 mg QW N  10   10  10
Mean  67.8 1320 141
Median  71.0 1420 146
SD  18.1  499  53.5
25 mg BIW N  10   10  10
Mean 137 1580 150
Median 161 1610 115
SD  36.8  660  81.1
50 mg BIW N  14   14  14
Mean 118 3350 383
Median 108 3030 392
SD  46.8 1550 156
T max (h) C max (ng ml−1) C min (ng ml−1) C avg (ng ml−1) AUCweek12 (mg h l−1) Fluct. %
Week 12
25 mg QW N  8    8    7    7   7  7
Mean 85.6 1260  592  976 164 79.8
Median 77.0 1460  528 1210 203 91.5
SD 42.9  611  466  555  93.2 27.1
25 mg BIW N  6    6    5    5   5  5
Mean 60.5 2470 1470 1910 321 51.1
Median 45.5 2550 1670 1740 292 56.4
SD 52.7  523  567  496  83.4 28.0
Placeboa BIW N  7    7    7    7   7  7
Mean 68.6 2870 1560 2070 347 59.3
Median 72.0 2890 1710 2340 393 59.2
SD 46.8 1610  767 1040 174 16.7
50 mg BIW N 10   10    7    7  10  7
Mean 69.3 4900 3100 3670 600 49.3
Median 59.2 4480 3310 3400 542 60.4
SD 48.1 2490 1560 1980 291 29.1
Week 24
25 mg QW N  5    5    5    5   5  5
Mean 47.6 1560  962 1250 210 46.3
Median 59.0 1620  904 1300 218 52.7
SD 33.6  321  183  183 30.7 20.7
25 mg BIW N  5    5    5    5   5  5
Mean 67.5 2770 1750 2110 355 67.5
Median 39.8 2710 1900 2220 373 39.8
SD 67.1  899  902  953 160 67.1
50 mg BIW N 12   12   10   10  10 10
Mean 84.5 4000 2230 2660 448 33.1
Median 80.0 3560 2460 2760 463 33.9
SD 56.6 2980 1400 1480 248 19.7
  • a Week 24 after receiving active 25-mg BIW treatment for 12 weeks. Tmax, time of the maximum concentration; Cmax, maximum concentration; Cmin, minimum concentration; Cavg, average concentration; AUCweek12, area under the curve within week 12; AUCweek24, area under the curve within week 24; Fluct, fluctuation around the average concentration in percentage.

The concentration–time profiles indicate minimal to modest accumulation of etanercept after multiple dosing. The accumulation ratios (calculated as the ratio between the mean AUC at weeks 12 and 24 vs. week 1) are 1.33 (week 12) and 1.35 (week 24) for the 25-mg QW arm; 2.38 (week 12) and 2.61 (week 24) for the 25-mg BIW arm; and 1.77 (week 12) and 1.48 (week 24) for the 50-mg BIW arm.

The etanercept concentration values at the respective times for the 25-mg BIW dosing are consistent across all three studies. The same is true for the concentration values at the respective times for the 50-mg BIW dosing across studies 2 and 3. This is illustrated in Figure 4a,b for 25 mg BIW and 50 mg BIW, respectively. The placebo group in study 3, which started active treatment with 25 mg BIW at week 12, converged to the steady-state concentration typical for this dose.

Details are in the caption following the image


Mean (± SD) etanercept trough serum concentration–time profiles for the various dosing arms in all studies. (a) study 1 (●), study 2 (▾), study 3 (○); (b) study 2 (▾), study 3 (○)

A comparison of the concentration–time data obtained in psoriasis and in RA shows that the PK of etanercept in psoriasis and RA are similar. As shown in Table 6, the PK profiles measured in a phase 3 study with 25 mg BIW etanercept in RA subjects [14] were comparable to the profiles in the respective arms of studies 2 and 3. The similarity in etanercept steady-state PK between RA and psoriasis is supported by the comparison of the PK parameters estimated for RA and psoriasis from the PK subsets of psoriasis study 3 and an RA study in which a weekly profile was measured after administration of a 25-mg BIW dose [19], as shown in Table 7. This similarity is extended to the PK parameters estimated for the 50-mg QW dose arm in the RA study.

Table 6.
Concentration–time profiles after subcutaneously administered 25 mg BIW etanercept in rheumatoid arthritis (RA) and psoriasis subjects
Time (week) RA Psoriasis
Etanercept concentrations (ng ml−1)
Study A [14] Study 2 Study 3
N Conc. (SD) N Conc. (SD) N Conc. (SD)
 4 24 1470 (680) 178 1440 (1160) 138 1390 (1000)
 8 23 1810 (810) 184 1790 (1200) 143 1710 (974)
12 22 2150 (1100) 186 1900 (1110) 143 1990 (1030)
24 23 1780 (910) NA NA 131 2110 (1000)
  • NA, Data not available.
Table 7.
Steady-state pharmacokinetic parameters from psoriasis study 3 (week 12) and a rheumatoid arthritis (RA) study with 25-mg BIW and 50-mg QW doses (week 8)
Pharmacokinetic parameter Mean ± SD Psoriasis study 3a Etanercept 25 mg BIW Week 12 RA studya,b
Etanercept 25 mg BIW Week 8 Etanercept 50 mg QW Week 8
C max (ng ml−1) 2470 ± 523 2610 ± 1220 2400 ± 1530
C min (ng ml−1)  1470 ± 567 1420 ± 730 1210 ± 694
AUC (mg h l−1)  321 ± 83.4  316 ± 135  297 ± 166
T max (h)  60.5 ± 52.7   61.8 ± 28.8  53.0 ± 35.0
  • a Based on the PK subsets in both studies.
  • b [18].

Discussion

This manuscript presents, for the first time, pharmacokinetic data from clinical studies in subjects with moderate-to-severe plaque psoriasis who were treated with etanercept. The results presented are summarized from a total of more than 1300 subjects across three multicentre trials conducted in North America and Western Europe. The large number of subjects studied and the consistency of results across studies underline the reliability of the conclusions drawn.

Both sparse samples (trough values by design) and more intensive weekly profiles (five samples per week) were evaluated. The concentration–time profiles with all three dosing regimens show considerable interindividual as well as intraindividual variability, which is typical for protein molecule drugs and is consistent with the results of previous etanercept studies, both in psoriasis and in other indications.

In all psoriasis clinical studies, the concentration–time profiles of the active arms display dose proportionality, with the concentrations in the 50-mg BIW arm approximately twice as high as the values measured in the 25-mg BIW arm and almost four times higher than the concentrations obtained after the 25-mg QW dose. The PK results within the various dosing arms are highly consistent across the three clinical trials.

All three active doses produced minimal to modest accumulation after multiple dosing. In both studies 2 and 3, the concentration–time profiles displayed a decrease between weeks 2 and 4, followed by gradual increase towards the steady-state concentrations. The reasons for this unexpected decrease of the concentration–time profiles are unknown. A mechanistic explanation could be parameter drift of the system due to the slow and complex processes of the large molecule distribution into and elimination from the body after the initial few doses. The course of the concentration–time profiles after week 4, however, followed the expected course towards steady state. As the foremost determinant of the drug efficacy is the exposure at steady state, the observed fluctuation would not be expected to affect the efficacy profile. Indeed, this was the case as evaluated by the significant improvement in the mean percent change in PASI scores within 2 weeks from the start of therapy [9–11].

The weekly profiles taken with the PK subset of study 3 confirm that the concentration–time profiles at steady state are smooth, characterized by fluctuation values in the range of 50% for the BIW dosing. The latter is due to the slow absorption and even slower elimination rates.

We recognize that questions may arise as to the reliability of the NCA estimates in the PK subset of study 3 (Table 5) due to the small sample size and limited sampling schemes. It can be assumed that, due to the flat concentration–time profiles of etanercept, especially close to or at steady state, the uncertainty in Tmax estimates will be the largest, while the uncertainty in Cmax and AUC should be lower. The latter expectation was confirmed by the observed variability in those estimates (SD in Table 5). While Tmax had the largest variability (SD higher than 50% of the mean, occasionally close to or exceeding 100%), Cmax and AUC estimates were accompanied by coefficients of variation in the range of 30–60%. Compared with the corresponding parameters estimated from simulated profiles using the population PK model [17], which was developed using a significant dataset and has been carefully qualified, the values of the NCA estimates showed that the Cmax and Cmin were within 15–20% of the population PK model-derived values for the 25-mg BIW dosing arm. This 15–20% range was comparable to the accuracy and precision range of the etanercept assay implemented. The NCA Tmax values differed from the model-derived values by up to 120%, which was expected.

A comparison between the PK parameters in psoriasis subjects and previously published data from studies in RA show that the concentration–time profiles of etanercept in both indications are very similar. This provides evidence that the PK behaviour of the drug is mainly determined by the properties of the molecule and does not depend strongly on the targeted disease. Any subtle differences between the observed PK parameters may be attributed more to differences in the demographic characteristics typical for the particular indication (e.g. psoriasis subjects were predominantly men, younger and heavier compared with an RA population that was predominantly women, older and leaner), rather than to any underlying mechanistic or disease-related factors.

Furthermore, the comparison between etanercept PK in RA and psoriasis provides evidence that the similarity can be extended to the PK parameters estimated with a 50-mg QW dose. The latter is an indication that in psoriasis, by analogy to the RA case, the 25-mg BIW dose will yield similar weekly exposure to the 50-mg QW dosing regimen. The latter, combined with the smoothness and dose dependency of the steady-state PK, opens the opportunity to shift to a less frequent QW dosing regimen in psoriasis.

The pharmacokinetic, pharmacodynamic and clinical efficacy information accumulated in these psoriasis studies will enable a rigorous formal study of the dose–exposure–response relationship using population analysis and modelling methods. Such efforts are currently under way and, as a result, the interindividual and intraindividual variability observed will be quantified and the factors contributing to the interindividual variability will be assessed.

Etanercept has been approved for RA since 1998. Approvals for other rheumatological diseases (i.e. juvenile RA, psoriatic arthritis and ankylosing spondylitis) followed subsequently. The current report extends our understanding of this therapeutic agent. Further, it provides strong evidence for consistency of its pharmacokinetic behaviour in chronic plaque psoriasis, which represents a very distinct patient population.

The clinical studies were conducted with the decisive participation of the members of the Etanercept Psoriasis Study Group (for a full member list see [9–11]). Ann Dugan BS, and Yumi Kim PhD were responsible for the study conduct. Mr Abosaleem Bassam coordinated the bioassay of the pharmacokinetic samples. Ting Chang PhD provided editorial assistance. Mrs Mary Ann Simiens, Mrs Nicole Coronado and Mr Naren Narayanan were instrumental in the preparation of this manuscript.