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Clinical Pharmacokinetics of Etanercept: A Fully Humanized Soluble Recombinant Tumor Necrosis Factor Receptor Fusion Protein

From Clinical Pharmacology, Wyeth Pharmaceticals, Collegeville, Pennsylvania.

Address for reprints: Honghui Zhou, PhD, FCP, Clinical Pharmacology, Wyeth Pharmaceuticals, Collegeville, PA 19426.

	ABSTRACT

TOP ABSTRACT PHARMACODYNAMIC PROPERTIES OF... ANALYTICAL METHODS DRUG FORMULATIONS SINGLE-DOSE PHARMACOKINETICS MULTIPLE-DOSE PHARMACOKINETICS EFFECT OF DEMOGRAPHIC... PHARMACOKINETICS IN SPECIAL... DRUG-DRUG INTERACTIONS PHARMACODYNAMIC STUDIES EXPOSURE-RESPONSE RELATIONSHIPS CONCLUSION ACKNOWLEDGEMENTS REFERENCES

 
Etanercept, a fully humanized soluble recombinant tumor necrosis factor receptor fusion protein, is an approved treatment for rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and psoriasis. Etanercept is absorbed slowly from the site of subcutaneous injection, with time to peak concentration at approximately 48 to 60 hours, and is cleared slowly from the body with a t_1/2 of 70 to 100 hours. The absolute bioavailability of etanercept was 58% in healthy subjects following subcutaneous administration. The 25-mg twice-weekly dosage regimen generates systemic exposures comparable to 50 mg once weekly, as predicted by pharmacokinetic modeling and simulation and later confirmed by clinical studies. The pharmacokinetics of etanercept in patients with rheumatoid arthritis are comparable to those in healthy individuals and patients with ankylosing spondylitis, congestive heart failure, and psoriasis. In children with polyarticular-course juvenile rheumatoid arthritis, after subcutaneous doses of 0.4 mg/kg twice weekly, the clearance of etanercept may be slightly reduced in children aged 4 to 8 years. Pharmacokinetic simulation predicts that a dose of 0.8 mg/kg once weekly generates comparable systemic exposure as 0.4 mg/kg twice weekly. No requirement for etanercept dosage adjustment is needed when etanercept is coadministered with warfarin, digoxin, or methotrexate.

Key Words: Etanercept • pharmacokinetics

Rheumatoid arthritis affects approximately 1% of the overall population in many countries.² It is a symmetric inflammatory polyarthritis characterized by bone and cartilage degradation, as well as a systemic wasting phenotype. The underlying cause of this disease remains unknown, but inflammatory cytokines, particularly TNF, play an important role in the development and propagation of articular inflammation and joint destruction.³ In addition, TNF has been implicated in the pathogenesis of psoriatic arthritis, ankylosing spondylitis, and psoriasis. For example, TNF is overexpressed in the synovia, synovial fluid, and skin lesions of patients with psoriatic arthritis compared to controls⁴ and in the sacroiliac joints of patients with ankylosing spondylitis.⁵

This article reviews the clinical pharmacokinetics of etanercept in healthy individuals, special populations, and the target patient populations.

	PHARMACODYNAMIC PROPERTIES OF ETANERCEPT

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Tumor necrosis factor is a cytokine that is involved in the development and maintenance of the immune system. It is a pivotal cytokine in inflammation, and its critical role has been demonstrated in a number of diseases such as RA, ankylosing spondylitis, Crohn's disease, and psoriasis. It also appears to be important in the development and maintenance of granulomas. Etanercept is a fully humanized, soluble, dimeric fusion protein consisting of 2 copies of the extracellular ligand-binding portion of the human TNF p75 receptor linked to the portion of human immunoglobulin G₁. It binds to TNF, thereby blocking its interaction with cell surface receptors and attenuating its pro-inflammatory effects.

	ANALYTICAL METHODS

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Etanercept serum concentrations were measured with enzyme-linked immunosorbent assay (ELISA) methodology.⁶ Serum etanercept concentrations were determined by a validated ELISA with a limit of quantitation of 0.3 ng/mL based on 1:5 minimum sample dilution. Specificity of the ELISA was demonstrated against a panel of human cytokines and cytokine receptors, including IL-1, IL-1b, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, GM-CSF, TNF, TNFß, IL-1R, and IL-4R. The antibodies used in the ELISA do not distinguish between recombinant and endogenous TNFr.

	DRUG FORMULATIONS

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Etanercept is supplied as a sterile, lyophilized powder in glass vials that contain 25 mg etanercept. After reconstitution with 1.0 mL sterile bacteriostatic water for injection, etanercept is suitable for subcutaneous (SC) injection. Injection sites should be rotated among the thigh, abdomen, and upper arm, and new injections should be given as least 1 inch away from an old site and never into areas where the skin is tender, bruised, red, or hard.

In the United States, the recommended dose of ENBREL for adult patients with RA, psoriatic arthritis, or ankylosing spondylitis is 50 mg per week given as two 25-mg SC injections at separate sites. The dose should be administered as two 25-mg injections given either on the same day or 3 or 4 days apart. The recommended starting dose for adult patients with psoriasis is a 50-mg dose given twice weekly (administered 3-4 days apart) for 3 months followed by a reduction to a maintenance dose of 50 mg per week. The recommended dose for pediatric patients aged 4 to 17 years with active polyarticular-course JRA is 0.8 mg/kg per week (up to a maximum of 50 mg per week). The maximum dose that should be administered at a single injection site is 25 mg. Therefore, for pediatric patients weighing more than 31 kg, the total weekly dose should be administered as 2 SC injections, either on the same day or 3 or 4 days apart. The dose for pediatric patients weighing 31 kg or less should be administered as a single SC injection once weekly.

	SINGLE-DOSE PHARMACOKINETICS

TOP ABSTRACT PHARMACODYNAMIC PROPERTIES OF... ANALYTICAL METHODS DRUG FORMULATIONS SINGLE-DOSE PHARMACOKINETICS MULTIPLE-DOSE PHARMACOKINETICS EFFECT OF DEMOGRAPHIC... PHARMACOKINETICS IN SPECIAL... DRUG-DRUG INTERACTIONS PHARMACODYNAMIC STUDIES EXPOSURE-RESPONSE RELATIONSHIPS CONCLUSION ACKNOWLEDGEMENTS REFERENCES

 
Absorption and Absolute Bioavailability
When a single 25-mg dose of etanercept was administered SC to 26 healthy subjects, etanercept was slowly absorbed from its SC injection sites, reaching a mean peak concentration of 1460 ± 720 ng/mL at 51 ± 14 hours.⁷ Mean absolute bioavailability after SC administration was 58.0% in 6 healthy subjects who received a single dose of 10 mg etanercept⁸; the mean etanercept concentration-time curves following both SC and intravenous administrations are illustrated in Figure 1.

View larger version (27K): [in this window] [in a new window]   Figure 1. Mean ± SD serum concentration-time profiles of etanercept following subcutaneous (SC) and intravenous administration of 10 mg etanercept in healthy subjects.

Nonlinear mixed-effect modeling results from 10 clinical studies of etanercept administered SC or intravenously to healthy subjects (n = 53) and to patients with RA (n = 212) predicted similar (62.6%) absolute bioavailability.⁹

Distribution
Following a single SC administration of etanercept in healthy subjects, its apparent volume of distribution was small (12 ± 6L).⁷ Following 25 mg SC twice weekly of etanercept for 24 weeks, the apparent volume of distribution was 18.5 L.¹⁰ Assuming 60% bioavailability, the volume of distribution of etanercept could be approximately 6 to 11 L, which is slightly larger than the plasma volume of 3.75 L (5% blood volume in a 75-kg subject) but smaller than that of extracellular water (16 L). For etanercept, a macromolecule with an apparent molecular weight of approximately 150 kD, its extravascular distribution is expected to be very small to nonexistent.¹¹ In one of the early clinical studies in patients with RA, arthrocentesis was performed on a subset of subjects to obtain synovial fluid samples for the determination of pharmacodynamic markers, such as IL-6, IL-1Ra, and so on. Three samples with remaining synovial fluid were used for the determination of etanercept concentration. The results, albeit limited, suggested that etanercept penetrates into synovial fluid and reaches concentrations that are comparable to serum concentrations (Table I).

Elimination
It is assumed that following binding of etanercept to TNF, the complex is metabolized through peptide and amino acid pathways with either recycling of amino acids or elimination in bile and urine.⁷

Dose Proportionality
Following SC administration of etanercept, dose proportionality in etanercept steady-state concentrations was observed from 10 mg/wk to 100 mg/wk, as shown in Figure 2.

View larger version (14K): [in this window] [in a new window]   Figure 2. Relationship between etanercept steady-state concentrations and weekly dose of etanercept following subcutaneous administration.

	MULTIPLE-DOSE PHARMACOKINETICS

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Rheumatoid Arthritis
The single-dose and multiple-dose pharmacokinetics of etanercept in patients with RA were examined for 24 weeks. They received a single 25-mg etanercept dose SC, followed in 3 weeks by 25 mg twice weekly for 6 months.¹⁰ The single-dose results observed in this study provide parameter estimates that are qualitatively similar to the pharmacokinetic parameters observed in healthy subjects and patients with RA following the single dose. The drug was absorbed slowly, reaching peak concentrations 2 or 3 days after dose administration. The mean C_max of 1072 ng/mL observed in this study is somewhat lower than the mean of 1460 ng/mL observed in healthy subjects.⁷ The drug is eliminated slowly, with a low clearance and relatively long half-life of 102 ± 30 hours.

The multiple-dose results observed in this study also provide estimates that are both predictable from the results of the single-dose portion of this study and are consistent with results observed in other studies. Dosing every 72 to 96 hours would be predicted to result in the accumulation of 2- to 3-fold in patients with half-lives of approximately 100 hours. The median accumulation ratio observed following 24 weeks of twice-weekly treatment was 2.7, with a range of 1.4 to 16.7. Table II contains a summary of noncompartmental pharmacokinetic parameters following a single 25-mg SC dose and after 24 weeks of twice-weekly 25-mg SC dosing.

Consistent with its elimination rate and dose frequency, etanercept C_max after the final dose was approximately 2-fold higher than that after the first dose. The t_max appears to occur sooner following repeated dosing and may be an artifact of infrequent blood sampling (24-hour intervals) during the 24- to 72-hour time period.

There was no change in etanercept pharmacokinetic parameters observed in patients with RA during 6 months of treatment. The apparent clearance observed during multiple dosing was highly variable both within each patient as well as between patients. Overall, the apparent clearance of etanercept does not change with chronic SC dosing.

Given the slow absorption and elimination of etanercept following SC administration, it is anticipated that the dosing regimen of 50 mg once weekly will yield a comparable systemic exposure to that of 25 mg twice weekly. The comparable concentration-time profiles of etanercept as well as similar efficacy and safety between both regimens were observed in a clinical study.¹²

Juvenile Rheumatoid Arthritis
Nonlinear mixed-effect model analysis with NONMEM and bootstrapping was performed using the etanercept pharmacokinetic data from a clinical trial in 69 patients with JRA aged 4 to 17 years.¹³ The population pharmacokinetic model below could adequately describe etanercept serum concentration-time profiles for twice-weekly subcutaneous dosing of 0.4 mg/kg.

Based on the final population pharmacokinetic parameters obtained herein, a Monte Carlo clinical trial simulation experiment was conducted to compare the pharmacokinetic profiles of 200 pediatric patients with JRA who randomly received either etanercept 0.4 mg/kg SC twice weekly or 0.8 mg/kg once weekly for 12 weeks. Simulations using the population pharmacokinetic parameters obtained herein confirmed that 0.8 mg/kg once weekly and 0.4 mg/kg twice weekly SC of etanercept will yield an overlapping steady-state time-concentration profile and are expected to yield equivalent clinical outcomes. This has been the basis of the recent Food and Drug Administration (FDA) approval of the 0.8-mg/kg once-weekly regimen in pediatric patients with JRA.

Ankylosing Spondylitis
In a multicenter, double-blind, parallel, placebo-controlled, randomized study to evaluate the efficacy and safety of etanercept in the treatment of adult patients with ankylosing spondylitis, sparse pharmacokinetic samples for etanercept were obtained at weeks 4 and 12 from 43 patients with ankylosing spondylitis (median age, 45 years). A population pharmacokinetic analysis using NONMEM was conducted to characterize the disposition of etanercept in this patient population. It has been noted that ankylosing spondylitis does not appear to alter the disposition of etanercept.⁹

Psoriasis
The pharmacokinetics of etanercept have been studied in several phase III clinical studies in patients with psoriasis.¹⁴ In general, pharmacokinetic results of etanercept were highly consistent across these studies. In addition, the pharmacokinetics in the patients with psoriasis were in good agreement with those in the patients with RA.

	EFFECT OF DEMOGRAPHIC CHARACTERISTICS ON PHARMACOKINETICS

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Status of Rheumatoid Arthritis
In a pooled pharmacokinetic analysis in which 212 patients with RA and 53 healthy subjects were included,⁹ the presence of RA was found to have significant impact on the absorption rate constant (k_a). Healthy subjects had a 47% higher absorption rate constant than the patients with RA. However, its clinical relevance is considered limited.

Age
Zhou et al⁹ identified age (<17 years) as one of the most important covariates in the population pharmacokinetic analysis based on the pooled data from 10 clinical studies. A positive correlation between age (<17 years) and apparent clearance was observed. The dependence of clearance (CL) on age was no longer apparent when age was 17 years and older. No apparent impact of aging (>65 years) on etanercept clearance was observed.

Body Size
Lee et al¹⁵ identified body weight as an important covariate for both apparent clearance (CL/F) and apparent volume of distribution (V/F) based on their mixed-effect analysis of the pharmacokinetic data from adult rheumatoid arthritis patients. On a separate analysis based on the pharmacokinetic data from 69 JRA patients, body surface area was a significant covariate for CL/F, whereas body weight was significant for V/F.¹³ This finding justified the approved "mg/kg" dosage regimen for etanercept in JRA patients.

Gender
Lee et al¹⁵ found that the population mean for CL/F in adult female patients was 0.117 L/h (95% confidence interval [CI]: 0.108-0.130 L/h), which was slightly lower than the adult male value of 0.138 L/h (95% CI: 0.118-0.163 L/h), but this difference was not statistically significant. A similar finding was also observed in JRA patients with the population mean CL/F of 0.0576 L/h (95% CI: 0.0525-0.0657 L/h) for females and 0.0772 L/h (95% CI: 0.066-0.0870 L/h) for males.¹³

Ethnic Origin
Nonwhite patients with RA had a 38% larger value of CL/F than white patients based on the population pharmacokinetic analysis, but caution should be exercised in interpreting this result, given the small number of nonwhite subjects included in this analysis.¹⁵ In a separate mixed-effect population pharmacokinetic analysis, white subjects had a slightly larger apparent volume of distribution than did nonwhite subjects. Nevertheless, this difference was likely due to the larger body weight observed in white subjects.⁹

	PHARMACOKINETICS IN SPECIAL POPULATIONS

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Hepatic and Renal Dysfunction
No comprehensive studies have been performed to assess the pharmacokinetics of etanercept in patients with either hepatic or renal dysfunction.

Chronic Heart Failure
Heart failure can affect the pharmacokinetics of many medications, although unfortunately, not in a predictable manner.^16,17 An open-label pharmacokinetic study was conducted in 11 patients with New York Heart Association (NYHA) class II-IV heart failure who received subcutaneous administration of 12 mg/m² (maximum dose 25 mg) twice weekly. The CL/F values (0.138 L/h) reported in these heart failure patients¹⁸ are similar to those for healthy subjects and patients with RA.⁹

Lactating Women
No formal clinical study has been conducted in lactating women to investigate the excretion of etanercept in human milk that is subsequently absorbed systemically by their infants. A case study has been recently reported¹⁹ to estimate etanercept excretion in human breast milk in a 30-year-old woman with RA receiving etanercept 25 mg twice weekly for 4 weeks after delivery. Although there was a small amount of etanercept excreted into breast milk, the risk that this small amount of etanercept could be ingested and observed orally by a nursing infant and reach pharmacologic concentrations remains speculative and not very likely. Nevertheless, a decision should be made whether to discontinue nursing or etanercept in nursing mothers.

	DRUG-DRUG INTERACTIONS

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Warfarin
In a nonrandomized, 3-period crossover study, 12 healthy male subjects received a single oral 25-mg dose of warfarin after an overnight fast, followed by twice-weekly 25-mg SC doses of etanercept for 7 doses. The last dose of etanercept was administered concurrently with a second dose of warfarin. Etanercept did not affect the pharmacokinetics and pharmacodynamics of warfarin. All ratios of C_max and AUC for pharmacokinetics (R- and S-enantiomer of warfarin) and the international normalized ratio (INR) for pharmacodynamics fell within the confidence interval of 0.8 to 1.25. The comparability of S-enantiomer or R-enantiomer (not shown here) of warfarin systemic exposures with and without coadministration of etanercept is also illustrated in Figure 3. Warfarin also did not cause a clinically significant alteration in the pharmacokinetics (PK) of etanercept. No dosage adjustment is needed in cases in which warfarin and etanercept are coadministered.⁶

View larger version (28K): [in this window] [in a new window]   Figure 3. Individual and mean serum concentration-time profiles of S-warfarin after administration of warfarin alone (day 1) and plus etanercept (day 29) in 12 healthy subjects.

Digoxin
In a nonrandomized, 3-period crossover study, 12 healthy male subjects received loading oral doses of digoxin 0.5 mg every 12 hours on day 1 and 0.25 mg every 12 hours on day 2, followed by a daily maintenance dose of 0.25 mg for a total of 27 days.²⁰ Etanercept was administered as a twice-weekly 25-mg subcutaneous dose beginning on day 9 and continuing up to day 37 for a total of 9 doses. Serial blood samples for etanercept serum and digoxin plasma concentrations were collected after the last dose during each period, day 8 for digoxin alone, day 27 for digoxin and etanercept together, and day 37 for etanercept alone. Urine samples were collected over 24 hours on the digoxin sampling days. All ratios of C_max and AUC for the pharmacokinetics of digoxin fell within the 90% confidence interval of 0.8 to 1.25. The similarity of digoxin systemic exposure with and without coadministration of etanercept is also illustrated in Figure 4. Although not considered clinically relevant, the mean C_max and AUC of etanercept were 4.2% and 12.5% lower, respectively, when etanercept was given with digoxin than when administered alone. There were no clinically relevant changes in the electrocardiogram (ECG) parameters, and adverse events did not increase when both drugs were combined. In conclusion, there is no clinically relevant interaction between etanercept and digoxin, and both drugs can be safely coadministered without the need for a dosage adjustment.

View larger version (31K): [in this window] [in a new window]   Figure 4. Individual and mean serum concentration-time profiles of digoxin at steady state after administration of digoxin alone (day 8) and plus etanercept (day 27) in 12 healthy subjects.

Methotrexate
Methotrexate is frequently used with anti-TNF biologics in the treatment of rheumatoid arthritis. It has been shown that the concurrent administration of methotrexate could decrease the clearance of 2 monoclonal antibodies specific for TNF.^21-24 The combination of etanercept and methotrexate in the large-scale TEMPO study was found to be significantly better in reducing disease activity, improving functional disability, and retarding radiographic progression compared with methotrexate or etanercept alone.²⁵ To optimize the combination therapy of etanercept and methotrexate, it is crucial to understand if the concomitant administration of methotrexate can alter the pharmacokinetics of etanercept. A population-based analysis approach was applied to determine the effect of concurrent methotrexate administration on the pharmacokinetics of etanercept. The pharmacokinetics of etanercept were not altered by the concurrent administration of methotrexate in patients with RA. Thus, no etanercept dose adjustment is needed for patients taking concurrent methotrexate.²⁶

Anakinra
The etiology of RA remains unclear, but it is thought to be mediated in part by antigen-driven T cells and macrophages that produce interleukin-1 (IL-1) and TNF, 2 cytokines involved in the inflammatory cascade.^27,28 Combination treatment with anakinra, a recombinant IL-1 receptor antagonist and polyethylene glycol-conjugated soluble TNF receptor type I, resulted in better improvement in the symptoms of adjuvant-induced and collagen-induced arthritis in rats relative to the improvement observed with either agent alone.^29,30 Therefore, a clinical study was designed to test the hypothesis that combination therapy with the anti-TNF agent etanercept and the anti-IL-1 agent anakinra, at their approved dosages, would safely provide superior efficacy relative to etanercept alone in patients with RA.³¹ Patients were randomly assigned in a 1:1:1 ratio to receive 25 mg of etanercept twice weekly plus anakinra placebo once daily, 25 mg of etanercept once weekly plus 100 mg of anakinra daily, or 25 mg of etanercept twice weekly plus 100 mg of anakinra once daily. Steady state was reached by week 4 for both etanercept and anakinra, and thus the data for all visits (ie, weeks 4, 12, and 24) were pooled for analysis. The pharmacokinetics of each agent appeared unaffected by the concomitant administration of the other.

	PHARMACODYNAMIC STUDIES

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The human endotoxin-challenged model is used as a model of the cardiovascular and inflammatory responses that occur during sepsis.³² The effect of etanercept on acute phase responses was evaluated in 18 healthy subjects given intravenous endotoxin (4 ng/kg). Subjects were randomized to receive placebo (n = 6), intravenous etanercept 10 mg/m² (n = 6), or intravenous etanercept 60 mg/m² (n = 6). Secondary cytokine levels were diminished, leukocyte margination and neutrophil recruitment was inhibited, and early activation of endothelial cells and neutrophils was blunted following etanercept treatment. Nevertheless, the febrile response to endotoxin was delayed but not diminished following etanercept, despite neutralization of TNF bioactivity and suppression of IL-1 and IL-6.³³ A remarkable finding of this study was that, although both etanercept doses provided a large excess of TNF neutralizing capacity, the lower dose exerted the most prominent anti-inflammatory effects. In view of that, another endotoxin-challenged study was conducted to determine the anti-inflammatory effects of an even lower dose of etanercept (6 mg/m²) during endotoxemia in healthy subjects. Twelve healthy subjects received intravenous endotoxin (2 ng/kg) preceded by infusion of either etanercept 6 mg/m² (n = 6) or vehicle (n = 6) from -30 minutes to directly before endotoxin injection.³⁴ Administration of etanercept at a dose of 6 mg/m² effectively neutralized TNF activity produced in response to intravenous endotoxin. Etanercept strongly inhibited endothelial cell activation (soluble E-selectin) and modestly reduced neutrophil responses but did not affect the release of secretory phospholipase A₂ or lipopolysaccaride-binding protein.

	EXPOSURE-RESPONSE RELATIONSHIPS

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ACR20 has been widely used in rheumatoid arthritis clinical trials and is the basis for regulatory decisions for antirheumatic agents claiming reduction in the signs and symptoms of rheumatoid arthritis.^35,36 ACR20 data from 80 placebo-treated patients in a phase III study were used to describe the placebo-time course of ACR20. Logistic regression with NONMEM was applied to describe the exposure-response relationship, with the cumulative area under the concentration-time curve as the exposure variable.¹⁵ Specifically, the model was used to quantify the probability of achieving ACR20 with the assumption that p is the probability of achieving ACR20, and the model has the following structure.

is an individual random effect in the logit transformation of p, and f (exposure, time) is a function of drug exposure. The model-predicted percentage of patients achieving ACR20 at 6 months after dosing of 25 mg subcutaneously twice weekly was 54.9%, comparable to the observed 52.9%.

	CONCLUSION

TOP ABSTRACT PHARMACODYNAMIC PROPERTIES OF... ANALYTICAL METHODS DRUG FORMULATIONS SINGLE-DOSE PHARMACOKINETICS MULTIPLE-DOSE PHARMACOKINETICS EFFECT OF DEMOGRAPHIC... PHARMACOKINETICS IN SPECIAL... DRUG-DRUG INTERACTIONS PHARMACODYNAMIC STUDIES EXPOSURE-RESPONSE RELATIONSHIPS CONCLUSION ACKNOWLEDGEMENTS REFERENCES

 
In the clinical trials performed, etanercept has been shown to be effective in the treatment of RA, JRA, psoriatic arthritis, ankylosing spondylitis, and psoriasis. To date, no clinically relevant drug-drug interactions between etanercept and other commonly prescribed drugs have been detected. The pharmacokinetic features discussed in this article may be a favorable aspect of treatment with etanercept as it is evaluated further in additional populations.

	ACKNOWLEDGEMENTS

TOP ABSTRACT PHARMACODYNAMIC PROPERTIES OF... ANALYTICAL METHODS DRUG FORMULATIONS SINGLE-DOSE PHARMACOKINETICS MULTIPLE-DOSE PHARMACOKINETICS EFFECT OF DEMOGRAPHIC... PHARMACOKINETICS IN SPECIAL... DRUG-DRUG INTERACTIONS PHARMACODYNAMIC STUDIES EXPOSURE-RESPONSE RELATIONSHIPS CONCLUSION ACKNOWLEDGEMENTS REFERENCES

 
I thank Dr Philip Mayer for his thoughtful comments and review of this manuscript. I also thank Dr Howard Lee and Dr Dong-Seok Yim at Georgetown University for kindly providing the simulation data in the pediatric population.

	REFERENCES

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