The pharmacokinetics of etanercept in patients with heart failure

Although the cause of disease progression is multifactorial, recent studies have demonstrated that the development of symptomatic heart failure is associated with an increase in circulating levels of the proinflammatory cytokine tumour necrosis factor (TNF) [1, 2]. Thus, investigators proposed that inhibition of TNF expression or bioavailability might have salutory effects in patients with symptomatic heart failure.

Etanercept (TNFR : Fc, Enbrel®) is a recombinant, human, fusion protein that binds to TNF, prohibiting its proinflammatory action. After subcutaneous administration, its pharmacokinetic parameters have been characterized in healthy volunteers and patients with rheumatoid arthritis [3, 4]. It is slowly absorbed (t_max=51–72 h) and slowly cleared (CL/F = 0.089–0.137 l h⁻¹; t_½ = 68–115 h). Because of its large molecular size etanercept may be eliminated by the reticuloendothelial system of the liver or spleen [3]. Etanercept is presently undergoing evaluation as a therapeutic option for patients with heart failure in two clinical trials; one in the US (RENAISSANCE) and a second in Europe, Australia and New Zealand (RECOVER).

Heart failure can affect the pharmacokinetic characteristics of many medications, although unfortunately, not in a predictable manner [5, 6]. The purpose of this study was to describe the pharmacokinetics of etanercept in patients with heart failure.

Eleven patients, nine males and two females, with NYHA class II–IV heart failure participated in this open-label pharmacokinetic portion of a larger study after completing a double-blind, randomized multiple-dose safety trial [7]. Their ages ranged from 31 to 74 years. Mean creatinine clearance was 99 ml min⁻¹ (range 48–134 ml min⁻¹). Concomitant medications had been stable for at least 1 month prior to randomization.

Patients had received a dose of 12 mg m⁻² (maximum dose 25 mg) of etanercept (Enbrel, Immunex Corporation) by subcutaneous injection twice weekly for 12 weeks. Twice-weekly dosing necessitated uneven dosage intervals of 72 h and 96 h. Care was taken that all patients be studied during a 96 h dosing interval. Serial serum samples were collected by separate venipuncture before and at 2, 4, 12, 24, 36, 48, 60, 72, and 96 h after drug administration. Each sample was immediately centrifuged in the cold and the supernatant removed and frozen.

Etanercept serum concentrations were measured using an ELISA method with a limit of quantification of 0.3 ng ml⁻¹. The coefficient of variation for the quality controls was less than 7%. Adequate storage stability had been previously demonstrated.

The serum concentration data were analysed using a noncompartmental method [8]. The maximum serum concentration (C_max) and t_max were determined directly from the observed concentration data. The area under the concentration-time curve (AUC) was calculated using the linear trapezoidal rule. Apparent clearance after oral administration (CL/F) was calculated as a ratio of dosing rate to AUC. Summary statistics were calculated for concentration and for C_max, t_max, AUC, and CL/F for all patients.

Pharmacokinetic parameters for etanercept are shown in Table 1. Concentrations measured prior to dose administration (C_o) are also reported.

Table 1.

Multiple-dose etanercept pharmacokinetic parameters in heart failure patients.

Patient	Dose (mg)	Cmax (mg l−1)	tmax (h)	AUC (mg l−1 h)	CL/F (ml h−1)	Co (mg l−1)
120	21.96	2.34	72	192*	114	1.90
124	25.00	2.66	24	221	113	1.83
125	25.00	3.72	36	263*	95.1	1.39
126	21.60	3.61	96	269	80.4	2.18
129	18.24	2.13	96	105	174	0.69
130	25.00	1.39	36	111*	225	0.96
132	24.72	2.38	36	207	119	1.77
136	25.00	2.20	12	128	196	1.41
138	25.00	1.41	36	109*	229	1.10
143	22.32	2.42	24	198	113	1.57
145	25.00	1.50	36	123	204	0.64
Mean		2.34	46	175	138	1.40
s.d.		0.79	29	62	44	0.51

^*Time discrepancies in 96 h sample; AUC extrapolated from 72 h.

Etanercept was generally well tolerated in the patients studied [7]. Mild, injection-site reactions were the primary adverse events related to study drug administration. These occurred in 10% of patients treated with etanercept on at least one occasion, and disappeared after the first month.

This publication provides the first pharmacokinetic data for etanercept in patients with heart failure. The very small number of patients studied limit this report to a preliminary estimate of true parameter values, but the CL/F values reported here are similar to those reported for healthy volunteers and patients with rheumatoid arthritis after single doses.