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Enfuvirtide Does Not Require Dose-adjustment in Patients with Chronic Renal Failure: The Results of a Pharmacokinetic Study of Enfuvirtide in HIV-1-infected Patients with Impaired Renal Function (NP17586)
Pablo Tebas*1, N Bellos2, C Lucasti3, G Richmond4, E Godofsky5, I Patel6, N Buss7, Y Y Chiu6, L Rowell8, and M Salgo6
1Univ of Pennsylvania, Philadelphia, US; 2Southwest Infectious Disease Assoc, Dallas, TX, US; 3South Jersey Infectious Disease, Somers Point, NJ, US; 4North Broward Hosp District, Ft Lauderdale, FL, US; 5Bach & Godofsky, Bradenton, FL, US; 6Roche, Nutley, NJ, US; 7Roche, Basel, Switzerland; and 8Roche, Welwyn, UK
Background: Renal failure is
common among HIV-infected patients, but data on dose adjustments of ART in HIV+
individuals are limited. Enfuvirtide (ENF), the only approved fusion inhibitor,
is a 36 amino acid peptide administered by subcutaneous injection twice daily.
ENF has a high bioavailability (84.3%), small volume of distribution (5.48 L),
low systemic clearance (1.4 L/h), and moderately high protein binding (92%).
ENF is primarily eliminated via catabolism to its constituent amino acids and
has been shown to have a low potential for drug–drug interactions.
Methods: We evaluated the
influence of renal impairment and hemodialysis on the pharmacokinetics of ENF
in HIV+ patients receiving HAART. The study was an open-label,
parallel group study. Group A included patients with renal creatinine clearance
(CL) of 11 to 35 mL/min; group B, patients with
end-stage renal disease (ESRD) requiring hemodialysis (renal creatinine CL ≤10
mL/min); group C, patients with normal renal function
(renal creatinine CL >80 mL/min). A single 90-mg
dose of ENF was administered subcutaneously to patients in groups A and C and a
single 90-mg dose of ENF was administered subcutaneously to group B on 2
occasions, a dialysis and a nondialysis day. After each
dose a full 48-hour pharmacokinetic profile was collected. A comparison to pharmacokinetic
parameters from past studies was also performed.
Results: ENF was well
tolerated. (Pharmacokinetic parameters are shown in the table.) The number of
adverse events was 1, 3, and 1 in groups A, B, and C, respectively. All adverse
events were mild or moderate in severity. Of these, only mild headache (possibly),
and mild injection site parasthesia (probably) (1
patient in group B) were considered related to treatment.
|
Group
(creatinine CL)
|
N
|
Cmax
(mg/mL)
|
AUCinf (mg.h/mL)
|
t1/2
(h)
|
|
A (11 to 35 mL/min)
|
4
|
5.72±1.82
|
80.3±17.3
|
4.94±1.18
|
|
B (<10 mL/min) non-dialysis day
|
8
|
5.34±2.36
|
71.1±20.6
|
5.60±1.29
|
|
B (<10 mL/min) dialysis day
|
7
|
6.31±3.06
|
66.9±30.9
|
6.07±2.06
|
|
C (>80 mL/min)
|
8
|
3.79±1.22
|
49.6±9.90
|
6.15±5.34
|
|
All values
Mean ± SD
|
|
|
|
|
Conclusions: Pharmacokinetic
exposure observed in patients with ESRD or impaired renal function were
slightly higher than patients with normal renal function and similar to historical
Cmax and AUC values from studies in patients
with normal renal function. The safety profile of a single dose of ENF was
similar in the 3 groups. ENF does not require adjustment in patients with impaired
renal function.
|
