Clinical Trial Result Information
Title of Study:
Single-dose study of pharmacokinetics of enfuvirtide (FUZEON, T20/RO29-9800) in HIV-1 infected subjects with renal impairment.
Fast Facts:
| Protocol number: | NP17586 |
| Sponsor: | Hoffmann-La Roche Ltd. |
| Company division: | Pharmaceutical |
| Product name: | Fuzeon |
| Generic name: | enfuvirtide |
| Phase of development: | IV |
| Therapeutic area, approved indication: | HIV Infections |
| Date of report: | 6/1/2006 |
Clinical study summary:
This study was an open-label, parallel group study of Fuzeon (enfuvirtide) in HIV-1 infected subjects with varying degrees of renal function. Study groups were as follows:
Group A: HIV-1 infected subjects with severe renal impairment (renal creatinine clearance 11 to 35 mL/min).
Group B: HIV-1 infected subjects with end-stage renal impairment requiring hemodialysis (renal creatinine clearance ≤ 10 mL/min).
Group C: HIV-1 infected subjects with normal renal function (renal creatinine clearance > 80 mL/min).
Study center(s) :
Five centers in the United States.
Objectives:
The objectives of the study were to examine the influence of a severe degree of renal impairment and hemodialysis on the pharmacokinetics of Fuzeon in HIV-1 infected subjects.
Methodology:
Following screening, all subjects reported to the clinic on the morning of study Day 1, Period 1 and received a single 90 mg dose of Fuzeon injected subcutaneously into the abdomen.
Subjects in Group B returned to the clinic between 1 and 4 weeks after the first dose and received another single 90 mg dose of Fuzeon subcutaneously on Day 1 of Period 2. One dose was administered on a non hemodialysis day and the other was administered on a hemodialysis day. For subjects receiving Fuzeon on their scheduled dialysis day, dialysis was performed 6 hours after the Fuzeon dose.
On each Fuzeon dosing day, blood samples were collected for pharmacokinetic analysis prior to dosing and at intervals after dosing.
For subjects in group B undergoing hemodialysis on the day of dosing, one sample of venous blood was collected prior to the hemodialysis procedure, then paired samples from the lines entering and leaving the hemodialysis chamber were collected at the midpoint and at the end of the procedure.
Number of patients (planned/analyzed):
Planned: 24 subjects. Enrolled: 20 subjects.
Diagnosis and main criteria for inclusion:
HIV-1 infected males or females between 18 and 64 years old. Renally compromised subjects who were known to the investigator and had been followed long enough to establish that they had reasonably stable renal function as assessed by creatinine clearance monitoring.
Test product, dose and mode of administration or test procedure:
Fuzeon 90-mg administered subcutaneously in the abdomen.
Duration of treatment:
A single dose for groups A and C; two doses (one on a dialysis, and one on a non-dialysis, day) for group B
Criteria for evaluation (efficacy, safety):
Pharmacokinetics: Plasma concentrations of enfuvirtide were determined using the LC/MS/MS method. The following pharmacokinetic parameters were estimated for enfuvirtide using model-independent techniques: Cmax, tmax, t½, CL/F, AUClast, AUC0-inf, and kel.
The extraction ratio of the hemodialysis procedure was estimated by measuring simultaneously concentrations of enfuvirtide in samples collected from the lines entering and leaving the hemodialysis chamber.
Safety: Safety parameters included adverse events (including deaths and serious adverse events), premature withdrawals due to adverse events, local injection site reactions, clinical laboratory tests (hematology, serum chemistry, and urinalysis), electrocardiograms (ECGs), and vital signs.
Statistical methods:
Enfuvirtide plasma concentrations and computed pharmacokinetic parameters were listed and summarized by renal function.
The relationship between renal impairment and pharmacokinetics of enfuvirtide was assessed by regressing the enfuvirtide CL/F onto creatinine clearance. Comparison of Groups A and C and Groups B (non-hemodialysis day) and C was done using an analysis of variance. Confidence intervals (90%) for the difference in computed parameter least squares means was calculated and expressed as a percentage of the reference (Group C).
The same procedures were used to assess the extraction of enfuvirtide by the hemodialysis procedure by comparing the AUCinf estimates on non-hemodialysis and hemodialysis days. In addition, the dialysis clearance and extraction ratio was determined from samples collected from the lines entering and leaving the hemodialysis chamber.
Summary (efficacy, safety, other results):
Pharmacokinetics: Mean Cmax and AUCinf for subjects with severe renal impairment (Group A) were higher than for subjects with normal renal function. CL/F was lower for subjects with severe renal impairment than for subjects with normal renal function. Thus, patients with severe renal function had 38% (1.88 – 1.17/1.88) lower enfuvirtide clearance than patients with normal renal function.
Mean Cmax and AUCinf for subjects with end stage renal impairment requiring hemodialysis (Group B) were higher on the non-dialysis day than those for patients with normal renal function and comparable to those for patients with severe renal impairment. Mean CL/F was lower for dialysis subjects on the non-dialysis day than for subjects with normal renal function. Thus, dialysis subjects had 28% (1.88 - 1.36/1.88) lower enfuvirtide clearance on the non-dialysis day than subjects with normal renal function.
Mean Cmax, AUCinf, and CL/F for dialysis subjects on the dialysis day were comparable to those on the non-dialysis day. Mean CL/F was lower for dialysis subjects on the dialysis day than for subjects with normal renal function. Thus, dialysis subjects had 14% (1.88 – 1.62/1.88) lower enfuvirtide clearance on the dialysis day than subjects with normal renal function.
ANOVA testing of AUCinf and Cmax showed that none of the 90% confidence intervals were within the 80 125% range for the following: 1) between the severe renal impairment group and the normal renal function group; 2) between the dialysis group on the non-dialysis day and the normal renal function group; and 3) between the dialysis group on the non-dialysis day and on dialysis day.
Safety: One subject in Group A, 3 subjects in Group B, and 1 subject in Group C had an adverse event during the study. Adverse events in Groups A and C included an upper respiratory tract infection and local swelling, respectively. Adverse events in Group B included headache, injection site paresthesia, pain in extremity, increased body temperature, nausea, and vomiting. Headache and injection site paresthesia were judged by the investigator as related to Fuzeon. All adverse events were mild or moderate in intensity.
No subjects in Groups A or C and 4 subjects in Group B had a local injection site reaction. Each of these reactions was associated with slight induration and each lasted for 1 day. Three of these subjects had no pain associated with these reactions. One subject reported mild tenderness at the injection site within 1 hour of enfuvirtide injection, but this pain did not persist for longer than 1 hour following injection.
No deaths, serious adverse events, or premature withdrawals due to adverse events occurred during the study.
Five subjects had marked laboratory abnormalities (glucose, glycosuria, RBC, GGT, hematuria, proteinuria). With the exception of the subject with marked GGT, each marked abnormality was an isolated occurrence. One subject in Group A (high blood pressure) and one subject in Group B (elevated temperature) had an abnormal vital sign during the study. Two subjects in Group A, one subject in Group B, and one subject in Group C had an ECG abnormality during the study. All of the ECG abnormalities were present at screening and persisted throughout the study.
Conclusions:
The safety profile of Fuzeon in subjects with normal renal function, severe renal impairment, and end stage renal impairment requiring hemodialysis was similar. Less than 13% of the drug was removed during the dialysis procedure for subjects with end stage renal impairment which supported the observation of similar pharmacokinetic parameters between the non-dialysis and dialysis days. Subjects with severe renal function had 38% lower enfuvirtide clearance than subjects with normal renal function. Subjects on dialysis had 14% (dialysis day) to 28% (non-dialysis day) lower enfuvirtide clearance than subjects with normal renal function.
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