Tebas, Pablo MD*; Bellos, Nicholas MD†; Lucasti, Christopher DO‡; Richmond, Gary MD§; Godofsky, Eliot MD∥; Patel, Indravadan PhD¶; Chiu, Yu-Yuan PhD¶; Evans, Claire RGN#; Rowell, Lucy MSc#; Salgo, Miklos MD, PhD¶
From the *University of Pennsylvania, Philadelphia, PA; †Southwest Infectious Disease Associates, Dallas, TX; ‡South Jersey Infectious Disease, Somers Point, NJ; §North Broward Hospital District, Ft. Lauderdale, FL; ∥Bach and Godofsky, Bradenton, FL; ¶Roche, Nutley, NJ; and #Roche, Welwyn, UK.
Received for publication December 20, 2006; accepted November 14, 2007.
This trial was sponsored by Roche, Pablo Tebas, and the University of Pennsylvania. I was supported by AI068632 and AI045008.
Drs. Chui, Evans, Rowell, and Salgo are Roche employees. Dr. Godofsky is on the Roche Speaker Bureau. Pablo Tebas receives clinical trial support from NIH, Roche, Tibotec, Pfizer, Merck, VGX, BMS, VIRxSYS, and Schering. He has been a consultant for BMS, Tibotec, and Merck.
Correspondence to: Pablo Tebas, MD, Hospital of the University of Pennsylvania, Silverstein, Suite D, 3400 Spruce Street, Philadelphia, PA 19104 (e-mail: firstname.lastname@example.org).
Objective: The aim of this study was to examine the influence of kidney disease and hemodialysis on the pharmacokinetics of enfuvirtide.
Design: An open-label, multicenter, parallel group study of HIV-1-infected patients with varying degrees of kidney dysfunction.
Methods: A 90-mg dose of enfuvirtide was administered by subcutaneous injection to 3 groups of patients: group A, patients with normal kidney function; group B, patients with chronic kidney disease; and group C, patients with end-stage renal disease (ESRD) requiring dialysis. Patients with ESRD requiring dialysis received the 90-mg dose of enfuvirtide on 2 separate occasions; a dialysis day and a nondialysis day. After each dose, a full 48-hour pharmacokinetic profile was collected and pharmacokinetic parameters were estimated using model-independent techniques.
Results: Enfuvirtide area under the curve (AUC∞) and maximum observed enfuvirtide plasma concentration (Cmax) for patients with normal kidney function (group A) was 49.6 μg·h/mL and 3.79 μg/mL, respectively. Patients with chronic kidney disease (group B) had higher AUC∞ (80.3 μg·h/mL) and Cmax (5.72 μg/mL), which was similar to patients with ESRD (group C) on both nondialysis days (AUC∞ 71.1 μg·h/mL; Cmax 5.34 μg/mL) and dialysis days (AUC∞ 66.9 μg·h/mL; Cmax 6.31 μg/mL). An average of <13% of enfuvirtide was removed during the dialysis procedure. The incidence of adverse events was comparable for all study groups.
Conclusion: Enfuvirtide exposure observed in patients with ESRD requiring dialysis or chronic kidney disease was slightly higher than in patients with normal kidney function and similar to historical Cmax and AUC values from studies in patients with normal kidney function. Thus, enfuvirtide does not require dosage adjustment in patients with impaired kidney function.
Renal problems are frequent in patients with HIV infection. HIV-associated nephropathy is the third most common cause of end-stage renal disease (ESRD) among African American individuals between the ages of 24 and 60.1 Thanks to the availability of potent antiretroviral therapies, the survival of HIV-infected patients with chronic kidney disease has improved dramatically in the past decade, although their survival rate still lags behind that of patients without kidney failure.2 Even though there are guidelines about the use of antiretrovirals in HIV-infected patients with chronic kidney failure, many of the recommendations are based on extrapolations of research and clinical guidelines involving the general population with kidney disease.3 To develop more accurate dosing guidelines for antiretrovirals, it is important to perform pharmacokinetic studies in patients living with HIV disease and chronic kidney disease.
Enfuvirtide, the only approved fusion inhibitor, is a 36 amino acid peptide with potent antiretroviral activity in patients with evidence of resistance to other drug classes.4,5 Enfuvirtide requires administration twice daily by subcutaneous injections (90 mg each) and has been shown to have a high bioavailability (84%), small volume of distribution (5.48 L), low systemic clearance (1.4 L/h), and moderately high protein binding (92%). Enfuvirtide is primarily eliminated via catabolism to its constituent amino acids and has been shown to have a low potential for drug-drug interactions.6
Only 1 case report has been published evaluating the pharmacokinetics of enfuvirtide in an HIV-infected patient with impaired renal function.7 The purpose of the present study was to evaluate the pharmacokinetics of enfuvirtide in HIV-infected patients with different degrees of renal impairment.
PATIENTS AND METHODS
Patients and Study Design
We evaluated the influence of kidney impairment and hemodialysis on the pharmacokinetics of enfuvirtide in HIV-positive patients receiving highly active antiretroviral therapy (HAART). The study was an open-label, multicenter, parallel group study of enfuvirtide in HIV-1-infected patients aged 18 to 64 years. Three groups of individuals with stable renal function for at least 3 months were enrolled:
Group A: patients with normal kidney function (plasma creatinine clearance [CLcr] >80 mL/min)
Group B: patients with chronic kidney disease (CLcr of 11 to 35 mL/min)
Group C: patients with ESRD requiring hemodialysis (CLcr ≤10 mL/min)
A single 90-mg dose of enfuvirtide was administered subcutaneously in patients in groups A and B. A single 90-mg dose of enfuvirtide was administered subcutaneously to group C on 2 occasions, a dialysis and a nondialysis day, with a minimum washout period of 1 week between the doses. After each dose, a full 48-hour pharmacokinetic profile was collected. Comparisons to pharmacokinetic parameters from historical studies were also made.8
Blood samples were collected before dosing, then at 1, 2, 3, 4, 6, 8, 10, 12, 24, 32, and 48 hours after administration of enfuvirtide. CLcr was calculated from plasma creatinine using the Cockcroft-Gault equation. Determination of plasma enfuvirtide concentrations was by liquid chromatography with tandem mass spectrometric detection. Pharmacokinetic parameters included maximum observed enfuvirtide plasma concentration (Cmax); time of maximum plasma concentration (tmax); enfuvirtide exposure, expressed as area under the plasma concentration-time curve from 0 to infinity (AUC∞); apparent clearance of enfuvirtide, computed as dose/AUC∞ (CL/F); and the terminal elimination half-life (t½). Pharmacokinetic parameters were estimated using model-independent techniques. The dialysis clearance and extraction ratio of the hemodialysis procedure was estimated by simultaneously measuring concentrations of enfuvirtide in samples collected from the lines entering and leaving the hemodialysis chamber. Drug exposure (Cmax and AUC) information obtained in this study were compared to those obtained in 6 other studies in individuals with normal kidney function.8
Analysis of variance (ANOVA) for Cmax and AUC∞ was performed for all patients who completed the treatment period(s) and had sufficient pharmacokinetic data. Confidence intervals (90%) for the difference in least squares means were calculated for pharmacokinetic parameters and expressed as a percentage of the reference (group A). However, the difficulty of enrolling a sufficient number of patients with HIV and chronic kidney disease precluded attempts to achieve statistical significance in this study. Despite the small sample size, the planned number of patients was of the same order as those enrolled in previous pharmacokinetic studies and allows conclusions of clinical significance to be drawn.
Initially, a total of 24 patients were planned for enrollment (8 per group). However, recruitment of HIV-infected patients with chronic kidney disease (group B) proved difficult, and as a result only 4 patients were enrolled in this group. Therefore 20 patients (17 males and 3 females) were enrolled in the entire study: 4 subjects in group B (chronic kidney disease, CLcr 11 to 35 mL/min), and 8 patients in each of groups A (normal kidney function, CLcr >80 mL/min) and group C (ESRD, requiring dialysis, CLcr ≤10 mL/min). Patients were mostly men (only 1 patient in each group was a woman). Body weight (mean ± standard deviation [SD]) was 83.7 ± 15.6 kg for group A, 72.5 ± 21.5 kg for group B, and 85.1 ± 25.2 kg for group C. CLcr (mean ± SD) was 133 ± 30.1, 24.3 ± 6.1, and 13.3 ± 5.8 mL/min for groups A, B, and C, respectively. Several patients with ESRD in group C had baseline CLcr >10 mL/min as specified in the protocol. These patients were granted a waiver for inclusion in the study because they were undergoing dialysis and therefore had a slightly improved apparent CLcr.
Nineteen patients were included in the pharmacokinetic analysis-1 patient from group C was excluded on dialysis day due to incomplete plasma data. All 20 subjects were included in the safety analysis.
Descriptive statistics for pharmacokinetic parameters after subcutaneous administration of a 90-mg dose of enfuvirtide are summarized in Table 1, and mean enfuvirtide plasma concentration-time profiles by study group are shown in Figure 1. Exposure to enfuvirtide was greater for patients in group B (AUC∞ 80.3 ± 17.3 μg·h/mL; Cmax 5.72 ± 1.82 μg/mL), who had chronic kidney disease, than for group A patients (AUC∞ 49.6 ± 9.9 μg·h/mL; Cmax 3.79 ± 1.22 μg/mL), who had normal kidney function. Clearance of enfuvirtide was lower in patients in group B than those in group A (CL/F 1.17 ± 0.299 L/h and 1.88 ± 0.385 L/h, respectively). Patients with ESRD requiring dialysis, group C, also had a higher enfuvirtide exposure (AUC∞ 71.1 ± 20.6 μg·h/mL; Cmax 5.34 ± 2.36 μg/mL) and lower enfuvirtide clearance (CL/F 1.36 ± 0.379 L/h) on the nondialysis day than did patients with normal kidney function. On the dialysis day, both maximum plasma concentration and clearance of enfuvirtide were slightly increased (6.31 ± 3.06 μg/mL and 1.62 ± 0.735 L/h, respectively), and AUC∞ was reduced (66.9 ± 30.9 μg·h/mL), compared with values for the nondialysis day. The mean dialysis plasma clearance was 3.01 ± 4.65 L/h at midpoint and 2.01 ± 2.66 L/h at endpoint of the dialysis procedure. The extraction ratio was 0.128 ± 0.195 at midpoint and 0.086 ± 0.095 at endpoint; thus, there was only limited removal of enfuvirtide during the dialysis procedure (an average of <13%). Linear regression analysis of the total study population found only a weak correlation between pharmacokinetic parameters and CLcr. The best correlation was observed between CL/F and CLcr with a coefficient of determination (r2) of 0.331 and a coefficient of correlation (r) of 0.575. Both Cmax and AUC values in patients with chronic kidney disease were within the historical ranges seen in previous studies involving patients with normal kidney function.8
Enfuvirtide was well tolerated. No deaths or premature withdrawals due to adverse events occurred during the study. The numbers of adverse events were 1, 1, and 3 in groups A, B, and C respectively. All adverse events were mild or moderate in severity. Of these, only mild headache was considered possibly and mild injection site paresthesia was considered probably (1 patient in group C) related to treatment. Other adverse events that occurred in individual patients but were considered not related to the study drug included upper respiratory tract infection, local swelling, pain in the extremities, increased body temperature, pyrexia, nausea, and vomiting.
The present study evaluated the pharmacokinetics and safety of enfuvirtide for the treatment of HIV-infected patients who had normal kidney function, chronic kidney disease with a CLcr of <35 mL/min, or ESRD requiring dialysis. Exposure to enfuvirtide for patients with normal kidney function (AUC∞ of 49.6 μg·h/mL and Cmax 3.79 μg/mL) was slightly lower in this study than has previously been reported.9,10 This may be due in part to the relatively small sample size (n = 8) and to the higher mean body weight for patients with normal kidney function in this study (83.5 kg) compared with earlier studies. Population pharmacokinetic analysis has shown clearance of enfuvirtide to increase with increasing body weight. However, resultant changes in exposure were in the same range as those reported in previous studies, did not affect efficacy or safety, and therefore did not necessitate any dosage adjustment.11
Exposure to enfuvirtide for patients with chronic kidney disease appeared slightly higher than exposure levels in patients with normal kidney function. The mean AUC∞ for patients with chronic kidney disease (group B) was 1.6 times greater than that seen in patients from the current study with normal kidney function but within the range reported in published trials conducted in subjects with normal kidney function.9,10 The apparent increase in enfuvirtide exposure might be explained by the observation that these group B patients also had a mean 38% lower enfuvirtide clearance than did patients with normal kidney function. The maximal enfuvirtide plasma concentration (5.72 μg/mL) was also greater than in the study patients with normal kidney function (3.79 μg/mL), although comparable to previously published data. In addition, this higher enfuvirtide exposure is at a level that has not previously been associated with any increase in adverse events or serious adverse events.11
Hemodialysis patients had a 14% (dialysis day) or 28% (nondialysis day) lower enfuvirtide clearance and 34% (dialysis day) or 43% (nondialysis day) higher enfuvirtide exposure, compared with study patients with normal kidney function. Dialysis did not have a measurable effect on the pharmacokinetics of enfuvirtide; an average of <13% of the enfuvirtide was removed during the dialysis procedure. Enfuvirtide clearance increased by 19.1% (CL/F 1.62 vs. 1.36 L/hr) and AUC∞ was reduced by only 5.9% (71.1 vs. 66.9 μg·h/mL) on the dialysis day compared to the nondialysis day. Pharmacokinetic parameters for patients requiring hemodialysis (CLcr <10 mL/min) were similar to those obtained from patients in this study who had chronic kidney disease but who did not require hemodialysis (CLcr 11 to 35 mL/min).
The single-dose safety profile of enfuvirtide was comparable for all study groups, with an overall 25% incidence of adverse events and no adverse event considered serious. These results are consistent with those of earlier clinical studies that reported the majority of adverse events with enfuvirtide to be only of mild or moderate severity and noted no increase in the frequency of adverse or serious adverse events at similar levels of enfuvirtide exposure.5,12,13
The similarity of enfuvirtide exposures in HIV-infected patients with normal kidney function and in those with chronic kidney disease, together with the lack of any observed adverse events associated with these levels of exposure seen in this or other studies, suggest that enfuvirtide does not require dosage adjustment in HIV-infected patients with chronic kidney disease.
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