Phase I Dose Escalation Study To Evaluate the Safety and Pharmacokinetic Profile of Tefibazumab in Subjects with End-Stage Renal Disease Requiring Hemodialysis

Abstract

Two cohorts of four subjects requiring hemodialysis received tefibazumab (10 or 20 mg/kg). The mean elimination half-life was between 17 and 18 days, the average volume of distribution was 7.3 liters, and the average clearance was 12 ml/h for both dose groups. At a dose of 20 mg/kg of body weight, plasma levels were 88 μg/ml at 21 days.

Infections due to Staphylococcus aureus are a major medical and public health problem, with high mortality and morbidity compounded by increasing rates of antibiotic resistance (5). Patients with end-stage renal disease (ESRD) are at high risk for developing S. aureus bacteremia (2) and account for 12% of hospital-associated (3) and 32% of community-acquired (9) S. aureus infections.

Aurexis (tefibazumab), a humanized monoclonal antibody that binds to the surface-expressed adhesin protein clumping factor A, is in development as an adjunctive therapy for serious S. aureus infections (6, 7). In healthy volunteers, single doses of tefibazumab of from 2 to 20 mg/kg of body weight demonstrated mean elimination half-lives of 20 to 23 days. In addition, no detectable immune response to tefibazumab was found (10). We conducted a single-center, 8-week, open-label, dose escalation clinical trial to evaluate the safety and pharmacokinetic (PK) profile of tefibazumab in subjects with ESRD requiring hemodialysis.

Adult subjects ≥18 years of age with ESRD requiring hemodialysis were eligible to participate in this clinical trial. Written informed consent was obtained from each subject. Exclusion criteria included pregnancy, active infection, receipt of immune globulin or investigational drug in the past 30 days, and history of allergy to immune globulin.

The study was conducted from November 2004 to February 2005 at DaVita Clinical Research (Minneapolis, MN). Four subjects were administered single doses of 10 mg/kg intravenously over 30 min. Safety data through day 8 were reviewed prior to the enrollment of subjects into the 20-mg/kg dose cohort. Safety was monitored by physical examinations, clinical laboratory tests, and adverse-experience assessments.

Blood samples were collected within 30 min of the start of infusion; at 1, 6, 12, and 24 h postinfusion; and on study days 3, 4, 8, 15, 29, 43, and 57. The time intervals between dialysis and PK sampling times (before, after, or during) were noted but varied between and within the subjects. Blood samples were collected into heparinized tubes, plasma separated, and stored at −70°C until assayed. Tefibazumab levels were determined by an enzyme-linked immunosorbent assay using a standard curve over the range of 2 to 250 ng/ml with a coefficient of variation of <15% (10). Samples were diluted to allow all assay results to be read within the range of the assay. Anti-tefibazumab antibody titers were determined by an enzyme-linked immunosorbent assay (10). The cut-point value to identify positive anti-tefibazumab plasma samples was defined as the mean absorbance value of 1:10 dilutions of the negative controls and plate blanks plus three standard deviations (8).

Categorical data were summarized by frequency and, where applicable, percentage of subjects. Continuous measures were summarized by the number of observations and mean, standard deviation, median, minimum, and maximum values. Pharmacokinetic parameters were determined by noncompartmental methods using the WinNonlin software program (Pharsight Corporation, Cary, NC).

All subjects received 95% or more of their treatment infusion and were included in the safety and pharmacokinetic analyses. Each dose cohort consisted of three males and one female subject. The mean ages for the 10- and 20-mg/kg dose groups were 52 and 43 years, respectively (P was not significant), and mean weights (± standard deviations) were 89 (± 21) and 77 (± 15) kg (P was not significant).

No unsuspected safety events were identified among this small cohort. Nineteen adverse events, the majority of which were mild or moderate in intensity, occurred among six subjects. Only two adverse events occurred in more than one subject during the study: upper respiratory infection and back pain. One subject, who received a dose of 20 mg/kg, reported a headache on day 1 that was considered possibly related to the study drug and that resolved without treatment on the same day. Two subjects experienced serious adverse events (exacerbation of chronic obstructive airway disease and elective back surgery); neither event was considered related to the study drug. One subject developed a facial rash 17 days after receiving a dose of 10 mg/kg. The rash resolved the same day. Other nonserious events that occurred among single patients included leukopenia, tachycardia, nausea, vomiting, and fluid overload.

No significant changes in vital signs were observed. None of the observed laboratory abnormalities were considered clinically significant, and all were considered related to ESRD and/or underlying conditions. None of the subjects had detectable plasma antitefibazumab titers at anytime tested.

Tefibazumab exhibited linear kinetics across doses of 10 and 20 mg/kg in subjects with ESRD (Fig. 1 and Table 1). Tefibazumab levels of >100 μg/ml were observed at 4 days for the 10-mg/kg dose cohort and 15 days for the 20-mg/kg dose cohort. Mean plasma levels for the tefibazumab 20-mg/kg dose cohort were 119 μg/ml on day 15 and 88 μg/ml on day 22. Preclinical animal studies suggest that plasma levels of tefibazumab of >100 μg/ml provided optimal protection against S. aureus infection (1). The values for maximum concentration of drug in serum (C_max) and area under the concentration-time curve from 0 to infinity (AUC_0-∞) increased proportionally with increased dose, but those for clearance (CL), volume of distribution (V), and terminal elimination rate constant were similar for both doses.

FIG. 1.

Mean (± standard deviations [error bars]) tefibazumab plasma concentrations by dose cohort.

TABLE 1.

Mean (± SD) tefibazumab pharmacokinetic parameters

Parametera	Dose cohort
	10 mg/kg (n = 4)	20 mg/kg (n = 4)
Cmax (μg/ml)	257.90 (70.89)	415.08 (48.83)
Tmax (h)b	1.50 (1.48, 1.50)	1.50 (1.35, 1.68)
t1/2 (h)	439.35 (155.78)	416.69 (10.07)
V (liter)	7.43 (0.59)	7.11 (1.49)
CL (ml/h)	12.65 (3.54)	11.80 (2.30)
AUC0-last (μg · h/ml)	64,020 (15,864)	118,036 (9,410)
AUC0-∞ (μg · h/ml)	72,363 (19,072)	130,473 (10,985)
λz (h)	0.0017 (0.00062)	0.0017 (0.000040)

^aT_max, time to maximum concentration of drug in serum; λ_z, terminal elimination rate constant.

^bMedian (minimum, maximum) T_max based on the start of infusion.

Noncompartmental analysis suggests that tefibazumab administered as a single intravenous dose in subjects with ESRD over 30 min exhibited linear PK at doses of 10 to 20 mg/kg. Plasma concentrations decreased in a biphasic manner. The small V approaching that of plasma, low CL, and long half-life (t_1/2) values of tefibazumab are similar to those that have been seen previously with other monoclonal antibodies (4). There were no major differences in the PK parameters across subjects (coefficient of variation, <36%, except for C_min), suggesting that the relationship of the PK sample to hemodialysis (before, after, or during) did not impact the PK results in this population.

While the study was limited by the small number of subjects, no unique safety considerations were observed for subjects with ESRD compared with those for healthy subjects. The distribution of adverse events among the dose cohorts does not suggest a relationship between adverse-event incidence and dose. While serious adverse-event were expected among a group of subjects with chronic disease, none were considered associated with the use of tefibazumab.

The pharmacokinetic parameters were similar to those in subjects with normal renal function. The t_1/2 was slightly shorter than the 21 days previously seen but unlikely to be clinically significant. For future clinical trials, subjects undergoing hemodialysis for ESRD may receive the same dose and schedule of tefibazumab administered to subjects with normal renal function.