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PHARMACOKINETICS AND PHARMACODYNAMICS/SPECIAL POPULATIONS

Pharmacokinetics and Pharmacodynamics of Pegfilgrastim in Subjects With Various Degrees of Renal Function

Bing-Bing Yang, PhD, Anna Kido, BS, Margaret Salfi, MS, Suzanne Swan, MD and John T. Sullivan, MB, ChB

From Amgen Inc, Thousand Oaks, California (Dr Yang, Ms Kido, Ms Salfi, Dr Sullivan) and DaVita Clinical Research and Hennepin County Med Center, Minneapolis, Minnesota (Dr Swan).

Address for reprints: Bing-Bing Yang, PhD, Amgen Inc, Departments of Pharmacokinetics & Drug Metabolism, Mail Stop: 28-3-B, Thousand Oaks, CA 91320; e-mail: byang{at}amgen.com.


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
A phase I study was conducted to evaluate the effects of renal function on the pharmacokinetics and pharmacodynamics (absolute neutrophil count [ANC]) of pegfilgrastim in nonneutropenic subjects. Thirty subjects categorized into 5 renal function groups (normal, mildly impaired, moderately impaired, severely impaired, and end-stage renal disease) received 1 subcutaneous injection of pegfilgrastim at 6 mg. The ANC profiles after pegfilgrastim administration were similar across different renal function groups. No discernable correlation between pharmacokinetic parameter values and degree of renal impairment was observed; the mean values ranged from 147 to 201 ng/mL for Cmax and from 7469 to 8513 ngxh/mL for AUC. Results suggest that the kidney has no important role in the elimination of pegfilgrastim. Therefore, no dosage adjustment for renal impairment is indicated for pegfilgrastim.

Key Words: Pegfilgrastim • renal function • pharmacokinetics • pharmacodynamics

Granulocyte colony-stimulating factor (G-CSF) is an endogenous hematopoietic growth factor that selectively simulates granulopoietic cells of the neutrophil lineage.1 It acts at all stages of neutrophil development: increasing the proliferation and differentiation of neutrophils from committed progenitor cells and enhancing the survival and function of mature neutrophils.2 Filgrastim is a recombinant methionyl human G-CSF that is produced in genetically modified Escherichia coli bacteria.3,4 It has been used extensively to treat chemotherapy-induced neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs. Because of its short circulating half-life, daily injections of filgrastim are necessary to maintain its therapeutic effects. Therefore, pegfilgrastim, a pegylated filgrastim, was developed as a second-generation molecule that reduces the frequency of injections while maintaining its therapeutic effects.5,6

Pegfilgrastim is produced by covalently attaching a 20-kD polyethylene glycol (PEG) molecule to the N-terminus of filgrastim. In vitro studies showed that the biologic activity and mechanism of action of pegfilgrastim were identical to those of filgrastim; in vivo testing in mice revealed that pegfilgrastim increased absolute neutrophil count (ANC, a pharmacodynamic endpoint) for a substantially longer period of time than filgrastim.7 Indeed, PEG modification of proteins has been demonstrated to sustain the duration of action by decreasing rates of cellular uptake and proteolysis as well as reducing renal clearance, which is one of the primary clearance mechanisms for filgrastim.8,9

Filgrastim has a molecular weight of 18.8 kD. Therapeutic proteins of this size are thought to be filtered by the glomeruli in the kidney and reabsorbed into the proximal tubules, in which degradation occurs.10-12 In contrast, pegfilgrastim has a molecular weight of 38.8 kD, and its large hydrodynamic size prevents its filtration by the glomeruli. Results from unilateral and bilateral nephrectomy studies in rats have shown that the kidney plays an important role in the elimination of filgrastim.13,14 The exposure to pegfilgrastim was similar between sham-operated and bilaterally nephrectomized rats, suggesting that the kidney had no major role in the elimination of pegfilgrastim.14

Given that pegfilgrastim could be given to patients with renal impairment, it is important to confirm an absence of alteration of pharmacokinetics or pharmacodynamics in humans with abnormal kidney function. Preliminary results from this study have been previously reported in abstract format.15


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Study Design
This was a phase I, single-center, open-label study that was approved by the Institutional Review Board, Human Subject Research Committee, at the clinical study center in Minneapolis, Minnesota. All subjects provided written informed consent before entering the study. Subject health, as evaluated by medical history, physical examination, and clinical laboratory measurements, was monitored throughout the study.

Thirty-one subjects (22 men and 9 women) were enrolled into this study and received study drug. Thirty subjects completed the study; 1 subject with normal renal function withdrew early. Subjects were assigned to 1 of 5 groups (n = 6/group) according to their renal function as follows: normal (CLcr >80 mL/min/1.73 m2), mildly impaired (CLcr = 50-80 mL/min/1.73 m2), moderately impaired (CLcr = 30-49 mL/min/1.73 m2), severely impaired (CLcr <30 mL/min/1.73 m2), and end-stage renal disease (ESRD) undergoing hemodialysis. For all subjects except those with ESRD, CLcr was estimated based on a 24-hour urine collection conducted before drug administration and using the following formula:

Formula
where urine Cr was the urine creatinine concentration, serum Cr was the serum creatinine concentration at the midpoint of the collection period, and time was the total time of urine collection.

Each subject received a single subcutaneous (SC) injection of pegfilgrastim (Neulasta, Amgen Inc, Thousand Oaks, California) 6 mg/kg. Serum samples for pegfilgrastim measurement were collected predose; at 1, 2, 4, 8, 12, 16, 24, 36, and 48 hours; and daily up to 336 hours postdose and were stored at –70°C before analysis. Subjects remained in the study center through completion of the 48-hour postdose procedures. All subjects with ESRD underwent hemodialysis 3 times per week, with each session lasting approximately 4 hours. These subjects with ESRD received pegfilgrastim on a nondialysis day. On the days of hemodialysis, pharmacokinetic samples were collected either before or after hemodialysis.

Analytical Methodology
Serum concentrations of pegfilgrastim were analyzed with a commercially available enzyme-linked immunosorbent assay (ELISA; Quantikine human G-CSF immunoassay kit, R&D Systems, Inc, Minneapolis, Minneapolis). Briefly, microtiter immunoassay plates were coated with murine monoclonal anti-G-CSF antibody. Standard and quality control samples along with study samples were added to the wells for a final assay matrix of 25% human serum. The immobilized antibody bound any pegfilgrastim present. After any unbound pegfilgrastim was washed away with a wash buffer from the R&D kit, a polyclonal anti-G-CSF antibody, conjugated with horseradish peroxidase, was added to the wells. After a washing step, a substrate solution (tetramethylbenaidine and peroxidase solution) for color development was added. The reaction was stopped with 2 N sulfuric acid, and the intensity of the color was measured by a spectrophotometric plate reader at a wavelength of 450 nm and at a reference wavelength of 650 nm. The dynamic range was 0.031 to 4.000 ng/mL, with the lower limit of quantification (LLOQ) ranging from 0.166 to 0.302 ng/mL. This ELISA does not distinguish pegfilgrastim from filgrastim or endogenous G-CSF.

The samples for ANC measurement were analyzed in a laboratory certified by the Clinical Laboratory Improvement Amendments (CLIA), and ANC value was either recorded or calculated by the summation of segmented neutrophils and band cells.

Data Analysis
Individual pegfilgrastim pharmacokinetic and pharmacodynamic parameters were calculated for each subject using noncompartmental analysis of serum concentration and ANC data, respectively (WinNonlin Professional, Pharsight Corp, Mountain View, California).

Pharmacokinetics. Pegfilgrastim concentrations less than the LLOQ were set to 0 before data analysis. The maximum concentration (Cmax) and the time it occurred (tmax) after dosing were recorded as observed. Terminal half-life (t1/2) was calculated as Formula, where kel was the first-order terminal rate constant estimated via linear regression of the terminal log-linear decay phase. The area under the serum concentration-time curve (AUC0-last) from time 0 to the time of the last measurable concentration (Clast) was estimated using the linear/log trapezoidal method. AUC0-{infty} was estimated as the and C /k values:

Formula

Pharmacodynamics. The maximum ANC (ANC_Cmax) and the time it occurred (ANC_tmax) were recorded as observed. The area under the baseline-corrected ANC-time curve from time 0 to 336 hours postdose (ANC_AUC) was calculated using the same method as for pharmacokinetic parameter AUC.

Statistical Methods
Baseline characteristics, the pharmacokinetic parameter values of pegfilgrastim, and the ANC parameter values were summarized by renal function group using descriptive statistics.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
The baseline characteristics of the subjects who participated in this study are summarized in Table I.


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  		Table I Baseline Characteristics of Subjects Participated in the Study

 
Pharmacokinetics. The serum concentrations for all samples collected before pegfilgrastim administration, which would reflect endogenous G-CSF concentrations, if measurable, were below the limit of quantification, except for 1 subject in the ESRD group. Because the pegfilgrastim concentration before dosing (0.683 ng/mL) for that ESRD subject was close to the limit of quantification and was much lower than other measured pegfilgrastim concentrations for that subject, no baseline correction was performed before data analyses.


Figure 1
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  		Figure 1. Mean (SEM) serum pegfilgrastim concentration-time profiles in subjects with various degrees of renal function after subcutaneous (SC) administration of 6 mg pegfilgrastim. ESRD, end-stage renal disease.

 
The mean serum pegfilgrastim concentration-time and ANC-time profiles after pegfilgrastim administration for each group are shown in Figure 1. After reaching a peak (median: 24-36 hours postdose), the serum pegfilgrastim concentrations declined in parallel for all groups, suggesting that the elimination was similar in subjects with different degrees of renal function. None of the pharmacokinetic parameter values changed consistently with increasing severity of renal impairment (Table II). Scatterplots of the individual Cmax and AUC values suggest that the variability in group mean values can be accounted for by individual variability within the group (Figure 2). Subjects with ESRD were assigned a CLcr value of 2 mL/min, as suggested in the literature.16


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  		Table II Pharmacokinetic Parameter Values of Pegfilgrastim After Subcutaneous Administration of 6 mg Pegfilgrastim to Subjects With Various Degrees of Renal Function

 
Pharmacodynamics. On average, a substantial increase was observed 24 hours after dosing; peak values (7-9 times higher than the baseline value) occurred 60 to 96 hours after dosing and returned to baseline or near baseline levels by 336 hours after dosing. Similar to the pharmacokinetic results, no consistent trend in ANC parameters was observed with an increase in the severity of renal impairment (Figures 3, 4 and Table III).


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  		Table III Pharmacodynamic Parameter Values of Pegfilgrastim After Subcutaneous Administration of 6 mg Pegfilgrastim to Subjects With Various Degrees of Renal Function

 
Effect of hemodialysis. Throughout the study, subjects with ESRD went through the 4-hour hemodialysis session 6 times. Because the pharmacokinetics of pegfilgrastim and ANC profiles for these subjects were similar to those with different degrees of renal function, results suggested that hemodialysis had no impact on the pharmacokinetics and pharmacodynamics of pegfilgrastim.


Figure 2
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  		Figure 2. Individual pegfilgrastim pharmacokinetic parameter values in subjects with various degrees of renal function after subcutaneous (SC) administration of 6 mg pegfilgrastim. ESRD, endstage renal disease.

 
Safety. Pegfilgrastim administered subcutaneously at 6 mg was well tolerated. The most frequent treatment-related adverse events were headache and low back pain. Two subjects reported adverse events that were severe. One subject in the severe renal impairment group had a serious adverse event of altered mental status due to alcohol intoxication, pneumonia, dehydration, and severe hyperglycemia (blood glucose >500 mg/dL). The other subject was in the normal renal function group and reported low back pain, which was considered treatment related. No deaths or adverse events that led to withdrawal were reported during the study.


Figure 3
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  		Figure 3. Mean (SEM) absolute neutrophil count (ANC)–time profiles in subjects with various degrees of renal function after subcutaneous (SC) administration of 6 mg pegfilgrastim. ESRD, end-stage renal disease.

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Pegfilgrastim was developed to improve the patient's and health care provider's convenience of filgrastim. A pivotal phase III study demonstrated that a single injection of pegfilgrastim at 6 mg for up to a four 3-week chemotherapy cycle was as efficacious as daily injections of filgrastim at 5 µg/kg in decreasing the severity and duration of neutropenia and its complications in patients treated with myelosuppressive chemotherapy without greater toxicity.17 The longer duration of action of pegfilgrastim than that of filgrastim is attributed to the difference in the clearance mechanisms of these 2 drugs.


Figure 4
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  		Figure 4. Individual pegfilgrastim pharmacodynamic parameter values in subjects with various degrees of renal function after subcutaneous (SC) administration of 6 mg pegfilgrastim. ESRD, end-stage renal disease.

 
Results from unilateral and bilateral nephrectomy studies in rats showed that the kidney plays an important role in the elimination of filgrastim.13,14 It was reported that, after a single subcutaneous administration of filgrastim at 5 µg/kg, a trend toward higher peak serum filgrastim concentration, higher AUC, and lower apparent clearance was observed in subjects with end-stage renal diseases than subjects with creatinine clearance between 30 and 60 mL/min or healthy volunteers.18 In addition to renal clearance, data from studies in animals and humans suggest that circulating neutrophils play a significant role in the clearance of filgrastim, presumably mediated by G-CSF receptors on neutrophils and neutrophil precursors; this pathway is referred to as neutrophil-mediated clearance in this article.8,19-21

The hydrodynamic radius of pegfilgrastim is substantially greater than that for filgrastim because of the PEG moiety, and the large hydrodynamic radius should prevent pegfilgrastim from glomerular filtration in the kidney. Results from a bilateral nephrectomy study in rats showed that the kidney played an insignificant role in the elimination of pegfilgrastim,14 leaving neutrophil-mediated clearance to predominate. Therefore, when circulating neutrophils are low (such as during chemotherapy-induced neutropenia), pegfilgrastim stays in the circulation due to a decrease in the neutrophil-mediated clearance and is cleared from circulation only after ANC starts to recover.22-24 In contrast, alternative clearance mechanisms such as renal clearance take on greater importance for filgrastim during neutropenia. Accordingly, filgrastim must be given daily in the setting of neutropenia to provide the desired therapeutic effects.

The ELISA used in this study did not distinguish pegfilgrastim from endogenous G-CSF or filgrastim. Endogenous G-CSF concentrations are reported to be in the range of 12.3 to 15.0 pg/mL,25 which is below the limit of quantification of the ELISA used in this study. Therefore, as expected, the serum concentrations for all samples collected before pegfilgrastim administration were below the limit of quantification, except for 1 subject from the ESRD group who had a predose concentration that was close to the limit of quantification as described in the Results section.

A previous study was conducted to examine depegylation of another pegylated (12-kD PEG) filgrastim; pegylated filgrastim and its metabolites, if present, in rat serum were measured by using immunoaffinity chromatography coupled with immunochemical detection.26 Serum samples were collected from rats at 4 and 24 hours after intravenous (IV) administration of 100 µg/kg pegylated filgrastim. In addition to a peak corresponding to pegylated filgrastim, the chromatogram for the 4-hour samples showed a very small peak occurring in the region of filgrastim; however, the peak area was below the limit of quantification. No filgrastim or other compounds were detected for the 24-hour samples. Therefore, depegylation of the pegylated filgrastim used in that study was insignificant. Because the bonds between filgrastim and the PEG molecule for that pegylated filgrastim and for pegfilgrastim used in the current study were made using the same reductive alkylation chemistry technology, it is reasonable to conclude that depegylation of pegfilgrastim is insignificant.

In this study, the influence of renal impairment on the pharmacokinetics and pharmacodynamics of pegfilgrastim was examined in nonneutropenic human subjects. No apparent relationship was observed between degree of renal function and the pharmacokinetics or pharmacodynamics of pegfilgrastim. Although the intersubject variability of the pharmacokinetic parameters was noticeably high (the coefficients of variation ranged from 34% to 88% for Cmax and 38% to 94% for AUC0-{infty}), no clear trend was observed with increasing severity of renal impairment.

One limitation of this study is the difficulty in extrapolating these results from a nonneutropenic setting to a neutropenic setting. This is of particular importance to patients who receive chemotherapy agents, such as platinum agents and nitrosoureas, which have been demonstrated to induce neutropenia as well as nephrotoxicity. For practical reasons, a study in neutropenic subjects was not conducted. However, no relationship between pharmacokinetics and renal function would be expected in a neutropenic setting based on the characteristics of the molecule and the results of preclinical experiments in nephrectomized rats.14

Based on this study, renal function appears to have no impact on the pharmacokinetics and pharmacodynamics of pegfilgrastim; therefore, no dosage adjustment for renal impairment is indicated for pegfilgrastim.

DOI: 10.1177/0091270008320318

Editorial assistance was provided by Joan O'Byrne.

Financial disclosure: This work was supported by Amgen Inc. Drs Yang and Sullivan and Ms Kido are employees and stock-holders of Amgen, Inc. Ms Salfi is a former Amgen employee.


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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23. Holmes FA, Jones SE, O'Shaughnessy J, et al. Comparable efficacy and safety profiles of once-per-cycle pegfilgrastim and daily injection filgrastim in chemotherapy-induced neutropenia: a multicenter dose-finding study in women with breast cancer. Ann Oncol. 2002;13: 903-909.[Abstract/Free Full Text]

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HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS