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PHARMACOKINETICS |
From Amgen Inc, Thousand Oaks, California (Dr Gillespie, Dr Zia-Amirhosseini, Ms Salfi, Dr Kakkar, Ms Wang, Dr Gupta, Dr Smith, Dr Sullivan), and Christchurch Clinical Studies Trust, Christchurch, New Zealand (Dr Robson).
Address for reprints: Address for correspondence: B. Gillespie, PharmD, Amgen Inc, One Amgen Center Drive, MS 38-3-A, Thousand Oaks, CA 91320-1799; e-mail: bgillesp{at}amgen.com.
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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N23KGF) decreases the incidence, severity, and duration of oral mucositis. The objectives of this open-label study were to evaluate the pharmacokinetics of single-dose palifermin in subjects with varying degrees of renal function. A single 90-mcg/kg intravenous dose of palifermin was administered to 31 subjects with varying levels of renal function (normal to requiring hemodialysis). Pharmacokinetic analyses were conducted using serum palifermin concentrations. There was considerable overlap in mean palifermin serum clearance among the groups, ranging from 318 to 495 mL/h/kg, indicating that the level of renal function did not affect clearance in humans; thus, no dose adjustment of palifermin is indicated for patients with renal dysfunction.
Key Words: Palifermin • renal clearance • keratinocyte growth factor • chronic kidney disease • mucositis
Keratinocyte growth factor (KGF), originally purified from a conditioned medium of cells of a human embryonic lung fibroblast cell line, is a member of the fibroblast growth factor family. Palifermin (N23KGF) is a human KGF produced by recombinant DNA technology in Escherichia coli. Palifermin is a water-soluble, 140 amino acid protein with a molecular weight of 16.3 kilodaltons. It differs from endogenous human KGF in that the first 23 N-terminal amino acids have been deleted to improve protein stability. Palifermin is approved in North America, Europe, and Australia for decreasing the incidence and duration of severe OM.12 Palifermin is reasonably tolerated in both healthy volunteers and cancer patients at the doses and schedules tested. Most of the observed toxicities, including skin reactions such as rash, flushing, and edema, and oral-related reactions such as increased saliva production, tongue thickness, and taste distortions were reversible, mild or moderate in severity, and likely related to the known pharmacologic activity of palifermin. Some patients experienced transient, asymptomatic elevations of amylase and lipase levels, but there currently does not appear to be evidence of any association with pancreatitis.
After single IV doses of 20 to 250 mcg/kg (healthy subjects) and 60 mcg/kg (cancer patients), palifermin concentrations declined rapidly (more than 95% decrease) in the first 30 minutes postdose. A slight increase or plateau in concentration occurred at approximately 1 to 4 hours, followed by a terminal decline phase. Palifermin exhibited linear pharmacokinetics with extravascular distribution. On average, total body clearance (CL) appeared to be 2- to 4-fold higher, and the volume of distribution at steady state (Vss) was 2-fold higher in cancer patients compared with healthy subjects after a 60-mcg/kg single dose of palifermin. The elimination half-life (t
) was similar between healthy subjects and cancer patients, with a mean value of 4.5 hours.13 An electrochemiluminescence (ECL)-based binding assay was performed on posttreatment sera from 645 palifermin patients in clinical studies to test for antipalifermin antibodies. Twelve (2%) of these 645 patients tested positive for antibodies to palifermin following treatment. None of the samples had evidence of neutralizing activity in a cell-based assay. To date, the safety and efficacy of palifermin have not been established in patients with nonhematologic malignancies, although studies are ongoing in solid tumor settings.
Given the relatively small size (for a therapeutic protein) of palifermin (16.3 kilodaltons), it is possible that it is cleared through the kidneys. Proteins of similar size such as anakinra (an interleukin 1 receptor antagonist) are renally cleared.14 Thus, further investigation was warranted to determine whether CL was altered in humans with impaired renal function. Accordingly, this study was designed to evaluate the impact of renal function on the pharmacokinetics of palifermin as well as to assess the safety and tolerability of a single IV palifermin 90 mcg/kg dose in subjects with varying degrees of renal function.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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18 years of age, with a body mass index (BMI) of 18 to 34 kg/m2, and had laboratory findings (clinical chemistry, hematology, and urinalysis at screening and day -1) within normal limits (other than indices of renal failure). Subjects had to be free of clinically significant disease (other than expected pathology related to their renal condition) and to have a normal or acceptable physical examination and electrocardiogram (ECG). Subjects could not participate if they had a history of epididymitis or groin pain or a history of malignancy.
Subjects were selected according to estimates of creatinine clearance (CLcr), a common surrogate marker for glomerular filtration rate (GFR) calculated by the Cockcroft-Gault equation.15
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As shown in Table I, renal function was categorized based on the estimated CLcr as prescribed in regulatory guidelines.16
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All subjects provided signed informed consent, and the Canterbury Regional Ethics Committee approved the protocol before the start of the trial. This study was conducted in accordance with US Food and Drug Administration and International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) regulations and guidelines.
Study Design and Procedures
This was a single-dose, open-label, phase 1 study to assess the effects of renal function on the pharmacokinetics, safety, and tolerability of palifermin after a single IV injection. It was conducted at a single study center in Christchurch, New Zealand (Christchurch Clinical Studies Trust). Each subject received a 90-mcg/kg IV bolus (administered over 1 minute) of palifermin (Kepivance), which was supplied as a vial containing 6.25 mg of a lyophilized, sterile white powder (Amgen Inc, Thousand Oaks, Calif) and reconstituted with 1.2 mL Sterile Water for Injection (United States Pharmacopeia).
Selection of the dose of palifermin used in this study, 90 mcg/kg, was based on the hypothesis that renal impairment may compromise palifermin elimination. Thus, the dose was planned so that serum palifermin concentrations would not significantly exceed those achieved in previous palifermin studies (up to 250 mcg/kg, single dose). In the HSCT setting, a daily dose of 60 mcg/kg is used for 3 consecutive days before and 3 consecutive days after myelotoxic therapy. Because previous studies found that the pharmacokinetics of palifermin were approximately linear, with no significant accumulation after repeated daily doses of 60 mcg/kg, extrapolation of the current single-dose results in subjects with renal impairment to different doses and dosing schedules is reasonable.17
Blood Sampling and Concentration Measurements
Blood samples for pharmacokinetic analysis were collected predose; at 2, 15, and 30 minutes after dosing; and at 1, 2, 4, 8, 12, 16, 24, 36, 48, 72, 96, and 120 hours after dosing. Three milliliters of whole blood was collected by venipuncture from subjects into a red-top Vacutainer tube containing no additives or anticoagulants. For subjects in group 5 (ESRD), 2 blood samples were drawn on dialysis days, that is, the 48- and 120-hour samples. These samples were drawn predialysis. Upon collection, blood samples were processed to generate serum, and they were stored at -70°C (±10°C). Laboratory blood samples for clinical chemistry, hematology, and urinalysis assessments were collected at screening; the day before dosing (day -1); at 12, 24, 48, and 120 hours after dosing; and on day 15 after dosing. Subjects remained in the study center through completion of the 48-hour postdose procedures (day 3). Blood samples for palifermin seroreactivity were collected predose on day 1 and on day 45 ± 3 days.
Determination of Palifermin Serum Concentrations
Serum palifermin concentrations were determined using an enzyme-linked immunosorbent assay (ELISA). The experimental plate was precoated with a mouse antipalifermin monoclonal antibody 1G4, and palifermin was bound by the immobilized antibody. After unbound substances were washed away, a biotinylated mouse antipalifermin monoclonal antibody A1 was added to the wells. A mixture of VECTASTAIN ABC reagent (avidin DH and biotinylated horseradish peroxidase H reagent) was added to the wells after a wash to remove any unbound conjugate. After a final wash, a substrate solution containing tetramethylbenzidine and hydrogen peroxide was added to the wells. Colorimetric reaction developed in proportion to the amount of palifermin bound to the antibody coated on the plate. Color development was stopped with phosphoric acid, and the intensity of the color was measured at 450 nm with reference at wavelength of 650 nm. The assay range was 0.072 to 1.800 ng/mL. The accuracy of the assay ranged from 95% to 106%, with 6% to 16% variability.
Statistical Analyses
The planned sample size was 30 (6 subjects in each group), based on practical considerations and sample sizes typically used in this type of study. Pharmacokinetic parameters were summarized by renal function group. In addition, 95% confidence intervals were constructed around the ratios of the geometric means of the impaired renal function groups relative to subjects with normal renal function. Adverse event tabulations included all subjects who received the study drug.
Pharmacokinetic Assessment
The primary pharmacokinetic end point was the CL of palifermin. Additional secondary end points included the estimated initial concentration (C0), Vss, area under the concentration-time curve from time 0 to infinity (AUC0-
), AUC from time 0 to the time of the last quantifiable concentration (AUC0-t), t associated with the terminal phase, and mean residence time (MRT).
Pharmacokinetic analysis was conducted using noncompartmental methods in WinNonlin Professional version 3.3 (Pharsight Corp, Mountain View, Calif) using Model 201. Serum concentrations of palifermin were plotted on a semi-log scale, and data points describing the terminal log-linear segment of the elimination phase were identified. Linear regression was used to estimate the rate constant for the terminal log-linear phase of the concentration-time curve (
z). Elimination half-life was calculated as the natural log of 2 (ln 2) divided by z.
AUC0-t was calculated by the linear-log trapezoidal method. AUCt- was calculated by dividing the predicted concentration at the time of the last quantifiable concentration by z. AUC0- was the summation of AUC0-t and AUCt-. Systemic CL was calculated as dose/AUC0-. Area under the moment curve (AUMC) was computed using the log-linear trapezoidal method, and Vss was calculated as the product of dose x AUMC divided by AUC2. Mean residence time was computed as AUMC/AUC.
Safety Assessment
Safety end points included the incidence of adverse events and clinically significant changes in vital signs; ECGs; clinical laboratory tests, including National Cancer Institute's Common Toxicity Criteria (NCI-CTC, version 3.0) grade increases from baseline in serum amylase or lipase levels (grade 0 = within normal limits and grade 4 = greater than 5.0 times the upper limit of the normal range)18; and the incidence of neutralizing antibodies to palifermin.
All subjects who received palifermin were included in the safety analyses. Safety end points included adverse events, changes in vital signs, clinical laboratory measurements, ECGs, physical examinations, and the incidence of neutralizing antibodies. Increases in serum amylase and lipase concentrations were categorized based on NCI-CTC criteria. Slit-lamp eye examinations were conducted to rule out or detect evidence of cataracts and/or corneal edema.
Determination of Antibody Concentrations
Seroreactivity testing was performed via screening immunoassay followed by bioassay for reactive samples at Amgen's Clinical Immunology Laboratory (Thousand Oaks, Calif). Blood samples were initially analyzed for the presence of antibodies capable of binding to palifermin using an ECL-based immunoassay using a MSD sector PR (Meso Scale Diagnostics, Gaithersburg, Md) with a sensitivity of 100 ng/mL. Reactive samples (ratio of the mean ECL value of the sample divided by the mean ECL value of the negative control 1.61) were run in a cell-based assay to test for neutralizing antibodies to palifermin. The bioassay used a human KGF receptor/erythropoietin receptor chimera-transfected murine cell line 32D. This assay was capable of detecting neutralizing activity associated with 500 ng/mL of a polyclonal purified antipalifermin antibody. Samples were initially tested for their ability to inhibit 100 pg/mL of palifermin.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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65 years, and in all other groups, no more than 1 subject was 65 years. Body mass indices were similar among all groups.
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Pharmacokinetics
The palifermin pharmacokinetic serum concentration profiles were similar across groups (Figure 1). Serum concentrations declined rapidly within 30 minutes after dosing and exhibited a slight increase or plateau within 1 to 4 hours postdose, before a terminal decline phase. Generally, the individual values for systemic clearance of palifermin were similar in all subject groups (Figure 2). Pharmacokinetic parameters dependent on the estimation of t were not calculated for 1 subject with normal renal function because of the lack of a well-defined elimination phase. In addition, 1 subject with severe CKD had pharmacokinetic parameter values that substantially differed from the mean; therefore, summary statistics were calculated including and excluding this subject.
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values ranged from 4.5 to 7.7 hours.
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Safety and Tolerability
Adverse events. All 31 subjects received a single dose of 90 mcg/kg palifermin. No deaths occurred on study or within 30 days of palifermin administration, and no subject discontinued the study because of an adverse event. A total of 26 (84%) subjects reported at least 1 adverse event during the study, none of which was reported as a serious adverse event. With 1 exception, all adverse events were of mild to moderate severity. A 42-year-old white male with ESRD and insulin-dependent diabetes mellitus had significantly abnormal glucose concentrations, which were successfully treated and not considered related to study drug.
The most commonly reported adverse events (Table V) included fatigue in 8 (26%) subjects, headache in 7 (23%), and oral soft-tissue disorder (a "coated" sensation in the mouth and/or on the tongue) in 5 (16%). With the exception of 1 case of stomatitis in a subject with normal kidney function, and 1 incidence of fatigue and 2 cases of stomatitis in the moderate CKD group, all adverse events were considered related to study drug by the investigator. A relationship between renal function and incidence or type of adverse events was not observed.
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Amylase and lipase concentrations. Increases in serum amylase concentrations of grades 1, 2, or 3 (n = 9, 2, and 1 subjects, respectively) were observed for 12 (39%) subjects. More subjects in the severe CKD (n = 4) and ESRD (n = 4) groups had increases in amylase concentrations compared with subjects in other groups. Similarly, increases in serum lipase concentrations of grades 1, 2, 3, or 4 (n = 4, 5, 3, and 1 subjects, respectively) were reported for 13 (42%) subjects, with a single (3%) subject in the normal renal function group having a grade 4 increase. Across groups, mean serum amylase and lipase concentrations increased from day -1 to day 3 or 6 and returned to normal or baseline by day 15. No relationship was observed between the grade changes in amylase/lipase concentrations and palifermin exposure (Figures 4 and 5).
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One subject with severe CKD had serum palifermin concentrations that were substantially higher than those of the rest of the group. This subject reported mild musculoskeletal soft-tissue pain and swelling (location not specified) that began on day 4 and lasted 1 to 2 days. The same subject also had increases in serum amylase levels (from 148 IU/L at baseline to 324 IU/L on day 3) and lipase levels (from 105 IU/L at baseline to 446 IU/L on day 3).
Vital signs, physical findings, and antibody analysis. No clinically significant or consistent changes were observed in vital signs, weight, urinalysis, ECGs, or slit-lamp evaluations. In addition, no subject tested positive for antibodies to palifermin.
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Considerable overlap was observed in palifermin CL, and no consistent trend of increase or decrease in mean palifermin pharmacokinetic parameters was associated with the level of renal function in this study. The largest difference in palifermin CL, relative to the control subjects, was observed in the severe renal impairment group. When interpreting this finding, it is important to keep in mind the small sample size and that there was 1 subject in the severe group whose CL was substantially lower than that of the other subjects. The cause of this subject's reduced palifermin CL is not evident. Nevertheless, if renal CL did play a major role in the elimination of palifermin, it would be reasonable to expect that the difference from normal subjects would be even more extreme for ESRD subjects than in severe subjects. Because this is not the case, there does not appear to be evidence to suggest that renal function has a clinically significant impact on the CL of palifermin.
Hemodialysis was not likely to have altered the palifermin pharmacokinetic profile to any significant extent, as the molecular weight (16.3 kilodaltons) of palifermin renders it unlikely to be dialyzable and because most of the drug was likely cleared within 24 hours of dosing, during which time subjects were not dialyzed. Because of the lack of biologic plausibility, we did not formally test whether palifermin was dialyzable.
Palifermin was generally well tolerated among subjects with various degrees of renal function at this dose, with all but 1 adverse event classified as mild or moderate in severity. No particular relationship was detected between the level of renal function and incidence or type of adverse events in the current study, albeit the power to detect such differences was low. Nevertheless, 1 subject in group 4 (severe CKD) had serum palifermin concentrations that were substantially higher than those of the rest of the group (an approximately 20-fold higher concentration at the 2-minute sampling time relative to the mean concentration value at this time point for other subjects in the group). The CLcr (5.29 mL/min) for this subject was the lowest estimated CLcr value in the study (patients on hemodialysis did not have CLcr estimated). This subject had 1 adverse event of mild musculoskeletal soft-tissue pain and swelling (location not specified) that began on day 4 and lasted for 1 to 2 days. Increases in serum amylase (148 IU/L at baseline and 324 IU/L on day 3) and lipase (105 IU/L at baseline and 446 IU/L on day 3) were also reported for this subject. Baseline levels of both amylase and lipase were higher in subjects with greater levels of renal impairment. Because the concentration of these enzymes are known to be affected by renal function, this pattern was not unexpected.20 The additional increases in amylase and lipase after administration of palifermin were also predicted based on previous clinical studies.12 Importantly, no clinical sequelae were noted. In general, exposure to palifermin was similar between subjects with grade 0 through 3 amylase/lipase increases. The exposure in the 1 subject with a grade 4 lipase change was also similar to that observed in the rest of the subjects. Transient adverse events consistent with the known pharmacologic properties of palifermin and reported in other clinical studies, such as a coating on the tongue, were observed and resolved without treatment.12,21 Finally, no subject formed antipalifermin antibodies.
In conclusion, these findings indicate that a subject's level of renal function does not appear to affect palifermin clearance or tolerability. Therefore, dose adjustment of palifermin is not indicated for patients with renal impairment.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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REFERENCES |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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