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PHARMACOKINETICS AND PHARMACODYNAMICS |
From Amgen, Inc, Thousand Oaks, California.
Address for reprints: Bing-Bing Yang, PhD, Amgen, Inc, One Amgen Center Drive, Thousand Oaks, CA 91320; e-mail: byang{at}amgen.com.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
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Key Words: PK/PD modeling • G-CSF • nonlinear kinetics • pegfilgrastim • pharmacodynamics
Pegfilgrastim is a sustained-duration form of filgrastim, produced by covalently binding a 20-kd polyethylene glycol molecule to the N-terminal methionine residue of filgrastim.6 Results from in vitro proliferation, receptor binding, and neutrophil function studies demonstrate that filgrastim and pegfilgrastim have the same mechanism of action.7 However, pegfilgrastim in vivo has sustained effects on granulopoiesis compared with filgrastim.8 Filgrastim is eliminated predominantly by neutrophil G-CSF receptor-mediated clearance9 and by renal clearance.10 During chemotherapy-induced neutropenia, nonreceptor-mediated clearance is the primary route for filgrastim and pegfilgrastim elimination. The sustained effects of pegfilgrastim have been attributed to decreased renal clearance of the pegylated molecule with a higher hydrodynamic radius.10
A phase I study was conducted to evaluate the pharmacokinetics, pharmacodynamics, and safety of pegfilgrastim in healthy subjects. To assess the relationship between serum concentrations of pegfilgrastim and granulopoietic effects of the drug, as well a to define the relationship between neutrophil counts and pegfilgrastim clearance, a semimechanistic pharmacokinetic-pharmacodynamic model was established. Pharmacokinetic data and pharmacokinetic-pharmacodynamic modeling are presented herein, expanding on descriptive pharmacodynamics and safety results previously reported.11
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Study Drug
Pegfilgrastim (Neulasta®) was manufactured by Amgen, Inc (Thousand Oaks, Calif) and was supplied in single-use, preservative-free vials as a sterile, clear 1.2-mL solution at 10 mg/mL. To equalize the volume of study drug administered to each subject, pegfilgrastim was diluted with diluent to a 3-mL solution before injection to the subjects.
Study Design
This was an open-label, single-dose, dose escalation study. Thirty-two healthy subjects received a single dose of 30, 60, 100, or 300 µg protein/kg pegfilgrastim (8 subjects/dose group) on day 1. Pegfilgrastim was administered as two 1.5-mL subcutaneous injections on day 1 at 2 different injection sites (the deltoid area of both arms) within 1 minute of each other. Blood samples for pegfilgrastim concentration measurement were collected before pegfilgrastim administration and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, and 48 hours after the second injection of pegfilgrastim and then daily until day 15. Serum samples were stored at -70°C until assayed for pegfilgrastim. Blood samples for differential white cell counts were collected concurrently with all pharmacokinetic samples.
Sample Analysis
Pegfilgrastim serum concentration measurement. Pegfilgrastim concentrations in serum were analyzed by an enzyme-linked immunosorbent assay (ELISA, QuantikineTM Human G-CSF Immunoassay Kit, R&D Systems, Inc, Minneapolis, Minn). Microtiter immunoassay plates were coated with murine monoclonal anti-G-CSF antibody. Standard and quality control samples containing known amounts of pegfilgrastim along with samples containing unknown amounts of pegfilgrastim were added to the wells. After a 2-hour incubation at room temperature, the plates were washed with a buffer to remove unbound protein. Then, a goat polyclonal antibody against G-CSF conjugated with horseradish peroxidase was added to the wells for a 2-hour incubation at room temperature. After another washing step, a substrate solution (tetramethylbenzidine peroxidase 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. A log-log fit was used to estimate pegfilgrastim concentration in human serum. The lower limit of quantitation of the assay was 0.031 ng/mL serum. The precision ranged from 1% to 14% within an assay and from 5% to 9% between assays. The accuracy ranged from 95% to 119% within an assay and from 93% to 107% between assays.
Hematology evaluation. Whole-blood samples were analyzed immediately after collection at the testing site (PPD Pharmaco, Austin, Tex). The absolute neutrophil count (ANC) was calculated as the total white blood cell count times the percentage of total neutrophils.
Data Analyses
Noncompartmental pharmacokinetic analysis. Pharmacokinetic parameters were calculated for each subject using noncompartmental analysis of serum pegfilgrastim concentration-time data (WinNonlin Professional, Pharsight Corp, Mountain View, Calif). The maximum concentration (Cmax) and the time it occurred (tmax) after dosing were recorded as observed. The area under the serum concentration-time curve, AUC(0-last), was estimated using the linear trapezoidal method from time 0 to last, the time of the last quantifiable concentration (Clast). The first-order terminal rate constant (kel) was estimated using linear regression of the terminal log-linear decay phase. The terminal half-life (t
) was calculated as ln(2) divided by kel. The area under the curve calculated from time 0 to infinity, AUC(0-
), was estimated as the sum of corresponding AUC(0-last) and Clast/kel values. Apparent clearance (CL/F) was estimated as dose divided by AUC(0-). Pharmacokinetic/pharmacodynamic modeling and simulation. Mean pegfilgrastim serum concentration data and peripheral blood band cell and segmented neutrophil counts from all dose groups were modeled simultaneously. Pegfilgrastim serum concentration data were modeled using a 1-compartment model with a first-order, delayed absorption process; the elimination of pegfilgrastim was described by parallel G-CSF receptor-mediated clearance (CLN/F) and linear clearance (CLlin/F) (Figure 1). The G-CSF receptor-mediated clearance was described as follows:
 | (1) |
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A maturation-structured cytokinetic model was developed to describe the granulopoietic effects of pegfilgrastim and the feedback regulation of pegfilgrastim clearance (Figure 2). The model construct was based on the biology of normal human granulopoiesis.12 The starting point of the pharmacodynamic model was the production of metamyelocytes from the last maturational step of mitotic precursors. The most distal effect of the drug, expansion of the mitotic promyelocyte and myelocyte pools, was empirically described by a Hill equation. Serum concentrations of pegfilgrastim were assumed to stimulate mitosis and mobilization of band cells and segmented neutrophils in bone marrow and increase adhesion of peripheral blood band cells (Bp) and segmented neutrophils (Sp) to blood vessels (a process known as margination), causing a change in the volume of distribution of the circulating neutrophils.
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Change in metamyelocyte mass after stimulation of mitotic precursors was described by 3 transit compartments represented by the following differential equations:
 | (2) |
 | (3) |
 | (4) |
where Mi is the mass in the ith metamyelocyte compartment, S0 is the baseline metamyelocyte influx rate, Emit is the maximum rate of metamyelocyte influx that can be elicited by pegfilgrastim, 
meta is the baseline mean maturation time of the metamyelocytes, and the constant, "3," represents the number of transit compartments; the number of transit compartments modulates the variance of the maturation time. The parameter fmmt is the maximum fraction by which the baseline mean maturation time can be decreased by pegfilgrastim. EC50 is the serum concentration of pegfilgrastim that exerts half-maximum granulopoietic effects and was assumed to be the same for effects on mitosis, maturation, mobilization, and margination. The EC90 for mitosis, maturation, and mobilization was calculated by multiplying the EC50 by 9.
Change in the band cell mass in bone marrow was described by the following differential equations:
 | (5) |
 | (6) |
 | (7) |
where Bi is the mass in the ith band cell compartment, Eband is the maximum rate of band cell flux from the bone marrow pool to the circulating neutrophil pool that can be elicited by pegfilgrastim, and band is the mean maturation time of bone marrow band cells, which was fixed at 66 hours based on published values.13-15
Change in the segmented neutrophil mass in bone marrow was described by the following differential equations:
 | (8) |
 | (9) |
 | (10) |
where Si is the mass in the ith bone marrow segmented neutrophil compartment, Eseg is the maximum rate of segmented neutrophil flux from the bone marrow pool to the circulating neutrophil pool that can be elicited by pegfilgrastim, seg is the mean maturation time of segmented neutrophils in bone marrow, and kig is a sink that describes ineffective granulopoiesis, or loss of cells in bone marrow before mobilization to circulation.16 The maturation times of bone marrow-segmented neutrophils was fixed at 95 hours based on published values.13-15
The change in band cell and segmented neutrophil counts in peripheral blood was described as
 | (11) |
 | (12) |
where BP and SP are neutrophil counts unadjusted for changes in neutrophil margination, kbpmat is the rate constant for maturation of peripheral blood band cells to segmented neutrophils, and k
is the rate constant for neutrophil elimination from peripheral blood, which was assumed to be the same for band cells and segmented neutrophils. Margination was modeled as a rapid expansion of the relative, blood neutrophil dilution volume, VN, where
 | (13) |
Emarg is the increase in baseline neutrophil dilution volume that can be induced by pegfilgrastim, and 
N is the Hill coefficient. The half-life of the circulating segmented neutrophil, t1/2,seg, was calculated as ln(2) divided by k.
Model Fitting and Parameter Estimation
Modeling was conducted using SAAM II (SAAM Institute, Seattle, Wash). Numerical integration was conducted in SAAM II using the Rosenbrock method with an adjustable step size.17 Goodness of fit was evaluated by asymptotic standard deviations for estimated parameters and by weighted residual plots. The relative goodness of fit for different structural models was evaluated using the objective function value or the Akaike information criterion.18
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Pharmacokinetics of Pegfilgrastim
Mean concentration-time profiles of pegfilgrastim after subcutaneous administration are presented in Figure 3. The mean Cmax value increased more than dose proportionally; a 10-fold increase in the dose resulted in an approximately 25-fold increase in mean (±SD) Cmax from 43.6 ± 20.0 ng/mL to 1070 ± 360 ng/mL (Table II). The median tmax occurred later as the dose increased from 8 hours at 30 µg/kg to 24 hours at 300 µg/kg. The mean serum clearance of pegfilgrastim decreased from 38.6 ± 15.4 mL/h/kg to 5.19 ± 2.31 mL/h/kg, as the dose increased from 30 to 300 µg/kg. At the terminal phase, the serum concentrations of pegfilgrastim for all groups declined in parallel with a mean terminal t ranging from 46.3 ± 10.3 to 62.1 ± 5.8 hours.
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Pharmacodynamics of Pegfilgrastim
Mean ANC-time profiles after subcutaneous administration are presented in Figure 3. During the first hour of pegfilgrastim administration, a transient decrease in ANC was observed. This decrease was followed by a rapid and significant increase in ANC. The ANC profiles demonstrated a clear dose response both in the magnitude and in the duration of elevation. The ANC parameters were presented previously.11 In brief, the median maximum ANC value increased with increasing dose and was reached in 1.5 days at 30 µg/kg and in approximately 2 days at 60 µg/kg and 100 µg/kg; ANC continued to increase at the 300-µg/kg group until reaching a maximum at 4 days postdose. The median area over the baseline effect curve increased with increasing dose from 101 x 109 cells·day/L at 30 µg/kg to 223 x 109 cells·day/L at 300 µg/kg.
Pharmacokinetic/Pharmacodynamic Modeling
Mean pegfilgrastim serum concentration data, band cell counts, and segmented neutrophil counts from all dose groups were modeled simultaneously. The fit of the model to the pegfilgrastim serum concentration and ANC profiles is illustrated in Figure 4. The model fit to the differential neutrophil counts is shown in Figure 5. The model accurately described the dose-dependent pharmacokinetic and pharmacodynamic behavior of pegfilgrastim.
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Pharmacodynamic parameter estimates are listed in Table IV. The pharmacodynamic model included effects of pegfilgrastim on margination, mitosis, and mobilization. Margination was described as a pegfilgrastim-dependent expansion of the dilution volume of peripheral blood neutrophils. Based on the model estimate of Emarg, pegfilgrastim could elicit a 4-fold increase in the apparent neutrophil dilution volume. Pegfilgrastim was assumed to increase the production rate of metamyelocytes in marrow through effects on mitotic precursor cells. A comparison of the baseline apparent production rate (S0) to the maximum production rate elicited by pegfilgrastim (Emit) suggests that pegfilgrastim could amplify myelocyte mass by a maximum factor of 4. Accelerated emergence of neutrophils into peripheral blood was modeled as the pegfilgrastim-dependent release of marrow band cells and segmented neutrophils into blood; the model predicted the increased proportion of band cells in circulation. The model estimate for the maximum rate of segmented neutrophil flux into blood (Eseg) was nearly 3 times as fast as the maximum flux rate for band cells (Eband), which contributed to maintenance of a higher proportion of segmented neutrophils in blood at all dose levels. The model fit was not improved by assuming different EC50 values for margination, mitosis, mobilization, and maturation; therefore, the same EC50 was applied to all processes. The EC50 estimate for pegfilgrastim-mediated effects was 9.86 ng/mL.
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Elimination of neutrophils from peripheral blood was modeled using various assumptions, including different elimination rate constants for band cells and segmented neutrophils and the presence or absence of band cell maturation in peripheral blood. The best model fit was obtained when assuming an identical, first-order elimination rate constant for both neutrophil populations and assuming peripheral maturation of band cells into segmented neutrophils. The estimated half-life for mature, segmented neutrophils in peripheral blood was approximately 9 hours.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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In healthy subjects, the pharmacokinetics of pegfilgrastim was nonlinear in a dose range of 30 to 300 µg/kg; the clearance of pegfilgrastim decreased with increasing dose, which is attributed to the neutrophil G-CSF receptor-mediated pathway. The terminal half-life was independent of dose (Table II), suggesting that pegfilgrastim serum concentrations at the terminal phase fell below levels saturating G-CSF receptors. The nonlinear pharmacokinetic profiles across doses could not be modeled with a constant Vmax for the Michaelis-Menten clearance process. Pharmacokinetic modeling required that the Vmax change in proportion to peripheral neutrophil counts, consistent with a G-CSF receptor-mediated clearance mechanism. The low rate of pegfilgrastim clearance by a neutrophil-independent, linear pathway may explain the prolonged exposure to drug and sustained effects during chemotherapy-induced neutropenia.8 During neutropenia, the linear clearance pathway is expected to be the predominant elimination pathway for pegfilgrastim because of the decreased numbers of neutrophils and neutrophil precursors in blood and marrow. In contrast, filgrastim has a more rapid linear clearance rate, attributed to renal clearance of the smaller molecule,10 which necessitates daily administration of the drug to maintain therapeutic concentrations in serum.
After administration of pegfilgrastim, a transient decrease in ANC followed by a rapid, dose-dependent increase in ANC was observed. The transient decrease in ANC, which occurred within the first hour after dosing, has also been observed following administration of filgrastim.21 The initial transient decrease in ANC may be the result of neutrophil margination to endothelial cells, followed by neutrophil demargination and, finally, by an increase in neutrophil proliferation and accelerated release of mature neutrophils from bone marrow.22,23 A dose-dependent increase in the percentage of band cells in peripheral blood was observed. The appearance of the younger, band cell population in peripheral blood—also observed after dosing with filgrastim5—suggests that pegfilgrastim stimulates early release of neutrophils from marrow.
A maturation-structured model of granulopoiesis was established to describe the relationship between pegfilgrastim serum concentrations and neutrophil counts in peripheral blood (Figures 1 and 2). Modeling predicted that pegfilgrastim could elicit a maximum 4-fold increase in the rate of metamyelocyte production. Consistent with the modeling results, neutrophil kinetic studies of filgrastim in healthy subjects have shown that filgrastim exerts mitotic effects primarily on promyelocytes and myelocytes, with a 2- to 3-fold amplification of mitosis and a minimal delay before influx of metamyelocytes.24,25
Differential effects of pegfilgrastim on blood neutrophil populations were modeled as a pegfilgrastim-dependent flux of younger neutrophils, including band cells and segmented neutrophils through early release from marrow and a decrease in maturation time. Band cells are juvenile neutrophils and differ from mature, segmented neutrophils primarily by the shape of the nucleus. Modeling the differential neutrophil counts provides insight into mechanisms by which pegfilgrastim mobilizes neutrophils from marrow and stimulates neutrophil recovery following chemotherapy. Daily filgrastim doses of 30 and 300 µg in healthy subjects have been demonstrated to shorten the neutrophil marrow transit time to 4.3 ± 0.2 days and 2.9 ± 0.1 days, respectively, compared with a 6.3 ± 0.3-day transit time in subjects in the control group, as determined by a flash labeling study with 3H-TdR.25 As suggested by the model, this decreased transit time may be due, in part, to the early release of band cells and segmented neutrophils from bone marrow. The early release of neutrophils and accelerated precursor maturation may be important contributors to accelerated ANC recovery after myelosuppressive chemotherapy.
Pegfilgrastim promoted rapid margination of peripheral blood neutrophils (Figure 4); this effect was modeled as an expansion of neutrophil dilution volume, consistent with a study of filgrastim in rats.26 In rats receiving a single dose of filgrastim before an intravenous (IV) tracer injection of labeled neutrophils, the initial concentration of the labeled neutrophils was reduced to about one third of that in control animals, consistent with a rapid effect on the initial dilution volume of the blood neutrophil pool. The margination of neutrophils after administration of filgrastim to healthy subjects has also been modeled using the assumption of an expanded neutrophil dilution volume.27 Following administration of the 300-µg/kg dose, a sharp cusp in the neutrophil counts was observed on day 5. Based on modeling, this sharp peak appears to be due to demargination of neutrophils as serum pegfilgrastim concentrations decline rapidly and the effects on neutrophil dilution volume are reversed. The cusp was not predicted by the model if the margination effects were not included. Elimination of neutrophils from blood was modeled as a first-order loss, as numerous kinetic studies of labeled autologous neutrophils have demonstrated that neutrophils are eliminated randomly from circulation and not by senescence; the model estimate of segmented neutrophil half-life was consistent with these published results.13,25
The modeling-derived EC50 (9.86 ng/mL) and EC90 (88.7 ng/mL) for the mitotic, mobilization, and maturational effects of pegfilgrastim in healthy subjects agree with exposure-response data collected in patients receiving chemotherapy. In patients with non-small-cell lung cancer who received carboplatin and paclitaxel, patients receiving 30 µg/kg pegfilgrastim experienced a lower ANC nadir and a slower ANC recovery compared to patients receiving 100- and 300-µg/kg doses.8 The 100- and 300-µg/kg doses produced similar ANC profiles, suggesting that those doses produced serum levels on the plateau of the concentration-response curve. Consistent with this observation, the serum levels during the period of neutropenia in patients receiving 30 µg/kg were less than 10 ng/mL (below the EC50) and were approximately 100 ng/mL (above the EC90) in patients receiving a 100-µg/kg dose. In patients with breast cancer who received doxorubicin and docetaxel, a 60-µg/kg dose of pegfilgrastim resulted in a slower ANC recovery and a longer duration of grade 4 neutropenia compared to patients receiving a 100-µg/kg dose.19 Serum levels in the breast cancer patients receiving the 60-µg/kg dose were approximately 10 to 20 ng/mL (just above the EC50) during neutropenia and were above the EC90 in patients receiving 100 µg/kg pegfilgrastim. The pharmacokinetic-pharmacodynamic relationship in healthy subjects appears to predict the optimum serum concentrations of pegfilgrastim in cancer patients receiving different chemotherapy regimens.
In summary, pegfilgrastim exhibited nonlinear pharmacokinetics in healthy subjects and produced dose-dependent increases in band cell and segmented neutrophil counts in peripheral blood, consistent with the biology of G-CSF-mediated granulopoiesis. A mechanistic pharmacokinetic-pharmacodynamic model incorporating feedback regulation of pegfilgrastim clearance by neutrophils accurately described the dose-dependent pharmacokinetics and pharmacodynamics of the drug in healthy volunteers. The pharmacokinetic-pharmacodynamic model may have future applicability in the modeling and simulation of pegfilgrastim therapy in various settings of chemotherapy-induced neutropenia.
Dr Roskos, Ms Lum, Ms Lockbaum, Dr Schwab, and Dr Yang are currently or were previously employed at Amgen, Inc and are shareholders of Amgen stock.
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REFERENCES |
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