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Clinical Trial Simulation of a 200-µg Fixed Dose of Darbepoetin Alfa in Chemotherapy-Induced Anemia

Clinical Trial Simulation of a 200-µg Fixed Dose of Darbepoetin Alfa in Chemotherapy-Induced Anemia

ABSTRACT: Our objective was to assess, using clinical trial simulation, the feasibility of a fixed 200-µg dose of darbepoetin alfa (Aranesp) administered every 2 weeks in chemotherapy-induced anemia. A pharmacokinetic/pharmacodynamic model was developed using clinical data from 547 cancer patients who received darbepoetin alfa at various doses and schedules. Monte Carlo simulations were performed for weight-based (3 µg/kg every 2 weeks) and fixed-dose (200 µg every 2 weeks) regimens and were compared with observed clinical data. Mean hemoglobin changes from baseline to end of treatment were +1.61 g/dL, +1.83 g/dL, and +1.79 g/dL for observed data, the weight-based simulation, and the fixed-dose simulation, respectively. The rates of required transfusions (hemoglobin ≤ 8 g/dL) were also similar between groups. For patients between 45 and 95 kg (over 90% of the population), the impact of a fixed dose on mean hemoglobin change was negligible. There was a slight weight effect at body weight extremes (< 45 kg and > 95 kg). Clinical outcomes from simulations of weight-based and fixed dosing of darbepoetin alfa were similar to those of observed weight-based data. Given the weight distribution of a typical cancer population, the majority would be expected to benefit equally from weight-based and fixed-dose darbepoetin alfa in the amelioration of chemotherapy-induced anemia. [ONCOLOGY 16(Suppl 11):37-44, 2002]

Anemia is a common complication in patients with
cancer.[1,2] Anemia, defined by low hemoglobin or a low red blood cell (RBC) count,
can be a consequence of the myelotoxicity of the chemotherapy regimen
(especially platinum-containing regimens) or an inherent effect of the cancer
itself (particularly in multiple myeloma, lymphomas, or metastatic bone
disease). Although approximately 50% of patients receiving chemotherapy can
experience anemia of varying severity,[3] and despite the attendant morbidities—which
can include fatigue and cognitive and other central nervous system effects[4,5]—anemia
represents an undertreated complication in cancer patients.

Since its introduction in 1989, recombinant human erythropoietin (rHuEPO) has
been a mainstay for the treatment of cancer-related anemia that reduces the need
for RBC transfusions.[6] When anemic cancer patients receiving chemotherapy were
treated with a standard regimen of rHuEPO, hemoglobin response (defined as an
increase in hemoglobin ³ 2 g/dL) was seen in 53% of patients.[7]
Additionally, the requirement for blood transfusions was significantly decreased
and quality-of-life indices were significantly improved.

Recommended dosing of rHuEPO is three times weekly, although weekly regimens
are commonly utilized in cancer patients.[8] This requirement for frequent
dosing is due to the
relatively short serum half-life of
rHuEPO. In response to this shortcoming in dosing profile, a novel molecule was
designed. Site-directed mutagenesis was employed to modify the amino acid
backbone of human erythropoietin to allow for additional N-linked sialic acid-containing carbohydrate
chains. These additional sialic acid moieties act to slow the clearance of the
glycoprotein and hence prolong the serum half-life.

The resulting molecule, darbepoetin alfa (Aranesp), is a unique
erythropoietic protein with a greater in vivo potency relative to rHuEPO.[9]
This increased biologic activity is due primarily to the slower clearance of the
molecule. Following intravenous administration to patients with chronic kidney
disease, the terminal half-life was 25.3 hours, approximately threefold longer
than that of rHuEPO.[10] In subcutaneous usage, the rate of absorption from the
subcutaneous administration site controls the elimination rate. Following
subcutaneous administration, the terminal half-life of darbepoetin alfa was 48.8
hours, approximately twofold longer than that for intravenous administration,
with a bioavailability of 37%.

In phase II dose-finding trials, clear dose-dependent increases in hemoglobin
response were seen.[11] In a placebo-controlled phase III study of 320 anemic
lung cancer patients receiving platinum-containing chemotherapy, statistically
significant improvements favoring darbepoetin alfa vs placebo were seen in the
proportion of patients with a hematopoietic response (66% vs 24%), in patients
requiring transfusions (26% vs 60%), and in the mean number of transfusions per
patient (1.14 vs 2.64).[12] Darbepoetin alfa is approved in the United States
and
Europe for the treatment of anemia associated with chronic renal failure
(including dialysis and predialysis patients) and in the United States for the
treatment of chemotherapy
induced anemia in patients with nonmyeloid malignancies.

Due to the longer serum half-life, darbepoetin alfa should be administered
less frequently than rHuEPO.[13] This provides obvious advantages for both
patients and health-care providers. The current recommendation for rHuEPO dosing
in cancer patients with chemotherapy-induced anemia is a starting dose of 150
U/kg three times weekly, adjusted in accordance with resulting hemoglobin
levels.[14] Approved dosing for darbepoetin alfa in this same setting is 2.25
µg/kg once weekly.[13] However, a comparative study indicated that darbepoetin
alfa administered at 1.5 µg/kg once weekly produced a similar mean hemoglobin
change from baseline as the above three-times-weekly regimen of rHuEPO.[11,15]

Alternative dosing strategies for darbepoetin alfa have been tested that more
fully exploit the pharmacokinetic profile. These include dosing every 2
weeks,[11] where it has been demonstrated that darbepoetin alfa at 3 µg/kg every
2 weeks produced the same hematopoietic response as rHuEPO given at 40,000 U
once weekly—a typical weekly dose. Even longer dosing intervals are being
explored to coincide with the cycle of chemotherapy (viz, every 3 weeks and
every 4 weeks).[16]

An additional dosing paradigm that might serve to enhance the utility of
darbepoetin alfa is a fixed dose, ie, a dosing regimen independent of patients’
body weight. A fixed dose would contribute to the simplicity of darbepoetin alfa
usage and, by the administration of the entire contents of a vial, eliminate
wasted product. However, a thorough understanding of the pharmacokinetic/pharmacodynamic
profile of darbepoetin alfa is necessary to ensure the success of a fixed-dose
strategy. Other relevant considerations would include the distribution of body
weight in the oncology population, the potential for under- or overdosing
patients, and attendant benefit/risk issues.

Clinical trial simulation that includes the integration of pharmacokinetic
and pharmacodynamic modeling has been advocated as a means of applying modeling
techniques to drug development.[17-20] The Monte Carlo method is one such
technique for performing clinical trial simulation.[21] Pharmacokinetic/pharmacodynamic
modeling based on population analysis with subsequent Monte Carlo simulations
would potentially provide the best and least biased estimate of the anticipated
hemoglobin response both within the treated population and for an individual
with specific characteristics. This methodology permits the incorporation of
measures of variability and uncertainty into pharmacokinetic/pharmacodynamic
modeling.[22-26] Monte Carlo simulation uses prior information, such as baseline
body weight and hemoglobin concentration, and parameter estimates (from the
pharmacokinetic/pharmacodynamic model), and allows multiple sampling of these
quantitatively defined probability distributions and the subsequent computation
of model outputs. This method allows for a more rigorous assessment of
variability of response than simpler (mean parameter or deterministic) methods.

This paper presents the results of a clinical trial simulation using the
Monte Carlo method that assesses the predicted hematopoietic response of a fixed
dose of darbepoetin alfa (200 µg every 2 weeks) vs modeled results for a
weight-based dose (3 µg/kg every 2 weeks). Model validation was performed
by comparing predicted outcomes for weight-based dosing with observed clinical
data from weight-based dosing.

Methods

Source of Clinical Data

Clinical data for 547 patients were utilized in generating the model for the
simulation. These patients had participated in one of three Amgen-sponsored
clinical trials of darbepoetin alfa for chemotherapy-induced anemia (study
numbers 980290, 980291, and 20000174).[11,16,27] These trials were similar in
nature, all being conducted in a multicycle chemotherapy setting for adult
patients with solid tumors. Patients were required to have a baseline hemoglobin

£
11 g/dL for study eligibility. The trials investigated various doses and
schedules of darbepoetin alfa in a randomized sequential- or parallel-cohort
structure. Doses and schedules of darbepoetin alfa that were studied included
0.5 through 18 µg/kg given every week, every 2 weeks, every 3 weeks,
and every 4 weeks (a total of 18 different regimens) over a 12-week
treatment period.

Table 1 gives descriptive statistics on the demographics of the 547 patients
whose data were used in the model development. Over two-thirds of the population
were female, due to the prevalence of breast and gynecologic cancer patients
treated in these trials. Across the three trials, the mean age of the patients
was 61 years (range: 20 to 91 years). Mean body weight was 70 kg (range: 39 to
129 kg). Tumor types represented in this population included—in descending
order of prevalence—breast, lung, gastrointestinal, gynecologic, and
genitourinary. Platinum-containing regimens were used in approximately 38% of
patients across all three studies.

In addition to serial hemoglobin levels representing the pharmaco
dynamic response, serum drug levels for the pharmacokinetic response were
measured intensively in five patients given darbepoetin alfa doses of 0.5, 1.5,
or 4.5 mg/kg once weekly subcutaneously, and were also measured predose and 48
hours postdose in 211 patients at certain dosing time points. Observed clinical
data from 33 patients in study 980290[11] who received darbepoetin alfa in
a 3.0 µg/kg every-2-week regimen were utilized for comparison with the
simulated fixed dose and the simulated weight-based dose.

Modeling and Simulation Procedures

Pharmacokinetic/pharmacodynamic modeling and clinical trial simulation were
used to evaluate every-2-week dosing of darbepoetin alfa and to assess the
impact of a fixed dose on predicted response and its variability. The modeling
and clinical trial simulation steps were as follows: (1) fitting and optimizing
the model to data from the three darbepoetin alfa clinical studies (described
above), (2) developing a clinical trial simulation platform by incorporating
relevant clinical study design elements, and (3) performing clinical trial
simulations to evaluate the impact of a fixed dose of darbepoetin alfa on predicted response and its variability.

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