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, and despite the attendant morbiditieswhich 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(Drug information on erythropoietin) (rHuEPO) has been a mainstay for the treatment of cancer-related anemia that reduces the need for RBC transfusions. 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. 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. 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(Drug information on darbepoetin alfa) (Aranesp), is a unique erythropoietic protein with a greater in vivo potency relative to rHuEPO. 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. 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. 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). 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. 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. Approved dosing for darbepoetin alfa in this same setting is 2.25 µg/kg once weekly. 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, 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 weeklya 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).
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. 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.
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 includedin descending order of prevalencebreast, 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 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.