Pharmacokinetics

PHARMACOKINETICS

The pharmacokinetic profiles of HGFs obtained in different studies should not be compared directly due to the clinically relevant differences in doses, admin-istration routes, and study populations. For example, patients with advanced cancer typically receive chemotherapeutic agents, antibiotics, and other ther-apeutic interventions that may directly alter the disposition of HGFs or affect the organs that metabolize and eliminate these growth factors. Patients undergoing bone marrow transplantation typically are exposed to an even wider variety of therapeutic interventions.

Filgrastim, Lenograstim, and Pegfilgrastim

Filgrastim exhibits first-order kinetics and increasing plasma concentrations with increasing doses (Roskos et al., 1998). Filgrastim is rapidly absorbed after subcutaneous administration, achieving peak concen-trations in 2–8 hours. The elimination half-life of filgrastim is approximately 3.5 hours in both healthy volunteers and patients with cancer, and after intravenous as well as subcutaneous administration.

The pharmacokinetics of lenograstim are dose and time dependent. Peak serum concentration after either subcutaneous or intravenous administration is dose dependent. The serum half-life is 3 to 4 hours for subcutaneous administration and 1 to 1.5 hours for intravenous administration.

Pegfilgrastim has nonlinear pharmacokinetics in patients with cancer and decreased clearance with increased dose; the half-life of pegfilgrastim is 15 to 80 hours after subcutaneous administration. The prolonged half-life is thought to be due to the “self-regulation” of pegfilgrastim and neutrophil binding (Johnston et al., 2000).

Sargramostim and Molgramostim

Pharmacokinetic parameters of sargramostim are simi-lar between healthy individuals and patients (Armitage, 1998). In patients with advanced cancer, sargramostim is rapidly absorbed after subcutaneous administration, achieving peak concentrations in 2 hours. After intrave-nous infusion over 2 hours, serum concentrations initially decline rapidly (t1/2 alpha¼12–17 minutes) and then more slowly (t1/2 beta¼ 2 hours). Elimination is primarily by non-renal pathways.

In pharmacokinetic studies with molgramos-tim, maximum serum concentration and area-under-the-concentration-versus-time curve increased withboth subcutaneous and intravenous administration but serum concentration was higher for a longer period of time after intravenous dosing (Armitage, 1998). Immunoreactive molgramostim can be de-tected in the urine of patients, supporting a renal route of elimination. The reported half-life after intravenous administration is 0.24 to 1.18 hours; mean half-life after subcutaneous administration is 3.6 hours.

Epoetin Alfa, Epoetin Beta, and Darbepoetin Alfa

Epoetin alfa and epoetin beta follow first-order kinetics (Elliott et al., 2004). Serum concentrations peak 5 to 24 hours after subcutaneous administration and are lower than after intravenous administration. The elimination half-life of intravenously adminis-tered rhEPO is 4 to 13 hours in patients with chronic renal failure and approximately 20% shorter in healthy volunteers. The reported elimination half-life is longer after subcutaneous administration and results in more-sustained plasma concentrations (Erslev, 1991; Markham and Bryson, 1995).

Because of its increased carbohydrate content and sialic acid changes, darbepoetin alfa has a threefold longer serum half-life in animal models compared with rhEPO, which was substantiated in a double-blind, randomized, crossover trial in humans (Macdougall et al., 1999). The area-under-the-serum-concentration-time curve was significantly greater for darbepoetin alfa compared with rhEPO, and volume of distribution was similar for both products. The peak concentration of darbepoetin alfa administered subcutaneously was about 10% of that after intrave-nous administration, and bioavailability was approxi-mately 37% by the subcutaneous route. The longer half-life of darbepoetin alfa may confer a clinical advantage over rhEPO by allowing less frequent dosing when treating patients for anemia of chronic renal failure or anemia associated with cancer or chemotherapy or both.

Ancestim

Ancestim follows first-order kinetics after a single subcutaneous injection to normal healthy volunteers and to patients with cancer. After subcutaneous administration (dose range 5–15 mg/kg) to healthy men, ancestim was absorbed slowly, reaching peak concentrations between 8 and 72 hours. The mean absorption half-life was 41 hours, with an initial lag time of approximately 2 hours. Elimination is also first order, with a half-life of 5 hours; hence, absorption is rate limiting. In patients with cancer, a single dose of 5 to 50 mg/kg produced a mean peak serum concentration approximately 15 hours after administration. Both absorption and elimination followed first-order kinetics with a t1/2 of 36 and2.6 hours, respectively. The pharmacokinetics of ancestim are very similar between healthy volunteers and patients with cancer.

Oprelvekin

Oprelvekin administered as a single, 50 mg/kg dose to men showed a terminal half-life of 6.9 – 1.7 hours. Clearance of oprelvekin decreases with patient age and clearance in infants and children is 1.2- to 1.6-fold greater than in adults and adolescents.