Pharmacokinetic study of darbepoetin alfa: Absorption, distribution, and excretion after a single intravenous and subcutaneous administration to rats

Abstract

KRN321 is a hyperglycosylated analogue of recombinant human erythropoietin (rHuEPO, epoetin alfa), and its absorption, distribution, and excretion have been studied after a single intravenous and subcutaneous administration of 125I-KRN321 at a dose of 0.5 microg kg-1 to male rats. The half-lives of immunoreactive radioactivity in the terminal phase after intravenous and subcutaneous administration were 14.05 and 14.36 h, respectively, and the bioavailability rate after subcutaneous administration was 47%. The total radioactivity in tissues was lower than that in the serum in all tissues excluding the thyroid gland and skin at the injection site (subcutaneous administration). The maximum concentrations were observed in the bone marrow or skin at the injection site followed by the thyroid gland, kidneys, adrenal glands, spleen, lungs, stomach and bladder. The radioactivity found in trichloroacetic acid-precipitated fractions suggested that a high-molecular weight compound, unchanged or mixed with endogenous protein, distributed to the tissues after administration. The whole-body autoradiographic findings in both groups were in agreement with the tissue distribution mentioned above. The blood cell uptake of KRN321 was low for both groups. The excretion ratios of radioactivity into urine and faeces up to 168 h were 71.4 and 14.1% after the intravenous administration and 74.9 and 12.0% after the subcutaneous administration. There was no difference in the excretion profile of radioactivity between the two groups.

Mechanistic Determinants of Biotherapeutics Absorption Following SC Administration

“…Following SC administration of 125 I-darbepoetin !, at a dose volume of 1 mL/kg, whole body autoradiograms showed a wide spreading of radioactivity in the hypodermis of rats at 4 and 24 h post-dose (Fig. 4) (73). Martin and co-workers demonstrated the wide lateral distribution of an antibody after SC administration to mice by positron-emission tomography (74).…”

Single Dose Darbepoetin Alfa is Useful in Reducing Red Cell Transfusions in Leukemic Children Receiving Chemotherapy

“…Being a synthetic, chemically modified EPO analogue with a longer half-life and a slower rate of absorption compared to other ESAs [2,5,10], darbepoetin alfa was used in our patients as a single subcutaneous injection of 2.25 ug/kg. Almost 68.5% of our patients receiving darbepoetin required transfusion compared to 92% of the control group.…”

“…Darbepoetin alfa is a novel erythropoiesis-stimulating protein developed for the treatment of anemia. It is a hyperglycosylated analogue of recombinant human EPO with the same mechanism of action but with a three-fold longer half-life after intravenous or subcutaneous administration in humans [2,5].  M. Zachariah et al…”