No abstract

Darbepoetin alfa is a novel erythropoiesis-stimulating protein with a two- to threefold longer half-life than recombinant human erythropoietin (epoetin) in adult patients with chronic kidney disease (CKD). This randomized, open-label, crossover study was conducted to determine the pharmacokinetic profile of darbepoetin alfa in pediatric patients with CKD. Twelve patients 3-16 years of age with CKD were randomized and received a single 0.5 micro g/kg dose of darbepoetin alfa administered intravenously (IV) or subcutaneously (SC). After a 14- to 16-day washout period, patients received an identical dose of darbepoetin alfa by the alternate route. After IV administration, the mean clearance of darbepoetin alfa was 2.3 ml/h per kg, with a mean terminal half-life of 22.1 h. After SC administration, absorption was rate limiting, with a mean terminal half-life of 42.8 h and a mean bioavailability of 54%. Comparison of these results with those from a previous study of darbepoetin alfa in adult patients indicated that the disposition of darbepoetin alfa administered IV or SC is similar in adult and pediatric patients, although absorption may be slightly more rapid in pediatric patients after SC dosing. The mean terminal half-life of darbepoetin alfa in this study was approximately two- to fourfold longer than that previously reported for epoetin in pediatric patients.

The contribution of the lymphatics to the absorption and systemic availability of recombinant human epoetin alfa (rHuEPO) following s.c. injection was examined using a cannulated sheep model. Parallel studies were conducted in sheep where a single bolus dose was administered either by i.v. (10, 100, or 1000 IU/kg) or s.c. (400 IU/kg) injection. The first s.c. group served as a control for the calculation of absolute bioavailability. In the second group, the efferent popliteal lymphatic duct was cannulated and peripheral lymph draining the injection site was continuously collected. In the third group, the thoracic duct was cannulated to allow collection of central lymph just prior to entry into the systemic circulation. Blood was periodically sampled from all animals, and concentrations in serum and lymph were determined by enzyme-linked immunosorbent assay. The cumulative amount of rHuEPO recovered in peripheral and central lymph was 83.9 Ϯ 6.6% and 75.3 Ϯ 3.9% of the administered dose, respectively, indicating almost complete absorption from the s.c. injection site and minimal clearance during transit through the lymphatic system. After i.v. administration, the systemic clearance of rHuEPO decreased with increasing dose, reflecting capacity-limited elimination kinetics. A pharmacokinetic model was developed to simultaneously fit experimental data for all treatment groups and estimate bioavailability. The direct measurement of Ͼ75% of the dose in peripheral and central lymph independently verifies the calculated bioavailability of 87% and demonstrates the major role of the lymphatic route in the overall s.c. bioavailability of rHuEPO after s.c. administration with this animal model. Erythropoietin (EPO) is a renally synthesized 30.4-kDa glycoprotein involved in the regulation of red blood cell proliferation and differentiation. Recombinant human epoetin alfa (rHuEPO) has been extensively utilized in the treatment of anemia associated with chronic renal failure, AIDS, and chemotherapy.Pharmacokinetic studies of rHuEPO have demonstrated dose-dependent disposition in humans (Flaharty et al., 1990;Veng-Pedersen et al., 1995), monkeys (Ramakrishnan et al., 2003), sheep (Veng-Pedersen et al., 1999), and rats (Kato et al., 1997) after i.v. administration. In these studies, nonlinear kinetics were characterized by decreased clearance with increasing dose. Although the exact elimination pathway has not been fully elucidated, studies comparing clearance (CL), mean residence time (MRT), and terminal half-life (t 1/2 ) preand postablation of the bone marrow in sheep, have provided significant evidence that elimination occurs predominantly in the bone marrow (Chapel et al., 2001). The capacity-limited CL is likely to be a receptor-mediated endocytosis by erythroid progenitor cells and has been described previously using a Michaelis-Menten-type elimination (Kato et al., 1997;Veng-Pedersen et al., 1999;Ramakrishnan et al., 2003). Although EPO receptors appear to have an important role in the distribution of EPO outside...

Anaemia is a common occurrence in patients with cancer, and currently can be treated in several ways. Novel erythropoiesis stimulating protein (NESP, darbepoetin alfa) was created using site-directed mutagenesis to have 8 more sialic acid side chains than recombinant human erythropoietin (rHuEPO). The additional sialic acid content has resulted in an approximately 3-fold greater half-life relative to rHuEPO in patients with chronic renal failure. This study evaluates the pharmacokinetic profile of NESP in patients receiving multiple cycles of chemotherapy. Anaemic patients (haemoglobin ≤ 11.0 g dl −1 ) who had non-myeloid malignancies received NESP weekly (2.25 mcg kg −1 wk −1 ) under the supervision of a physician, starting on day 1 of chemotherapy for 3 chemotherapy cycles given at 3-week intervals. Blood samples were collected during chemotherapy cycles 1 and 3 for pharmacokinetic analysis. All patients were followed for 4 weeks after treatment. NESP was well tolerated by all patients. After a single dose during chemotherapy cycle 1, pharmacokinetic parameters (mean (SD), n ) for the first 15 patients were: T max 86.1 (22.8) h ( n = 14); C max 9.0 (5.1) ng ml −1 ( n = 14); t 1/2,z 32.6 (11.8) h ( n = 7); CL/F 3.7 (1.0) ml h −1 kg −1 ( n = 7). The subjects for whom all parameters could be calculated may represent a sub-group of the entire population. Similar results were obtained in cycle 3. In addition, haemoglobin response data suggests that, in this patient population, dosing less frequently than the 3 times weekly doses used for rHuEPO may be possible while improving anaemia. © 2001 Cance Cancer Research Campaign

Domagrozumab, a monoclonal antibody that binds to myostatin, is being developed for Duchenne muscular dystrophy (DMD) boys following a first-in-human study in healthy adults. Literature reporting pharmacokinetic parameters of monoclonal antibodies suggested that body-weight- and body-surface-area-adjusted clearance and volume of distribution estimates between adults and children are similar for subjects older than 6 years. Population modeling identified a Michaelis-Menten binding kinetics model to optimally characterize the target mediated drug disposition profile of domagrozumab and identified body mass index on the volume of distribution as the only significant covariate. Model parameters were predicted with high-precision pharmacokinetics (clearance 1.01 × 10 L/[h·kg]; central volume of distribution 457 × 10 L/kg; maximum elimination rate 17.5 × 10 nmol/[h·kg], Km 10.6 nmol/L) and pharmacodynamics (myostatin turnover rate 457 × 10 h ; complex removal rate 90 × 10 h ; half-saturation constant 4.32 nmol/L) and were used to predict target coverage for dosage selection in the DMD population. Additionally, allometric approaches (estimated scaling exponents (standard error) for clearance and volume were 0.81 [0.01] and 0.98 [0.02], respectively) in conjunction with a separate analysis to obtain the population mean weight and standard deviation suggested that if dosed per body weight, an only 11% difference in clearance is expected between the heaviest and lightest patient, thus preventing the need for dose adjustment. In summary, quantitative approaches were instrumental in bridging and derisking the fast-track development of domagrozumab in DMD.