Pulmonary delivery of powders and solutions containing recombinant human granulocyte colony-stimulating factor (rhG-CSF) to the rabbit.
Two powder formulations (MMAD < 4 microns) containing rhG-CSF were insufflated (IF) via an endotracheal tube at doses of 5, 75 or 500 micrograms/kg to New Zealand white rabbits. Doses of 5 and 500 micrograms/kg of solutions were administered by intratracheal instillation (IT), subcutaneous (SC) injection in the thigh and intravenous injection (i.v.) via the marginal ear vein. Blood samples were removed at regular intervals from an indwelling jugular catheter. Blood was analyzed directly for total white blood cell counts (WBC). Plasma was assayed for rhG-CSF by a specific ELISA. The distribution of radioactive dose in lung tissue was found after administering Tc99m HSA in solution or when incorporated into powders. The pharmacokinetics and pharmacodynamics were determined for all routes of administration. High dose IV concentration vs. time profiles declined biexponentially (t1/2 alpha = 0.6 +/- 0.2 hrs, t 1/2 beta = 4.6 +/- 0.2 hrs, n = 8). Clearance was does dependent (11.6 +/- 2.6 [500 micrograms/kg, n = 8] vs; 21.8 +/- 3.3 ml/hr/kg [5 micrograms/kg, n = 5]). A normal systemic response was obtained after IF, indicating that rhG-CSF retains activity in the solid state. Dissolution and absorption of rhG-CSF from the powders were not rate limiting. The plasma concentration vs. time profiles peaked at similar times to those after IT (Tmax 1-2 hrs) but were earlier than obtained after SC (Tmax 6-10 hrs). Powders were less efficiently dosed to the lung lobes after insufflation compared with instillates (14.7 +/- 10.5 vs. 60.1 +/- 10.6%), resulting in bioavailabilities ranging from 5 to 33%.(ABSTRACT TRUNCATED AT 250 WORDS)
Amgen Inc., Thousand Oaks, CA 91320.
R W
RW
Niven
F D
FD
Lott
A Y
AY
Ip
J M
JM
Cribbs
D000280:Administration, Inhalation; D000818:Animals; D001682:Biological Availability; D004339:Drug Compounding; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage* / Q000493:pharmacokinetics; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D007442:Intubation, Intratracheal; D008168:Lung / Q000378:metabolism*; D008855:Microscopy, Electron, Scanning; D010316:Particle Size; D011208:Powders; D011817:Rabbits; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics; D012996:Solutions; D013667:Technetium / Q000493:pharmacokinetics
D011208:Powders; D011994:Recombinant Proteins; D012996:Solutions; D013667:Technetium; D016178:Granulocyte-Macrophage Colony-Stimulating Factor