Pharmacokinetics of a hematoregulatory peptide (SK&F107647) in healthy male volunteers and in patients with colorectal or pancreatic adenocarcinoma not amenable to standard therapy.
OBJECTIVE
To describe the pharmacokinetics of SK&F 107647, a synthetic hematoregulatory peptide, in healthy volunteers and in patients with adenocarcinoma.


METHODS
SK&F 107647 pharmacokinetics were evaluated in 2 dose-escalation studies. Volunteers received SK&F 107647 as single 15-minute iv infusion doses of 1, 10, 100, 500, and 1,000 microg/kg. Cancer patients received 2-hour iv infusions of 0.001, 0.01, 0.1 and 1 microg/kg once daily for 10 days. Drug concentrations were quantified in plasma and urine of healthy volunteers and on days 1 and 10 in plasma of cancer patients receiving the two top dose levels.


RESULTS
In volunteers, mean clearance (CL) ranged from 76.7 to 101 ml/hour/kg; mean volume of distribution at steady-state (Vss) ranged from 175 to 268 ml/kg. Most of the administered dose was renally excreted as intact peptide within 24 hours postinfusion. In patients, mean CL was 57.6 ml/hour/kg, mean Vss ranged from 128 to 150 ml/kg and terminal half-life from 2.1 to 3.4 hours. There was little accumulation of drug. In both studies, linear pharmacokinetics was observed. Clearance approached normal glomerular filtration rate (GFR) in volunteers and correlated with creatinine clearance in cancer patients.


CONCLUSIONS
SK&F 107647 exhibits linear pharmacokinetics, a small Vss, and clearance, primarily renal, approaching normal GFR.
Zia-Amirhosseini
P
P
SmithKline Beecham Pharmaceuticals, Department of Drug Metabolism and Pharmacokinetics, King of Prussia, Pennsylvania, USA. parnian_zia-amirhosseini-1@sbphrd.com
Harris
R Z
RZ
Cowley
H C
HC
Valle
J W
JW
Citerone
D R
DR
Boppana
V K
VK
Scarffe
H
H
Watson
P
P
Davis
C B
CB
D000230:Adenocarcinoma / Q000097:blood / Q000378:metabolism* / Q000652:urine; D000276:Adjuvants, Immunologic / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000097:blood / Q000378:metabolism* / Q000652:urine; D006801:Humans; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D010190:Pancreatic Neoplasms / Q000097:blood / Q000378:metabolism* / Q000652:urine; D011863:Radioimmunoassay
D000276:Adjuvants, Immunologic; D009842:Oligopeptides; C086049:SK&F 107647