Pharmacokinetics of a novel surface-active agent, purified poloxamer 188, in rat, rabbit, dog and man.
Purified poloxamer 188 (PP188) is a non-ionic, block copolymer surfactant that is currently being evaluated clinically in sickle cell disease vaso-occlusive crisis and acute chest syndrome and preclinically in spinal cord injury and muscular dystrophy. This paper describes the pharmacokinetics of PP188 in rats, pregnant rats, pregnant rabbits, dogs and humans. Plasma protein binding interaction studies demonstrated no clinically significant effects on narcotic analgesics, hydroxyurea, warfarin, diazepam or digitoxin, but an increase in free fraction for propranolol. The plasma concentrations increased proportionate with increasing dose in all species tested. Renal clearance accounted for 90% of total plasma clearance in man. A single metabolite was detected and quantified in the plasma from dogs and humans that was cleared more slowly than parent drug. Allometric scaling of plasma clearance and volume of distribution at steady-state (Vss) across species provided good predictions of the pharmacokinetic parameters in humans. Based on the comparative pharmacokinetics of PP188 in rat, rabbit, dog and man, all three animal species were appropriate models for evaluating various aspects of PP188's toxicological profile.
Grindel
J Michael
JM
Drug Development, CytRx Corporation, Norcross, GA 30092, USA. grindelm@cytrx.com
Jaworski
Ted
T
Emanuele
R Martin
RM
Culbreth
Paula
P
D000704:Analysis of Variance; D000818:Animals; D019540:Area Under Curve; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D016014:Linear Models; D008297:Male; D020442:Poloxamer / Q000493:pharmacokinetics*; D011247:Pregnancy; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D013501:Surface-Active Agents / Q000493:pharmacokinetics*
D013501:Surface-Active Agents; D020442:Poloxamer