Safety of purified poloxamer 188 in sickle cell disease: phase I study of a non-ionic surfactant in the management of acute chest syndrome.

Acute chest syndrome (ACS) is the most common cause of death in patients with sickle cell anemia. Its management is primarily palliative. We performed a Phase I evaluation of purified poloxamer 188 (a non-ionic surfactant) in the management of ACS. Forty-three patients with sickle cell disease and ACS were treated with doses as high as 2960 mg/day by continuous intravenous (IV) infusion. The maximum tolerated dose has not been identified. No evidence of renal toxicity or other limiting adverse events were found. One adult patient died due to sepsis and adult respiratory distress syndrome, which were unrelated to treatment. Poloxamer 188 is safe to administer to patients with ACS, and preliminary data suggest that it may shorten its duration and the length of hospitalization in a dose related manner. Children appeared to benefit more than adults. The data and safety profile justify further studies with purified poloxamer 188 in the treatment of ACS.

Distribution, metabolism, and excretion of a novel surface-active agent, purified poloxamer 188, in rats, dogs, and humans.

Purified poloxamer 188 (PP188) is a nonionic, block copolymer surfactant with hemorheologic, antithrombotic, and anti-adhesive properties. PP188 is being studied in phase III clinical trials in sickle cell disease and has been found to be well tolerated and has demonstrated benefit in ameliorating the effects of acute painful vasoocclusive crisis. The disposition of PP188 was studied in rats, dogs, and humans to establish a basis for understanding the safety parameters in support of clinical trials. PP188 was primarily distributed in extracellular water with little or no uptake by red blood cells, and had its highest concentrations in highly perfused tissues such as the kidney, liver, spleen, lymph nodes, and gastrointestinal tract. PP188 had no apparent effect on P450 isozymes in vitro. Metabolism was limited (< 5% of dose) with a higher molecular weight copolymer being the only other material detected in plasma or urine. Renal clearance was the controlling route of clearance for PP188 from the body. The 48-h intravenous infusion doses of PP188 were cleared in all species by approximately 1 week after the cessation of dose administration. PP188's disposition is a model for other nonionic block copolymers with similar physical and chemical properties.

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.