title: Pharmacokinetics of SN2310, an injectable emulsion that incorporates a new derivative of SN-38 in patients with advanced solid tumors.
abstract: SN2310 is an injectable emulsion composed of vitamin E, a succinate derivative, as well as 7-ethyl-10-hydroxycamptothecin (SN-38), the active metabolite of irinotecan. Single intravenous doses of 15, 20, 25, and 30 mg/m(2) of SN2310 emulsion were administered in a total of 26 patients with advanced solid malignancies. Serial blood samples were collected and concentrations of SN2310, SN-38, and SN-38 glucuronide were assayed. Mean systemic clearance of SN2310 ranged between 1.91 and 2.02 L/h/m(2) . Peak concentrations of SN-38 were observed at the end of infusion, suggesting a fast metabolic conversion of SN2310 to its active form, SN-38. Mean t1/2 values of SN-38 across the 20-30 mg/m(2) dose levels (131-199 h) were 33-55-fold longer than those observed for SN2310. The systemic exposure of SN-38 increased in a proportional manner over the dose range studied. SN2310 emulsion displayed an improved safety profile as compared with irinotecan. The most significant safety risk was neutropenia. Considering the rapid formation of SN-38, the proportional increase in exposure levels, and its longer elimination half-life, less frequent dosing of SN2310 emulsion may be considered for the treatment of patients with advanced solid malignancies.
authors.affiliation: Pharsight, A Certara Company, Montreal, Quebec, Canada.
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Marier
authors.forename: Leng
authors.initials: L
authors.lastname: Pheng
authors.forename: My My
authors.initials: MM
authors.lastname: Trinh
authors.forename: Howard A
authors.initials: HA
authors.lastname: Burris
authors.forename: Suzanne
authors.initials: S
authors.lastname: Jones
authors.forename: Kirsten
authors.initials: K
authors.lastname: Anderson
authors.forename: Serina
authors.initials: S
authors.lastname: Warner
authors.forename: David
authors.initials: D
authors.lastname: Porubek
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D019540:Area Under Curve; D002166:Camptothecin / Q000008:administration & dosage* / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D002626:Chemistry, Pharmaceutical; D004655:Emulsions; D005260:Female; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D000077146:Irinotecan; D008297:Male; D020714:Maximum Tolerated Dose; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy*; D009503:Neutropenia / Q000139:chemically induced; D013386:Succinates / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D013678:Technology, Pharmaceutical / Q000379:methods; D014810:Vitamin E / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004655:Emulsions; D013386:Succinates; D014810:Vitamin E; D000077146:Irinotecan; D002166:Camptothecin