title: Safety, tolerability, and pharmacokinetics of a capsule formulation of DRF-1042, a novel camptothecin analog, in refractory cancer patients in a bridging phase I study.
abstract: The purpose of this bridging phase I study was to characterize the toxicity, pharmacokinetics, and antitumor effects of a capsule formulation of DRF-1042, a novel camptothecin analog, in refractory solid tumor patients. DRF-1042 was given daily for 5 consecutive days for 2 weeks, repeated every 3 weeks at 81 mg/m(2). Adverse events were monitored following NCI-CTC. Blood samples were processed for bioanalysis using a validated high-performance liquid chromatography method. The pharmacokinetics of lactone and total (lactone + carboxylate) forms was determined on days 1 and 12 using a noncompartmental pharmacokinetic method. Pharmacokinetic data with the capsule formulation were compared with previously reported pharmacokinetic parameters with a suspension formulation. Efficacy was evaluated by applying World Health Organization criteria. Six patients received 10 courses of therapy. Thrombocytopenia and diarrhea were dose-limiting toxicities. The upper limit of the area under the curve of DRF-1042 (lactone and total) with the capsule formulation was higher than a suspension formulation at a similar dose on day 1 (lactone: capsule = 8.53 microMxh, suspension = 5.33 microMxh; total: capsule = 393 microMxh, suspension = 176 microMxh) and day 12 (lactone: capsule = 22.1 microMxh, suspension = 6.1 microMxh; total: capsule = 1302 microMxh, suspension = 309 microMxh). The upper limit of the area under the curve of DRF-1042 (lactone and total) was higher under fed conditions (lactone = 15.9 microMxh, total = 605 microMxh) relative to fasted conditions (lactone = 8.53 microMxh, total = 393 microMxh) on day 1. One patient experienced stable disease. The toxicity and pharmacokinetics of the capsule correlated well with the suspension. The recommended phase II dose is 81 mg/m(2).
authors.affiliation: Dr. Reddy's Laboratories, Discovery Research, Bollaram Road, Miyapur, Hyderabad-500 049, India.
authors.forename: Arani
authors.initials: A
authors.lastname: Chatterjee
authors.forename: Raghunadharao
authors.initials: R
authors.lastname: Digumarti
authors.forename: Kasiram
authors.initials: K
authors.lastname: Katneni
authors.forename: Vijay V
authors.initials: VV
authors.lastname: Upreti
authors.forename: Rao N V S
authors.initials: RN
authors.lastname: Mamidi
authors.forename: Ramesh
authors.initials: R
authors.lastname: Mullangi
authors.forename: Anjna
authors.initials: A
authors.lastname: Surath
authors.forename: Maddali L
authors.initials: ML
authors.lastname: Srinivas
authors.forename: Srihari
authors.initials: S
authors.lastname: Uppalapati
authors.forename: Sangeeta
authors.initials: S
authors.lastname: Jiwatani
authors.forename: Nuggehally R
authors.initials: NR
authors.lastname: Srinivas
mesh_terms: D000328:Adult; D000368:Aged; D002166:Camptothecin / Q000009:adverse effects* / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002214:Capsules; D002626:Chemistry, Pharmaceutical; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood* / Q000188:drug therapy*; D013921:Thrombocytopenia / Q000139:chemically induced
chemical_list: D002214:Capsules; C484816:DRF-1042; D002166:Camptothecin