An update on satraplatin: the first orally available platinum anticancer drug.
This update focuses on the clinical development of the first orally available platinum-containing anticancer drug, satraplatin (JM216, BMS 182751, BMY 45594). Satraplatin was selected for clinical study on the basis of possessing several promising preclinical features the first of which is it's potent in vitro growth inhibitory properties against several tumour types (mean IC(50) approximately 1 microM). Secondly, it possesses in vivo oral antitumour activity against a variety of murine and human sc. tumour models, broadly comparable to the level of activity obtainable with parenterally administered cisplatin or carboplatin. Lastly, it has a relatively mild toxicity profile with myelosuppression being dose-limiting. Satraplatin entered clinical trials in 1992 and is now undergoing Phase III evaluation. Non-linear pharmacokinetics, probably due to saturable absorption, was observed when the drug was administered as a bolus every 3 - 4 weeks. Subsequent Phase II trials have used a daily schedule for five consecutive days, at doses of around 120 mg/m(2)/day. The drug produced relatively mild side effects with controllable nausea and vomiting and, as predicted from the mouse studies, myelosuppression as the dose-limiting effect (neutropoenia and thrombocytopoenia). Combination trials are also ongoing with paclitaxel or radiation. The metabolism of satraplatin is complex, with at least six biotransformation products observed in the plasma of patients. The platinum(II) complex JM118 is the main metabolite, three other minor metabolites have been identified, there is no detectable parent drug. Tumour responses have been recorded, particularly in patients with small cell lung cancer and hormone refractory prostate cancer. These clinical studies with satraplatin indicate that oral platinum-based chemotherapy is feasible.
Kelland
L R
LR
CRC Centre for Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey SM2 5NG, UK. lloyd@icr.ac.uk.
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy*; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; C081294:satraplatin