Potent and non-specific inhibition of cytochrome P450 by JM216, a new oral platinum agent

Abstract

Summary Bis-acetato-ammine-dichloro-cyclohexylamine-platinum (IV) (Fukuoka et al. 1991: McGuire et al. 1996. These agents available today are. however, generally administered intravenously. The development of an oral platinum drug has been desired to improve the quality of life of patients receiving cancer chemotherapy in terms of easy administration. Bis-acetato-ammine-dichloro-cvclohexylamineplatinum (IV). JM2 16. is the first oral antineoplastic platinum agent currently under development. In preclinical studies. JM' 16 exhibited in vitro and in vivo anti-tumour efficacy comparable with cisplatin and carboplatin. and an activity against cell lines that were resistant to cisplatin (Kelland et al. 1993). Several phase H clinical trials of JM216 monotherapy have already been performed in the United States and Europe. and a phase I study has finished in Japan (Groen et al. 1996: Fujii et al. 1997: Peereboom et al. 1997. Further, some combination regimens of JM216 with other anti-tumour agents. such as taxans. can be expected. but no information on the potential dru2 interactions bet-een JM2 16 and other drugs has been reported.The metabolic pathway of the drug is complicated and has not been well understood (Raynaud et al. 1996). However, there are some implications that metabolism of JM216 might affect drugmetabolizing enzymes in the liver. First. at least six metabolites were detected in plasma samples from patients who received JM216 (Raynaud et al. 1996). Four of them were also obtained by in mvitro incubations with fresh human plasma. whereas the

Phase 1 trial and pharmacokinetic study of the oral platinum analog satraplatin in children and young adults with refractory solid tumors including brain tumors

“…The toxicity profile in our pediatric population was similar to that in adults, and myelosuppression was the DLT. Myelosuppression was delayed with a median neutrophil nadir in cycle 1 occurring on day 27 (range 5-42,) and platelet count nadir on day 27 (range [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30]. This was similar to adults where median neutrophil nadir occurred on day 21 (range 2-63) and median platelet count nadir occurred on day 21 (range 2-64).…”

“…As satraplatin pharmacokinetics have been shown to be influenced by renal function in adults, we compared satraplatin pharmacokinetic parameters to patients' baseline serum creatinine, blood urea nitrogen, and estimated creatinine clearance (eCrCl) based on the Schwartz formula. Additionally, as platinum species are heavily protein bound, and because satraplatin undergoes reductive activation by heme and is metabolized by the liver, pharmacokinetic parameters were also compared to patients' red blood cell count, hemoglobin concentration, serum total protein, serum albumin, and liver function tests (alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, and total and direct bilirubin) .…”

Satraplatin: leading the new generation of oral platinum agents

“…JM-216 inhibition of CYP450 in human liver microsomes was investigated by measuring the inhibition potential (IC 50 and K i ) on prototype reactions in a study by Ando and co-workers [36]. The IC 50 values were 0.3 – 10 mM, indicating strong and nonspecific inhibitory effects of JM-216.…”

Evaluation of Satraplatin in Dogs with Spontaneously Occurring Malignant Tumors

“…Satraplatin enters the cell primarily by passive diffusion, likely because of its enhanced lipophilicity 13 . Satraplatin also has been shown to inhibit cytochrome P450, 14 and resistance to satraplatin may occur by glutathione conjugation 15 …”