CIS-AMINEDICHLORO(2-METHYLPYRIDINE)PLATINUM(II) (AMD473), A NOVEL STERICALLY HINDERED PLATINUM COMPLEX - IN-VIVO ACTIVITY, TOXICOLOGY, AND PHARMACOKINETICS IN MICE

A novel sterically hindered platinum complex, AMD473 [cis-amminedichlo ro(2-methylpyridine) platinum(II)I, designed primarily to be less susc eptible to inactivation by thiols, has shown irt vitro activity agains t several ovarian carcinoma cell lines. Notably, AMD473 has shown acti vity in vitro in human carcinoma cells that have acquired cisplatin re sistance due to reduced drug transport (41M/41McisR) or enhanced DNA r epair/increased tolerance of platinum-DNA adducts (CH1/CH1cisR). In th is study, we show that AMD473, at its maximum tolerated dose of 35-40 mg/kg i.p. administration, produced marked irt vivo antitumor activity against a variety of murine (ADJ/PC6 plasmacytoma, L1210 leukemia) an d human ovarian carcinoma xenograft models, including several possessi ng acquired resistance to cisplatin [ADJ/PC6cisR, L1210cisR, CH1cisR, and HX110 (carboplatin-resistant)]. In the ADJ/PC6 model, an increased therapeutic index was noted following oral as opposed to i.p. adminis tration. In a head-to-head comparison using CH1cisR xenografts and equ itoxic doses (q7d x 4 schedule), comparative growth delays were as fol lows: AMD473, 34 days; cisplatin, 10.4 days; carboplatin, 6.4 days; an d JM216 (p.o. administration), 3.5 days (in a previous experiment, the trans-platinum complex JM335 induced a growth delay of 5.4 days again st this model). In this model, oral activity was also noted with a gro wth delay of 34 days at 400 mg/kg every 7 days (total of four doses). In addition, AMD473 showed promising activity against CH1 xenografts t hat had regrown following initial treatment with cisplatin (additional growth delay of 30 days over that observed for retreatment with cispl atin). Across the whole panel of cisplatin-sensitive to cisplatin-resi stant human ovarian carcinoma xenografts, AMD473 showed improved or at least comparable activity to that observed for an equitoxic dose (4 m g/kg) and schedule of cisplatin. Platinum pharmacokinetics showed that following i.v. administration of 20 mg/kg AMD473 in saline to Balb/c( -) mice bearing murine plasmacytoma (ADJ/PC6), a biexponential decay w as observed in the plasma with a rapid distribution t(1/2 alpha) of 24 min followed by a slow elimination t(1/2 beta) of 44 h. Platinum accu mulated in various organs with platinum tissue to plasma area under th e curve ratios of 8.6 for liver and kidney, 5.7 for spleen, 3.7 for he art, 5.2 for lung, and 5 for tumor. The plasma and tissue concentratio n time curve following i.p. administration was similar to that observe d following i.v. administration, with a bioavailability of 89%. When A MD473 was given p.o., the platinum absorption was rapid (K-01 of 30 mi n) and the bioavailability was 40%. A less than proportional increase in area under the curve and C-max was noted in tissue, plasma, and pla sma ultrafiltrate following increasing oral doses of AMD473. In vitro , with AMD473, the rate of binding to different plasma proteins was ap proximately half of that of cisplatin. Following administration of 45 mg/kg i.p. in oil, 33% of the administered platinum was eliminated in the urine after 24 h, and 40% was eliminated after 72 h. Fecal recover y represented 13% of the administered dose after 3 days. Similar resul ts were observed following oral and i.v. administration of 20 mg/kg, b ut significantly more was excreted in the feces (over 50% of the admin istered dose) following oral administration of 400 mg/kg, showing that absorption might be a limiting factor by this route of administration . The dose-limiting toxicity for AMD473 in mice was myelosuppression, and no renal toxicity was observed. The promising antitumor activity o f AMD473, together with its lack of nephrotoxicity and favorable pharm acokinetic profile, suggests that AMD473 is a good candidate for clini cal development. AMD473 is entering Phase I clinical trials under the auspices of the United Kingdom Cancer Research Campaign in 1997.