Schedule dependency of orally administered bis-acetato-ammine-dichloro-cyclohexylamine-platinum(IV) (JM216) in vivo.
JM216 is a novel antitumor platinum(IV) complex displaying oral activity, dose-limiting myelosuppression, and a lack of nephro- and neurotoxicity in rodents. It has been selected for clinical evaluation. The schedule dependency of its antitumor action against a murine (ADJ/PC6 plasmacytoma) and a human tumor model (PXN109T/C ovarian carcinoma xenograft) was studied in vivo. Single dose (q21d), once a day dosing for 5 consecutive days (q21d or q28d), and once a day dosing indefinitely (chronic daily dosing) administration schedules were compared. Against the murine ADJ/PC6 plasmacytoma, daily x5 administration improved the tolerance, antitumor potency, and therapeutic index of oral JM216, compared to single dose administration, whereas no advantage was found for fractionating cisplatin dosages. Against the PXN109T/C human ovarian carcinoma xenograft, oral JM216, given at dose levels delivering a equivalent total dose on single dose (200 mg/kg q21d), daily x5 (40 mg/kg/day q21d) and chronic daily dosing (9.5 mg/kg/d) schedules, showed superior tumor growth delays (55 +/- 15 days; P < 0.05) and maximal tumor regression (10 +/- 11% of initial tumor volume; P < 0.001) with the daily x5 schedule. Gastrointestinal toxicity (P < 0.05) and mild nephrotoxicity (P < 0.01) complicated the chronic daily dosing schedule, while leukopenia (P < 0.02) and thrombocytopenia (P < 0.01) were dose-limiting for the single dose and daily x5 administration, respectively. Peak plasma ultrafiltrate (PUF) platinum levels were below cytotoxic levels (PUF Cmax, 0.11 +/- 0.066 mg/l) at the maximally tolerable dose for the chronic dosing schedule (9.5 mg/kg). Peak PUF platinum levels did not increase significantly with a 5-fold increase in dosage from 40 mg/kg (PUF Cmax 1.5 +/- 0.11 mg/l) to 200 mg/kg (PUF Cmax, 2.4 +/- 0.44 mg/l; P > 0.05). In conclusion, these data demonstrate antitumor schedule dependency for oral JM216 in vivo, independently in two tumor model systems, and with nonlinear pharmacokinetics after its oral administration to mice. Optimal antitumor activity, tolerance, and pharmacokinetics occurred with daily x5 dosing, and this has prompted the clinical evaluation of this administration schedule.
Drug Development Section, Institute of Cancer Research, Belmont, Sutton, Surrey, United Kingdom.
M J
MJ
McKeage
L R
LR
Kelland
F E
FE
Boxall
M R
MR
Valenti
M
M
Jones
P M
PM
Goddard
J
J
Gwynne
K R
KR
Harrap
D000231:Adenocarcinoma, Papillary / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001835:Body Weight / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage / Q000493:pharmacokinetics; D004334:Drug Administration Schedule; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D007970:Leukopenia / Q000139:chemically induced; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009944:Organoplatinum Compounds / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D013921:Thrombocytopenia / Q000139:chemically induced; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; C081294:satraplatin; D002945:Cisplatin