Phase I/II trial of a P-glycoprotein inhibitor, Zosuquidar.3HCl trihydrochloride (LY335979), given orally in combination with the CHOP regimen in patients with non-Hodgkin's lymphoma.
A phase I/II trial was performed to investigate the safety and tolerance of zosuquidar.3HCL, a potent inhibitor of P-glycoprotein (P-gp), when administered orally alone and in combination with the CHOP regimen in patients with untreated non-Hodgkin's lymphoma and to determine whether zosuquidar.3HCL affects pharmacokinetics of doxorubicin and vincristine. Doses of CHOP remained constant and the doses of zosuquidar.3HCL were increased from 200 to 500 mg per dose. A total of 15 patients were treated at three dose levels. A target dose providing peak and trough levels compatible with prolonged modulation of P-gp function was obtained in patients receiving three doses of 500 mg of zosuquidar.3HCL p.o. At this dose level, toxicity was minimal and no enhancement of CHOP-related toxicity was observed. Zosuquidar.3HCL did not significantly affect the pharmacokinetics of doxorubicin and had moderate effects on the pharmacokinetics of vincristine. Zosuquidar.3HCL can be safely administered with CHOP therapy using a 24-h schedule.
Morschhauser
Franck
F
Service des Maladies du Sang, Hopital C. Huriez, Lille, France.
Zinzani
Pier Luigi
PL
Burgess
Michael
M
Sloots
Lisette
L
Bouafia
Fadela
F
Dumontet
Charles
C
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D019540:Area Under Curve; D003520:Cyclophosphamide / Q000008:administration & dosage; D003986:Dibenzocycloheptenes / Q000627:therapeutic use*; D004317:Doxorubicin / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D006801:Humans; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D011239:Prednisolone / Q000008:administration & dosage; D011804:Quinolines / Q000627:therapeutic use*; D016896:Treatment Outcome; D014750:Vincristine / Q000008:administration & dosage
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D003986:Dibenzocycloheptenes; D011804:Quinolines; D014750:Vincristine; D004317:Doxorubicin; C095179:zosuquidar trihydrochloride; D003520:Cyclophosphamide; D011239:Prednisolone