Relationship between exposure and toxicity in high-dose chemotherapy with cyclophosphamide, thiotepa and carboplatin.
BACKGROUND
High-dose chemotherapy in combination with peripheral blood progenitor cell transplantation is widely used in the treatment of several malignancies. The use of high-dose chemotherapy can be complicated by the occurrence of severe and sometimes life threatening toxicity. A wide interpatient variability in toxicity is encountered, which may be caused by variability in the pharmacokinetics of the agents. The aim of this study was to establish the pharmacokinetics of cyclophosphamide, thiotepa, carboplatin and all relevant metabolites in a widely used high-dose combination and to study possible relationships between the pharmacokinetics and toxicity.


METHODS
Blood samples were collected from patients treated with modifications of the CTCb regimen consisting of cyclophosphamide (1000-1500 mg/m2/day), carboplatin (265-400 mg/m2/day) and thiotepa (80-120 mg/m2/day) as short infusions for four consecutive days. Thiotepa and its main metabolite tepa, ultrafilterable carboplatin, cyclophosphamide and its activated metabolites 4-hydroxycyclophosphamide and phosphoramide mustard were determined. Pharmacokinetics were assessed with the use of population pharmacokinetic analyses. Relationship between the area under the concentration-time curves (AUCs) of these compounds and toxicity were tested.


RESULTS
A total of 46 patients (83 courses of chemotherapy) was included. Relationships were identified between elevation of transaminases and the thiotepa and tepa AUC, mucositis and the tepa AUC and ototoxicity and the carboplatin AUC. A strong trend between the 4-hydroxycyclophosphamide AUC and veno-occlusive disease was found.


CONCLUSIONS
The complex pharmacokinetics of the different agents and their metabolites have been established and several relationships between the pharmacokinetics and toxicity were identified. These findings may form the basis for further treatment optimisation and dose-individualisation in this high-dose chemotherapy combination.
Huitema
A D R
AD
Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, Amsterdam. apahu@slznl
Spaander
M
M
Mathĵt
R A A
RA
Tibben
M M
MM
Holtkamp
M J
MJ
Beijnen
J H
JH
Rodenhuis
S
S
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D016190:Carboplatin / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D003520:Cyclophosphamide / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D009373:Neoplasms, Germ Cell and Embryonal / Q000188:drug therapy / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D013852:Thiotepa / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D014018:Tissue Distribution
D003520:Cyclophosphamide; D013852:Thiotepa; D016190:Carboplatin