Factors for hematopoietic toxicity of carboplatin: refining the targeting of carboplatin systemic exposure.
OBJECTIVE
Area under the curve (AUC) dosing is routinely carried out for carboplatin, but the chosen target AUC values remain largely empirical. This multicenter pharmacokinetic-pharmacodynamic (PK-PD) study was performed to determine the covariates involved in the interindividual variability of carboplatin hematotoxicity that should be considered when choosing individual target AUCs.


METHODS
Three hundred eighty-three patients received carboplatin as part of established regimens. A semi-physiologic population PK-PD model was applied to describe separately the time course of absolute neutrophil and platelet counts using NONMEM software. The plasma ultrafiltrable carboplatin concentration (C(Carbo)) was assumed to inhibit the proliferation of blood cell precursors through a linear model: drug effect = slope × C(Carbo). The slope corresponds to the patients' sensitivity to carboplatin hematotoxicity. The relationships between the patients' sensitivity to the neutropenic or thrombopenic effects of carboplatin and various covariates, including associated chemotherapies, demographic, biologic, and pharmacogenetic data, were studied.


RESULTS
The sensitivity of carboplatin-induced thrombocytopenia decreased in the case of concomitant paclitaxel chemotherapy (slope decreased by 24%), whereas it increased with coadministration of etoposide and gemcitabine (slope increased by 45% and 133%, respectively). For neutropenia, the sensitivity increased when carboplatin was combined with other cytotoxics (slope increased by 76%).


CONCLUSIONS
This study provides useful information to clinicians to better estimate the hematopoietic toxicity of carboplatin and thus choose more rationally carboplatin target AUCs as a function of pretreatment or concomitantly administered chemotherapies. For example, an AUC of 5 mg/mL · min is associated with a risk of grade 3 or 4 thrombocytopenia of 2% in combination with paclitaxel versus 38% with gemcitabine in a non-pretreated patient.
Schmitt
Antonin
A
Institut Claudius-Regaud and EA3035 University of Toulouse, Toulouse, France.
Gladieff
Laurence
L
Laffont
Céline M
CM
Evrard
Alexandre
A
Boyer
Jean-Christophe
JC
Lansiaux
Amélie
A
Bobin-Dubigeon
Christine
C
Etienne-Grimaldi
Marie-Christine
MC
Boisdron-Celle
Michèle
M
Mousseau
Mireille
M
Pinguet
Frédéric
F
Floquet
Anne
A
Billaud
Eliane M
EM
Durdux
Catherine
C
Le Guellec
Chantal
C
Mazières
Julien
J
Lafont
Thierry
T
Ollivier
Florent
F
Concordet
Didier
D
Chatelut
Etienne
E
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001792:Blood Platelets / Q000187:drug effects; D016190:Carboplatin / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D049109:Cell Proliferation / Q000187:drug effects; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D005047:Etoposide / Q000008:administration & dosage; D005260:Female; D005602:France; D006801:Humans; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009503:Neutropenia / Q000097:blood / Q000139:chemically induced*; D009504:Neutrophils / Q000187:drug effects; D017239:Paclitaxel / Q000008:administration & dosage; D010976:Platelet Count; D011446:Prospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D013921:Thrombocytopenia / Q000097:blood / Q000139:chemically induced*; D055815:Young Adult; D000093542:Gemcitabine
D000970:Antineoplastic Agents; D003841:Deoxycytidine; D005047:Etoposide; D016190:Carboplatin; D017239:Paclitaxel; D000093542:Gemcitabine