Altered etoposide pharmacokinetics and time to engraftment in pediatric patients undergoing autologous bone marrow transplantation.
OBJECTIVE
To determine the pharmacokinetics and clinical response of high-dose etoposide in combination with carboplatin for pediatric cancer patients undergoing autologous bone marrow transplant.


METHODS
Pharmacokinetic parameters for etoposide were determined at doses of 960, 1,200, and 1,500 mg/m2 when given with high-dose carboplatin and followed by autologous marrow rescue. Twenty-nine patients (age 1.6 to 23 years) with refractory or relapsed solid tumors were studied. Etoposide was administered in three divided doses as a 6-hour infusion on alternate days with carboplatin. Etoposide concentrations (n = 14) were determined during and following each of three doses. Patient characteristics, drug dose, and pharmacokinetic parameters were examined as predictors of marrow engraftment as reflected by recovery of granulocytes and platelets.


RESULTS
The median values for clearance (Cl) and terminal half-life (T1/2 beta) of etoposide were 14.3 mL/min/m2 (range, 6.8 to 29.6) and 5.9 hours (range, 3.7 to 39). After adjustment for body size, Cl and volume of distribution did not correlate with any laboratory parameter or patient characteristic. However, seven patients who received concomitant anticonvulsant therapy had significantly higher (P < .01) average etoposide Cl values (23.7 mL/min/m2) than 22 patients who did not receive drugs known to alter hepatic metabolism (13.4 mL/min/m2). The median etoposide Cl value in patients who received concurrent carboplatin but no anticonvulsant agents is substantially lower than values previously reported in either children or adults. Higher etoposide concentrations were significantly associated with longer times to recovery of granulocyte and platelet counts.


CONCLUSIONS
Etoposide Cl is significantly higher in patients who receive concomitant anticonvulsant therapy, which is consistent with clinically important hepatic enzyme induction. The lower etoposide Cl associated with high-dose carboplatin suggests that carboplatin may impair etoposide metabolism. Furthermore, high etoposide concentrations appeared to prolong time to recovery of hematopoietic function.
Pharmaceutical and Hematology/Oncology Departments, St Jude Children's Research Hospital, Memphis, TN 38105.
J H
JH
Rodman
D J
DJ
Murry
T
T
Madden
V M
VM
Santana
D000293:Adolescent; D000328:Adult; D000927:Anticonvulsants / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016026:Bone Marrow Transplantation; D016190:Carboplatin / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D004347:Drug Interactions; D005047:Etoposide / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006207:Half-Life; D006801:Humans; D007223:Infant; D008657:Metabolic Clearance Rate; D009369:Neoplasms / Q000188:drug therapy / Q000628:therapy*; D014182:Transplantation, Autologous
D000927:Anticonvulsants; D005047:Etoposide; D016190:Carboplatin