Altered etoposide pharmacokinetics and time to engraftment in pediatric patients undergoing autologous bone marrow transplantation

John H. Rodman, Daryl J. Murry, Timothy Madden, Victor M. Santana

Research output: Contribution to journalArticle

65 Citations (Scopus)

Abstract

Purpose: To determine the pharmacokinetics and clinical response of high- dose etoposide in combination with carboplatin for pediatric cancer patients undergoing autologous bone marrow transplant. Patients and 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 (CI) and terminal half-life (T( 1/2 )β) 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. Conclusion: 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.

Original languageEnglish (US)
Pages (from-to)2390-2397
Number of pages8
JournalJournal of Clinical Oncology
Volume12
Issue number11
DOIs
StatePublished - Nov 1994

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Autologous Transplantation
Etoposide
Bone Marrow Transplantation
Pharmacokinetics
Pediatrics
Carboplatin
Anticonvulsants
Bone Marrow
Granulocytes
Enzyme Induction
Liver
Recovery of Function
Body Size
Platelet Count
Pharmaceutical Preparations
Half-Life
Neoplasms
Blood Platelets

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Altered etoposide pharmacokinetics and time to engraftment in pediatric patients undergoing autologous bone marrow transplantation. / Rodman, John H.; Murry, Daryl J.; Madden, Timothy; Santana, Victor M.

In: Journal of Clinical Oncology, Vol. 12, No. 11, 11.1994, p. 2390-2397.

Research output: Contribution to journalArticle

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abstract = "Purpose: To determine the pharmacokinetics and clinical response of high- dose etoposide in combination with carboplatin for pediatric cancer patients undergoing autologous bone marrow transplant. Patients and 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 (CI) and terminal half-life (T( 1/2 )β) 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. Conclusion: 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.",
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N2 - Purpose: To determine the pharmacokinetics and clinical response of high- dose etoposide in combination with carboplatin for pediatric cancer patients undergoing autologous bone marrow transplant. Patients and 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 (CI) and terminal half-life (T( 1/2 )β) 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. Conclusion: 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.

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