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Increased teniposide clearance with concomitant anticonvulsant therapy
D K Baker1, M V Relling, C H Pui
1Pharmacokinetics and Pharmacodynamics Section, St Jude Children's Research Hospital, Memphis, TN 38105.
Insights
Concomitant use of anticonvulsants like phenobarbital or phenytoin significantly increases teniposide clearance in pediatric patients. This pharmacokinetic interaction may reduce the efficacy of teniposide chemotherapy.
Area of Science:
- Pharmacokinetics
- Pediatric Oncology
- Drug Interactions
Background:
- Teniposide is a chemotherapy agent used in treating acute lymphocytic leukemia.
- Anticonvulsant medications are often co-administered in pediatric patients undergoing cancer treatment.
- Potential pharmacokinetic interactions between teniposide and anticonvulsants require investigation.
Purpose of the Study:
- To evaluate a potential pharmacokinetic interaction between teniposide and anticonvulsant medications.
- To assess the impact of anticonvulsants on teniposide systemic clearance in pediatric patients.
Main Methods:
- Systemic clearance of teniposide was determined in pediatric patients with acute lymphocytic leukemia receiving anticonvulsants.
- Plasma concentrations of teniposide were measured using high-performance liquid chromatography (HPLC).
- Data were analyzed using a two-compartment model and compared to a control group without anticonvulsants.
Main Results:
- Systemic clearance of teniposide was significantly higher (2- to 3-fold increase) in patients receiving anticonvulsants (32 mL/min/m2) compared to controls (13 mL/min/m2).
- P-value < .001 indicated a statistically significant difference in clearance.
- Clearance values in control patients were consistent with previously published data.
Conclusions:
- Concomitant phenobarbital or phenytoin therapy significantly increases teniposide systemic clearance.
- This substantial reduction in systemic exposure may compromise teniposide's therapeutic efficacy.
- Further studies are warranted to adjust dosing regimens when teniposide is used with these anticonvulsants.
Purpose:
A possible pharmacokinetic interaction between teniposide and anticonvulsant medications was evaluated in pediatric patients.
Patients And Methods:
The systemic clearance of teniposide was determined in six pediatric patients with acute lymphocytic leukemia receiving concomitant therapy with anticonvulsants. Clearance was then compared with a control group of patients treated with the same protocol therapy and matched for age at diagnosis, sex, and race but not receiving anticonvulsants or other agents known to induce hepatic metabolism or alter protein binding of drugs. Eight blood samples were obtained during and after 4-hour infusions of teniposide, and plasma concentrations were measured by a specific high-performance liquid chromatography (HPLC) assay. A two-compartment model was fitted to each subject's data.
Results:
The mean systemic clearance (range) for the six anticonvulsant-treated patients studied during 22 courses of therapy was 32 mL/min/m2 (range, 21 to 54 mL/min/m2), significantly higher (P less than .001) than the mean value of 13 mL/min/m2 (range, 7 to 17 mL/min/m2) for the control patients studied during 26 courses of therapy. Clearance estimates for control patients were similar to previously published values for pediatric patients.
Conclusion:
These data indicate that the systemic clearance of teniposide is consistently increased two- to three-fold by concomitant phenobarbital or phenytoin therapy. The consequent substantial reduction in systemic exposure may reduce teniposide's efficacy.