TY - JOUR
T1 - The effect of atovaquone on etoposide pharmacokinetics in children with acute lymphoblastic leukemia
AU - Van De Poll, Matthijs E.C.
AU - Relling, Mary V.
AU - Schuetz, Erin G.
AU - Harrison, Patricia L.
AU - Hughes, Walter
AU - Flynn, Patricia M.
N1 - Funding Information:
Acknowledgements We thank research nurse Ms. Diane Brand, and Mr. Ken Cox, Kazuto Yasuda and Dr. Lu-Bin Lan for technical assistance. This project was funded in part with federal funds from the National Institutes of Health, Bethesda, Md., Cancer Center CORE Gr ant nos. 21765, CA51001, ES 08658, and N01-DK-92310, a Center of Excellence Grant from the State of Tennessee, and American Lebanese Syrian Associated Charities (ALSAC).
PY - 2001
Y1 - 2001
N2 - Purpose: The use of trimethoprim/sulfamethoxazole in the prevention of Pneumocystis carinii pneumonia in patients with acute lymphoblastic leukemia (ALL) may cause undesirable adverse effects: fungal overgrowth, neutropenia, and drug resistance. A possible alternative is atovaquone, a hydroxynaphthoquinone with anti-Pneumocystis carinii activity. However, it is not known if atovaquone alters the disposition or adverse effects of antileukemic drugs. Methods: Using a crossover study design, we compared the pharmaco-kinetics of etoposide and its CYP3A4-formed catechol metabolite when given as a 300 mg/m2 i.v. infusion following daily atovaquone versus trimethoprim/sulfamethoxazole in nine patients. Results: The area under the concentration time curve (AUC) of etoposide, etoposide catechol and the catechol to etoposide AUC ratio were slightly higher (a median of 8.6%, 28.4%, and 25.9%) following atovaquone as compared to trimethoprim/sulfamethoxazole (P=0.055, P=0.031 and P=0.023), respectively. In vitro analysis in human liver microsomes showed modest inhibition of etoposide catechol formation in the presence of atovaquone. Using uptake of 3H-vinblastine in L-MDR1 cells, atovaquone was shown to inhibit P-glycoprotein with an apparent Ki of 95.6 μM. Conclusions: Although the effect of atovaquone on etoposide disposition was modest, in light of the fact that the risk of etoposide-related secondary acute myeloid leukemia has been linked to minor changes in schedule and concurrent therapy, we suggest caution with the simultaneous administration of atovaquone and etoposide, particularly if used with other CYP3A4/P-glycoprotein substrates.
AB - Purpose: The use of trimethoprim/sulfamethoxazole in the prevention of Pneumocystis carinii pneumonia in patients with acute lymphoblastic leukemia (ALL) may cause undesirable adverse effects: fungal overgrowth, neutropenia, and drug resistance. A possible alternative is atovaquone, a hydroxynaphthoquinone with anti-Pneumocystis carinii activity. However, it is not known if atovaquone alters the disposition or adverse effects of antileukemic drugs. Methods: Using a crossover study design, we compared the pharmaco-kinetics of etoposide and its CYP3A4-formed catechol metabolite when given as a 300 mg/m2 i.v. infusion following daily atovaquone versus trimethoprim/sulfamethoxazole in nine patients. Results: The area under the concentration time curve (AUC) of etoposide, etoposide catechol and the catechol to etoposide AUC ratio were slightly higher (a median of 8.6%, 28.4%, and 25.9%) following atovaquone as compared to trimethoprim/sulfamethoxazole (P=0.055, P=0.031 and P=0.023), respectively. In vitro analysis in human liver microsomes showed modest inhibition of etoposide catechol formation in the presence of atovaquone. Using uptake of 3H-vinblastine in L-MDR1 cells, atovaquone was shown to inhibit P-glycoprotein with an apparent Ki of 95.6 μM. Conclusions: Although the effect of atovaquone on etoposide disposition was modest, in light of the fact that the risk of etoposide-related secondary acute myeloid leukemia has been linked to minor changes in schedule and concurrent therapy, we suggest caution with the simultaneous administration of atovaquone and etoposide, particularly if used with other CYP3A4/P-glycoprotein substrates.
KW - Atovaquone
KW - CYP3A4
KW - Cotrimoxazole
KW - Etoposide
KW - P-glycoprotein
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U2 - 10.1007/s002800000250
DO - 10.1007/s002800000250
M3 - Article
C2 - 11459198
AN - SCOPUS:0035019446
SN - 0344-5704
VL - 47
SP - 467
EP - 472
JO - Cancer Chemotherapy and Pharmacology
JF - Cancer Chemotherapy and Pharmacology
IS - 6
ER -