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Published on: September 18, 2013
The effect of atovaquone on etoposide pharmacokinetics in children with acute lymphoblastic leukemia
M E van de Poll1, M V Relling, E G Schuetz
1Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
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 pharmacokinetics 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 microM.
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.
Insights
Atovaquone may slightly alter etoposide pharmacokinetics in acute lymphoblastic leukemia patients. Caution is advised when using atovaquone with etoposide due to potential drug interactions.
Area of Science:
- Pharmacology and Oncology
- Drug Metabolism and Interactions
Background:
- Trimethoprim/sulfamethoxazole for Pneumocystis pneumonia prophylaxis in acute lymphoblastic leukemia (ALL) can cause adverse effects.
- Atovaquone is a potential alternative, but its interactions with antileukemic drugs are not well understood.
Purpose of the Study:
- To compare the pharmacokinetics of etoposide and its metabolite when co-administered with atovaquone versus trimethoprim/sulfamethoxazole.
- To assess potential drug-drug interactions between atovaquone and etoposide.
Main Methods:
- A crossover study design involving nine ALL patients.
- Comparison of etoposide and etoposide catechol pharmacokinetics after IV infusion.
- In vitro studies using human liver microsomes and L-MDR1 cells to evaluate enzyme inhibition and transporter interactions.
Main Results:
- Atovaquone led to a modest, though statistically significant, increase in etoposide and etoposide catechol exposure (AUC).
- Atovaquone demonstrated modest inhibition of etoposide catechol formation in vitro.
- Atovaquone was found to inhibit P-glycoprotein.
Conclusions:
- The interaction between atovaquone and etoposide disposition is modest.
- Caution is recommended for the co-administration of atovaquone and etoposide, especially with other CYP3A4/P-glycoprotein substrates, due to the risk of secondary malignancies.
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