The effect of atovaquone on etoposide pharmacokinetics in children with acute lymphoblastic leukemia

Purpose: The use of trimethoprim/sulfamethoxazole in the prevention of Pneu mocystis carinii pneumonia in patients with acute lymphoblastic leukemia (A LL) may cause undesirable adverse effects: fungal overgrowth, neutropenia, and drug resistance. A possible alternative is atovaquone, a hydroxynaphtho quinone with anti-Pneumocystis carinii activity. However, it is not known i f atovaquone alters the disposition or adverse effects of antileukemic drug s. Methods: Using a crossover study design, we compared the pharmacokinetic s of etoposide and its CYP3A4-formed catechol metabolite when given as a 30 0 mg/m(2) i.v. infusion following daily atovaquone versus trimethoprim/sulf amethoxazole in nine patients. Results: The area under the concentration ti me curve (AUC) of etoposide, etoposide catechol and the catechol to etoposi de AUC ratio were slightly higher (a median of 8.6%, 28.4%, and 25.9%) foll owing atovaquone as compared to trimethoprim/sulfamethoxazole (P = 0.055, P = 0.031 and P = 0.023), respectively. In vitro analysis in human liver mic rosomes showed modest inhibition of etoposide catechol formation in the pre sence of atovaquone. Using uptake of H-3-vinblastine in L-MDR1 cells, atova quone was shown to inhibit P-glycoprotein with an apparent Ki of 95.6 muM. 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 con current therapy, we suggest caution with the simultaneous administration of atovaquone and etoposide, particularly if used with other CYP3A4/P-glycopr otein substrates.