Rifampicin Atovaquone

Other compounds producing some inhibition of ZDV conjugation were oxazepam, salicylic acid, and acetylsalicyclic acid. More recently, Trapnell et al. examined the inhibition of ZDV at a more relevant concentration of 20 pM in bovine serum albumin (BSA)-activated microsomes by atovaquone, methadone, fluconazole, and valproic acid at therapeutically relevant concentrations (127). Both fluconazole and valproic acid inhibited ZDV glucuronidation by more than 50% at therapeutic concentrations. Clinical interaction studies have been conducted with methadone, fluconazole, naproxen, probenecid, rifampicin, and valproic acid (see Table 10). 

RIFAMYCINS ANTIMALARIALS -ATOVAQUONE Both rifampicin and rifabutin L atovaquone levels, although the effect is greater with rifampicin (1AUC 50% cf. with 34% rifabutin) Uncertain because atovaquone is predominantly excreted unchanged via the gastrointestinal route Avoid co-administration with rifampicin. Take care with rifabutin and watch for poor response to atovaquone... 

The use of proguanil plus atovaquone has been reviewed (14). Neuropsychiatric adverse events were more frequent with mefloquine, whereas other adverse events occurred with similar frequencies as with chloroquine plus proguanil and mefloquine. Proguanil plus atovaquone is contraindicated in severe renal insufficiency. Co-administration of proguanil plus atovaquone with rifampicin is not recommended because of reductions in plasma atovaquone concentrations. 

A steady-state study in 13 HIV-positive subjects found that the use of atovaquone 750 mg twice daily with rifampicin 600 mg four times daily for 14 days resulted in a more than 50% reduction in the atovaquone AUC and serum levels, but a more than 30% rise in rifampicin AUC and serum levels. ... 

Rifampicin reduces serum atovaquone levels by about 50% whereas atovaquone modestly raises serum rifampicin levels. The combination should be avoided because of the likelihood of sub-therapeutic atovaquone levels. Rifabutin caused a lesser 34% decrease in atovaquone levels, which the manufacturer considers may also reduce efficacy. 

Information is limited but these pharmaeokinetie interactions appear to be established. Their clinical importance is unknown, but it seems highly likely that the efficacy of atovaquone will be reduced in the presence of rifampicin. The combination should therefore be avoided. 

The effect of rifabutin is less than rifampicin, and the authors of the above report suggested that no atovaquone dosage adjustment is needed. However, in the UK, the manufacturer of atovaquone still considers that rifabutin use could result in subtherapeutic atovaquone levels in some patients, and they also advise against the concurrent use of this combination. ... 

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