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Drug Interaction between Antimalarial Drugs and Efavirenz
Polina German*1, B Greenhouse1, C Coates1, G Dorsey1, P Rosenthal1, E Charlebois1, N Lindegardh2,3, N Lindegardh2,3, D Havlir1, and F Aweeka1
1Univ of California, San Francisco, US; 2Mahidol Univ, Bangkok, Thailand; and 3Ctr for Tropical Med, Univ of Oxford, UK
Background: Artemisinin-based
combination therapies (ACT) are new treatments for malaria that offer marked
improvements in efficacy. A leading ACT, artesunate
(AS) plus amodiaquine (AQ), is now approved for
first-line treatment of malaria in 15 African countries. Both drugs are
believed to be safe in 3-day regimens, but AQ was associated with hepatitis
when used for long-term chemoprophylaxis. ART may interact with AQ and its
active metabolite desethylamodiaquine (DEAQ), which
are both eliminated through CYP450. We enrolled healthy HIV-uninfected
volunteers to determine whether efavirenz (EFV)
affects pharmacokinetics of AQ/DEAQ.
Methods: Healthy volunteers received a 3-day course of
AQ 600 mg/AS 250 mg once daily followed by EFV 600 mg once daily (days 7 to 23)
and AQ/AS (days 18 to 20). AQ/DEAQ
plasma concentrations were measured over 96 hours on days 3 and 20. EFV plasma
concentrations were measured over 12 hours on day 20. Non-compartmental pharmacokinetics
analysis was used for estimates of area under the plasma concentration versus
time curve (AUC). AUC0-96(h·ng/mL) and AUC0-24(h·μg/mL) were estimated for AQ/DEAQ and EFV,
respectively. Laboratory tests including
liver function tests were monitored throughout the study.
Results: The study was terminated after the first 2
subjects developed asymptomatic but significant elevations in liver transaminases following completion of the study. Addition
of EFV to AQ resulted in AUC increases of 114 and 302% for AQ and AUC decreases
of 23.7 and 8.5% for DEAQ for the first 2 subjects, respectively. EFV AUC was
at or above historical results for healthy volunteers. Other infectious or
metabolic etiologies were excluded as causes of transaminase
elevations. Three additional subjects were withdrawn from the study following 3
days of AQ/AS and 0, 7 and 9 days of EFV and did not exhibit LFT elevations.
Conclusions: EFV inhibited metabolism of AQ. Increases in
AQ exposure was the likely cause of hepatotoxicity. Liver
function monitoring may be appropriate in individuals requiring AQ/AS treatment
for malaria in the setting of chronic EFV therapy. Unexpected hepatotoxicity led to the termination of AQ/AS interaction
study with EFV. Artemether/lumefantrine interaction
studies with ART are ongoing.
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