Background: The effect of ethanol on the pharmacokinetics (PK) of drugs has not been fully investigated. Of HIV-infected subjects, 25% are heavy drinkers and susceptible to drug-drug interactions between ethanol and antiretroviral therapy. Ethanol may induce cytochrome p450 (CYP) metabolism when used chronically. However, when taken acutely, ethanol will inhibit drug metabolism due to competition with CYP isozymes. It is hypothesized that chronic ethanol use will result in diminished HIV protease inhibitor (PI) exposure while acute ethanol use will result in increased PI exposure.

Methods: HIV-infected subjects managed with nelfinavir (NFV) (n = 27) or indinavir (IDV) (n = 8) were enrolled prospectively to evaluate the acute and chronic effects of ethanol on PI PK. Subjects were controlled for additional interacting drugs (e.g., second PI or efavirenz). Subjects were stratified into 2 groups: I) those with a history of heavy drinking (> 70 drinks monthly) (HD) and II) those characterized as light/non-drinkers (< 30 drinks/month) (LD). HD underwent PI PK evaluations on 2 subsequent study days: A) in the absence of ethanol and B) with acute administration of ethanol (target blood concentration of 0.10 mg/dL) LD served as controls and had a PI PK evaluation in the absence of ethanol. Serial blood sampling occurred over the dosing interval (8 h for IDV and 12 h for NFV). Validated LC-tandem MS was used for quantitation and non-compartmental PK analysis used to determine drug exposure (AUC_0-τ). Statistical analysis was carried out using the paired and unpaired t tests with significance as p < 0.05. Results are reported as mean (± standard deviation).

Results: NFV exposure was comparable under chronic and acute ethanol conditions in HD. HD AUC (n = 12) was 17% higher than AUC for LD (ns) (n = 15). IDV exposure in HD (n = 3) was also comparable under acute and chronic conditions (data not shown).

 

Conclusions: Results to date suggest minimal effect of ethanol on PI exposure. The slight increase in NFV AUC with ethanol use implies ethanol co-administration can occur without risk of suboptimum PI exposure. Furthermore, there appears to be no difference in the effect of ethanol on PI PK when used chronically versus acutely.