Efavirenz trough concentrations were similar under both meal conditions; however, peak concentrations were increased by 47% during administration with a moderate-fat Ugandan meal. However, food did not alter the proportion of patients with efavirenz concentrations above the threshold of 4,000
ng/mL 12 hours after dosing. In 2001, Marzolini et al. reported an approximately 2.5-fold increase in the frequency of sustained central nervous system (CNS) toxicity among patients with efavirenz concentrations above 4,000
ng/mL versus patients with concentrations between 1,000 and 4,000
]. However, this threshold was not confirmed in a larger analysis which found a correlation between symptoms and plasma levels only in the first week of treatment [12
], instead single-nucleotide polymorphisms of drug-metabolizing enzymes were shown to be more predictive of efavirenz pharmacokinetics and clinical outcomes.
Efavirenz is primarily metabolised by hepatic CYP2B6 [7
]. In the ACTG A5097s study, a gene-dose effect for efavirenz pharmacokinetics was observed among patients with CYP2B6 polymorphisms with three-fold-higher efavirenz exposure among CYP2B6
516T/T homozygotes as compared to G/G homozygotes, and with intermediate values for G/T heterozygotes [13
]. A subsequent analysis revealed that the composite CYP2B6
516 G→T and 983 T→C genotype best predicted efavirenz pharmacokinetics, suggesting a slow-metaboliser genotype for efavirenz. Among Caucasians, this genotype was associated with a first CNS adverse event (P
= 0.04). Surprisingly, among Black patients (in whom slow-metaboliser genotypes are more frequent), no association was found [14
]. Instead, Black patients with the slow-metaboliser genotype had a lower incidence of virologic failure than other races (P
= 0.02) [14
]. The authors of that study postulated that higher efavirenz concentrations among patients with the slow-metaboliser genotype could permit continued suppression of HIV-1 during episodes of treatment interruption [14
Therefore, the clinical relevance of the moderately increased efavirenz concentrations observed with food in the current study is a balance between the risk of increased toxicity (at the onset of therapy) and the potential benefit of higher efavirenz exposures leading to a lower incidence of virologic failure, based on the assumption that dosing efavirenz with food would have analogous effects to those seen among Blacks with the slow-metaboliser genotype in the ACTG study.
In the present study, only two patients had efavirenz concentrations in the expected range for patients with the CYP2B6 516TT genotype. For other patients, food modestly increased exposure, but absolute concentrations did not attain values of the two patients under either meal condition. Although the genotype of those two patients is not known, one can postulate that genetic influence on efavirenz metabolism plays a more significant role than food on efavirenz pharmacokinetics and efavirenz-related toxicity.
Although the patients in the current study reported no adverse events, formal psychometric testing was not conducted and mild changes in CNS function cannot be completely ruled out. Importantly, these patients had received efavirenz-based therapy for a minimum of seven months prior to enrolment. Since efavirenz-related CNS toxicity tends to resolve within the first few weeks of treatment [7
], the safety findings of the current study may not be representative of safety outcomes among patients initiating efavirenz-based regimens. Nevertheless, the findings from the current study suggest that stable patients may administer efavirenz-containing regimens without meal restrictions.
For tenofovir, peak concentrations were unaffected by food intake while tenofovir exposure was marginally increased by food. Emtricitabine exposure and peak concentrations were only mildly reduced (13% and 17%, resp.) by a meal. Tenofovir is a nucleotide reverse transcriptase inhibitor which undergoes intracellular phosphorylation in two steps to its active diphosphate anabolite. Like tenofovir, emtricitabine undergoes intracellular phosphorylation. However, emtricitabine undergoes phosphorylation in three steps to its active triphosphate. For these two drugs, mild and transient changes in plasma concentrations are unlikely to be of clinical relevance as drug effect is not only dependent on absorption and elimination but also on the rate and extent of intracellular phosphorylation [15
]. Consequently, TDF and emtricitabine may be taken with or without food.
In general, for lipophilic drugs, absorption is improved by food, particularly food containing fat [16
]. Efavirenz is lipophilic, and enhanced absorption with fat is expected. The diester derivative of tenofovir (TDF) was specifically developed to improve the lipophilicity of tenofovir and enhance oral bioavailability [17
]; thus, enhanced absorption with fat would also be expected. The increases in tenofovir exposure seen in the current study were of lesser magnitude than those reported with single-dose TDF which may relate to less fat being used in the present study than the single-dose study which had 50% of the calories of a 700–1,000 Kcal meal derived from fat [6
]. In contrast to TDF and efavirenz, emtricitabine is an acidic hydrophilic molecule [19
]. Fat may interfere with emtricitabine dissolution, and food may delay dissolution of the tablet by reducing gastric pH, resulting in lower emtricitabine exposures with food.
In conclusion, a fat-containing meal moderately increased efavirenz steady-state peak concentrations. In contrast, pharmacokinetic parameters of tenofovir and emtricitabine were mildly affected by food, and those changes do not appear clinically significant. Since efavirenz-related central nervous system toxicity may be concentration dependent, patients experiencing these toxicities should take the FDC tablet without food. However, for patients without toxicities, the FDC can be taken without regard to meals.