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Effect of food on rilpivirine/emtricitabine/tenofovir disoproxil fumarate, an antiretroviral single-tablet regimen for the treatment of HIV infection
 
 
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Abstract
 
The effect of food on rilpivirine/emtricitabine/tenofovir disoproxil fumarate single-tablet regimen (STR) was evaluated in healthy subjects. Subjects (N = 24) received rilpivirine/emtricitabine/tenofovir disoproxil fumarate (25/200/300 mg) under fasted or fed conditions (light [390 kcal, 12 g fat]; standard [540 kcal, 21 g fat]) followed by pharmacokinetic (PK) sampling. The 90% confidence interval (CI) of the geometric mean ratio for rilpivirine, emtricitabine, tenofovir exposure was estimated for fed versus fasted dosing and light versus standard meal, with equivalence boundaries of 80 - 125%. Safety was assessed throughout study. Twenty-three subjects completed the study; one discontinued due to protocol violation. Adverse events were mild to moderate. Emtricitabine PK was unaffected. Tenofovir AUCinf was 38% and 28% higher, respectively, with standard and light meal versus fasted. Rilpivirine AUCinf and Cmax were 16% and 26% higher with a standard, and 9% and 34% with a light meal, respectively, versus fasted. Compared to standard meal, the lower limit of rilpivirine AUClast and AUCinf when taken with the light meal were narrowly below the equivalence bounds (79.9 and 79.2, respectively), rilpivirine Cmax was narrowly above (129).
 
Rilpivirine/emtricitabine/tenofovir disoproxil fumarate should be administered with food, which can be a standard or light meal.
 
Rilpivirine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) that is approved by the U.S. Food and Drug Administration (FDA) for the treatment of HIV-1 infection when coadministered with a background regimen of other antiretroviral agents such as nucleoside (or nucleotide) reverse transcriptase inhibitors (N(t)RTIs).[1, 2] A single-tablet regimen (STR) tablet containing rilpivirine/emtricitabine/tenofovir disoproxil fumarate (RPV/FTC/TDF), also approved by the FDA, has been shown to be bioequivalent to the single agents, and has demonstrated non-inferior efficacy to efavirenz/emtricitabine/tenofovir disoproxil fumarate in treatment-naïve adults with HIV-1 infection, based on HIV RNA levels (viral load) <50 copies/mL at 48 weeks.[3] In this study, the RPV/FTC/TDF single tablet regimen (STR) demonstrated a statistically significant difference in efficacy (favoring the RPV/FTC/TDF STR) compared to the efavirenz/emtricitabine/tenofovir disoproxil fumarate STR among subjects with low baseline viral load (≤100,000 copies/mL), and was non-inferior among subjects with high baseline viral load (>100,000 copies/mL).[3] RPV/FTC/TDF was well-tolerated with fewer adverse events across all grades and fewer discontinuations due to adverse events (3% vs. 9%; P < 0.001).
 
RPV/FTC/TDF has also been demonstrated to provide efficacy in maintaining virologic suppression that was non-inferior to a ritonavir-boosted protease inhibitor antiretroviral (ARV) therapy when switching suppressed (i.e., <50 copies/mL) patients as compared to patients continuing on the ritonavir-boosted protease inhibitor, and had a better safety/tolerability profile with regard to adverse events (diarrhea, upset stomach) and lipid changes.[4]
 
The dosing recommendation for rilpivirine is administration with a meal to ensure optimal bioavailability, and in all clinical studies, rilpivirine administration was under fed conditions. This recommendation is based on food effect data from two Phase 1 studies evaluating the rilpivirine single agent tablet in healthy subjects.[5, 6]. The first food effect study was conducted evaluating the PK of rilpivirine (25, 50, 100, and 150 mg) following a fed versus fasted conditions.[5] When administered under fed conditions (estimated 600–800 kcal, 25–35 g of fat), rilpivirine Cmax and AUC were approximately 71% and 45% higher, respectively, compared with fasted conditions. The second food effect study was conducted evaluating the PK of rilpivirine (75 mg) following a standard breakfast (533 kcal, 21 g fat), a high-fat breakfast (928 kcal, 56 g fat), a protein-rich drink, or under fasted conditions; a light meal was not evaluated.[6] The study findings showed that, in comparison to administering rilpivirine under fasted conditions, a ∼74% higher mean Cmax and ∼59% higher mean AUCinf was observed following a standard breakfast and ∼64% higher mean Cmax and ∼48% higher mean AUCinf following a high-fat breakfast. In comparison to administering rilpivirine following a standard breakfast, the mean Cmax and AUCinf was ∼46% and 41% lower, respectively, following administration under fasted conditions. Rilpivirine administered with a protein-rich drink showed comparable exposures as fasted administration. No difference in rilpivirine PK parameters was observed upon administration with a high-fat breakfast compared to a standard breakfast.
 
RPV/FTC/TDF STR has been shown to be bioequivalent to the individual components emtricitabine, rilpivirine, and tenofovir disoproxil fumarate when administered under fed conditions[7]. The present study evaluated the effect of food (light and standard meal) on the pharmacokinetics of tenofovir, emtricitabine, and rilpivirine, when administered as the RPV/FTC/TDF single-tablet formulation.
 
Pharmacokinetics
 
Rilpivirine

 
The plasma concentration–time profiles of rilpivirine (n = 24) following single-dose administration of the RPV/FTC/TDF STR with a standard meal (540 kcal, 21 g fat), light meal (390 kcal, 12 g fat) or under fasted conditions are shown in Figure 1. Corresponding rilpivirine PK parameters and the test versus reference treatment comparisons are presented in Table 1. Rilpivirine plasma concentrations were higher following the RPV/FTC/TDF STR administration with a standard or light meal, as compared to fasted conditions, and the corresponding 90% CIs of the GMR for rilpivirine PK parameters (AUClast, AUCinf, and Cmax) were above 80–125%, indicating a food effect. Rilpivirine median Tmax was slightly longer when taken with a standard meal compared to fasted but the inter-quartile range was comparable, while T½ was comparable under fed versus fasted conditions. When the standard meal was used as the reference treatment, the lower limit of the 90% CIs of the GMR for rilpivirine exposures (AUClast and AUCinf) when taken with the light meal were narrowly below the lack of food effect boundary (79.9 and 79.2, respectively), as noted in Table 1.
 
Emtricitabine
 
The plasma concentration–time profiles of emtricitabine (n = 24) following single-dose administration of the RPV/FTC/TDF STR with a standard meal (540 kcal, 21 g fat), light meal (390 kcal, 12 g fat) or under fasted conditions are shown in Figure 2, and emtricitabine PK parameters, GMR and 90% CIs are presented in Table 2. Emtricitabine PK was comparable across treatments and the 90% CIs of the GMR for emtricitabine PK parameters were within the boundary of 80–125%, indicating a lack of food effect.
 
Tenofovir
 
The tenofovir plasma concentration–time profiles (n = 24) following single-dose administration of the RPV/FTC/TDF STR with a standard meal (540 kcal, 21 g fat), light meal (390 kcal, 12 g fat) or under fasted conditions are shown in Figure 3, with PK parameters, GMR, and 90% CIs in Table 3. Tenofovir plasma concentrations were higher following the RPV/FTC/TDF STR administration with a standard or light meal, as compared to fasted conditions, while tenofovir Tmax and T½ were comparable under fasted and fed conditions. The 90% CIs of the GMR for tenofovir exposure were above 80–125% following administration with standard or light meal, as compared with fasted conditions, indicating a food effect. Relative to the standard meal, tenofovir AUC was within the lack of food effect boundary following administration with a light meal, while Cmax was slightly lower.
 
Discussion
 
The effects of food on the PK of rilpivirine, emtricitabine, and tenofovir when administered as the RPV/FTC/TDF STR were evaluated in a balanced crossover study. When administered following a meal, rilpivirine and tenofovir plasma exposures were higher compared to fasted administration, while emtricitabine exposures were unaffected. Although a food effect was noted for rilpivirine in the present study, the observed increase in its systemic exposure in the presence of food was notably lower than historical data for rilpivirine administered as the single agent. Rilpivirine AUCs were ∼60% higher with a standard or high-fat meal for the single agent, when compared to the fasting state, with no difference between the standard or high-fat meal.[6] Although the Phase 2 and 3 studies of rilpivirine single agent did not have specific recommendations regarding the meal that the drug was administered with (e.g., kcal, fat content, etc), strong emphasis has been placed in administering rilpivirine single agent with a meal due to the notable food effect for rilpivirine single agent. Prior to the availability of the present data, RPV/FTC/TDF STR dosing has been recommended with a meal based on food effect data with the rilpivirine single agent using the standard and high-fat meals noted above.[8] However, the present study with the STR showed smaller increases in rilpivirine AUCinf of 16% and 9%, respectively, with a standard meal and a light meal versus fasted dosing. Comparison of the effects of the standard breakfast (540 kcal, 21 g fat) on rilpivirine PK in the present study versus historical data for the single agent with a standard breakfast of similar caloric and fat content (533 kcal, 21 g fat) suggests that the RPV/FTC/TDF STR is less susceptible to food-based changes in rilpivirine PK than the rilpivirine single agent tablet. The mechanism and/or formulation characteristics leading to the RPV/FTC/TDF STR being less susceptible to food effects versus the single agent are currently unknown and further investigation may be necessary to elucidate the potential cause.
 
In this context, it is of particular interest/importance that the impact of a light meal was evaluated for the STR, which was not done for the rilpivirine single agent. Relative to the standard meal (i.e., 540 kcal, 21 g fat), RPV/FTC/TDF STR dosing with a light meal (390 kcal, 12 g fat) resulted in essentially comparable rilpivirine exposures, with the GMR (90% CI) narrowly above the upper bound of equivalence (125%) for rilpivirine Cmax (129%) and within the upper bound and narrowly below the lower bound for equivalence (80%) for AUC (79.9% for AUClast and 79.2% for AUCinf). Overall, these data indicate that RPV/FTC/TDF STR can be administered with a light meal or food, which may be more convenient and/or representative of actual clinical dosing for HIV patients. The present data are thus considered particularly helpful for clinicians in managing patients that receive RPV/FTC/TDF STR. No data, however, are available upon administration of RPV/FTC/TDF STR with a nutritional drink, such as a protein-rich drink. Upon administration of rilpivirine single agent with a protein-rich drink rilpivirine exposures were comparable to those observed under fasted administration[6], and thus is not recommended as a substitute for food for the STR as well as the single agent.[1, 8] The effects of food on emtricitabine and tenofovir PK following RPV/FTC/TDF STR administration were consistent with historical data for other formulations with these agents. As also seen with the emtricitabine capsule[9], the emtricitabine/tenofovir disoproxil fumarate co-formulated tablet[10], and the elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate STR[11], emtricitabine exposures were unaffected with fed versus fasted dosing when administered as the RPV/FTC/TDF STR. Historically, tenofovir exposures have been slightly higher under fed versus fasted conditions in crossover studies with the emtricitabine/tenofovir disoproxil fumarate co-formulated tablet[10] and the elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate STR[11]. In the present study, compared to fasted condition, tenofovir AUCinf was 28% and 38% higher with light and standard meals, respectively, and corresponding values for Cmax were 12% and 32% higher. These changes are in the range of the food effects seen historically with other tenofovir disoproxil fumarate containing products (Cmax and AUC increase of 20% and 25%, respectively with elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate STR; 15% and 35% with emtricitabine/tenofovir disoproxil fumarate co-formulated tablet). In the present study, relative to a standard breakfast, the 90% CI for tenofovir AUC was within the equivalence bounds when RPV/FTC/TDF was administered with a light meal. Although the Cmax was slightly lower, this was not considered to be clinically relevant.
 
In conclusion, although both the RPV/FTC/TDF STR and the rilpivirine single agent are recommended to be administered under fed conditions, a lesser food effect on rilpivirine plasma exposures was observed with the STR versus single agent. In addition, the study shows that following a standard meal or a light meal, no clinically relevant differences in rilpivirine exposures were observed. Accordingly, the RPV/FTC/TDF STR may be administered with a standard or a light meal, which may be practical and convenient for HIV-infected patients receiving this regimen.

 
 
 
 
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