Elvitegravir is a novel low-molecular-weight integrase strand transfer inhibitor (INSTI) with antiviral activity, originally developed by Japan Tobacco, Inc. (Tokyo, Japan). It was discovered through screening assays of human immunodeficiency virus type 1 (HIV-1) integrase inhibitory activity using HIV-1 integrase obtained after genetic engineering of the full-length genome sequence of the NL4-3 strain of HIV-1.
Cobicistat, marketed by Gilead Sciences, Inc. (Foster City, CA), is a new chemical entity and structural analogue of ritonavir with no antiretroviral activity. It is a more specific, mechanism-based CYP3A inhibitor than ritonavir that enhances or “boosts” the exposure of CYP3A substrates. Cobicistat inhibits human CYP3A selectively and potently with metabolic activation-dependent activity. It enhances the bioavailability of coadministered drugs such as elvitegravir, which are metabolized by CYP3A and decreases their clearance. The activity of cobicistat as a booster is equivalent to that of low-dose ritonavir. Cobicistat has no antiretroviral activity, and can therefore be used as a booster without concern that drug-resistant virus strains may develop, even in regimens that do not contain a protease inhibitor.
A single-tablet regimen (STR) of elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (EVG/COBI/FTC/TDF, Stribild®) contains 150 mg of elvitegravir and 150 mg of cobicistat, as well as 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate, which are the recommended backbones for initial treatment of HIV-1-infected patients. It is the first INSTI-containing combination tablet that can be taken once daily for treatment of HIV-1 infection, and the Antiretroviral Guidelines for Adults and Adolescents recommend EVG/COBI/FTC/TDF STR as the preferred regimen for antiretroviral therapy-naive patients. EVG/COBI/FTC/TDF STR was approved in August 2012 in the USA, March 2013 in Japan, and May 2013 in the EU, and is currently available commercially as a new treatment option for patients who wish to take fewer tablets less frequently.
The pharmacokinetics of elvitegravir, cobicistat, emtricitabine, and tenofovir, the four components of EVG/COBI/FTC/TDF STR, have been studied before in healthy subjects and HIV-1-infected patients in the USA. The oral bioavailability of elvitegravir and tenofovir is affected by food intake.[3, 7] A food interaction study showed that the mean AUCinf and Cmax of these components of EVG/COBI/FTC/TDF STR administered orally were increased by 34% and 24%, respectively, when administered with a meal (373 kcal, 20% fat), as compared with fasting conditions. Therefore, in a clinical setting, it is recommended that EVG/COBI/FTC/TDF STR be taken with a meal. Although EVG/COBI/FTC/TDF STR has been approved for marketing in Japan and has already been administered to HIV-1-infected patients, the pharmacokinetics of these components have not yet been evaluated in Japanese subjects. In previous studies of the effects of food on pharmacokinetics, meals of approximately 400 and 800 kcal were evaluated,[3, 7] but the effects of meals containing fewer calories, such as protein-rich drinks, have remained unknown. If exposure to EVG/COBI/FTC/TDF STR administered with a protein-rich drink containing fewer calories was equivalent to that when administered with a standard breakfast, then patients treated with EVG/COBI/FTC/TDF STR would have more meal options.
The objectives of our present study were to confirm the effects of fasting conditions and two types of meal (a nutritional protein-rich drink and a standard meal) on the pharmacokinetics of elvitegravir, cobicistat, emtricitabine, and tenofovir in Japanese subjects taking the EVG/COBI/FTC/TDF single-tablet formulation.
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The present randomized, open-label, single-dose, three-treatment, three-period, three-sequence crossover study involving HIV-negative healthy adult Japanese subjects was designed to determine the pharmacokinetic characteristics of EVG/COBI/FTC/TDF STR when administered with a standard breakfast and with a nutritional protein-rich drink, as well in a fasted state. This represents the first study in which EVG/COBI/FTC/TDF STR has been administered to Japanese subjects, and the effect of taking a nutritional protein-rich drink, which had never been evaluated previously, was also assessed as a new meal condition.
Compared with administration with a standard breakfast, administration in a fasted state resulted in 50% and 55% decreases in the mean AUCinf and Cmax values for elvitegravir, and the 90% CIs of GMR for elvitegravir pharmacokinetic parameters were below the equivalence limits, indicating that bioavailability in a fasted state was not equivalent to that of administration with a standard meal. By contrast, these values following administration with a nutritional protein-rich drink were essentially comparable to those following administration with a standard breakfast, the two fed conditions appearing to be bioequivalent to each other, and the 90% CI of GMR being narrowly above the upper limit of equivalence (1.25) for elvitegravir Cmax (1.27). No changes in cobicistat or emtricitabine pharmacokinetics were observed among the three treatment regimes, that is, administration in a fasted state and with two types of meals, confirming that all of the treatments involving cobicistat and emtricitabine were bioequivalent. On the other hand, administration in a fasted state resulted in an approximate 30% decrease of AUCinf and Cmax for tenofovir compared with administration with a standard breakfast. However, the 90% CI for tenofovir AUCinf following administration with a nutritional protein-rich drink was within the equivalence limits following administration with a standard breakfast. While Cmax was slightly lower, this was not considered to be clinically relevant. These results revealed that the contents of a meal taken before administration of EVG/COBI/FTC/TDF STR did not affect the pharmacokinetics of each analyte, and suggested that EVG/COBI/FTC/TDF STR can be administered with a light meal such as a nutritional protein-rich drink if patients cannot take a standard meal. The advantage of being able to take EVG/COBI/FTC/TDF STR without regard to meal type is that it imposes less of a burden on the patient, thus ensuring better compliance.
The effect of food on the bioavailability of each component following administration of EVG/COBI/FTC/TDF STR has been evaluated previously in 24 healthy adult non-Japanese subjects. This revealed that although the AUCs of cobicistat and emtricitabine were unaffected by food, the bioavailability of elvitegravir and tenofovir was decreased by 26% and 19%, respectively, in a fasted state, compared with administration with a meal of 373 kcal containing 20% fat. These findings were consistent with those of the present study. It is generally known that a hydrophobic drug becomes more soluble when given with a meal, leading to increased absorption of the drug. Elvitegravir is a hydrophobic drug, and this increase in bioavailability may be partly attributable to higher drug solubility in the presence of food.
To clarify any ethnic differences in pharmacokinetics retrospectively, the mean AUCs of elvitegravir, cobicistat, emtricitabine, and tenofovir upon administration in a fasted state determined in the previous US study to assess the effects of food on bioavailability were compared with those observed in the present study (Tables 1 and 2). This revealed that the AUCs of these components, except for tenofovir, were nearly equivalent between Japanese and non-Japanese subjects. Tenofovir AUC tended to be increased slightly (22.3%) in Japanese subjects; however, it seems unlikely that this increase would be clinically significant. Body weight might also influence tenofovir clearance. Therefore, one possible reason for the increased tenofovir exposure in our present study would have been that the body weight of our Japanese subjects was about 10 kg lower than that of the subjects in the US study. Therefore, it can be considered that the pharmacokinetic profile of EVG/COBI/FTC/TDF STR does not show any marked ethnic differences.
The pharmacokinetics of tenofovir administered as tenofovir disoproxil fumarate alone and as a combination tablet (emtricitabine/tenofovir disoproxil fumarate, Truvada®) had been evaluated previously in healthy Japanese male subjects. Compared with the data for tenofovir exposure following single-dose administration of tenofovir disoproxil fumarate 300 mg or emtricitabine/tenofovir disoproxil fumarate in six subjects in a fasted state, AUCinf for tenofovir was found to be higher in the presence of cobicistat in the present study. No differences in the half-lives of tenofovir were observed following tenofovir monotherapy versus concomitant administration with cobicistat. Tenofovir is renally eliminated and is not a substrate or inhibitor of CYP; also, no clinically significant interactions are evident between tenofovir and many hepatically eliminated drugs.[11, 12] Cobicistat inhibits CYP3A as well as many drug transporters including P-glycoprotein. Therefore, any increase in tenofovir AUC may be the result of higher relative bioavailability attributable to co-administration of cobicistat. It has been hypothesized that the mechanism responsible for this interaction is intestinal inhibition of P-glycoprotein by cobicistat, resulting in an increase of tenofovir absorption.[5, 13, 14] Similar increases in tenofovir absorption have also been reported after co-administration with ritonavir and other protease inhibitors.[15-19] The results for tenofovir obtained in the present study were comparable to those for AUC of tenofovir following administration in combination with ritonavir and other protease inhibitors.
Previous clinical pharmacokinetic/pharmacodynamic studies of 10-day elvitegravir monotherapy in HIV-infected patients have indicated a clear association between the antiviral activity and the plasma trough concentration (Ctau).[1, 20] Administration of elvitegravir with cobicistat resulted in a substantially higher Ctau and robust antiviral activity. Elvitegravir demonstrated a sufficient effect when the mean Ctau was approximately 10-fold the 95% inhibitory concentration (IC95), adjusted for the in vitro protein-binding rate (45 ng/mL).[1, 20, 21] Population pharmacokinetics analysis in phase 2 and 3 studies has indicated that the mean Ctau value in HIV-infected patients administered cobicistat-boosted elvitegravir was 451 ng/mL (%CV; 58). The virological response rates (participants with ≤50 copies/mL HIV RNA at 48 weeks) in the phase 2 and 3 studies conducted for Ctau estimation were more than 90%.[22, 23] On the basis of these results, we consider that the target Ctau value would be nearly 10-fold the IC95. The mean C24 obtained in the present study was nearly 10-fold the IC95 under all treatment conditions, that is, administration with a standard breakfast, in a fasted state, and with a nutritional protein-rich drink.
The present study was conducted in healthy adult subjects, and no differences in elvitegravir pharmacokinetics were observed between them and HIV-1-infected patients.[1, 6] Therefore, it seems that these results can be extrapolated to the target population of HIV-1-infected patients.
In conclusion, the mean AUCinf of elvitegravir and tenofovir administered as components of EVG/COBI/FTC/TDF STR were shown to be decreased by 50% and 28%, respectively, following administration in a fasted state, relative to administration with a standard breakfast, whereas exposure to elvitegravir and tenofovir was comparable following administration with a nutritional protein-rich drink and with a standard breakfast. Food or a nutritional drink did not reduce the bioavailability of cobicistat or emtricitabine. On the basis of our results, it is recommended that EVG/COBI/FTC/TDF STR be given with food, and that no restrictions on the type of food ingested are necessary.