Pharmacokinetics and Bioavailability of an Integrase and Novel Pharmacoenhancer-Containing Single-Tablet Fixed-Dose Combination Regimen for the Treatment of HIV

Gilead Sciences, Inc, Foster City, CA 94404, USA.
JAIDS Journal of Acquired Immune Deficiency Syndromes (Impact Factor: 4.56). 11/2010; 55(3):323-9. DOI: 10.1097/QAI.0b013e3181eb376b
Source: PubMed


This study evaluated the relative bioavailability and pharmacokinetics of elvitegravir (EVG), emtricitabine (FTC), tenofovir disoproxil fumarate (TDF), and a investigational pharmacoenhancer, cobicistat (GS-9350, COBI) coformulated as a fixed-dose combination tablet (FDC) compared with ritonavir-boosted EVG and FTC + TDF in healthy subjects.
Subjects were randomized to 1 of 2 sequences. All treatments were administered in the morning for 10 days with food, separated by a 2-day washout. Blood samples were collected over 24 hours with the last dose of each treatment.
Forty-four subjects enrolled, 42 subjects completed all periods. All study treatments were generally well tolerated. Relative to ritonavir-boosted EVG, the geometric least-squares means ratios (GMR) [90% confidence interval (CI)] for EVG area under plasma concentration-time curve from time zero until the end of the dosing interval (AUC)tau, maximum concentration (Cmax), and trough concentration (Ctau) were 118 (110 to 126), 108 (100 to 116), and 110 (95.3 to 127), respectively, with EVG/COBI 150 mg/FTC/TDF. Relative to FTC + TDF, FTC GMR, and 90% CI were 127 (115 to 140) for AUCtau, 121 (107 to 137) for Cmax, and 126 (118 to 136) for Ctau; tenofovir (TFV) GMR and 90% CI were 118 (114 to 122), 130 (122 to 138), and 124 (119 to 129) for AUCtau, Cmax, and Ctau, respectively, with EVG/COBI 150 mg/FTC/TDF.
Fixed-dose combination tablet containing COBI 150 mg resulted in desired high EVG Ctau concentrations and clinically equivalent tenofovir and FTC exposures relative to currently approved individual agents and was thus selected for subsequent evaluation.

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    • "It is the first non-NNRTI-based STR containing 300 mg of TDF, 200 mg of FTC, 150 mg of EVG and 150 mg of COBI. EVG is an integrase inhibitor that selectively inhibits the strand-transfer step of integration process of viral DNA into the nucleic acid of the host [40, 41]. COBI is a pharmacokinetic enhancer that does not exert any ARV activity [42]. "
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    ABSTRACT: Combined antiretroviral therapy (cART) has evolved considerably over the past decades leading to a better control of human immunodeficiency virus replication. Recently, regimens have evolved so as to simplify dosing frequency and reduce pill burden to improve adherence. Several national and international guidelines suggest antiretroviral (ARV) regimen simplification as a method of improving adherence. Decreased cART adherence has been associated with both patient-related factors and regimen-related factors. Adherence rates are statistically higher when simpler, once-daily (OD) regimens are combined with smaller daily regimen pill burdens. The avoidance of selective non-adherence, where a patient takes part of a regimen but not the full regimen, is a further potential benefit offered by single-tablet regimens (STRs). Simplification of cART has been associated with a better quality of life (QoL). Although tempered by other factors, better adherence, higher QoL and patients’ preferences are all key points which might combine to assure long-lasting efficacy and durability of cART. All studies underlined the favorable tolerability profile of newer STRs. Three STRs are currently available. Tenofovir (TDF) plus emtricitabine (FTC)/efavirenz (EFV) was the first OD complete ARV regimen available as a STR. TDF plus FTC/rilpivirine is a second-generation STR. The most recently approved STR, TDF plus FTC/cobicistat/elvitegravir, is the first non-nucleoside reverse transcriptase inhibitor-based STR. All of them have shown excellent efficacy; safety and tolerability have been improved by more recent formulations. Several other STRs are anticipated both combining completely different drugs, abacavir (ABC) plus lamivudine (3TC)/dolutegravir, utilizing innovative formulations of older drugs, tenofovir alafenamide fumarate, or taking advance of bioequivalent drugs, lamivudine (3TC) plus ABC/EFV. The future challenge would be to develop completely alternative STRs (including for example protease inhibitors or new molecules) to extend the advantages of simplicity to heavily pre-treated individuals. Electronic supplementary material The online version of this article (doi:10.1007/s40121-014-0024-z) contains supplementary material, which is available to authorized users.
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    ABSTRACT: Introduction In August 2012, the US Food and Drug Administration (FDA) approved a new single tablet once-a-day therapy for treatment-naïve HIV patients. The new tablet contains emtricitabine and tenofovir disoproxil fumarate as well as elvitegravir and cobicistat, a pharmacokinetic enhancer which prolongs the effect of elvitegravir. The new tablet (EVG/COBI/FTC/TDF), known as Stribild® (Gilead Sciences, Foster City, CA, USA), is now the only FDA-approved single-tablet, once-daily, HIV medication that is composed of an integrase-inhibitor-based regimen. Methods Stribild has been tested in two randomized double-blind phase 3 clinical trials with 1,408 patients who had not been previously treated for HIV. In one trial, Stribild was compared to the single-tablet regimen gold standard medication known as Atripla® (Gilead Sciences, Foster City, CA, USA) that contains efavirenz, emtricitabine and tenofovir disoproxil fumarate (EFV/FTC/TDF). In the second clinical trial, Stribild was compared to another preferred treatment regimen of ritonavir-boosted atazanavir (ATV/RTV) with coformulated emtricitabine and tenofovir disoproxil fumarate (FTC/TDF, marketed as Truvada®; Gilead Sciences, Foster City, CA, USA). Results The outcomes of the two recently published trials at 48 weeks indicated that Stribild was noninferior to both of the standard treatment regimens in controlling viral load. In the Stribild versus Atripla trial, 305 of 348 patients (87.6%) on Stribild versus 296 of 352 patients (84.1%) on Atripla had an HIV ribonucleic acid (RNA) concentration of <50 copies/mL at week 48. In the Stribild versus ATV/RTV with Truvada trial, 316 of 353 patients (89.5%) on Stribild versus 308 of 355 patients (86.8%) on Atripla had an HIV RNA concentration of <50 copies/mL at 48 weeks. Conclusion Stribild had a favorable safety profile in the two recently published randomized, double-blind, phase 3 clinical trials. With the approval of Stribild, clinicians now have more flexibility in prescribing single-tablet regimens for patients.
    Full-text · Article · Dec 2013

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