Review of the safety, efficacy, and pharmacokinetics of elvitegravir with an emphasis on resource-limited settings

Figures & data

Table 1 Interactions between elvitegravir ± ritonavir and other drugs

Co-administered drug	Participants (completed study)	Duration	Dose		PK elvitegravir in % change			PK co-administered drug in % change			Comments
			Elvitegravir ± ritonavir	Co-administered drug	Cmax	AUCτ	Cτ	Cmax	AUCτ	Cτ
Zidovudine^Citation23	28 healthy subjects	27 days	200 mg + 100 mg QD day 8–27	300 mg BID day 1–7, 8–17	↑5%	↑5%	↑15%	↓12%	↓14%	NA	No dosage adjustment needed
Didanosine^Citation23,*	32 healthy subjects	17 days	200 mg + 100 mg QD day 5, 14–17	400 mg (EC capsule) QD day 1, 15	↓5%	↓3%	↑6%	↓16%	↓14%	NA	No dosage adjustment needed
Stavudine^Citation23,*	32 healthy subjects	17 days	200 mg + 100 mg QD day 5, 14–17	40 mg QD day 3, 17	↓4%	↓2%	↑24%	↓0.4%	↑7%	NA	No dosage adjustment needed
Abacavir^Citation23	26 healthy subjects	15 days	200 mg + 100 mg QD day 5–15	600 mg day 1, 15	↓5%	↓3%	↑6%	↓12%	↓17%	NA	No dosage adjustment needed
Rifabutin^Citation14	19 healthy volunteers	53 days	300 mg + 100 mg QD	150 mg EOD	↓8%	↓4%	↓6%	Rifabutin: ↓8% 25-o-dcRFB: ↑440%	Rifabutin: ↓6% 25-o-dcRFB: ↑851%	Rifabutin: ↑16% 25-o-dcRFB: ↑1836	Dose adjustment of rifabutin 150 mg EOD recommended with monitoring of adverse events
Atazanavir (boosted)^Citation19	53 healthy subjects	Study 1: 14 days, Study 2: 10 days	Study 1: 200 mg Study 2: 85 mg	300 mg + ritonavir 100 mg QD	Study 1: ↑85 Study 2: ↓9	Study 1: ↑100 Study 2: ↑7	Study 1: ↑188 Study 2: ↑38	Study 1: ↓16 Study 2: ↓3	Study 1: ↓21 Study 2: ↓11	Study 1: ↓35% Study 2: ↓17	Dose adjustment of EVG 85 mg recommended when co-administered with ATV/r 300/100 mg
Atazanavir (unboosted)^Citation18	15 healthy subjects	20 days	300 mg	400 mg	↑8%	↑7%	↓10%	3680 ng/mL	16300 ng·h/mL	74.5 ng/mL	Atazanavir exposures are lower than historical values
Darunavir§,^Citation15	20 healthy subjects	42 days	125 mg QD	600 mg + ritonavir 100 mg BID	↑13%	↑10%	↑18%	↓11%	↓11%	↓17%	No dosage adjustment needed
Tipranavir§,^Citation15	26 healthy subjects	42 days	200 mg QD	500 mg + ritonavir 200 mg BID	↑4%	↓8%	↓10%	↓8%	↓11%	↓11%	No dosage adjustment needed
Fosamprenavir^Citation16	31 healthy subjects	28 days	125 mg QD	700 mg + ritonavir 100 mg BID	No change	↓7%	↓4%	↓2%	↓1%	↑1%	No dosage adjustment needed
Lopinavir^Citation17	27 healthy subjects	14 days	125 mg QD	400 mg + ritonavir 100 mg BID	↑52%	↑75%	↑139%	↓1%	↓3%	↓8%	Dose reduction of elvitegravir to 85 mg is recommended
Maraviroc^Citation20	28 healthy subjects	20 days	150 mg + 100 mg QD	150 mg BID	↑1%	↑7%	↑9%	↑115%	↑186%	↑323%	Dose adjustment of maraviroc 150 mg BID recommended
Etravirine^Citation21	31 healthy volunteers	20 days	150 mg + 100 mg QD	200 mg BID	↑7%	↑6%	↑6%	↑2%	↓2%	↓10%	No dosage adjustment needed
Antacid^Citation24,σ	62 healthy subjects	Study 1: 11 days Study 2: 15 days	50 mg + 100 mg QD	20 mL together, 2 hours before, 2 hours after, 4 hours before, 4 hours after elvitegravir	Together with antacid: ↓47% 2 hours after antacid: ↓18% 4 hours after antacid: ↓5% 2 hours before antacid: ↓2% 4 hours before antacid: ↓ 21%	Together with antacid: ↓45% 2 hours after antacid: ↓15% 4 hours after antacid: ↓4% 2 hours before antacid: ↓2% 4 hours before antacid: ↓20%	Together with antacid: ↓41% 2 hours after antacid: ↓10% 4 hours after antacid: ↑4% 2 hours before antacid: no change 4 hours before antacid: ↓20%	NA	NA	NA	Administration of antacid and EVG should be separated by at least 2 hours
Omeprazole^Citation24,σ	62 healthy subjects	15 days	50 mg + 100 mg QD	40 mg QD	↓7%	↓1%	↓6%	NA	NA	NA	No dosage adjustment needed
Ketoconazole^Citation23	18 healthy subjects	15 days	150 mg + 100 mg QD	200 mg BID	↑17%	↑48%	↑67%	NA	NA	NA	Maximum recommended daily dose of ketoconazole is 200 mg
Norgestimate and ethinyl estradiol^Citation24	15 healthy subjects	56 days	150 mg + cobicistat 150 mg + tenofovir 300 mg + emtricitabine 200 mg	Combination oral contraceptive pill containing norgestimate (NGM) 0.180 mg, 0.215 mg, 0.250 mg and ethinyl estradiol (EE) 25 μg	NA	NA	NA	EE: ↓6% NGMN: ↑109%	EE: ↓25% NGMN: ↑126%	EE: ↓41% NGMN: ↑167%	Recommended ethinyl estradiol dose of the oral contraceptive is 30 μg

* Notes: Pharmacokinetic study of both didanosine and stavudine with elvitegravir was carried out in the same subjects;

§ pharmacokinetic study of both darunavir and tipranavir with elvitegravir was carried out in crossover design in the same subjects;

σ pharmacokinetic study of both antacid and omeprazole with elvitegravir was carried out in one study design.

Abbreviations: PK, pharmacokinetic; GMR, geometric mean ratio; C_max, maximum concentration; AUC_τ, area under the curve from time 0 to tau, where tau is the length of dosing interval; C_τ, tau concentration; NA, not available; QD, once a day; BID, twice a day; EOD, every other day; EC, enteric coated; EE, ethinyl estradiol; NGM, norgestimate; NGMN, norelgestromin (metabolite of norgestimate).

Table 2 Summary of published data on the efficacy, safety, and tolerability of elvitegravir (EVG)

Study	Design	EVG formulation	Sample size	Comparator	Outcomes	Comments
Efficacy
DeJesus et al^Citation7	Randomized dose-ranging monotherapy trial	200 mg, 400 mg, or 800 mg twice daily, or 50 mg once daily	40 HIV-positive treatment-naïve and experienced patients	Placebo	Significant reductions in HIV RNA in both treatment-naïve and experienced patients
Zolopa et al^Citation27	Phase II randomized, controlled, 48-week study. Partial blinding (to dose)	20 mg, 50 mg and 125 mg	278 treatment-experienced subjects	Ritonavir-boosted PI	Lowest dose arm stopped early due to inferiority. 50 mg arm demonstrated noninferiority. 125 mg arm demonstrated superiority
Cohen et al^Citation29	Phase II, 48-week randomized double-blinded trial	QUAD (EVG, cobicistat, emtricitabine and tenofovir)	71 treatment-naïve, HIV-positive patients	EFV/FTC/TDF	90% of the patients taking Quad and 83% of patients taking atripla achieved virological suppression	Quad associated with more rapid achievement of virological suppression
Molina et al^Citation31	Phase III multicenter, randomized, double-blind study	Ritonavir-boosted once-daily elvitegravir 150 mg (or 85 mg in patients receiving a background protease inhibitor of either atazanavir or lopinavir)		351 receiving ritonavir-boosted twice-daily raltegravir 400 mg	59% of elvitegravir-treated patients achieved virological suppression vs 58% for raltegravir-treated patients (intention-to-treat population; P = 0.001)	Preliminary results did not show greater barrier to resistance compared with raltegravir
Safety and tolerability
Zolopa et al^Citation27	Phase II randomized trial	Virological suppression	Virological suppression	Ritonavir-boosted PIs	Occurrence of adverse events and grade 3 or 4 laboratory toxicity similar across treatment groups	No dose-dependent increase in type of adverse event observed
Cohen et al^Citation29	Phase II randomized trial	Quad	71 treatment-naïve, HIV-positive patients	EFV/FTC/TDF	Lower percentage of drug-related adverse events compared with EFV/FTC/TDF (35% vs 57%) Quad induced fewer adverse events involving the central nervous system (drug-related central nervous system (17% vs 26%), and psychiatric (10% vs 44%)	Incidence of laboratory abnormalities. No grade 3/4 adverse events nor adverse events leading to discontinuation for patients receiving Quad

Abbreviations: EVG, elvitegravir; EFV/FTC/TBF, efavirenz/emtricitabine/tenofovir disoproxil fumarate; PI, protease inhibitors.

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