Skip Navigation LinksHome > September 2012 - Volume 7 - Issue 5 > Pharmacology of HIV integrase inhibitors
Current Opinion in HIV & AIDS:
doi: 10.1097/COH.0b013e328356e91c
INTEGRASE INHIBITORS: Edited by Charles Hicks and Esteban Martinez

Pharmacology of HIV integrase inhibitors

Adams, Jessica L.a; Greener, Benjamin N.a; Kashuba, Angela D.M.a,b

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Author Information

aDivision of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA

bUniversity of North Carolina Center for AIDS Research, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA

Correspondence to Angela D.M. Kashuba, BScPhm, PharmD, DABCP, Professor and Vice-Chair, Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, Director, UNC Center for AIDS Research Clinical Pharmacology and Analytical Chemistry Core, University of North Carolina at Chapel Hill, NC, USA. Tel: +1 919 966 9998; fax: +1 919 962 0644; e-mail: akashuba@unc.edu

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Abstract

Purpose of review: The purpose of this study is to review recent and relevant pharmacology data for three HIV integrase inhibitors: raltegravir (marketed), dolutegravir, and elvitegravir (both in phase III drug development).

Recent findings: Data from January 2011 to April 2012 were evaluated. These data better characterized integrase inhibitor pharmacokinetics, assessed dosing regimens, and investigated previously undescribed drug–drug interactions. Due to formulation challenges, raltegravir inter-patient and intra-patient pharmacokinetic variability is high. Twice-daily 400 mg dosing has been shown to be clinically superior to 800 mg once-daily dosing. A pediatric formulation of raltegravir with less variable pharmacokinetics and greater bioavailability was US Food and Drug Administration (US FDA)-approved in December 2011. Cobicistat-boosted elvitegravir, and the second-generation integrase inhibitor dolutegravir, have lower pharmacokinetic variability and are dosed once daily. Dolutegravir drug interactions are similar to raltegravir, whereas boosted elvitegravir participates in additional CYP3A-mediated interactions.

Summary: Raltegravir's potent antiretroviral activity has resulted in widespread use in both treatment-naïve and experienced patients. Dolutegravir and cobicistat-boosted elvitegravir have some pharmacokinetic advantages. Pharmacokinetic data in special populations (pregnancy, pediatrics) to optimize dosing are still required.

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INTRODUCTION

Integrase inhibitors are an important addition to antiretroviral therapy. With a unique mechanism of action, potent anti-HIV activity, and a mild side effect profile, raltegravir (the first integrase inhibitor) has become a vital part of therapy for both antiretroviral (ARV)-naïve and experienced patients. Dolutegravir and cobicistat-boosted elvitegravir have improved pharmacokinetic profiles, resulting in less variability within and between patients, and longer half-lives for once-daily dosing.

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RALTEGRAVIR

Raltegravir is dosed at 400 mg twice daily. In 35 HIV-positive, treatment-naïve patients given 100, 200, 400, or 600 mg of raltegravir or placebo twice daily for 10 days, raltegravir was found to be potent and well tolerated throughout the range of doses [1]. The C12h (or ‘trough’ concentration) geometric mean plasma concentrations at all doses exceeded 33 nM, the mean in-vitro 95% Inhibitory Concentration (IC95) for wild-type virus [1]. Raltegravir is metabolized by glucuronidation, primarily by uridine glucuronosyl transferase (UGT)1A1 [2]. Metabolism by this low-affinity, high-capacity pathway results in limited drug interactions. Table 1 summarizes the pharmacologic properties of the integrase inhibitors included in this review.

Table 1
Table 1
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Pharmacokinetic variability

Raltegravir has a high level of intra-patient and inter-patient pharmacokinetic variability. In a study of 15 HIV-infected patients [15▪], the raltegravir area under the concentration time curve from 0–12 h (AUC0–12h) ranged from 1495 to 49051 ng*h/ml. From two visits, intra-patient variability for C12h (or ‘trough’ concentration) and AUC0–12h ranged from 1 to 113%, and 1 to 77%, respectively. Despite this variability, raltegravir's large therapeutic window and mild side effect profile make this variability less clinically relevant.

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Pharmacokinetics of once-daily dosing
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Given raltegravir's wide therapeutic window, and the potential for improved adherence with once-daily dosing regimens, a study was conducted to determine once-daily efficacy and toxicity. The QDMRK study was a phase 3 noninferiority study comparing raltegravir 800 mg once daily with raltegravir 400 mg twice daily in combination with tenofovir and emtricitabine in 775 HIV+ patients with HIV RNA at least 5000 copies/ml [16▪▪]. After 48 weeks, once-daily dosing of 800 mg was found to be inferior to twice-daily dosing: 83% of the patients who were dosed once daily and 89% of patients dosed twice daily achieved a virologic response. Time to virologic response was significantly longer in the once-daily versus twice daily arm (log-rank test P = 0.008). Of those patients with HIV RNA above 100 000 copies/ml or CD4 cell counts below 200 cells/μl prior to initiating therapy, virologic response rates were 10% lower with once-daily dosing. The authors concluded that despite high response rates in both groups, once-daily raltegravir cannot be recommended. Because this study was a double-blinded, placebo-controlled study, potential adherence advantages of once-daily dosing over twice-daily dosing could not be assessed, and the authors concluded that these data are insufficient to recommend whether a once-daily regimen could be used in specific patients struggling with adherence to a twice-daily regimen.

Intensive pharmacokinetic analysis of a subset of 42 patients from the QDMRK study found the AUC to be similar between once and twice-daily dosing groups {least-squares mean (coefficient of variation%) of 30.87 (70) versus 13.14 (99) with a geometric mean ratio (GMR) [90% confidence interval (CI) of 1.17 (0.80–1.72]}. However, the concentrations at the end of the dosing interval were substantially lower in the once-daily dosing group [least-squares mean (coefficient of variation%) of 40 (111) versus 257 (167) with a GMR (90% CI) of 0.15 (0.09–0.26)] [16▪▪].

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Pharmacokinetics of pediatric dosing

In December 2011, the US Food and Drug Administration (US FDA) approved two new dosages of chewable tablets (100 and 25 mg) for pediatric populations. The approval was supported by a preliminary data analysis of the currently ongoing IMPAACT (International Maternal Pediatric Adolescent AIDS Clinical Trials) P1066 in which either the 400 mg film-coated tablets were given to HIV-positive children 6–18 years of age or the chewable tablets were given to children 2 to less than 12 years of age. Doses were given to target adult AUCs and C12h. Pharmacokinetic data from 10 children aged 6–11 years receiving the chewable tablets were analyzed to determine a pediatric dosing recommendation [17]. At 6 mg/kg, the raltegravir AUC0–12h was 22.6 μM*h (12.8–40.6 μM*h), with geometric mean C12h of 128 nM (62–397 nM). These exposures are similar to those measured in adults [median C12h 149 (60–245 nM)] [18]. When compared with the adult dosage form, the pharmacokinetic variability (expressed as coefficient of variation%) was significantly less for the chewable tablets: variability in AUC was 34% (compared with 120%) and variability in C12h was 84% (compared with 221%). The chewable tablets also have an overall increased bioavailability compared with the film-coated tablets with a 1.8-fold increase in AUC and a 3.2-fold higher Cmax[19].

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Drug–drug interactions

Raltegravir does not have the substantial drug–drug interaction potential of many other ARVs because it is metabolized by glucuronidation: a low-affinity, high-capacity pathway. The primary enzyme is UGT1A1, and interactions can occur when concomitant medications induce or inhibit the activity of this enzyme. For example, raltegravir's AUC decreased by 40% when used concomitantly with the potent UGT1A1 inducer rifampin [20]. Conversely, the UGT1A1 inhibitor atazanavir increased raltegravir's AUC by 72% [21].

Raltegravir interactions with protease inhibitors have been explored. The pharmacokinetics of raltegravir twice daily combined with darunavir/ritonavir once daily were investigated in 24 HIV-positive patients both in plasma and at the intracellular site of action [22▪]. This study found no remarkable interactions between agents, either in plasma or intracellularly, with AUC GMRs (90% CI) of 1.24 (1.13–1.45) for plasma darunavir, and 0.90 (0.73–to 1.44) for plasma raltegravir. A recent pharmacokinetic substudy of the EASIER-ANRS (Efficacy and safety of raltegravir in treatment-experienced HIV-1-infected patients switching from enfuvirtide-based regimens) 138 Trial measured tipranavir and darunavir concentrations in 20 HIV-positive patients at steady state before and after switching from enfuvirtide to raltegravir [23▪]. The GMRs (90% CI) for tipranavir C12h, Cmax, and AUC were 0.49 (0.42–0.56), 0.76 (0.63–0.92), and 0.67 (0.55–0.82). The GMRs (90% CI) for darunavir C12h, Cmax, and AUC were 0.82 (0.61–1.10), 0.68 (0.59–0.79), and 0.64 (0.53–0.77). The reason for these decreased tipranavir and darunavir concentrations is not apparent. The authors suggest that these decreased concentrations may have been due to previously increased protease inhibitor concentrations while on enfuvirtide therapy, or by unknown drug transporter effects. However, there were no virologic failures observed up to 48 weeks while on raltegravir. The effect of tipranavir on raltegravir concentrations was not measured in this study, although a previous investigation revealed a 55% decrease in raltegravir C12h when combined with tipranavir/ritonavir without significant changes to AUC [24].

Lersivirine, a non-nucleoside reverse transcriptase inhibitor (NNRTI) currently in development, is glucuronidated by UGT2B7 and metabolized by CYP3A4. A recent pharmacokinetic study in which lersivirine was given in combination with raltegravir to 18 healthy volunteers found a 15–29% decrease in raltegravir AUC and Cmax and a 25% mean increase in the C12h. No significant changes in lersivirine's pharmacokinetic parameters were seen. The authors concluded that lersivirine and raltegravir could likely be co-administered without need for dose adjustments [25▪]. Additionally, the NNRTI rilpivirine was studied and also found to have little effect on the concentrations of raltegravir when used in combination [26].

Hepatitis C co-infection occurs in about 25% of HIV-infected patients in the USA [27]. With a lower drug interaction potential than other ARVs, raltegravir is a good option for co-infected patients requiring treatment of both HIV and hepatitis C. A recent study evaluated the pharmacokinetics of raltegravir and ribavirin when dosed separately and together [28▪]. No statistically significant changes in the pharmacokinetic parameters of raltegravir were observed when given with ribavirin, but a decrease in ribavirin Cmax [GMR (95% CI) 0.79 (0.62–1.00)] and an increase in Tmax [GMR (95% CI) 1.39 (1.08–1.78)] were observed. With no additional safety concerns, the authors concluded that the changes to ribavirin Cmax and Tmax are not likely to have a clinically significant impact. Additionally, raltegravir has been studied in combination with the hepatitis C protease inhibitors bocepravir and telaprevir. No clinically significant interaction was found with either drug. GMRs (90% CI) for raltegravir AUC and Cmax were 1.01 (0.85–1.20) and 1.09 (0.89–1.33), respectively, when given with bocepravir [29▪]. When given with telaprevir, least-squares mean ratios (90% CI) for raltegravir AUC, Cmax, and Cmin were increased: 1.31 (1.03–1.67), 1.26 (0.97–1.62), and 1.78 (1.26–2.53), respectively [30▪].

Tuberculosis is a common opportunistic infection in HIV-positive patients. Rifampin is known to potently induce UGT1A1, and therefore a 100% increase in raltegravir dose is required when the two are used together [20,31]. In-vitro studies have previously determined that rifabutin is a less potent inducer of UGT1A1, and the United States Department of Health and Human Services guidelines do not recommend a raltegravir dose adjustment when used concomitantly [18,31]. A pharmacokinetic study was recently conducted to correlate these in-vitro data with clinical effects [32▪]. In 19 healthy participants, raltegravir was given at 400 mg twice daily for 4 days alone, then with rifabutin 300 mg daily for 14 days. The GMR of the AUC of raltegravir and rifabutin versus raltegravir alone (90% CI) was 1.19 (0.86–1.63), the C12h ratio was 0.80 (0.68–0.94), and the Cmax ratio was 1.39 (0.87–2.21). On the basis of these data, the authors concluded that rifabutin alterations of raltegravir exposure are not clinically relevant. A summary of previously evaluated drug–drug interactions between integrase inhibitors and commonly co-administered agents is provided in Table 2.

Table 2-a Integrase ...
Table 2-a Integrase ...
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ELVITEGRAVIR

Table 2-b Integrase ...
Table 2-b Integrase ...
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Table 2-c Integrase ...
Table 2-c Integrase ...
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Elvitegravir (GS-9137, JTK-303) is a first-generation integrase strand-transfer inhibitor currently in phase 3 clinical testing by Gilead Sciences, Inc. (Foster City, CA, USA). As elvitegravir undergoes extensive primary metabolism by hepatic and intestinal cytochrome P450 (CYP)3A and secondary metabolism by UGT1A1/3, its pharmacokinetics has been evaluated with the CYP3A inhibitors ritonavir and cobicistat (an investigational compound). These pharmacokinetic ‘boosting’ agents were considered to render elvitegravir's pharmacokinetic profile more favorable to once-daily dosing [4].

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Pharmacokinetics and boosting

Elvitegravir has an elimination half-life of approximately 3 h when dosed alone and 9 h when dosed with ritonavir 100 mg [5]. DeJesus et al. have suggested that the antiviral activity of elvitegravir can be described by a simple Emax model fitted to C24h (or ‘trough’ concentrations) rather than Cmax or AUC0–24h. Elvitegravir dose selection has therefore been based on maintaining C24h approximately 10-fold above the protein-adjusted IC95 of 45 ng/ml [5].

An early 10-day monotherapy study in both treatment-experienced and treatment-naive patients demonstrated a potent reduction in HIV-1 RNA with a mean log10 change from baseline of −1.91 ± 0.60 with elvitegravir 800 mg twice-daily dosing or −1.99 ± 0.38 with elvitegravir 50 mg once-daily dosing boosted by ritonavir 100 mg [5]. Although similar in short-term antiviral response, the exposure achieved with elvitegravir 50 mg boosted with 100 mg of ritonavir (AUC0–24h = 8840 ng*h/ml, 26% coefficient of variation; C24h = 135.0 ng/ml, 37% coefficient of variation) could not be achieved with twice-daily 800 mg dosing of elvitegravir alone (AUC0–24h = 3570 ng*h/ml, 37% coefficient of variation; C24h = 48.0 ng/ml, 33% coefficient of variation) [5]. Maximal boosting of elvitegravir is observed with 100 mg of ritonavir: no further reduction in apparent oral clearance occurs with 200 mg of ritonavir [6,56].

Cobicistat (Gilead Sciences, Foster City, CA, USA), a potent inhibitor of CYP3A that lacks antiviral activity and has demonstrated a favorable safety profile, is under development as a pharmacokinetic boosting agent for elvitegravir and protease inhibitors. A once-daily fixed dose Quad regimen containing elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/ tenofovir 300 mg is currently in phase 3 trials [7]. The Quad formulation has recently demonstrated 48-week noninferiority in treatment-naïve HIV-infected patients to atazanavir/ritonavir and emtricitabine/tenofovir (90 vs. 87%, respectively) and to efavirenz/emtricitabine/tenofovir (88 vs. 84%, respectively) in maintenance of viral RNA 50 copies/ml or less [57,58].

Once-daily elvitegravir has been compared directly with twice-daily raltegravir in an ongoing phase 3, randomized, double-blind, double-dummy trial of 702 treatment-experienced HIV-1 infected patients receiving a ritonavir-boosted background regimen [59▪]. Elvitegravir was found to be noninferior to raltegravir (P = 0.001) with 59 and 58% achieving the primary endpoint of maintenance of less than 50 HIV-1 RNA copies/ml through 48 weeks.

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Drug–drug interactions

It has previously been shown that ritonavir-boosted elvitegravir does not participate in clinically important drug interactions with the NNRTI etravirine, or the protease inhibitors darunavir/ritonavir, tipranavir/ritonavir, and fosamprenavir/ritonavir [37–39]. However, UGT1A1-mediated inhibition interactions between elvitegravir/ritonavir and lopinavir/ritonavir or atazanavir/ritonavir suggest that the elvitegravir dose should be reduced from 150 to 85 mg [40,42]. Consistent with this recommendation, elvitegravir 85 mg/cobicistat 150 mg co-administered with atazanavir results in comparable elvitegravir exposure with an 83% increase in C24h compared with elvitegravir 150 mg/cobicistat 150 mg [41▪]. Cobicistat-boosted elvitegravir should be administered with food for a 34 and 87% increase in AUC0–inf with low and high calorie meals, respectively [8]. Although no clinically important interaction was observed with omeprazole or famotidine, elvitegravir should be separated from aluminum and magnesium-containing antacids by 2 h [45,46]. Administration of ritonavir-boosted elvitegravir results in a 2–4-fold increase in maraviroc Cmax, AUC0–24, and C24h, and requires a 50% decrease in maraviroc dose to 150 mg [43]. Elvitegravir/ritonavir can be co-administered with rifabutin 150 mg every other day, resulting in comparable rifabutin exposure with a 5–20-fold increase in rifabutin metabolite [44]. As elviegravir C24h decreased 67.1% when elvitegravir/cobicistat was co-administered with rifabutin 150 mg every other day, this combination should be avoided [41▪]. As elvitegravir must be administered with a boosting agent, additional interactions with CYP3A substrates are likely to occur due to potent CYP3A inhibition by cobicistat or ritonavir.

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DOLUTEGRAVIR

Dolutegravir (S/GSK1349572) is a second-generation HIV integrase inhibitor in development by Shionogi and ViiV Healthcare. Dolutegravir is currently in phase 3 testing in treatment-naive and treatment-experienced patients as a once-daily and a once- or twice-daily 50 mg dose, respectively [60,61▪,62,63]. It is primarily metabolized via UGT1A1 with a minor contribution by CYP3A, and is a substrate for P-glycoprotein. Dolutegravir did not alter oral midazolam exposure, suggesting that it is not an inducer or inhibitor of CYP3A [11].

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Pharmacokinetics

Dolutegravir has a terminal half-life of approximately 12–15 h [11,12▪▪]. It does not require boosting and its favorable pharmacokinetic profile is characterized by relatively low variability (C24h, 25–26% coefficient of variation) [11,12▪▪]. Dolutegravir AUC0–24h and Cmax are slightly less than dose proportional over the range of 2–50 mg following single and multiple doses [12▪▪]. Because of the nonlinear change in Cmax and AUC seen with increasing dose, a twice-daily 50 mg regimen is being evaluated in the phase 3 ARV-experienced clinical trial rather than a once-daily 100 mg dose [12▪▪,60,62].

A monotherapy study in integrase inhibitor-naive HIV-1-infected adults demonstrated a 2.48 mean log10 reduction in HIV-1 RNA following 10 days of dolutegravir 50 mg daily [12▪▪]. This reduction was sustained 4 days after discontinuation of dolutegravir, likely due to plasma concentrations maintained above the protein adjusted IC90. Similar to elvitegravir, the exposure–response relationship is best described by incorporation of C24h into the Emax model. Overall, variability in exposure was minimal: 50 mg dosing to steady-state conditions achieved a geometric mean Cmax of 3.34 μg/ml (16% coefficient of variation), an AUC0–24h of 43.4 μg*h/ml (20% coefficient of variation), a t1/2 of 12.0 h (22% coefficient of variation), and a C24h of 0.83 μg/ml (26% coefficient of variation) [12▪▪]. A pediatric granule formulation of dolutegravir is currently in development. Preliminary data suggest that granules mixed in purified water have increased exposure compared with the tablet formulation with a geometric least-squares mean ratio (90% CI) for AUC0-inf of 1.57 (1.45–1.69) [64].

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Drug–drug interactions

The effect of food on dolutegravir pharmacokinetics has been evaluated in a single-dose crossover study [13▪]. The median Tmax increased from 2 h to 3, 4, and 5 h for low-fat, moderate-fat, and high-fat meals, respectively, suggesting that fat content of meals impacts the absorption of dolutegravir. Whereas AUC0-inf increased from 33 to 66% when taken with food, inter-individual variability was comparable with other studies [12▪▪,13▪]. These changes in exposure are not expected to impact safety or efficacy, and dolutegravir can be dosed without regard to food.

Dolutegravir AUC0-inf is reduced by greater than three-fold when co-administered with antacids. Therefore antacid administration should be delayed by at least 2 h after dolutegravir dosing. Although AUC0–24h was reduced from a geometric mean of 34.6 μg*h/ml (31% coefficient of variation) to 23.0 μg*h/ml (29% coefficient of variation) with multivitamins containing divalent cations and to 30.0 μg*h/ml (22% coefficient of variation) with omeprazole, no dolutegravir dosage adjustment is necessary [55▪].

Dolutegravir does not interact with the nucleoside reverse transcriptase inhibitor (NRTI) tenofovir, or the protease inhibitor lopinavir/ritonavir [47,50▪]. Darunavir/ritonavir reduces dolutegravir C24h from 0.77 μg/ml (29% coefficient of variation) to 0.45 μg/ml (37% coefficient of variation), and AUC0–24h from 36.9 μg*h/ml (19% coefficient of variation) to 27.3 μg*h/ml (23% coefficient of variation). However, this interaction is considered modest and clinically unimportant [50▪]. Atazanavir and atazanavir/ritonavir administration results in increased dolutegravir AUC0–24h (91 and 62%), Cmax (50 and 34%), and C24h (180 and 121%). This interaction is unlikely to impact safety and no dosage adjustment is suggested [51▪].

The interaction between dolutegravir and etravirine has also been characterized both alone and with boosted protease inhibitors. Etravirine reduced dolutegravir AUC0–24h greater than three-fold and C24h greater than 10-fold. Introduction of boosted darunavir or lopinavir to the regimen restored exposure comparable with dolutegravir alone. Etravirine should only be administered with dolutegravir if darunavir/ritonavir or lopinavir/ritonavir is included in therapy [49▪]. Efavirenz and tipranavir/ritonavir decreased dolutegravir AUC0–24 h by 57 and 59%, Cmax by 39 and 46%, and C24h by 75 and 76% [48▪]. Despite these significant reductions in exposure, the authors conclude that dolutegravir C24h remains far above the IC90, so no dosage adjustment is necessary.

Studies investigating dolutegravir interactions with the antimycobacterial agents rifampin and rifabutin have also been completed [53▪,54▪]. Rifampin 600 mg once daily administered with dolutegravir 50 mg twice daily resulted in minor increases in dolutegravir AUC0–24 h (33%) and C24h (22%) compared with dolutegravir 50 mg once-daily dosing [53▪]. This dose adjustment is not necessary with rifabutin 300 mg once daily as co-administration results in only a modest 30% decrease in dolutegravir C24h[54▪].

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INTEGRASE INHIBITOR IN CLINICAL DEVELOPMENT

S/GSK1265744, an integrase inhibitor initially evaluated in a once-daily oral formulation, is currently being developed into a novel, long-acting parenteral product. Phase 1 studies are ongoing to determine the optimal dose and frequency of administration and to gather information regarding safety and efficacy. S/GSK1265744 is being investigated for monthly to quarterly administration. This dosing strategy could lead to improved adherence and viral control in select patients, and may be amenable to prophylaxis against HIV infection [65].

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CONCLUSION

The integrase inhibitors are potent ARVs with considerably lower drug interaction potential than NNRTIs or protease inhibitors. For these reasons, as well as a mild side effect profile, raltegravir has become an agent widely used in both ARV-naïve regimens, as well as a novel agent for use in treatment-experienced patients. The emerging HIV integrase inhibitors elvitegravir and dolutegravir have many of the same advantages and potential uses as raltegravir with more favorable pharmacokinetics and dosing. Pharmacologic data are still needed in special populations (e.g. pregnancy) and to elucidate additional drug interactions.

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Acknowledgements

None.

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Conflicts of interest

The authors are supported by NIH grants U01AI095031–01 and CFAR 5P30AI050410-13.

Jessica Adams has grant support from Viiv. Angela Kashuba has grant support from Viiv, Jansen, and Gilead and has received honoraria from Merck and BMS.

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REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

▪ of special interest

▪▪ of outstanding interest

Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 487–488).

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REFERENCES

1. Markowitz M, Morales-Ramirez JO, Nguyen BY, et al. Antiretroviral activity, pharmacokinetics, and tolerability of MK-0518, a novel inhibitor of HIV-1 integrase, dosed as monotherapy for 10 days in treatment-naïve HIV-1-infected individuals. J Acquir Immune Defic Syndr 2006; 43:509–515.

2. Kassahun K, McIntosh I, Cui D, et al. Metabolism and disposition in humans of raltegravir (MK-0518), an anti-AIDS drug targeting the human immunodeficiency virus 1 integrase enzyme. Drug Metab Dispos 2007; 35:1657–1663.

3. Isentress [package insert]. Whitehouse Station, NJ: Merck & Co. Inc.; 2011.

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5. DeJesus E, Berger D, Markowitz M, et al. Antiviral activity, pharmacokinetics, and dose response of the HIV-1 integrase inhibitor GS-9137 (JTK-303) in treatment-naive and treatment-experienced patients. J Acquir Immune Defic Syndr 2006; 43:1–5.

6. Mathias AA, West S, Hui J, et al. Dose-response of ritonavir on hepatic CYP3A activity and elvitegravir oral exposure. Clin Pharmacol Ther 2009; 85:64–70.

7. German P, Warren D, West S, et al. Pharmacokinetics and bioavailability of an integrase and novel pharmacoenhancer-containing single-tablet fixed-dose combination regimen for the treatment of HIV. J Acquir Immune Defic Syndr 2010; 55:323–329.

8. German P, Warren D, Wei L, et al. Effect of food on pharmacokinetics of elvitegravir, emtricitabine, tenofovir DF and the pharmacoenhancer GS-9350 as a fixed-dose combination tablet. 49th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 12–15, 2009; San Francisco, CA. Poster A1-1300.

9. German P, Wei X, Mizuno V, et al. Pharmacokinetics of elvitegravir and cobicistat in subjects with severe renal impairment. 13th International Workshop on Clinical Pharmacology of HIV Therapy; April 16–18, 2012; Barcelona, Spain. Abstract P_38.

10. Ramanathan S, Rhee M, Shen G, et al. Pharmacokinetics and safety of boosted-elvitegravir in subjects with hepatic impairment. 13th International Workshop on Clinical Pharmacology of HIV Therapy; April 16–18, 2012; Barcelona, Spain. Abstract P_40.

11. Min S, Song I, Borland J, et al. Pharmacokinetics and safety of S/GSK1349572, a next-generation HIV integrase inhibitor, in healthy volunteers. Antimicrob Agents Chemother 2010; 54:254–258.

12▪▪. Min S, Sloan L, DeJesus E, et al. Antiviral activity, safety, and pharmacokinetics/pharmacodynamics of dolutegravir as 10-day monotherapy in HIV-1-infected adults. AIDS 2011; 25:1737–1745.

This study provides a comprehensive evaluation of dolutegravir pharmacokinetics, inter-patient variability, and pharmacodynamics following multiple doses.

13▪. Song I, Borland J, Chen S, et al. Effect of food on the pharmacokinetics of the integrase inhibitor dolutegravir. Antimicrob Agents Chemother 2012; 56:1627–1629.

This study concluded that although food results in higher dolutegravir exposure, this change is unlikely to alter safety or efficacy.

14. Song I, Borland J, Savina P, et al. Pharmacokinetics of dolutegravir in subjects with moderate hepatic impairment. 19th Conference on Retroviruses and Opportunistic Infections; March 5–8, 2012; Seattle, WA. Paper #608.

15▪. Cattaneo D, Gervasoni C, Meraviglia P, et al. Inter- and intra-patient variability of raltegravir pharmacokinetics in HIV-1 infected subjects. J Antimicrob Chemother 2012; 67:460–464.

HIV-infected patients on a regimen containing raltegravir had raltegravir concentrations measured over 4 h at two consecutive visits and showed highly variable pharmacokinetics both between patients and within the same patients on different days.

16▪▪. Eron JJ, Rockstroh JK, Reynes J, et al. Raltegravir once daily or twice daily in previously untreated patients with HIV-1: a randomized, active-controlled, phase 3 noninferiority trial. Lancet Infect Dis 2011; 11:907–915.

Raltegravir 800 mg once daily produced virologic response rates of 83% compared with 89% for raltegravir 400 mg twice daily, but the time to achieve confirmed virologic response was longer in the once-daily group and there were lower response rates for patients with baseline viral loads above 100 000 copies/ml or with CD4 cell counts below 200 cells/ul. The authors concluded that raltegravir 800 mg once daily cannot be recommended in place of 400 mg twice daily.

17. Nachman S, Samson P, Acosta E, et al. Pharmacokinetic (PK), safety, and efficacy data on cohort IIA: youth aged 6 to 11 years from IMPAACT P1066: a phase I/II study to evaluate raltegravir (RAL) in HIV-1 infected youth. 17th Conference on Retroviruses and Opportunistic Infections; Feb 16–19, 2010; San Francisco, CA. Paper #873.

18. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. October 14, 2011; 1–167. Available at http://http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed March 2012.

19. Brainard DM, Gendrano IN, Jin B, et al. A pharmacologic comparison of adult and pediatric formulations of raltegravir (RAL) in healthy adults. 17th Conference on Retroviruses and Opportunistic Infections; February 16–19, 2010; San Francisco, CA. Paper #872.

20. Wenning LA, Hanley WD, Brainard DM, et al. Effect of rifampin, a potent inducer of drug-metabolizing enzymes, on the pharmacokinetics of raltegravir. Antimicrob Agents Chemother 2009; 53:2852–2856.

21. Iwamoto M, Wenning LA, Petry AS, et al. Atazanavir modestly increases plasma levels of raltegravir in healthy subjects. Clin Infect Dis 2008; 47:137–140.

22▪. Jackson A, Watson V, Back D, et al. Plasma and intracellular pharmacokinetics of darunavir/ritonavir once daily and raltegravir once and twice daily in HIV-1 infected individuals. J Acquir Immune Defic Syndr 2011; 58:450–457.

The interaction between raltegravir and darunavir was assessed in HIV-positive patients on an ARV regimen. Overall, no remarkable interactions were seen between raltegravir and darunavir.

23▪. Goldwirt L, Braun J, de Castro N, et al. Switch from enfuvirtide to raltegravir lowers plasma concentrations of darunavir and tipranavir: a pharmacokinetic substudy of the EASIER-ANRS 138 trail. Antimicrob Agents Chemother 2011; 55:3613–3615.

The concentrations of darunavir and tipranavir were measured in HIV-infected patients before and after switching from enfuvirtide to raltegravir. AUC, trough concentrations, and Cmax were decreased for both darunavir and tipranavir, but the clinical impact of those decreases is unknown.

24. Hanley WD, Wenning LA, Moreau A, et al. Effect of tipranavir-ritonavir on pharmacokinetics of raltegravir. Antimicrob Agents Chemother 2009; 53:2752–2755.

25▪. Vourvahis M, Langdon G, LaBadie RR, et al. Pharmacokinetic effects of coadministration of lersivirine with raltegravir or maraviroc in healthy subjects. Antimicrob Agents Chemother 2012; 56:887–892.

The concentration changes of raltegravir when co-administered with lersivirine were measured at steady state. Clinically nonsignificant decrease in mean AUC and Cmax were observed, and increase in mean trough concentrations.

26. Crauwels H, Stevens M, De La Rosa G, Boven K. Absence of pharmacokinetic interaction between the NNRTI rilpivirine (TMC278) and the integrase inhibitor raltegravir. 19th Conference on Retroviruses and Opportunistic Infections; Mar 5–8 2012; Seattle, WA. Paper #617.

27. HIV and Viral Hepatitis. Center for Disease Control and Prevention. Atlanta, GA. Available from: http://http://www.cdc.gov/hiv/resources/factsheets/hepatitis.htm. Last Updated 17 Nov 2011. Accessed March 2012.

28▪. Ashby J, Garvey L, Erlwein OW, et al. Pharmacokinetic and safety profile of raltegravir and ribavirin, when dosed separately and together, in healthy volunteers. J Antimicrob Chemother 2011; 66:1340–1345.

The interaction between raltegravir and ribavirin was assessed in healthy volunteers. No significant differences in the pharmacokinetic parameters of raltegravir were observed, but the ribavirin Cmax was decreased and Tmax increased.

29▪. de Kanter C, Blonk M, Colbers A, et al. The influence of the HCV protease inhibitor bocepravir on the pharmacokinetics of the HIV integrase inhibitor raltegravir. 19th Conference on Retroviruses and Opportunistic Infections; Mar 5–8, 2012; Seattle, WA. Paper #772LB.

The interaction between bocepravir and raltegravir was assessed in healthy individuals and bocepravir was not found to affect raltegravir exposure.

30▪. van Heeswijk R, Garg V, Boogaerts G, et al. The pharmacokinetic interaction between telaprevir and raltegravir in healthy volunteers. 51st Interscience Conference on Antimicrobial Agents and Chemotherapy; Se 17–20, 2012; Chicago, IL. LB A1-1738a.

The interaction between telaprevir and raltegravir was studied in health volunteers and a clinically insignificant increase in raltegravir exposures was observed.

31. Reinbach B, de Sousa G, Dostert P, et al. Comparative effects of rifabutin and rifampicin on cytochromes P450 and UDP-glucuronosyl-transferases expression in fresh and cryopreserved human hepatocytes. Chem Biol Interact 1999; 121:37–48.

32▪. Brainard DM, Kassahun K, Wenning LA, et al. Lack of a clinically meaningful pharmacokinetic effect of rifabutin on raltegravir: in vitro/in vivo correlation. J Clin Pharmacol 2011; 51:943–950.

Rifabutin was not found to alter raltegravir pharmacokinetics to a clinically meaningful extent in vivo.

33. Wenning LA, Friedman EJ, Kost JT, et al. Lack of a significant drug interaction between raltegravir and tenofovir. Antimicrob Agents Chemother 2008; 52:3253–3258.

34. Kiser JJ, Bumpass JB, Meditz AL, et al. Effect of antacids on the pharmacokinetics of raltegravir in human immunodeficiency virus-seronegative volunteers. Antimicrob Agents Chemother 2010; 54:4999–5003.

35. Ramanathan R, Shen G, Hinkle J, et al. Pharmacokinetics of coadministered ritonavir-boosted elvitegravir and zidovudine, didanosine, stavudine, or abacavir. J Acquir Immune Defic Syndr 2007; 46:160–166.

36. Ramanathan S, Shen G, Cheng A, et al. Pharmacokinetics of emtricitabine, tenofovir, and GS-9137 following coadministration of emtricitabine/tenofovir disoproxil fumarate and ritonavir-boosted GS-9137. J Acquir Immune Defic Syndr 2007; 45:274–279.

37. Ramanathan S, Kakuda TN, Mack R, et al. Pharmacokinetics of elvitegravir and etravirine following coadministration of ritonavir-boosted elvitegravir and etravirine. Antivir Ther 2008; 13:1011–1017.

38. Mathias AA, Hinkle J, Shen G, et al. Effect of ritonavir-boosted tipranavir or darunavir on the steady-state pharmacokinetics of elvitegravir. J Acquir Immune Defic Syndr 2008; 49:156–162.

39. Ramanathan S, Mathias AA, Shen G, et al. Lack of clinically relevant drug–drug interaction between ritonavir-boosted GS-9137 (elvitegravir) and fosamprenavir/r. 4th IAS Conference on HIV Pathogenesis, Treatment, and Prevention; July 22–25, 2007; Sydney, Australia. Abstract WEPEB014.

40. Mathias A, Ramanathan S, Hinkle J, et al. Effect of atazanavir/r on the steady state pharmacokinetics of elvitegravir. 47th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 17–20, 2007; Chicago, IL. Abstract A-1417.

41▪. Ramanathan S, Wang H, Stondell T, et al. Pharmacokinetics and drug interaction profile of cobicistat boosted-EVG with atazanavir, rosuvastatin or rifabutin. 13th International Workshop on Clinical Pharmacology of HIV Therapy; Apr 16–18, 2012; Barcelona, Spain. Abstract O_03.

Co-administration of rifabutin and cobicistat-boosted elvitegravir resulted in trough concentrations lower than those expected from data with rifabutin and ritonavir-boosted elvitegravir. This study also assessed pharmacokinetics for elvitegravir/cobicistat administered with atazanavir or rosuvastatin.

42. Mathias A, Ramanathan S, Hinkle J, et al. A pharmacokinetic interaction between lopinavir/r and elvitegravir. 47th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 17–20, 2007; Chicago, IL. Abstract A-1418.

43. Ramanathan S, Abel S, Tweedy S, et al. Pharmacokinetic interaction of ritonavir-boosted elvitegravir and maraviroc. J Acquir Immune Defic Syndr 2010; 53:209–214.

44. German P, West S, Hui J, et al. Pharmacokinetic interaction between elvitegravir/ritonavir and dose-adjusted rifabutin. 9th International Workshop on Clinical Pharmacology of HIV Therapy; April 7–9, 2008; New Orleans, LA. Abstract P19.

45. Ramanathan S, Shen G, Hinkle J. Pharmacokinetic evaluation of drug interactions with ritonavir-boosted HIV integrase inhibitor GS-9137 (elvitegravir)and acid-reducing agents. 8th International Workshop on Clinical Pharmacology of HIV Therapy; April 16–18, 2007; Budapest, Hungary. Abstract 69.

46. Mathias A, Koziara J, Wei L, et al. Effect of acid reducing agents on the relative bioavailability and pharmacokinetics of cobicistat-boosted elvitegravir. 12th International Workshop on Clinical Pharmacology of HIV Therapy; April 13–15, 2011; Miami, FL. Abstract P_13.

47. Song I, Min SS, Borland J, et al. Lack of interaction between the HIV integrase inhibitor S/GSK1349572 and tenofovir in healthy subjects. J Acquir Immune Defic Syndr 2010; 55:365–367.

48▪. Song I, Borland J, Lou Y, et al. Effects of enzyme inducers, tipranavir and efavirenz, on the pharmacokinetics of the integrase inhibitor, dolutegravir (S/GSK1359572). 12th International Workshop on Clinical Pharmacology of HIV Therapy; April 13–15, 2011; Miami, FL. Abstract O_02.

Although significant decreases in dolutegravir exposure are observed with both tipranavir and efavirenz, dolutegravir trough concentrations remain multi-fold above the IC90.

49▪. Song I, Borland J, Min S, et al. Effects of etravirine alone and with ritonavir-boosted protease inhibitors on the pharmacokinetics of dolutegravir. Antimicrob Agents Chemother 2011; 55:3517–3521.

This article explains the clinically important interaction between etravirine and dolutegravir and rescue of dolutegravir's pharmacokinetic profile by co-administration of boosted protease inhibitors.

50▪. Song I, Min SS, Borland J, et al. The effect of lopinavir/ritonavir and darunavir/ritonavir on the HIV integrase inhibitor S/GSK1349572 in healthy participants. J Clin Pharmacol 2011; 51:237–242.

This study provides evidence that dolutegravir does not participate in clinically important interactions with the protease inhibitors lopinavir/ritonavir and darunavir/ritonavir.

51▪. Song I, Borland J, Chen S, et al. Effect of atazanavir and atazanavir/ritonavir on the pharmacokinetics of the next-generation HIV integrase inhibitor, S/GSK1349572. Br J Clin Pharmacol 2011; 72:103–108.

Although the investigators observed significant increases in dolutegravir exposure with atazanavir and atazanavir/ritonavir, likely due to UGT inhibition, they conclude that these changes are unlikely to negatively impact therapy.

52. Song I, Borland J, Chen S, et al. Effect of fosamprenavir/ritonavir on the pharmacokinetics of the integrase inhibitor, dolutegravir, in healthy subjects. 51st Interscience Conference on Antimicrobial Agents and Chemotherapy; September 17–20, 2011; Chicago, IL. Abstract A1-1727.

53▪. Dooley KE, Purdy E, Sayre P, et al. Safety, tolerability, and pharmacokinetics of the HIV integrase inhibitor dolutegravir given twice daily with rifampin: results of a Phase I study among healthy subjects. 19th Conference on Retroviruses and Opportunistic Infections; March 5–8, 2012; Seattle, WA. Paper #148.

This abstract provides evidence for increased dolutegravir dosing frequency when administered with rifampin.

54▪. Dooley KE, Sayre P, Borland J, et al. Pharmacokinetics, safety, and tolerability of the HIV integrase inhibitor dolutegravir co-administered with rifabutin in healthy subjects. 13th International Workshop on Clinical Pharmacology of HIV Therapy; April 16–18, 2012; Barcelona, Spain. Abstract P_11.

Rifabutin can be co-administered with dolutegravir without dose adjustment, despite a 30% decrease in dolutegravir trough concentration.

55▪. Patel P, Song I, Borland J, et al. Pharmacokinetics of the HIV integrase inhibitor S/GSK1349572 co-administered with acid-reducing agents and multivitamins in healthy volunteers. J Antimicrob Chemother 2011; 66:1567–1572.

This article highlights the clinically important interaction between antacids and dolutegravir.

56. Ramanathan S, Mathias AA, Hinkle J, Kearney BP. Clinical pharmacology of the HIV integrase inhibitor elvitegravir. 11th European AIDS Conference; October 24–27, 2007; Madrid, Spain. Abstract PS4/7.

57. DeJesus E, Rockstroh J, Henry K, et al. Week 48 results of an ongoing phase 3 study comparing elvitegravir/cobicistat/emtricitabine/tenofovir (Quad) with atazanavir/ritonavir plus emtricitabine/tenofovir in treatment-naïve HIV-1+ subjects showing efficacy, safety, and pharmacokinetics. 19th Conference on Retroviruses and Opportunistic Infections; March 5–8, 2012; Seattle, WA. Paper #627.

58. Sax P, DeJesus E, Millis A, et al. Elvitegravir/cobicistat/emtricitabine/tenofovir (Quad) has noninferior efficacy and favorable safety compared to efavirenz/emtricitabine/tenofovir in treatment-naïve HIV-1+ subjects. 19th Conference on Retroviruses and Opportunistic Infections; March 5–8, 2012; Seattle, WA. Paper #101.

59▪. Molina JM, Lamarca A, Andrade-Villanueva J, et al. Efficacy and safety of once daily elvitegravir versus twice daily raltegravir in treatment-experienced patients with HIV-1 receiving a ritonavir-boosted protease inhibitor: randomised, double-blind, phase 3, noninferiority study. Lancet Infect Dis 2012; 12:27–35.

This phase 3 clinical trial evaluates the safety and efficacy of once-daily ritonavir-boosted elvitegravir with raltegravir as an active comparator.

60. Soriano V, Cox J, Eron JJ, et al. Dolutegravir (DTG, s/GSK1349572) treatment of subjects with raltegravir (RAL) resistance: viral suppression at week 24 in VIKING study. 13th European AIDS Conference; October 12–15, 2011; Belgrade, Serbia. Abstract PS1/2.

61▪. van Lunzen J, Maggiolo F, Arribas JR, et al. Once daily dolutegravir (S/GSK1349572) in combination therapy in antiretroviral-naive adults with HIV: planned interim 48 week results from SPRING-1, a dose-ranging, randomised, phase 2b trial. Lancet Infect Dis 2012; 12:111–118.

This phase 3 clinical trial provides evidence for the efficacy and safety of dolutegravir in treatment-naïve patients.

62. Eron JJ, Kumar P, Lazzarin A, et al. DTG in subjects with HIV exhibiting RAL resistance: functional monotherapy results of VIKING study cohort II. 18th Conference on Retroviruses and Opportunistic Infections; Feb 27–Mar 2, 2011; Boston, MA. Paper #151LB.

63. Stellbrink HJ, Reynes J, Lazzarin A, et al. Dolutegravir in combination therapy exhibits rapid and sustained antiviral response in ARV-naive adults: 96-week results from SPRING-1 (ING112276). 19th Conference on Retroviruses and Opportunistic Infections; March 5–8, 2012; Seattle, WA. Paper #102LB.

64. Patel P, Song I, Borland J, et al. Pharmacokinetics of a dolutegravir pediatric granule formulation in healthy adult subjects. 19th Conference on Retroviruses and Opportunistic Infections; March 5–8, 2012; Seattle, WA. Paper #985.

65. Protocol Summaries: GSK1265744 [Internet]. 2012 [cited 2012 May 31]. Available from: http://http://www.gskclinicalstudyregister.com/protocol_comp_list.jsp;jsessionid = 02043C0461BBAF033065BDD0C951F31C?compound=Gsk1265744.

Keywords:

dolutegravir; elvitegravir; HIV integrase inhibitors; raltegravir

© 2012 Lippincott Williams & Wilkins, Inc.

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