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The purpose of this paper is to review recent and relevant pharmacology data for three HIV integrase inhibitors: raltegravir (marketed), dolutegravir and elvitegravir (both in Phase III drug development).
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- and intra-patient pharmacokinetic variability is high. Twice daily 400mg dosing has been shown to be clinically superior to 800mg once daily dosing. A pediatric formulation of raltegravir with less variable pharmacokinetics and greater bioavailability was 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, while boosted elvitegravir participates in additional CYP3A mediated interactions.
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.
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 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.
Raltegravir is dosed at 400mg twice daily. In 35 HIV positive, treatment naïve subjects given 100, 200, 400, or 600mg of raltegravir or placebo twice daily for 10 days, raltegravir was found to be potent and safe throughout the range of doses . The C12h (or “trough” concentration) geometric mean plasma concentrations at all doses exceeded 33nM, the mean in vitro IC95 for wild-type virus . Raltegravir is metabolized by glucuronidation primarily by uridine glucuronosyl transferase (UGT) 1A1 . 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.
Raltegravir has a high level of intra- and inter-patient pharmacokinetic variability. In a study of 15 HIV-infected patients , raltegravir area under the concentration time curve from 0–12hours (AUC 0–12h) 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.
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 non-inferiority study comparing raltegravir 800mg once daily to raltegravir 400mg twice daily in combination with tenofovir and emtricitabine in 775 HIV patients with HIV RNA ≥ 5000 copies/ml . After 48 weeks, once daily dosing of 800mg 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 >100,000 copies/ml or CD4 counts <200 cells/mm3 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-blind, 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 form the QDMRK study found the AUC to be similar between once and twice daily dosing groups (least-squares mean (CV %) of 30.87 (70) versus 13.14 (99) with a geometric mean ratio (90% 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 (CV %) of 40(111) versus 257(167) with a geometric mean ratio (90% CI) of 0.15(0.09–0.26).
In December 2011, the FDA approved two new dosages of chewable tablets (100mg and 25mg) for pediatric populations. The approval was supported by a preliminary data analysis of the currently-ongoing IMPAACT P1066 trial in which either the 400mg film-coated tablets were given to HIV positive children 6 to 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 to 11 years receiving the chewable tablets were analyzed to determine a pediatric dosing recommendation . At 6mg/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) . When compared to the adult dosage form, the pharmacokinetic variability (expressed as CV%) was significantly less for the chewable tablets: variability in AUC was 34% (compared to 120%) and variability in C12h was 84% (compared to 221%). The chewable tablets also have an overall increased bioavailability compared to the film-coated tablets with a 1.8-fold increase in AUC and a 3.2-fold higher Cmax .
Raltegravir does not have the substantial drug-drug interaction potential of many other antiretrovirals 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 . Conversely, the UGT1A1 inhibitor atazanavir increased raltegravir’s AUC by 72% .
Raltegravir interactions with protease inhibitors have been explored. The pharmacokinetics of raltegravir twice daily combined with darunavir/ritonavir once daily was investigated in 24 HIV positive patients both in plasma and at the intracellular site of action . This study found no remarkable interactions between either in plasma or intracellularly, with AUC geometric mean ratios (90% CI) of 1.24 (1.13 to 1.45) for plasma darunavir, and 0.90 (0.73 to 1.44) for plasma raltegravir. A recent pharmacokinetic substudy of the EASIER-ANRS 138 Trial measured tipranavir and darunavir concentrations in 20 HIV positive subjects at steady state before and after switching from efuvirtide to raltegravir . The geometric mean ratios (90% CI) for tipranavir C12h, Cmax, and AUC were 0.49 (0.42 to 0.56), 0.76 (0.63 to 0.92), and 0.67 (0.55 to 0.82). The geometric mean ratios (90% CI) for darunavir C12h, Cmax, and AUC were 0.82 (0.61 to 1.10), 0.68 (0.59 to 0.79), and 0.64 (0.53 to 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 PI 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 .
Lersivirine, an 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 . Additionally, the NNRTI rilprivirine was studied and also found to have little effect on the concentrations of raltegravir when used in combination .
Hepatitis C co-infection occurs in about 25% of HIV infected patients in the United States . With a lower drug interaction potential than other antiretrovirals, 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 dose separately and together . 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 to 1.00)) and an increase in Tmax (GMR (95% CI) = 1.39 (1.08 to 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. Geometric mean ratios (90% CI) for raltegravir AUC and Cmax were 1.01 (0.85 to 1.20) and 1.09 (0.89 to 1.33), respectively when given with bocepravir . When given with telaprevir, least squares mean ratios (90% CI) for raltegravir AUC, Cmax, and Cmin were increased 1.31 (1.03 to 1.67), 1.26 (0.97 to 1.62), and 1.78 (1.26 to 2.53), respectively .
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 DHHS 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 . In 19 healthy participants, raltegravir was given at 400mg twice daily for four days alone, then with rifabutin 300mg daily for 14 days. The geometric mean ratio of the AUC of raltegravir plus rifabutin versus raltegravir alone (90% confidence interval) was 1.19 (0.86 to 1.63), the C12h ratio was 0.80 (0.68 to 0.94), and the Cmax ratio was 1.39 (0.87 to 2.21). Based on 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 coadministered agents is provided in Table 2.
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]. 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 .
Elvitegravir has an elimination half-life of approximately 3 hours when dosed alone and 9 hours when dosed with ritonavir 100 mg . 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 .
An early 10 day monotherapy study in both treatment-experienced and treatment-naive subjects 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 boosted by ritonavir 100 mg . 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 %CV; C24h = 135.0 ng/mL, 37 %CV) could not be achieved with twice daily 800 mg dosing of elvitegravir alone (AUC0–24h = 3570 ng*h/mL, 37 %CV; C24h = 48.0 ng/mL, 33 %CV) . 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], 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 . The Quad formulation has recently demonstrated 48 week non-inferiority in treatment naïve HIV-infected patients to atazanavir/ritonavir plus emtricitabine/tenofovir (90% vs. 87%, respectively) and to efavirenz/emtricitabine/tenofovir (88% vs. 84%, respectively ) in maintenance of viral RNA ≤ 50 copies/mL [57,58].
Once daily elvitegravir has been compared directly to 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 . Elvitegravir was found to be non-inferior to raltegravir (p=0.001) with 59% and 58% achieving the primary endpoint of maintenance of <50 HIV-1 RNA copies/mL through 48 weeks.
It has previously been shown that ritonavir-boosted elvitegravir does not participate in clinically important drug interactions with the NNRTI etravirine, or the PIs darunavir/ritonavir, tipranavir/ritonavir, and fosamprenavir/ritonavir [37,38,39]. However, UGT1A1-mediated inhibition interactions between elvitegravir/ritonavir and lopinavir/ritonavir or atazanavir/ritonavir suggest that the elvitegravir dose should be reduced from 150 mg to 85 mg [40,42]. Consistent with this recommendation, elvitegravir 85 mg/cobicistat 150 mg coadministered with atazanavir results in comparable elvitegravir exposure with an 83% increase in C24h compared to elvitegravir 150mg/cobicistat 150 mg . Cobicistat boosted elvitegravir should be administered with food for a 34% and 87% increase in AUC0-inf with low and high calorie meals, respectively . Although no clinically important interaction was observed with omeprazole or famtotidine, elvitegravir should be separated from aluminum and magnesium containing antacids by two hours [45,46]. Administration of ritonavir-boosted elvitegravir results in a 2 to 4 fold increase in maraviroc Cmax, AUC0–24, and C24h, and requires a 50% decrease in maraviroc dose to 150 mg . Elvitegravir/ritonavir can be coadministered with rifabutin 150 mg every other day, resulting in comparable rifabutin exposure with a 5 to 20 fold increase in rifabutin metabolite . As elvitegravir C24h decreased 67.1% when elvitegravir/cobicistat was coadministered with rifabutin 150 mg every other day, this combination should be avoided . Since 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.
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 subjects as a once daily and a once or twice daily 50 mg dose, respectively [60–63]. 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 .
Dolutegravir has a terminal half-life of approximately 12 to 15 hours [11,12]. It does not require boosting and its favorable pharmacokinetic profile is characterized by relatively low variability (C24h, 25–26 %CV) [11,12]. Dolutegravir AUC0–24h and Cmax are slightly less than dose proportional over the range of 2 to 50 mg following single and multiple doses . Because of the decrease 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 single daily 100 mg dose .
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 . 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 %CV), an AUC0–24h of 43.4 μg*h/mL (20 %CV), a t1/2 of 12.0 h (22 %CV) and a C24h of 0.83 μg/mL (26 %CV) . A pediatric granule formulation of dolutegravir is currently in development. Preliminary data suggests that granules mixed in purified water have increased exposure compared to the tablet formulation with a geometric least squares mean ratio (90% CI) for AUC0-inf of 1.57 (1.45 to 1.69) .
The effect of food on dolutegravir pharmacokinetics has been evaluated in a single-dose crossover study . The median Tmax increased from 2 h to 3 h, 4 h, and 5 h for low-fat, moderate-fat, and high-fat meals, respectively, suggesting that fat content of meals impacts the absorption of dolutegravir. While AUC0-inf increased 33% to 66% when taken with food, inter-individual variability was comparable to 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 3-fold when coadministered with antacids. Therefore antacid administration should be delayed by at least 2 hours after dolutegravir dosing. Although AUC0–24h was reduced from a geometric mean of 34.6 μg*h/mL (31 %CV) to 23.0 μg*h/mL (29 %CV) with multivitamins containing divalent cations and to 30.0 μg*h/mL (22 %CV) with omeprazole, no dolutegravir dosage adjustment is necessary .
Dolutegravir does not interact with the NRTI tenofovir, or the PI lopinavir/ritonavir [47,50]. Darunavir/ritonavir reduces dolutegravir C24h from 0.77 μg/mL (29 %CV) to 0.45 μg/mL (37 %CV), and AUC0–24h from 36.9 μg*h/mL (19 %CV) to 27.3 μg*h/mL (23 %CV). However, this interaction is considered modest and clinically unimportant . 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 .
The interaction between dolutegravir and etravirine has also been characterized both alone and with boosted protease inhibitors. Etravirine reduced dolutegravir AUC0–24h greater than 3-fold and C24h greater than 10-fold. Introduction of boosted darunavir or lopinavir to the regimen restored exposure comparable to dolutegravir alone. Etravirine should only be administered with dolutegravir if darunavir/ritonavir or lopinavir/ritonavir is included in therapy . Efavirenz and tipranavir/ritonavir decreased dolutegravir AUC24 by 57% and 59%, Cmax by 39% and 46%, and C24h by 75% and 76% . 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 anti-mycobacterial agents, rifampin and rifabutin, have also been completed. Rifampin 600 mg once daily administered with dolutegravir 50 mg twice daily resulted in minor increases in dolutegravir AUC24h (33%) and C24h (22%) compared to dolutegravir 50 mg once daily dosing . This dose adjustment is not necessary with rifabutin 300 mg once daily since coadministration results in only a modest 30% decrease in dolutegravir C24h .
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 .
The integrase inhibitors are potent antiretrovirals with considerably lower drug interaction potential than non-nucleoside reverse transcriptase inhibitors or protease inhibitors. For these reasons, as well as a mild side effect profile, raltegravir has become an agent widely used in both antiretroviral 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 (eg pregnancy) and to elucidate additional drug interactions.
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.
Jessica L Adams, University of North Carolina at Chapel Hill, Eshelman School of Pharmacy, Chapel Hill, NC 27599-7569.
Benjamin N Greener, University of North Carolina at Chapel Hill, Eshelman School of Pharmacy, Chapel Hill, NC 27599-7569.
Angela DM Kashuba, 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, TEL: 919-966-9998 FAX: 919-962-0644.