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Pharmacokinetics of Coadministered Ritonavir-Boosted Elvitegravir and Zidovudine, Didanosine, Stavudine, or Abacavir

Ramanathan, Srinivasan PhD; Shen, Gong PhD; Hinkle, John PhD; Enejosa, Jeffrey MD; Kearney, Brian P PharmD

JAIDS Journal of Acquired Immune Deficiency Syndromes: October 1st, 2007 - Volume 46 - Issue 2 - p 160-166
doi: 10.1097/QAI.0b013e318151fd9a
Clinical Science
Free
SDC

Objective: To evaluate the potential for clinically relevant drug interactions between ritonavir-boosted elvitegravir (EVG/r) and the nucleoside reverse transcriptase inhibitors (NRTIs) zidovudine (ZDV), didanosine (ddI), stavudine (d4T), or abacavir (ABC) upon coadministration.

Methods: In 3 studies, healthy subjects were administered a single dose of ddI, d4T, or ABC, or multiple doses of ZDV, followed by multiple doses of EVG/r alone and together with an NRTI; pharmacokinetics (PK) of EVG and NRTIs were evaluated after individual administration and coadministration. Lack of PK alteration bounds (90% confidence intervals [CI]) for the NRTIs were based on the lack of PK-based dose adjustments per prescribing information.

Results: Twenty-four of 28, 32/32, and 24/26 subjects completed the ZDV-EVG/r, ddI/d4T-EVG/r, and ABC-EVG/r studies, respectively. All study drugs were well tolerated and no serious adverse events were noted. The PK of ZDV, its glucuronide (G-ZDV), d4T, ABC, and EVG were within the lack of PK alteration 90% CI bounds upon coadministration. Exposures of ddI were modestly (∼15%) lower, but these changes are unlikely to be clinically meaningful.

Conclusions: There are no clinically relevant drug interactions between EVG/r and the NRTIs zidovudine, didanosine, stavudine, or abacavir. These agents can be coadministered without dose adjustment.

From Gilead Sciences, Foster City, CA.

Received for publication May 4, 2007; accepted July 13, 2007.

Financial support for the clinical studies discussed in this manuscript was provided by Gilead Sciences, Inc.

The results of these studies were presented in part at the XVI International AIDS Conference, Toronto, Canada, August 13-18, 2006, and Eighth International Workshop on Clinical Pharmacology of HIV Therapy, Budapest, Hungary, April 16-18, 2007.

Informed consent was obtained from all subjects. This study was performed in compliance with current Good Clinical Practice (GCP) and was conducted by MDS Pharma Services, Phoenix, AZ, under the review of the MDS Pharma Services Institutional Review Board (IRB), whose operations are in compliance with Section 56 of Title 21 of the Code of Federal Regulations (CFR).

Correspondence to: Srinivasan Ramanathan, PhD, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404 (e-mail: sramanathan@gilead.com).

Despite tremendous progress over the past decade with newer therapeutic agents, the hazard ratio for mortality is estimated to be 2-fold greater for HIV-infected patients with triple-class-resistant virus compared to those resistant to a single class of antiretrovirals (ARVs).1-3 Strategies based on patient-specific treatments are recommended;4 however, the challenges of correctly interpreting resistance data5 and identifying the underlying causes of drug resistance and treatment failure preclude durable antiviral responses despite the use of optimized regimens in heavily pretreated patients.6 Indeed, data from the RESIST-1/RESIST-2 and POWER 1/POWER 2 studies indicated that treatment responses in patients receiving ritonavir-boosted comparator protease inhibitor (CPI/r) + optimized background regimen (OBR) were more than 2-fold and 4-fold lower, respectively, compared to those receiving tipranavir/r + OBR and darunavir/r + OBR.7-9 However, treatment responses with the newer agent (active arm) were diminished in the presence of multiple resistance-associated mutations, and specifically for tipranavir/r, <25% of patients overall achieved HIV RNA <50 copies/mL. These data highlight the need for new ARVs, particularly in novel drug classes, that are safe and efficacious, are not cross-resistant with ARV drugs from other classes, have desirable PK profiles that allow for once-daily dosing, and display minimal or easily managed clinical drug interactions.

Elvitegravir (GS-9137; EVG) is an HIV-1 integrase inhibitor that selectively and potently inhibits (protein binding-adjusted IC50 = 16 nmol/L) integration of viral DNA into the host chromosomal DNA. In a 10-day monotherapy study in treatment-naive and treatment-experienced HIV patients, EVG demonstrated potent exposure-dependent antiviral activity (mean reductions up to 2 log10 copies/mL) was well tolerated, and its antiviral response was best predicted by the plasma concentration at the end of the dosing interval (Cmin; Cτ).10 EVG undergoes metabolism primarily by cytochrome (CYP) P450-mediated oxidation (CYP3A4/5) and secondarily by glucuronidation (uridine glucuronosyltransferase [UGT] 1A1 and 1A3), producing corresponding metabolites M1 and M4. The M1 and M4 metabolites are markedly less potent than the parent drug (M1 by 5- to 18-fold and M4 by 10- to 38-fold in antiviral activity assays [data on file at Gilead Sciences, Foster City, CA]) and not present in plasma at substantial levels, and thus are not considered to contribute to the antiviral activity of EVG. Once-daily administration of EVG with low-dose ritonavir results in net inhibition of EVG metabolism in addition to a marked enhancement of exposure (∼20-fold) by a combination of enhanced oral bioavailability and reduced systemic clearance.11 Data from an ongoing randomized, active-controlled, dose-ranging, phase 2, 48-week study in HIV-infected treatment-experienced patients demonstrated that a 125 mg dose of ritonavir-boosted EVG was superior to a regimen (selected using resistance testing) of ritonavir-boosted comparator protease inhibitors (CPI/r) based on time-averaged change in viral load (DAVG) at 16 weeks (P = 0.01) and 24 weeks (P = 0.02) of treatment with a nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) ± T-20 OBR (DAVG24 mean log10 copies/mL, EVG: −1.7 versus CPI/r: −1.2).12 In addition, EVG was generally well tolerated, with no dose relationship observed for treatment-emergent grade 3 or grade 4 adverse events (AEs) or laboratory abnormalities, and fewer discontinuations due to AEs compared to the CPI/r arm. As an agent from a new therapeutic class with potent antiviral activity, a favorable emerging safety profile, and a simple once-daily dosing schedule to support regimen adherence, ritonavir-boosted EVG (EVG/r) offers tremendous potential, when given in combination with other ARVs, for the treatment of multiple-class-experienced HIV-infected patients.

Because they represent the first class of clinically approved ARVs, the most experience exists for NRTIs, with 2 agents from this class being established as the recommended ART backbone since the advent of highly active antiretroviral therapy (HAART) in treatment-naive and treatment-experienced HIV-infected patients.4 As such, unfavorable or unexpected drug interactions between the NRTIs and other regimen components can dramatically reduce the effectiveness of HAART and result in the development of resistance. We have recently established that coadministration of the fixed-dose combination of emtricitabine/tenofovir disoproxil fumarate, a highly efficacious NRTI backbone, and EVG/r is safe and does not result in clinically relevant drug interactions between emtricitabine or tenofovir and EVG.13 The present studies were performed to assess the critical issue of potential for clinically relevant drug interactions upon coadministration of EVG/r and other NRTIs, including zidovudine (ZDV), didanosine (ddI), stavudine (d4T), and abacavir (ABC). Based on the lack of alteration in EVG and emtricitabine PK upon EVG/r:emtricitabine coadministration, EVG/r:lamivudine interaction is unlikely and therefore not evaluated. The use of healthy subjects in this study removed potential confounding factors associated with a background regimen and avoided short-term changes in treatment regimen in HIV patients for the purpose of evaluating a pharmacokinetic interaction.

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METHODS

Subjects and Study Design

In 3 different studies, the potential for pharmacokinetic drug interaction between EVG/r:ZDV (study 1), EVG/r:ddI/d4T (study 2), or EVG/r:ABC (study 3) were evaluated. These were phase 1, single-center, open-label, crossover studies in healthy male and female (nonpregnant, nonlactating) subjects aged 18 to 45 years, inclusive. The studies evaluated single-dose PK of ddI, d4T, and ABC because of their short half-life and primarily extrahepatic biotransformation, and to minimize adverse events (hypersensitivity reactions for ABC), whereas multiple-dose PK of ZDV was evaluated owing to its hepatic glucuronidation by UDP-glucuronosyltranferase (UGT), in light of some degree of EVG metabolism by phase 2 enzymes. Subjects receiving EVG/r in the third period of study 1 were sampled for 48 hours (instead of 24 hours) to further estimate the half-life of EVG, including evaluation of its plasma profile in the context of a missed dose. Because ZDV is eliminated after hepatic glucuronidation primarily as zidovudine glucuronide (G-ZDV), plasma exposures of G-ZDV were also assessed. Owing to its longer half-life upon coadministration with ritonavir, multiple-dose PK of EVG was evaluated. Eligible subjects were administered the assigned treatments in a study as described in Table 1. The study protocol and informed-consent document were reviewed and approved by the study center's Institutional Review Board, and subjects provided written informed consent before study participation. The major eligibility criteria were that subjects be healthy based on medical history/physical exams/laboratory evaluations; nonsmoker; normal 12-lead electrocardiogram (ECG) results; hemoglobin ≥12.0 g/dL; creatinine clearance ≥80 mL/min; no evidence of HIV, HBV, or HCV infection; and use of at least 2 forms of contraception, including a barrier method. Exclusion criteria were plasma and blood donation within 7 and 56 days of study entry, respectively; history of difficulty donating blood; drug sensitivity/allergy; history of alcohol abuse; and use of prescription drugs within 30 days of study drug dosing except vitamins, acetaminophen, ibuprofen, and/or hormonal contraceptive.

TABLE 1

TABLE 1

Because EVG exposures are higher when taken with food and ZDV, d4T, and ABC can be taken without regard to meal, subjects received study drugs after an overnight fast in an open-label fashion immediately after a standardized morning meal (roughly 400 kcal) with 240 mL (8 fluid ounces) of water; ddI was administered 2 hours before the meal. Clinical-staff-observed dosing occurred on the first day of dosing and during the periods associated with PK sampling (study 1: days 6 to 8, 16 to 18, and 26 to 28; study 2: days 14 to 17; study 3: days 14 to 15), with subjects documenting clock-time and timing of dose relative to meals in diary cards on the remaining study days. On the days of PK sampling, subjects fasted until after collection of the 4-hour postdose blood draw. Subjects were allowed to consume water as desired except 1 hour before and 2 hours after study drug dosing. ZDV (Retrovir; GlaxoSmithKline, Middlesex, UK) was supplied as a 300-mg tablet, ddI (Videx EC; Bristol-Myers Squibb, New York, NY) as a 400-mg capsule, d4T (Zerit, Bristol-Myers Squibb) as a 40-mg capsule, ABC (Ziagen, GlaxoSmithKline) as a 300-mg tablet, EVG as a 200-mg tablet, and ritonavir as a 100-mg soft-gelatin capsule, all for oral administration. The dose of each NRTI represents the commercially marketed dose for the treatment of HIV-infected patients (>60 kg subjects for ddI and d4T). Pharmacokinetics samples were collected on study days as shown in Table 1 at the following times: for studies 1 and 2, predose (0) and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, and 24 hours postdose; for study 3, predose (0) and 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24 hours postdose. Blood samples were collected in Vacutainer (BD Diagnostics; Franklin Lakes, NJ) tubes containing the anticoagulant spray-dried K2EDTA and inverted several times to mix the blood and the anticoagulant. Samples were kept on wet ice or refrigerated for ≤30 minutes and centrifuged for 10 minutes at 1200 g (relative centrifugal force) in a refrigerated centrifuge set at ∼4°C to harvest plasma.

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Bioanalysis

Plasma concentrations of ddI, d4T, ABC, ZDV, G-ZDV, and EVG were determined using validated high-performance liquid chromatography/tandem mass spectrometry (HPLC/MS/MS) bioanalytic assays at Gilead Sciences (EVG from studies 1 and 3, ZDV, G-ZDV), Tandem Laboratories (Salt Lake City, UT; EVG from study 2), or Quest Pharmaceuticals Services (Newark, DE; ddI, d4T, and ABC). Briefly, assay details for the NRTIs are as follows (see Ramanathan et al13 for EVG assay conditions). The assay calibration curve was linear from 5 to 3000 ng/mL for ddI and d4T, 5 to 5000 ng/mL for ABC, 5 to 2000 ng/mL for ZDV, and 20 to 8000 ng/mL for G-ZDV. Accuracy, expressed as percentage bias, ranged from −4.0% to 4.2% for ddI, −3.1% to 5.2% for d4T, −4.1 to 3.0 for ABC, −7.0% to 8.0% for ZDV, and −4.3% to 4.6% for G-ZDV. Intra-assay precision ranged from −9.4% to 1.5% for ABC, −6.2% to 0.4% for ddI, 1.8% to 6.4% for d4T, −12.0% to 6.0% for ZDV, and −3.4% to 4.3% for G-ZDV.

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Pharmacokinetic Analyses

Pharmacokinetic parameters of the NRTIs, G-ZDV, and EVG were estimated by application of a nonlinear curve-fitting software package (WinNonlin Professional Edition, Version 5.0.1; Pharsight, Mountain View, CA) using noncompartmental methods. The parameters included maximum observed plasma concentration (Cmax), time to reach maximum concentration (Tmax), area under the concentration-time curve over the dosing interval (AUCτ), area under the concentration-time curve up to the last quantifiable concentration (AUClast) and up to infinity (AUC), elimination half-life (t1/2), and concentration at the end of dosing interval (Cτ; not applicable for NRTIs), as appropriate. All AUC estimates were calculated using the linear up-log down trapezoidal method.

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Statistical Analyses

A parametric (normal theory) analysis of variance (ANOVA) using a mixed-effects model appropriate for crossover design was fit to the natural logarithmic transformation of AUCτ (EVG, ZDV, G-ZDV), AUC/AUClast (ddI, d4T, ABC), Cmax (all analytes), and Cτ (EVG). Sample size for each study was based on the most variable exposure parameter of interest (Cmax, AUC, Cτ) for either EVG or the NRTI, and accounted for potential drop-outs. The final sample size provided at least 90% power to conclude lack of PK alteration based on the estimated ratio of geometric least squares means (GMR) of treatments (coadministered/alone) of 1.0, and associated 90% confidence interval (CI) range of 70% to 143% for EVG, 80% to 125% for d4T, 80% to 143% for ABC, 70% to 143% for ZDV/G-ZDV, 70% to 143% for ddI Cmax, and 80% to 125% for ddI AUClast/AUC. The 90% CI boundaries for lack of PK alteration (70% to 143%) were chosen based on the investigational status of EVG/r and, in particular, the lack of established dose-response relationship for safety and efficacy or a known intended commercial dose at the time of study conduct. The corresponding intervals for the NRTIs were based on the established lack of need for dose adjustment due to PK interactions as outlined in their prescribing information. The Cmax for ddI was set at 70% to 143% in an effort to enroll a reasonable number of subjects, given the high variability associated with this parameter. Subjects with an evaluable PK profile for a coadministered/alone dosing treatment pair were included in the PK analyses set for each analyte.

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RESULTS

Subject Demographics

Subject demographics across the 3 studies are presented in Table 2. The total number of enrolled subjects that were randomized and received at least 1 dose of study drug were 28 in study 1, 32 in study 2, and 26 in study 3. In all, 6 subjects discontinued prematurely: 4 in study 1 (2 due to adverse events, 1 withdrew consent, and 1 discontinued at investigator's discretion due to illicit drug use) and 2 in study 3 (1 due to noncompliance with study procedures and 1 at investigator's discretion due to illicit drug use). There were no discontinuations in study 2.

TABLE 2

TABLE 2

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Safety Results

EVG/r was generally well tolerated after administration alone or in combination with the NRTIs. The 2 discontinuations in study 1 were during the ZDV + EVG/r treatment due to a single grade 1 (mild) episode of vomiting (n = 1) and grade 1 abdominal distention (n = 1); both subjects had experienced nausea, vomiting, and/or abdominal bloating while receiving ZDV alone in an earlier treatment. Treatment-emergent AEs were reported in 12 of 28 (42.9%) subjects during ZDV administration, 13 of 24 (54.2%) subjects during EVG/r administration, and 14 of 26 (53.8%) during EVG/r + ZDV administration. The most frequently reported AEs across treatments were gastrointestinal system disorders (nausea and vomiting), headache, and dizziness. In study 2, treatment-emergent AEs were observed in 5 of 32 (15.6%) during ddI administration, 8 of 32 (25%) during d4T administration, 12 of 32 (37.5%) during EVG/r administration, 8 of 32 (25%) during EVG/r + ddI, and 7 of 32 (21.9%) subjects during EVG/r + d4T. The most frequently reported AEs were gastrointestinal system disorders (primarily dry lips, diarrhea, and nausea), headache, and dizziness. In study 3, treatment-emergent AEs (all grade 1) were observed in 5 of 26 (19.2%) subjects during ABC administration, 11 of 26 (42.3%) during EVG/r administration, and 7 of 24 (29.2%) during EVG/r + ABC administration. The most frequently reported AEs across treatments were gastrointestinal disorders, headache, and dizziness. All AEs were grade 1 in severity. No grade 4 laboratory abnormalities were reported in any of the 3 studies. The most common grade 3 laboratory abnormality was hematuria, which occurred in 5 female subjects across the 3 studies; all were assessed as likely related to menses. One subject reported grade 3 hypertriglyceridemia (nonfasting) during EVG/r administration in study 1; 2 subjects reported grade 3 hypercholesterolemia (nonfasting) in study 2 (1 subject on d4T and 1 subject on GS-9137/r). There were no consistent trends in hematology, chemistry, and urinalysis abnormalities.

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Pharmacokinetic Results

NRTI Pharmacokinetics

The plasma concentration-time profiles of ddI and ABC, after administration of each alone and with EVG/r, are presented in Figure 1A. Corresponding plasma profiles for ZDV (including G-ZDV) and d4T are shown in Figure 1B. Pharmacokinetic parameters for the NRTIs are presented in Table 3. All NRTIs displayed a rapid absorption phase and short half-life, and their overall exposures were consistent with historical data. ddI exhibited a higher-than-expected variability in the absorption phase, as reflected by the >50% coefficient of variation (%CV) for its Cmax. As evidenced by the similar plasma concentration-time profiles after their administration ± EVG/r, %GMR and the associated 90% CI for Cmax, AUClast, and AUC of ZDV, its metabolite G-ZDV, ABC, and d4T were contained within the predefined lack of alteration bounds (ZDV and G-ZDV: 70% to 143%, ABC: 80% to 143%, d4T: 80% to 125%). The %GMR for Cmax and AUC of ddI indicated 14% to 16% lower exposures after coadministration with EVG, and the 90% CI was below the predefined lower bound for lack of alteration (Cmax: 70% to 143%; AUC: 80% to 125%).

FIGURE 1

FIGURE 1

TABLE 3

TABLE 3

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Elvitegravir Pharmacokinetics

The plasma concentration-time profiles of EVG after EVG/r dosing alone and in combination with ddI or d4T are presented in Figure 2A. EVG plasma profiles after EVG/r ± ZDV and EVG/r ± ABC dosing are shown in Figure 2B. Pharmacokinetic parameters of EVG after EVG/r administration alone and with the NRTIs are presented in Table 4. Peak plasma concentrations of EVG were observed 4 hours post-EVG/r dose, and median t1/2 values ranged from 8.0 to 14.4 hours across studies and regimens. Consistent with the overlapping concentration-time profiles, NRTIs did not affect EVG pharmacokinetics with %GMR (90% CI) contained within the lack of PK alteration bounds (70% to 143%) for all coadministered treatments. EVG plasma exposures were significantly higher than the in vitro protein-binding adjusted IC95 up to 36 hours after EVG/r dosing (P < 0.0001).

FIGURE 2

FIGURE 2

TABLE 4

TABLE 4

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DISCUSSION

The present study demonstrated that coadministration of the HIV integrase inhibitor EVG/r with other commonly administered agents in the NRTI class such as ZDV, ddI, d4T, or ABC does not alter the pharmacokinetics of EVG or the NRTIs. Further, administration of EVG/r alone or with an NRTI was generally well tolerated. All AEs were grade 1 in severity and resolved on therapy. There were no serious AEs or grade 4 laboratory abnormalities reported in any subject. This favorable safety profile of EVG/r is consistent with prior published data for EVG/r in healthy subjects and HIV-infected patients.11-13

The 2 NRTIs evaluated in this study that undergo hepatic biotransformation via glucuronyltransferase were zidovudine (substantial)14 and abacavir (partial).15 Dose modification of ZDV has not been warranted for up to 106% increase or 47% decrease in ZDV exposures14 upon coadministration with other agents, presumably owing to the lack of an impact on intracellular concentrations of the active metabolite zidovudine triphosphate.16-18 ZDV exposures in the present study were within the predefined 90% CI bounds, indicating lack of pharmacokinetic alteration upon coadministration with EVG/r. Although ABC is only partially metabolized via glucuronidation and drug interaction data with other ARVs are limited, it appears to be susceptible to occasional unexplained interactions, such as decreases in exposure upon coadministration with tipranavir/r (TPV/r) and lopinavir/r of 40% to 50%19 and 32%,20 respectively. In contrast, ABC pharmacokinetics was unaffected upon coadministration with EVG/r in this study. Mean ddI exposures in the current study were ∼15% lower upon coadministration with EVG/r, while exhibiting similar plasma t1/2 values with or without EVG/r dosing. ddI displayed a highly variable absorption phase, regardless of administration with or without EVG/r, as reflected in higher %CV (>50%) for Cmax and larger observed root mean square error (rMSE) for Cmax (rMSE = 0.52) vs. the historical estimate used for sample size determination (rMSE = 0.36), which may explain the wide 90% CI bounds observed in the present study. Despite the distinct metabolic pathway of ddI (similar to elimination of endogenous purines), it is involved in modest interactions with inhibitors of the cytochrome P450 enzymes such as ciprofloxacin (↓16% ddI-AUC, ↓28% ddI-Cmax), ketoconazole (↓12% ddI-Cmax), and ritonavir (↓13% ddI-AUC, ↓16% ddI-Cmax).21 These changes in ddI exposures, along with those observed after coadministration with loperamide (↓23% ddI-Cmax) and indinavir (↓17% ddI-AUC), have not warranted dose modification. Thus, the slight decreases in ddI levels observed in the present study are not considered clinically meaningful. d4T was, given its partial conversion to thymine which then undergoes normal endogenous catabolism, the least likely of the presently evaluated NRTIs to have a potential for drug interaction with EVG/r, although coadministration with TPV/r results in decreased Cmax (↓24%) and AUC (↓16%) of d4T.18,22 As expected, coadministration of d4T and EVG/r had no effect on the PK of either agent.

The therapeutic potential of integrase inhibitors as highly efficacious ARVs has been clinically demonstrated for another agent in this class, where approximately 60% of treatment-experienced patients had %HIV RNA <50 copies/mL at week 16 after receiving twice-daily doses of the investigational agent raltegravir (MK-0518; Merck, Whitehouse Station, NJ) in addition to ritonavir-boosted, protease-inhibitor-containing OBR versus 33% to 36% of patients receiving placebo + OBR.23,24

The results of the current studies and studies of emtricitabine and tenofovir disoproxil fumarate that indicate lack of pharmacokinetic drug interaction support the continued development of ritonavir-boosted EVG. Due to high and persistent concentrations throughout the dosing interval, the addition of once-daily EVG to resistance-testing-guided, boosted protease inhibitor-containing regimens is under evaluation in advanced, multiclass treatment-experienced HIV-infected patients.11,12 The clinical development of EVG/r, a well-tolerated and potent integrase inhibitor, represents a significant advancement and holds promise for advanced, multiclass treatment-experienced HIV-infected patients. Importantly, the once-daily administration of EVG/r, facilitated by its long systemic half-life, encourages treatment adherence, which is critical in the context of “cocktail” regimens. In conclusion, EVG/r and the NRTIs ZDV, ddI, d4T or ABC do not undergo clinically relevant drug-drug interactions. These agents can be coadministered without dose adjustment in HIV-infected patients.

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REFERENCES

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14. Retrovir [US prescribing information]. Research Triangle Park, NC: GlaxoSmithKline; 2006.
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Keywords:

GS-9137; elvitegravir; integrase; NRTI; pharmacokinetics; drug interaction

© 2007 Lippincott Williams & Wilkins, Inc.