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Effect of Ritonavir-Boosted Tipranavir or Darunavir on the Steady-State Pharmacokinetics of Elvitegravir

Mathias, Anita A PhD*; Hinkle, John PhD*; Shen, Gong PhD*; Enejosa, Jeff MD*; Piliero, Peter J MD; Sekar, Vanitha PhD; Mack, Rebecca MS; Tomaka, Frank MD; Kearney, Brian P PharmD*

JAIDS Journal of Acquired Immune Deficiency Syndromes: October 2008 - Volume 49 - Issue 2 - p 156-162
doi: 10.1097/QAI.0b013e318183a982
Clinical Science

Objective: Elvitegravir (EVG) is in phase 3 development in combination with ritonavir (RTV)-boosted protease inhibitors in treatment-experienced, HIV-infected patients. Two studies evaluated pharmacokinetic (PK) interactions among EVG and RTV-boosted tipranavir (TPV/r) or darunavir (DRV/r).

Methods: Healthy volunteers received EVG/r alone (study 1: 200/100 mg once daily; study 2: 125/100 mg once daily), TPV/r (500/200 mg twice daily) or DRV/r (600/100 mg twice daily) alone, and EVG (200 or 125 mg as applicable) added to TPV/r (500/200 mg twice daily) or DRV/r (600/100 mg twice daily) in a randomized crossover design, with assessment of steady-state PK for EVG, TPV, DRV, and RTV. Safety was assessed by clinical monitoring. Studies were powered to conclude lack of an interaction if the 90% confidence interval for the geometric mean ratios of the AUCtau and Cmax for EVG, TPV, and DRV were within predefined no-effect boundaries. Trough concentrations were also assessed.

Results: No subjects discontinued for adverse events during treatment with EVG/r alone. On coadministration, AUCtau and Cmax of EVG and TPV and EVG and DRV were within prespecified no-effect boundaries versus treatment alone; trough concentrations were also not substantially altered.

Conclusions: The PK of EVG and TPV or DRV were not altered after coadministration of EVG with TPV/r or DRV/r. EVG PK was similar with varied RTV doses of 100 mg once daily, 100 mg twice daily, or 200 mg twice daily. EVG can be added to TPV/r or DRV/r regimens without dose adjustment.

From the *Clinical Research, Gilead Sciences, Inc, Foster City, CA; †Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, CT; and ‡Tibotec Pharmaceuticals, Ltd, Yardley, PA.

Received for publication December 20, 2007; accepted June 5, 2008.

This study was conducted by Gilead Sciences with bioanalytical support by Boehringer Ingelheim Pharmaceuticals and Tibotec Pharmaceuticals.

Presented at the 4th International AIDS Conference, July 22-25, 2007, Sydney, Australia.

Correspondence to: Anita A. Mathias, PhD, Clinical Research, Gilead Sciences, Inc, 333 Lakeside Drive, Foster City, CA 94404 (e-mail:

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The standard of care for the treatment of HIV infection involves the use of a combination of antiretroviral drugs to suppress viral replication to below detectable limits, increase CD4+ cell counts, and delay disease progression. Although multiple agents within several drug classes are available, resistance to these agents continues to develop, necessitating development of drugs targeting alternative steps in viral replication. Viral integrase is an attractive target for selective anti-HIV therapy because there is no known functional homologue in human cells.

Elvitegravir (EVG) is an HIV-1 integrase inhibitor that specifically inhibits the strand transfer step in the integration of proviral DNA into the host genome.1-4 In vitro, EVG exhibits potent anti-HIV-1 activity (protein binding-adjusted IC50, 16 nmol/L) against wild-type and nucleoside reverse transcriptase inhibitor, nonnucleoside reverse transcriptase inhibitor, and protease inhibitor (PI)-resistant laboratory strains.5 The preclinical absorption, distribution, metabolism, and elimination profile of EVG was characterized in vitro in human hepatocytes and in vivo. A clinical mass balance study demonstrated that after oral administration of EVG, several metabolites are produced, constituting <10% relative systemic exposure to parent based on area under the curve (AUC) relative to EVG.6 Two primary metabolites are M1, produced by CYP3A4, and M4, produced by UDP-glucuronosyltransferase 1A1/3 and are markedly less potent (5- to 38-fold) than EVG. Urinary elimination of EVG is a minor pathway, with <7% of dose excreted in the urine.

Coadministration of EVG with a low dose (100 mg) of ritonavir (RTV, “/r,” or Norvir) substantially increases the relative oral bioavailability and reduces the apparent clearance of EVG, with a resultant 20-fold improvement in systemic exposure (AUC) and achievement of high trough (Ctau) concentrations, thereby permitting once-daily dosing.7

EVG is currently in development for use in treatment-experienced patients. Tipranavir (TPV) (Aptivus) and darunavir (DRV; Prezista) are next-generation PIs indicated for use with RTV in treatment-experienced, HIV-infected patients. TPV and DRV share similarities to EVG in their elimination pathways, both are metabolized predominantly by CYP3A-mediated oxidation, and all 3 agents rely on low-dose RTV to enhance their pharmacokinetics (PK), particularly trough concentrations.8-11 Therefore, coadministration of these agents may result in altered PK profiles of either drug, either directly or via the modulating effects of RTV.

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Two phase 1 clinical studies were conducted to examine the drug-drug interaction potential between EVG and TPV/r (conducted at MDS Pharma Services, Phoenix, AZ) and between EVG and DRV/r (conducted at Covance, Inc, Dallas, TX).

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Study Population

Thirty-four (study 1, TPV/r) and 33 (study 2, DRV/r) healthy male and female subjects (nonpregnant/nonlactating) between 18 and 45 years of age and with calculated body mass index (BMI) from 19 to ≤30 were enrolled in the study. To rule out pregnancy, female subjects of childbearing potential had serum pregnancy testing at screening and at several time-points throughout the study. Subjects were also required to use double-barrier methods of contraception. Clinical laboratory values for all subjects had to be within the normal range, or if outside this range, deviations had to be assessed as clinically insignificant by the principal investigator and medical monitor. Subjects were excluded if they had a history or current clinically significant diseases/disorders or were receiving any medications for at least 30 days of commencing study drug with the exception of vitamins, acetaminophen, ibuprofen, and/or hormonal contraceptives. Subjects with a history of active alcohol use or chemical dependency were excluded. Additional restrictions included consumption of grapefruit juice and grapefruits, Seville orange juice, or calcium-fortified orange juice (containing ≥10% of calcium daily value) from 1 week before day 1 and throughout the study. As EVG/r simultaneously coadministered with antacids leads to lower EVG concentrations, putatively via complexation with the high concentrations of divalent cations, subjects were not allowed to consume antacids, sucralfate, or vitamin or mineral supplements that contain calcium, iron, or zinc from the day of the baseline visit until the study completed.12

The principal investigator reviewed medical histories and clinical laboratory evaluations and performed physical examinations before subject's enrollment in the study. Healthy volunteers were selected for this study population to remove the confounding effects of background antiretroviral and other therapies and to avoid the need to make multiple, short-term changes in treatment regimens of patients with HIV for the purpose of examining PK.

The study protocol(s) and informed consent document(s) were reviewed and approved by each study center's institutional review board, and subjects were provided written informed consent before study participation. The studies were carried out in accordance with the clinical research guidelines established by the basic principles defined in the US 21 CFR Part 312.20 and by the principles enunciated in the latest version of the Declaration of Helsinki.

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Study Design

Both the studies were open label, multiple sequence, and multiple dose, with subjects randomized at the baseline visit by William's crossover design to 1 of 6 unique sequences of treatments A, B, and C (ABC, ACB, BAC, BCA, CAB, and CBA). Each treatment was administered for 14 consecutive days for a total treatment period of 42 consecutive days. Subjects returned to the clinic on day 49 for a follow-up assessment. The treatments are described in Table 1.



Serial blood samples were collected at 0 (predose) and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24 hours after administration of treatments A and C for EVG concentration measures, and at 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, and 12 hours after administration of treatment B for measurement of TPV/r or DRV/r. The number, frequency, and timing of blood samples were based on the concentration-time profiles of the individual drugs. The blood samples were centrifuged, and plasma collected was frozen at −20°C or lower until analysis.

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Safety Assessments

Safety was evaluated by assessment of clinical laboratory tests and physical examinations including vital signs at baseline and at various times during the study. Adverse events were recorded throughout the study. Subjects were required to return to the clinic 7 days after the last PK visit for laboratory tests and adverse events. Adverse events were coded using the Medical Dictionary for Regulatory Activities version 8.0. Adverse events and abnormal laboratory values were graded according to the Gilead Sciences Modified National Institute of Allergy and Infectious Disease Common Toxicity Grading Scale (mild = 1, moderate = 2, severe = 3, possibly life threatening = 4).13

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Bioanalytical Procedures

Plasma concentrations of EVG, TPV, DRV, and RTV were determined using validated high-performance liquid chromatography/mass spectrometry bioanalytical assays at Gilead Sciences, Inc (EVG, studies 1 and 2, and RTV, study 2), Bioanalytical Systems, Inc (West Lafayette, IN; TPV and RTV, study 1), and Johnson & Johnson Pharmaceutical Research and Development (Belgium; DRV Study 2).

Briefly, the methods were as follows: EVG, its stable label isotope [internal standard (IS)], and RTV (in study 2 only with GS-9201 as the IS) were loaded on an Empore C8-SD solid-phase extraction column, washed with 0.1% formic acid in water, eluted with 10/90/0.1 water/acetonitrile/formic acid, diluted in 0.1% formic acid in water and injected on an YMC ODS-AM column, and separated using water/acetonitrile/formic acid as the mobile phase. The compounds were detected by mass spectrometry (MS/MS) using electrospray ionization in the positive mode and following ion transitions m/z 448 → 344 for EVG, m/z 456 → 344 for the EVG IS, m/z 721 → 268 for RTV, and m/z 632 → 438 for GS-9201.

Tipranavir, RTV (study 1), and PNU-109011 (IS) were extracted from human plasma by liquid/liquid extraction using ethyl acetate/hexane (9:1), followed by a hexane wash and then detection on a liquid chromatography/mass spectrometry (LC/MS/MS) system using 20 mM formic acid/10 mM acetic acid and acetonitrile (1:1) as the mobile phase. The compounds were detected using electrospray ionization in the positive mode and following ion transitions m/z 603.4 → 411.2 for TPV, m/z 721.4 → 296.3 for RTV, and 631.5 → 439.2 for the IS.

Darunavir and its IS (R419765) were extracted from human plasma by protein precipitation with acetonitrile, followed by detection using a triple quadrupole mass spectrometer in the positive ion mode and following ion transitions m/z 548 → 392 for DRV (R319064) and m/z 552 → 396 for IS R419765.

Quantitation was based on the peak area ratios of analyte/IS. Because of the wide range of expected concentrations, 2 sets of overlapping calibration curves and respective quality control sample pools were developed for TPV, RTV (study 1), and DRV. The assay calibration curve was linear from 20 to 10,000 ng/mL for EVG; 25 to 2000 ng/mL (low) and 1000 to 20,000 ng/mL (high) for TPV; 25 to 2000 ng/mL (low) and 1000 to 20,000 ng/mL (high) for RTV (study 1); 5 to 5000 ng/mL for RTV (study 2); and 25 to 2000 ng/mL (low) and 1000 to 20,000 ng/mL (high) for DRV. Inter- and intra-assay precision had <12% coefficient of variation, and accuracy was within 10% of the expected.

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PK Analysis

Pharmacokinetic parameters of EVG, TPV, RTV, and DRV were estimated by application of a nonlinear curve-fitting software package (WinNonlin software, Professional Edition, version 5.0.1; Pharsight Corporation, Mountain View, CA) using noncompartmental methods and included maximum observed plasma concentration (Cmax), time to reach maximum concentration (Tmax), last quantifiable concentration (Clast), time of Clast (Tlast), area under the concentration-time curve over the dosing interval (AUCtau), terminal elimination half-life (T1/2), and concentration at the end of dosing interval (Ctau).

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Statistical Analysis

Sample size for each study was based on the most variable exposure primary parameter of interest (Cmax or AUCtau) among EVG, TPV, or DRV. Based on available safety/adverse event data, an average (30% for study 1 and 50% for study 2) was built in the study sample size to account for potential dropouts.9,11 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 [% geometric mean ratio (GMR)] of treatments (coadministered:alone) of 100% and associated lack of interaction bounds of 70%-143% for EVG, 80%-143% for TPV, and 80%-125% for DRV. The boundaries for lack of PK interaction (70%-143%) were based on the investigational status of EVG/r and lack of selection of a final dose at the time of study conduct. The no-effect intervals for the TPV and DRV were based on their established exposure-response relationships with respect to safety and efficacy, specifically data in their prescribing information supporting the magnitude of PK interactions that do not require dose adjustments. For TPV, prescribing information does not recommend dose adjustment, despite documented interactions with drugs such as clarithromycin and fluconazole, which increase TPV exposure by 50% or greater.9 This observation suggests that a 143% upper bound can be applied without compromising the safety profile of TPV. Minimal information is available about the efficacy profile of TPV on lower exposures; thus, a stringent lower bound used for PK equivalence was applied (80%). For DRV, based on the concentration-response relationships for safety and efficacy in treatment-experienced patients at the time of study conduct, a lack of interaction bound of 80%-125% was applied.

A PK analysis set was defined for each analyte consisting of all randomized subjects who were treated with study drug and had evaluable PK profiles for each treatment pair (coadministered:alone). The safety analysis set included all subjects who received at least 1 dose of study drug(s). Demographic data and baseline characteristics were summarized using descriptive statistics. A parametric (normal theory) analysis of variance using a mixed effects model appropriate for crossover design was fit to the natural logarithmic transformation of AUCtau, Cmax, and Ctau, and 90% confidence intervals (CIs) were constructed for the ratio of geometric means of PK parameters. Lack of a PK alteration was concluded if the 90% CI for the GMR of the primary PK parameters (AUCtau and Cmax) was within the predefined boundaries for EVG, TPV, and DRV. Because of a higher variability normally associated with trough concentrations, the studies were not powered for equivalence of Ctau; however, Ctau was qualitatively examined at the bounds specified for Cmax or AUCtau. As RTV was used at subtherapeutic levels as a PK enhancer, exploratory analyses were conducted for RTV PK.

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Subject Demographics and Disposition

Thirty-four subjects enrolled in study 1, with 26 completing the study and included in the PK analysis sets. The safety analysis set contained 29 subjects for treatments A and B and 32 for treatment C. Eight subjects discontinued the study prematurely: 4 were withdrawn from the study by the investigator for safety or tolerability reasons that resolved after discontinuation, 3 withdrew consent, and 1 was withdrawn by the investigator for a protocol violation (positive pregnancy). Ethnic background of subjects was 76.5% Hispanic, 20.6% white, and 2.9% black, with approximate even proportion female subjects (52.9%) and male subjects. The mean age (SD) was 31 (7.2) years, mean weight (SD) at screening was 69.6 (11.2) kg, mean height (SD) was 167.2 (11.9) cm, and the mean BMI (SD) was 24.8 (2.34) kg/m2.

In study 2, 33 subjects were randomized and 20 completed the study. The safety analysis sets contained 29 subjects for treatment A, 27 for treatment B, and 28 for treatment C. Thirteen subjects discontinued the study prematurely: 7 withdrew consent because of schedule conflicts or difficult venipuncture, 3 were withdrawn from the study by the investigator for safety or tolerability reasons that resolved after discontinuation, 2 were withdrawn by the investigator for protocol violations (positive pregnancy and positive drug test), and 1 was lost to follow-up. Ethnic background of subjects was 63.6% white and 36.4% black by race, with a higher proportion of male subjects (57.6%) than female subjects. The mean (SD) age at baseline was 30 (8.1) years, mean weight at screening was 76.8 (13.2) kg, mean height at screening was 173.4 (11.6) cm, and the mean BMI was 25.5 (2.97) kg/m2.

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Safety Data

In both the studies, treatment with EVG/r alone was well tolerated, with no subjects discontinuing treatment, and treatment with an RTV-boosted PI alone or in combination with EVG was associated with a higher frequency of treatment-emergent and -related adverse events. All adverse events were grade 1 or 2. No grade 3 or 4 or serious adverse events occurred; there were no deaths. In the study of TPV/r with EVG, 5 grade 2 adverse events occurred in 4 subjects while subjects were treated with TPV/r plus EVG (elevated alanine aminotransferase, nausea, elevated aspartate aminotransferase, and generalized pruritus coincident with rash), 2 of which (elevated liver enzymes and rash) resulted in study discontinuation. The most frequent treatment-emergent and -related adverse events in this study were diarrhea and headache (17.2% of subjects) after administration of EVG/r alone, headache (24.1%) after administration of TPV/r, and nausea (43.8%) after administration of TPV/r plus EVG.

In the DRV/r study, the most frequent treatment-related adverse events by system organ class were gastrointestinal and nervous system disorders in subjects treated with EVG/r alone (10.3% each) and gastrointestinal disorders in subjects treated with DRV/r alone (22.2%) or with EVG (32.1%). In this study, there were 2, treatment-related, grade 2 adverse events of rash during which subjects were receiving DRV/r alone and that resulted in study discontinuation.

Despite consenting to explicit protocol requirements of contraception to avoid pregnancy, 1 subject in each study became pregnant during study; both were withdrawn by the investigator for a protocol violation. On follow-up, the subject from study 1 reported that her pregnancy was going well and had a normal delivery of a healthy infant. The subject in study 2 was lost to follow-up. At last contact with the subject at approximately 10 weeks' gestation, she reported no physical problems.

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In study 1, the PK analysis sets included 26 subjects. Mean (SD) EVG, TPV, and RTV plasma concentration-time profiles are presented in Figures 1A, B, and C, respectively. As presented in Table 2, steady-state EVG and TPV PK parameters were comparable between the 2 treatments (EVG plus TPV/r vs EVG/r or TPV/r alone) and the %GMR for EVG or TPV Cmax and AUCtau, and their associated 90% CIs were contained with the protocol-defined lack of interaction bounds of 70%-143% or 80%-143%, respectively. As mentioned previously, the study was not powered to statistically assess Ctau; however, qualitative examination of the GMR and associated 90% CIs around Ctau for EVG and TPV showed that the lower bound of 90% CI was only marginally below the respective lack of interaction boundaries. For EVG, the GMR was 90.4, and the lower bound of the 90% CI was 69.8. For TPV, the GMR was 88.9, and the lower bound of the 90% CI was 77.4. For both analytes, these marginally lower (~10%) values are not considered to be clinically relevant, in particular for TPV, as no dose adjustment is recommended for TPV when coadministered with ethinyl estradiol, which reduces TPV trough concentrations by nearly 30%.9





In study 2, the PK analysis set for EVG and DRV were 21 and 22 subjects, respectively. Mean (SD) EVG, DRV, and RTV plasma concentration-time profiles are presented in Figures 2A, B, and C, respectively. As presented in Table 3, the PK parameters for EVG were similar after administration of EVG/r alone or EVG in combination with DRV/r. The %GMR and the associated 90% CIs for all parameters, including Ctau, were contained with the protocol-defined lack of interaction bounds of 70%-143%. The PK of DRV (Table 3) after administration of multiple doses of DRV/r alone or with EVG were also similar and consistent with historical values.11,14





Statistical comparisons demonstrate that the GMR and the associated 90% CIs were contained with the protocol-defined lack of interaction bounds of 80%-143%. The GMR for DRV Ctau was 82.8, but the lower bound of associated 90% CI (73.7%) was slightly below the specified lack of interaction interval of 80%. This finding is similar to a previously reported finding that when DRV/r is coadministered with nevirapine or sertraline and based on the established concentration-response relationships for DRV, this difference is not considered clinically relevant.11

The PK parameters of RTV when administered at 100 mg once daily with EVG alone were similar in both the studies and to values reported in other clinical studies of EVG/r. The PK of RTV (Table 4) when administered as 200 mg twice daily with TPV with or without EVG or administered as 100 mg twice daily with DRV with or without EVG were similar. Because of the differences in dose and dosing intervals among treatments, RTV plasma PK comparisons of the primary PK parameters (Cmax and AUCtau) were performed only between treatments B and C. The %GMR and the corresponding 90% CIs for RTV Cmax, AUCtau, and Ctau were contained within PK equivalence bounds of 70%-143%, indicating that addition of EVG to TPV/r or DRV/r does not affect the PK of RTV.



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These 2 prospective, crossover drug interaction studies were conducted to assess the PK of the investigational integrase inhibitor EVG upon coadministration with TPV/r and DRV/r, next-generation PIs used in treatment-experienced patients. The dose used in study 1 was chosen at the inception of the development program when the potential dose for EVG was as high as 200 mg. Thus, these data appropriately examined the maximum potential for a PK interaction between these agents. The dosing regimen for EVG/r (125/100 mg once daily) in study 2 with DRV/r was selected as it represented the highest dose/exposure under evaluation in planned phase 2/3 studies.

Tipranavir and RTV exhibit complex PK properties; TPV is known to induce CYP3A and P-gp, whereas RTV is known to exhibit dose-dependent mixed inductive-inhibitive effects on CYP3A, with predominantly inductive effects on P-gp.15,16 EVG is predominantly metabolized by CYP3A, exhibits modest dose-dependent inductive effects on its CYP3A metabolism when administered without RTV, and is not a P-gp substrate (data on file; Gilead Sciences, Foster City, CA). Because of these PK properties, a 3-treatment, 6-sequence study design was used to closely examine the potential for an interaction. A similar study design was incorporated for studying the DRV/r with EVG interaction as DRV is a known substrate of CYP3A and P-gp.17 In both the studies, the 14-day duration of dosing provided steady-state conditions; statistical analysis noted no sequence or period effect in either study (data not shown).

Results from both the studies show that EVG plus TPV/r or DRV/r does not have clinically relevant PK drug interactions with AUCtau and Cmax for EVG and TPV or EVG and DRV, demonstrating similar exposures on coadministration.

As the goal of dosing regimens is to maintain effective drug concentrations over the dosing interval, in addition to primary PK parameters of interest (AUC and Cmax), trough concentrations of TPV, DRV, and EVG were also examined.18-20 The mean Ctau of TPV and DRV, respectively, were 25- and 5-fold greater than the protein-binding adjusted IC90 (TPV) and IC50 (DRV) for multiple PI-resistant HIV-1 on addition of EVG to their RTV-boosted regimens.21,22 In summary, the steady-state PK of EVG, TPV, or DRV were not altered after coadministration of EVG with RTV-boosted TPV or DRV, including maintenance of effective trough concentrations.

These studies also allowed for an exploration of RTV PKs across doses of 100 mg once or twice daily and 200 mg twice daily within the context of 2- and 3-way interactions with multiple cytochrome P450 substrates, inhibitors, and inducers. These analyses demonstrated that RTV PK on coadministration of EVG with either TPV or DRV were unaltered versus administration as TPV/r or DRV/r alone. In these studies, the RTV dosing regimen in the coadministered treatment was that used for the PI (400 and 200 mg daily, respectively), a significantly larger and twice as frequent dose than the 100 mg dose used for EVG alone. Despite these higher RTV exposures, the PK of EVG was unaffected versus once-daily administration of 100 mg, a finding that is consistent with data from an RTV dose-ranging study that reported that once-daily RTV doses of 50 to 100 mg are sufficient for EVG boosting, with no evidence for additional increases in EVG exposure with an RTV dose of 200 mg.23

Furthermore, these varying dosing regimens resulted in informative differences in RTV PK. Twice-daily doses of either 100 or 200 mg of RTV are associated with greater than predicted increases in RTV exposure compared with a 100 mg once-daily dose. As a potent, mechanism-based inhibitor of CYP3A, the apparent clearance of RTV would be expected to decrease with increasing dose/dosing interval, an observation consistent with the aforementioned findings.24

In both the studies, treatment with EVG/r alone was generally well tolerated, an observation consistent with other PK and the phase 2 study.25 Treatment with TPV/r or DRV/r either alone or in combination with EVG was associated with a higher frequency of treatment-emergent and -related adverse events, all of which were grade 1 or 2 and that resolved after discontinuation of study drug.

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The steady-state PK of EVG, TPV, and DRV were unaltered after coadministration of EVG with TPV/r or DRV/r, including maintenance of high trough concentrations. Higher doses and more frequent dosing of RTV with TPV or DRV did “not affect the PK of EVG when compared with once-daily administration of 100 mg of RTV.” Treatment with EVG/r alone was generally well tolerated. EVG may be combined with TPV/r or DRV/r regimens without dose adjustment.

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elvitegravir; GS-9137; tipranavir; darunavir; interaction

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