Pharmacokinetics and Safety of S/GSK1349572, a Next-Generation HIV Integrase Inhibitor, in Healthy Volunteers

doi:10.1128/AAC.00842-09

Antimicrob Agents Chemother. 2010 January; 54(1): 254–258.

Published online 2009 November 2. doi: 10.1128/AAC.00842-09

PMCID: PMC2798521

Pharmacokinetics and Safety of S/GSK1349572, a Next-Generation HIV Integrase Inhibitor, in Healthy Volunteers ^†

Sherene Min,¹ Ivy Song,¹ Julie Borland,¹ Shuguang Chen,¹ Yu Lou,¹ Tamio Fujiwara,² and Stephen C. Piscitelli¹^*

GlaxoSmithKline, Research Triangle Park, North Carolina,¹ Shionogi & Co., Ltd., Osaka, Japan²

^*Corresponding author. Mailing address: Infectious Diseases MDC, GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709. Phone: (919) 483-2523. Fax: (919) 315-5697. E-mail: stephen.c.piscitelli/at/gsk.com

Received June 22, 2009; Revised September 2, 2009; Accepted October 23, 2009.

This article has been cited by other articles in PMC.

Abstract

S/GSK1349572 is a novel integrase inhibitor with potent in vitro anti-HIV activity, an in vitro resistance profile different from those of other integrase inhibitors, and favorable preclinical safety and pharmacokinetics (PK). Randomized, double-blind, placebo-controlled single-dose and multiple-dose, dose escalation studies evaluated the PK, safety, and tolerability of S/GSK1349572 for healthy subjects. In the single-dose study, two cohorts of 10 subjects each (8 active, 2 receiving placebo) received suspension doses of 2, 5, 10, 25, 50, and 100 mg in an alternating panel design. In the multiple-dose study, three cohorts of 10 subjects each (8 active, 2 receiving placebo) received suspension doses of 10, 25, and 50 mg once daily for 10 days. A cytochrome P450 3A (CYP3A) substudy with midazolam was conducted with the 25-mg dose. Laboratory testing, vital signs, electrocardiograms (ECGs), and PK sampling were performed at regular intervals. S/GSK1349572 was well tolerated. Most adverse events (AEs) were mild, with a few moderate AEs reported. Headache was the most common AE. No clinically significant laboratory trends or ECG changes were noted. PK was linear over the dosage range studied. The steady-state geometric mean area under the concentration-time curve over a dosing interval (AUC_0-τ) and maximum concentration of the drug in plasma (C_max) ranged from 16.7 μg·h/ml (coefficient of variation [CV], 15%) and 1.5 μg/ml (CV, 24%) at a 10-mg dose to 76.8 μg·h/ml (CV, 19%) and 6.2 μg/ml (CV, 15%) at a 50-mg dose, respectively. The geometric mean steady-state concentration at the end of the dosing interval (C_τ) with a 50-mg dose was 1.6 μg/ml, approximately 25-fold higher than the protein-adjusted 90% inhibitory concentration (0.064 μg/ml). The half-life was approximately 15 h. S/GSK1349572 had no impact on midazolam exposure, indicating that it does not modulate CYP3A activity. The PK profile suggests that once-daily, low milligram doses will achieve therapeutic concentrations.

The introduction of human immunodeficiency virus (HIV) integrase inhibitors has ushered in a potent new class of drugs for HIV-infected individuals. These agents act upon a key viral target and demonstrate activity in treatment-experienced patients (4, 7, 9). Importantly, their adverse event (AE) profile does not appear to have many of the dose-limiting side effects of other classes, such as central nervous system disturbances, hyperlipidemia, and insulin resistance.

S/GSK1349572 is an investigational HIV integrase inhibitor that preferentially blocks the strand transfer step of integration of the viral genome into the host cell's DNA (6) and is designed to retain activity against raltegravir- and elvitegravir-resistant HIV. The proposed mechanism of inhibition involves the drug molecule chelating to two Mg²⁺ ions in the integrase DD(35)E catalytic active site. S/GSK1349572 was selected for clinical trials because nonclinical studies demonstrated a favorable safety profile, pharmacokinetics (PK) supporting once-daily dosing, and the potential for activity against raltegravir- and elvitegravir-resistant HIV. The primary route of metabolism is glucuronidation, and the compound does not demonstrate induction or inhibition of cytochrome P450 (CYP) isozymes in vitro. S/GSK1349572 demonstrates potent in vitro activity, with a 50% inhibitory concentration (IC₅₀) against HIV in peripheral blood mononuclear cells (PBMCs) of 0.51 nM and a protein-adjusted IC₉₀ of 0.064 μg/ml. The objective of these studies was to evaluate the safety and pharmacokinetics of S/GSK1349572 following single and repeat doses in healthy adult subjects.

MATERIALS AND METHODS

Subjects and design.

Randomized, double-blind, placebo-controlled single-dose and multiple-dose, dose escalation studies were conducted with healthy subjects. For both trials, subjects were healthy (as judged by a physical exam, medical history, and laboratory testing) nonsmoking males or females without childbearing potential. Subjects testing positive for anti-HIV antibody, anti-hepatitis C antibody, or hepatitis B surface antigen were excluded. Subjects were not allowed to receive any prescription or nonprescription drugs, including vitamins and herbal products, within 7 days of dosing and throughout the studies, unless this restriction was deemed unlikely to interfere with the conduct of the study or the safety of the individual subject.

The single-dose study utilized an alternating panel of two cohorts with 10 subjects each, 8 receiving S/GSK1349572 and 2 receiving placebo. Subjects randomized to placebo received placebo on all dosing occasions. S/GSK1394572 was administered as a suspension and was given after a 10-h fast. Doses were selected based on allometric scaling and preclinical toxicology studies and were then adjusted based on real-time PK analysis. The doses administered in the study were 2, 5, 10, 25, 50, and 100 mg, with the first cohort receiving 2, 10, and 50 mg and the second cohort receiving 5, 25, and 100 mg. Suspensions of the active drug and placebo were prepared by the study site pharmacist.

In the repeat-dose study, three cohorts received S/GSK1394572 as a suspension at doses of 10, 25, and 50 mg in the fasting state, once daily for 10 days. The 10-mg and 50-mg dose cohorts consisted of 8 active and 2 placebo subjects. The 25-mg dose cohort consisted of 10 active and 2 placebo subjects. All subjects in this cohort received 3 mg midazolam (MDZ), a CYP3A4 metabolic probe, given orally as the commercially available syrup alone on day −1 and with S/GSK1394572 25 mg on day 10.

For both trials, all subjects were admitted to the research unit on the evening prior to dosing with the investigational product (IP) and remained there until the 72-h postdose assessments were completed. Vital signs, electrocardiograms (ECGs), and laboratory tests were performed prior to dosing and through 72 h postdosing. Adverse events (AEs) were collected by patient interviews at regular intervals. The severities of AEs and laboratory abnormalities were assessed using the National Institute of Allergy and Infectious Diseases, Division of AIDS (DAIDS), grading table (5). Serial PK blood samples for plasma S/GSK1349572 concentrations were obtained predose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48, and 72 h postdose in the single-dose study. For the multiple-dose study, serial PK blood samples were obtained on days −1 and 10 for plasma MDZ concentrations and on days 1 and 10 predose and at 0.25, 0.5, 1, 2, 4, 8, 12, 24, 48, and 72 h postdose for plasma S/GSK1349572 concentrations. Daily predose samples were also collected on days 3 through 9. All subjects provided informed written consent, and the protocol was approved by the Ohio Valley Institutional Review Board and the Covance Clinical Research Unit (CRU) Institutional Review Board.

Bioanalytical methods.

Following extraction from plasma by protein precipitation, S/GSK1349572 and MDZ concentrations were determined by a validated high-performance liquid chromatography-tandem mass spectrometry method (PE Sciex Analyst, version 1.4.1; SMS2000, version 2.0) using a TurboIonSpray source and multiple reaction monitoring at GlaxoSmithKline. For analysis of S/GSK1349572, [²H₇ ¹⁵N]S/GSK1349572 was used as an internal standard. The validated linear concentration range was 5 to 5,000 ng/ml, and three concentrations of quality control (QC) samples were included in each run, at 20, 400, and 4,000 ng/ml. Based on the results of the analysis of these QC samples, the bias ranged from 0.0 to 3.5%, and the intra- and interassay coefficients of variation (CVs) were less than or equal to 7.2% and 5.4%, respectively. For MDZ, [¹³C₃ ²H₃]midazolam was used as an internal standard. The validated linear concentration range was 0.35 to 72 ng/ml, and three concentrations of QC samples were included in each run, at 1.4, 7.0, and 58 ng/ml. Based on the results of the analysis of these QC samples, the bias ranged from 2.8 to 9.4%, and the intra- and interassay coefficients of variation were less than or equal to 6.8% and 4.9%, respectively.

Pharmacokinetic analysis.

A noncompartmental pharmacokinetic analysis of the concentration-time data was performed with WinNonlin (version 4.1; Pharsight Corporation, Mountain View, CA). Plasma PK parameters for S/GSK1349572 were calculated for each treatment as follows: for the single-dose study and day 1 in the repeat-dose study, the area under the concentration-time curve from time zero to the last measurable concentration (AUC_0-t), the area under the concentration-time curve extrapolated to infinity (AUC_0-∞), the maximum observed concentration of the drug in plasma (C_max), the time of the maximum observed concentration of the drug in plasma (T_max), the terminal elimination phase half-life (t_1/2), the apparent oral clearance (CL/F), and the observed time point immediately prior to the first quantifiable concentration (T_lag) were assessed. In the repeat-dose study, the area under the concentration-time curve over a dosing interval (AUC_0-τ), C_ma_x, T_max, the predose concentration (C₀), the concentration at the end of the dosing interval (C_τ), and the minimum observed concentration of the drug in plasma (C_min) were assessed for day 10. The following PK parameters were calculated for MDZ: AUC_0-t and AUC_0-∞. The actual elapsed time from dosing was used to estimate all individual PK parameters.

Statistical analysis.

Descriptive statistics, including geometric means and 95% confidence intervals (CIs), were calculated for all PK parameters and summarized by the type of treatment. The dose proportionality of S/GSK1349572 PK parameters (AUC_0-t, AUC_0-∞, C_max) from the single-dose study or day 1 in the repeat-dose study and from day 10 (AUC_0-τ, C_max, C_min, and C_τ) in the repeat-dose study was assessed using the power model y = α × dose^β, where y denotes the PK parameter being analyzed and α depends on the subject. Dose proportionality implies that β = 1 and was assessed by estimating β along with its 90% CI. For the repeat-dose escalation, the time invariance ratios (ratio of AUC_0-τ on day 10 to AUC_0-∞ on day 1) and accumulation ratios (ratios of the day 10 AUC_0-τ to the day 1 AUC_0-24, of the day 10 C_max to the day 1 C_max, and of the day 10 C_τ to the day 1 C₂₄) were calculated as geometric least squares (GLS) means and assessed by analysis of variance with subjects as the random effect and day as the fixed effect. Achievement of steady state was assessed by visual inspection of plots and by calculation of the point estimate and 90% CI of the slope of the linear regression of the day 5 to 10 predose concentrations versus day by dose group. To support the claim that steady state was reached, the predose concentration slope estimate had to be close to zero or the 90% CI for the slope estimate had to include zero.

Following log transformation, the plasma midazolam AUC_0-t was analyzed using a mixed-effects model with treatment as the fixed effect and subject as the random effect. Point estimates and their associated 90% CIs were constructed for the differences between treatments (MDZ plus S/GSK1349572 minus MDZ alone). The point estimates and their associated 90% CIs were then back-transformed to provide point estimates and 90% CIs for the treatment ratios (MDZ plus S/GSK1349572 versus MDZ alone).

RESULTS

Demographics.

In the single-dose study, 20 male and 5 female subjects were enrolled. Thirteen subjects (52%) completed all study visits as planned. Twelve subjects (9 active, 3 on placebo), five of whom were replaced, withdrew from the study for the following reasons: investigator discretion (n = 7 [28%]), AEs (n = 2 [8%]), withdrawal of consent (n = 2 [8%]), and loss to follow up (n = 1 [4%]). The majority of subjects (85%) were white/Caucasian. The mean age was 31.8 years (range, 19 to 54 years), and the mean body mass index was 25.0 (range, 20.9 to 29.1). In the multiple-dose study, 27 male and 5 female subjects were enrolled. One (3%) subject was withdrawn due to investigator discretion. White/Caucasian subjects constituted 75% of the population. The mean age was 31.7 years (range, 18 to 50 years), and the mean body mass index was 25.1 (range, 19.7 to 30.0). For both studies, demographic characteristics were similar across treatment groups.

Safety. (i) Single-dose study.

S/GSK1349572 was generally well tolerated in single doses ranging from 2 mg to 100 mg. No serious or severe adverse events were reported during the study. Two subjects withdrew from the study due to AEs: one with a moderate, non-drug-related viral upper respiratory tract infection and the other with a mild, possibly drug-related, asymptomatic, 3-beat run of nonsustained ventricular tachycardia (a follow-up cardiology evaluation was unremarkable for cardiovascular disease). Few subjects in any treatment group reported any AEs, and the proportions of subjects reporting any AE were similar for the different treatment groups (Table (Table1).1). Two AEs, headache and somnolence, were reported by more than one subject. The majority of AEs were mild, and no dose-related trends were noted. AEs were infrequently considered by the investigator to be related to S/GSK1349572 (Table (Table1).1). No clinically significant trends in postdose laboratory abnormalities were evident. No clinical laboratory values were reported as AEs, and no grade 4 laboratory abnormalities were reported during the entire study. One subject experienced a treatment-emergent, grade 3, asymptomatic lipase elevation (263 U/liter; the normal level is 7 to 58 U/liter) 3 days after receiving 2 mg of S/GSK1349572; the lipase abnormality resolved 4 days later. This subject did not receive additional doses of S/GSK1349572. No clinically significant vital sign or ECG (telemetry or 12-lead ECG) abnormalities or trends were observed.

TABLE 1.

Adverse events reported by two or more subjects during the single-dose study with S/GSK1349572

(ii) Repeat-dose study.

Repeat doses of S/GSK1349572 ranging from 10 mg to 50 mg were generally well tolerated. No serious or severe AEs were reported. No subjects withdrew from the study due to an AE. Most AEs were mild in severity. No dose-related trends in AEs were observed, although more subjects receiving 50 mg S/GSK1349572 reported more AEs than subjects in the other treatment groups (Table (Table2).2). Headache and pharyngolaryngeal pain were the most common AEs. No clinically significant trends in postdose laboratory abnormalities, vital signs, or ECG values were evident. No grade 4 laboratory abnormalities were noted. One subject receiving 50 mg S/GSK1349572 had a treatment-emergent, asymptomatic grade 3 triglyceride elevation (728 mg/dl; normal level, 0 to 149 mg/dl), grade 2 alanine aminotransferase elevation (178 U/liter; normal level, 0 to 41 U/liter), and grade 2 aspartate transaminase elevation (101 U/liter; normal level, 0 to 36 U/liter) on day 10; other liver chemistries (including alkaline phosphatase and bilirubin) were within normal limits. This subject did not receive additional doses of S/GSK1349572, and all lab abnormalities resolved within 1 week.

TABLE 2.

Adverse events reported by two or more subjects in the repeat-dose study

Pharmacokinetics. (i) Single-dose study.

The mean concentration-time profiles following administration of single doses are shown in Fig. Fig.1.1. S/GSK1349572 was readily absorbed; the median maximum concentration was achieved between 0.5 and 1.25 h postdose. Plasma S/GSK1349572 concentrations subsequently declined biexponentially. Single-dose pharmacokinetic parameters of S/GSK1349572 are shown in Table Table3.3. The terminal elimination half-life (t_1/2) ranged from 13 to 15 h. The AUC increased proportionally as the dose increased from 2 mg to 100 mg, and C_max was slightly less than dose proportional.

FIG. 1.

Mean (± standard deviation) plasma concentration-time profiles for S/GSK1349572 following single-dose administration. The horizontal line represents an in vitro protein-adjusted IC₉₀ of 0.064 μg/ml.

TABLE 3.

Summary of selected plasma S/GSK1349572 pharmacokinetic parameters following single-dose administration

(ii) Repeat-dose study.

The day 10 pharmacokinetic parameters are shown in Table Table4,4, and mean concentration-time profiles are shown in Fig. Fig.2.2. AUC_0-τ and C_τ showed dose-proportional increases over the 10- to 50-mg dose range following repeat-dose administration. The increase in C_max was slightly less than dose proportional. C_min coincided with C₀, while C_τ values were slightly higher than C₀ and C_min. Steady-state was achieved by approximately day 5 of dosing. Following repeat-dose administration, the accumulation ratios for AUC, C_max, and C_τ ranged from 1.24 to 1.42, from 1.16 to 1.36, and from 1.29 to 1.53, respectively, across different dose levels. S/GSK1349572 exhibited time-independent pharmacokinetics in the dose range of 10 mg to 50 mg.

TABLE 4.

Summary of selected plasma S/GSK1349572 pharmacokinetic parameters following day 10 dose administration

FIG. 2.

Mean (± standard deviation) plasma concentration-time profiles for S/GSK1349572 on day 10 following repeat-dose administration. The horizontal line represents an in vitro protein-adjusted IC₉₀ of 0.064 μg/ml.

The plasma midazolam AUC_0-t values were similar for the coadministration of midazolam with 25 mg S/GSK1349572 (15.4 ng·h/ml on day 10 [CV, 41%]) and administration of midazolam alone (16.3 ng·h/ml on day −1 [CV, 23%]); the GLS mean ratio was 0.945 (90% CI, 0.815, 1.10). These data demonstrate that S/GSK1349572 does not induce or inhibit the CYP3A isozyme in vivo.

DISCUSSION

Integrase is an attractive target for HIV therapy, because it is an essential enzyme required for HIV replication. The primary role of integrase is to catalyze the insertion of viral DNA into the chromosomes of infected cells. Inhibition of this viral enzyme produces potent viral load declines in short-term monotherapy studies that are equal to or greater than those produced by previous drug classes (2, 3).

This was the first study that assessed the safety, tolerability, and plasma pharmacokinetics of S/GSK1349572 in healthy subjects. Single doses ranged from 2 mg to 100 mg, and repeat doses ranged from 10 mg to 50 mg once daily. S/GSK1349572 was safe and well tolerated across all doses for single- and repeat-dose administration. During the single-dose study, the most frequent AEs were headache and somnolence. During the repeat-dose study, headache and pharyngolaryngeal pain were the most commonly reported AEs. These AEs are common in phase I studies and may have been caused in part by confinement in the clinical unit, where subjects had caffeine restrictions and were at risk of viral infections due to the time of year. One subject in the single-dose study was noted to have asymptomatic lipase elevation, but no trend in lipase abnormalities was noted across all doses. Additionally, one subject in the repeat-dose study had asymptomatic triglyceride and liver enzyme elevations. The triglyceride abnormalities preceded the liver enzyme elevations, so it is plausible that the lipid abnormality caused the hepatitis. No trends in lipid or liver chemistry abnormalities were noted over all the dosing groups. No secondary cause for the pancreatic, lipid, or liver enzyme abnormalities was observed, so causality by S/GSK1349572 could not be excluded.

Following once-daily administration of S/GSK1349572, concentrations in plasma reached steady state by approximately 5 days of dosing, and moderate accumulation, with accumulation ratios ranging from 1.18 to 1.53 across different dose levels, was observed. These data are consistent with the observed half-life of 13 to 15 h. Low to moderate intersubject variability was observed in both single- and repeat-dose S/GSK1349572 PK, with the CV ranging from 9% to 41%. This is in contrast to a higher variability seen with raltegravir and most protease inhibitors (1, 3). The more predictable PK profile suggests a lower likelihood that subjects receiving S/GSK1349572 will fall at the extremes of exposures, which could result in toxicity or therapeutic failure, and provides a good foundation for understanding of the PK/pharmacodynamic relationship.

Coadministration of repeat doses of 25 mg S/GSK1349572 with a single dose of 3 mg midazolam resulted in no significant change in the plasma midazolam AUC, indicating no induction or inhibition effect of S/GSK1349572 on CYP3A activity. Thus, S/GSK1349572 is unlikely to affect the exposure of CYP3A substrates following coadministration. This is consistent with in vitro findings. In addition, preclinical studies suggest that glucuronidation is the primary pathway of metabolism, suggesting that S/GSK1349572 may demonstrate a drug interaction profile different from those of protease inhibitors and nonnucleoside reverse transcriptase inhibitors.

The PK parameter that best predicts efficacy for integrase inhibitors has not been well described. Recent data suggest that plasma raltegravir concentrations do not have a significant role in predicting efficacy (8). However, a monotherapy study with elvitegravir demonstrated that the C_min showed a strong correlation with antiviral activity (2). The good oral bioavailability of S/GSK1349572, combined with its moderate elimination half-life, results in once-daily dosing that achieves trough concentrations exceeding the protein-adjusted target concentration for HIV (0.064 μg/ml) by 5- to 26-fold, depending on the dose (Fig. (Fig.2).2). If trough concentrations are predictive of antiviral efficacy, the large inhibitory quotient (C_trough/90% inhibitory concentration) for S/GSK1349572 suggests that the compound will have potent activity in HIV-infected individuals.

The suspension formulation in this study was used to obtain an early evaluation of the pharmacokinetics of S/GSK1349572. Subsequently, a tablet formulation has been developed and is being used for studies of HIV-infected subjects. Ongoing dose-ranging trials are evaluating doses across the range of 10 mg to 50 mg once daily. Additional studies are evaluating the compound's potential for drug interactions. S/GSK1349572 demonstrates the profile of a next-generation integrase inhibitor with pharmacokinetics that allow once-daily, low milligram doses to achieve therapeutic concentrations without the need for pharmacokinetic boosters.

Acknowledgments

We thank all of the study volunteers and study site staff for their contributions to these studies.

Footnotes

Published ahead of print on 2 November 2009.

^†The authors have paid a fee to allow immediate free access to this article.

REFERENCES

1. Back, D., G. Gatti, C. Fletcher, R. Garaffo, R. Haubrich, R. Hoetelmans, M. Kurowski, A. Luber, C. Merry, and C. F. Perno. 2002. Therapeutic drug monitoring in HIV infection: current status and future directions. AIDS 16(Suppl. 1):S5-S37. [PubMed]

2. DeJesus, E., D. Berger, M. Markowitz, C. Cohen, T. Hawkins, P. Ruane, R. Elion, C. Farthing, L. Zhong, A. K. Cheng, D. McColl, and B. P. Kearney for the 183-0101 Study Team. 2006. Antiviral activity, pharmacokinetics, and dose response of the HIV-1 integrase inhibitor GS-9137 (JTK-303) in treatment-naïve and treatment-experienced patients. J. Acquir. Immune Defic. Syndr. 43:1-5. [PubMed]

3. Markowitz, M., J. O. Morales-Ramirez, B. Y. Nguyen, C. M. Kovacs, R. T. Steigbigel, D. A. Cooper, R. Liporace, R. Schwartz, R. Isaacs, L. R. Gilde, L. Wenning, J. Zhao, and H. Teppler. 2006. Antiretroviral activity, pharmacokinetics, and tolerability of MK-0518, a novel inhibitor of HIV-1 integrase, dosed as monotherapy for 10 days in treatment-naive HIV-1 infected individuals. J. Acquir. Immune Defic. Syndr. 43:509-515. [PubMed]

4. Markowitz, M., B. Y. Nguyen, E. Gotuzzo, F. Mendo, W. Ratanasuwan, C. Kovacs, G. Prada, J. O. Morales-Ramirez, C. S. Crumpacker, R. D. Isaacs, L. R. Gilde, H. Wan, M. D. Miller, L. A. Wenning, and H. Teppler; Protocol 004 Part II Study Team. 2007. Rapid and durable antiretroviral effect of the HIV-1 integrase inhibitor raltegravir as part of combination therapy in treatment-naive patients with HIV-1 infection: results of a 48-week controlled study. J. Acquir. Immune Defic. Syndr. 46:125-133. [PubMed]

5. National Institutes of Allergy and Infectious Diseases (NIAID), Division of Acquired Immunodeficiency Syndrome (DAIDS). December 2004. Table for grading the severity of adult and pediatric adverse events, version 1.0. http://rcc.tech-res.com/Document/safetyandpharmacovigilance/DAIDS_AE_GradingTable_Clarification_August2009_Final.pdf.

6. Pommier, Y., A. A. Johnson, and C. Marchand. 2005. Integrase inhibitors to treat HIV/AIDS. Nat. Rev. Drug Discov. 4:236-248. [PubMed]

7. Steigbigel, R. T., D. A. Cooper, P. N. Kumar, J. E. Eron, M. Schechter, M. Markowitz, M. R. Loutfy, J. L. Lennox, J. M. Gatell, J. K. Rockstroh, C. Katlama, P. Yeni, A. Lazzarin, B. Clotet, J. Zhao, J. Chen, D. M. Ryan, R. R. Rhodes, J. A. Killar, L. R. Gilde, K. M. Strohaier, A. R. Meibohm, M. D. Miller, D. J. Hazuda, M. L. Nessly, M. J. DiNubile, R. D. Isaacs, B. Y. Nguyen, and H. Teppler; BENCHMRK Study Teams. 2008. Raltegravir with optimized background therapy for resistant HIV-1 infection. N. Engl. J. Med. 359:339-354. [PubMed]

8. Wenning, L. A., E. Hwang, B. Y. Nguyen, H. Teppler, R. Danovich, M. Iwamoto, J. Wagner, D. Panebianco, and J. Stone. 2008. Pharmacokinetic/pharmacodynamic analyses for raltegravir in phase III studies in treatment-experienced HIV-infected patients following 48 weeks of treatment, abstr. H-4054. 48th Intersci. Conf. Antimicrob. Agents Chemother., Washington, DC. American Society for Microbiology, Washington, DC.

9. Zolopa, A. R., H. Lampiris, G. Blick, C. Walworth, L. Zhong, S. L. Chuck, B. P. Kearney, J. Enejosa, and A. K. Cheng. 2007. The HIV integrase inhibitor elvitegravir has potent and durable activity in treatment-experienced patients with active optimized background therapy, abstr. H-714. 47th Intersci. Conf. Antimicrob. Agents Chemother., Chicago, IL. American Society for Microbiology, Washington, DC.

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