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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
  JAIDS Journal of Acquired Immune Deficiency Syndromes: Volume 43(5) 15 December 2006 pp 509-515
[Rapid Communication]
Markowitz, Martin MD*; Morales-Ramirez, Javier O MD; Nguyen, Bach-Yen MD; Kovacs, Colin M MD; Steigbigel, Roy T MD; Cooper, David A MD, DSc; Liporace, Ralph MD#; Schwartz, Robert MD**; Isaacs, Robin MD; Gilde, Lucinda R BS; Wenning, Larissa PhD; Zhao, Jing PhD; Teppler, Hedy MD; and the Protocol 004 Study Team
From the *Aaron Diamond AIDS Research Center, The Rockefeller University, New York, NY; Clinical Research Puerto Rico, Inc., San Juan, PR; Merck Research Laboratories, Merck & Co., Inc., West Point, PA; Canadian Immunodeficiency Research Collaborative, Toronto, Ontario, Canada; State University of New York, Stony Brook, NY; St. Vincent's Hospital, and University of New South Wales, Sydney, Australia; #Albany Medical College, Albany, NY; and **Associates in Research, Fort Myers, FL.
Background: MK-0518 is a novel HIV-1 integrase strand transfer inhibitor with potent in vitro activity against HIV-1 (95% inhibitory concentration [IC95] = 33 nM in 50% human serum) and good bioavailability in uninfected subjects. This study explored the antiretroviral activity and safety of MK-0518 versus placebo for 10 days as monotherapy in antiretroviral therapy-naive HIV-1-infected patients with plasma HIV-1 RNA levels of at least 5000 copies/mL and CD4+ T-cell counts of at least 100 cells/mm3.
Methods: This was a multicenter, double-blind, randomized, placebo-controlled 2-part study, with the first part using MK-0518 in 1 of 4 doses (100, 200, 400, and 600 mg) versus placebo (randomized 1:1:1:1:1) given twice daily for 10 days of monotherapy. Patients were monitored for safety, pharmacokinetic parameters, and antiretroviral effect.
Results: Thirty-five patients were enrolled (6-8 patients per treatment group) and completed 10 days of therapy; the mean baseline log10 HIV RNA level ranged from 4.5 to 5.0 copies/mL in each group. On day 10, the mean decrease from baseline in the log10 HIV RNA level was -0.2 copies/mL for the placebo group and -1.9, -2.0, -1.7 and -2.2 log10 copies/mL for the MK-0518 100-, 200-, 400-, and 600-mg treatment groups, respectively. All dose groups had superior antiretroviral activity compared with placebo (P < 0.001 for comparison of each dose with placebo). At least 50% of patients in each MK-0518 dose group achieved an HIV RNA level <400 copies/mL by day 10. Mean trough MK-0518 concentrations at each dose exceeded the IC95 of 33 nM. Study therapy was generally well tolerated. The most common adverse experiences were headache and dizziness; these were similar between active and control groups. There were no discontinuations because of adverse experiences and no serious adverse experiences.
Advances in the understanding and treatment of HIV-1 infection have dramatically altered the morbidity and mortality associated with HIV-1 infection.1,2 Current therapies have been shown to exert potent and durable antiviral effects associated with immune reconstitution. Yet, the HIV-1 treatment landscape remains far from ideal.
The need for new drugs is constant and is a reflection of myriad issues. First and foremost are short- and long-term drug toxicities. In addition, primary and secondary drug resistance remains a serious problem. Currently, up to 25% of those newly infected harbor a virus resistant to at least 1 antiviral agent.3 Recent data suggest that primary resistance to nonnucleoside reverse transcriptase inhibitors in a variety of populations, including women using single-dose nevirapine to prevent mother-to-child transmission,4 adolescents,5 and men who have sex with men,3 may be as high as 15%.
Currently available oral medications in common use essentially target the viral reverse transcriptase or protease enzymes. The third enzyme encoded by the viral polymerase is integrase. HIV-1 integrase is encoded solely by the HIV-1genome and is essential for viral replication. Integrase inserts the viral DNA into the cellular genome via a pathway that includes 2 distinctive catalytic reactions: the 3_ endonucleolytic processing of the viral DNA ends and the subsequent strand transfer or integration of viral and cellular DNA.6,7 Loss of integrase activity results in the inability of the virus to complete its life cycle, and therefore provides a unique and specific antiviral target for drug development. The work of Hazuda and colleagues8 paved the way for the identification of clinically relevant inhibitors of HIV-1 integrase. With the development of a reliable biochemical screen, selective compounds that act as strand transfer inhibitors with antiviral activity have been identified and tested.8 One of these integrase inhibitors, L-000870812, exhibited highly robust antiviral activity in rhesus macaques infected with an HIV-simian immunodeficiency virus (SIV) chimeric virus, with a reduction in levels of plasma RNA from 107 to <250 copies/mL.9
MK-0518 is an investigational HIV-1 integrase inhibitor with potent in vitro activity, exhibiting a 95% inhibitory concentration (IC95) of 33 nM in the presence of 50% human serum. It is active against a wide range of wild-type and multidrug-resistant HIV-1 clinical isolates and has potent activity against viruses using CCR5 and/or CXCR4 coreceptors for entry.10,11 We present here the initial results of a 10-day monotherapy proof-of-concept study to establish the antiviral activity, pharmacokinetic (PK) profile, and tolerability of MK-0518 in a cohort of antiretroviral therapy (ART)-naive HIV-1-infected individuals.12 This article reports the data from the first part of a 2-part study in which the monotherapy phase is followed by a longer term combination therapy phase trial of MK-0518 versus efavirenz, each combined with 2 nucleoside reverse transcriptase inhibitors.
This was a multicenter, double-blind, randomized, placebo-controlled, dose-ranging study conducted in the United States, Australia, and Canada, which enrolled 35 HIV-infected patients who were ART naive. The protocol was approved by the institutional review board or ethical review committee of each of the 11 participating sites; written informed consent was obtained from each subject before study entry.
Study Population
Male and female subjects aged 18 years or older were eligible for the study if they were HIV-1-seropositive and had a plasma HIV-1 RNA level of 5000 copies/mL or greater and a CD4+ T-cell count of at least 100 cells/mm3 at screening. Patients were excluded if they received any form of approved or experimental ART or were previously treated with adefovir or lamivudine for any other viral infection for more than 7 days. Eligibility criteria also included hemoglobin ≥9.0 g/dL (female subject) or ≥10.0 g/dL (male subject); absolute neutrophil count ≥1000 cells/mm3; platelet count >100,000 cells/mm3; bilirubin ≦ upper limit of normal (ULN); alkaline phosphatase, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) all <1.5 times ULN; and creatinine within normal limits. Patients were excluded for evidence of active hepatitis, including hepatitis B and C virus, and for use of immune-based therapy or investigational agents within 1 month of study treatment. Prohibited medications included carbamazepine, phenobarbital, phenytoin, primidone, rifabutin, rifampin, herbal remedies such as St. John's wort and garlic supplements, and gemfibrozil. In addition, anticipating the use of efavirenz in part 2 of this study, medications contraindicated for use with efavirenz were prohibited in this study.
Study Design
This was the first part of a multicenter, double-blind (with in-house blinding), randomized, controlled, 2-part, dose-ranging study in ART-naive patients with HIV infection. Patients were stratified at entry by initial plasma HIV-1 RNA level (> or <50,000 copies/mL) and randomly assigned to 1 of 5 treatment groups for 10 days: MK-0518 (4 dose levels) or a matching placebo administered orally, without regard to food, at a dose strength of 100, 200, 400, or 600 mg twice daily. Central randomization with an interactive voice response system was used. Medication adherence was assessed by diary card and pill count. Study patients were seen in the clinic at screening; randomization (day 1); on days 2, 3, 4, 5, 8, and 10; and 14 days after treatment termination (day 24). Physical examination and safety laboratory assessments were performed at screening and on days 1, 5, 10, and 24. Pregnancy tests were performed on female patients of childbearing potential at screening and randomization (day 1). Plasma was collected for HIV-1 RNA levels at screening; before the first dose; 6 and 12 hours after the dose on day 1; and on days 2, 3, 4, 5, 8, 10, and 24. Plasma HIV-1 RNA levels were determined using the AMPLICOR HIV-1 Monitor Assay, version 1.5; if the result was below the level of quantification (LoQ) of 400 copies/mL, the UltraSensitive HIV-1 Monitor Assay (LoQ = 50 copies/mL) was used (both by Roche Molecular Diagnostics, Alameda, CA). A full PK profile was performed after the morning dose on day 10; plasma was collected before the first dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours after the dose and was shipped to BASi Northwest Laboratory (McMinnville, OR). Patients fasted overnight before the day 10 PK sampling and remained fasted until ~4 hours after dosing; after that time, there were no dietary restrictions. Drug concentrations were determined via high-performance liquid chromatography mass spectrometry/mass spectrometry (HPLC-MS/MS) using a validated assay with a lower LoQ of 2 ng/mL (4.5 nM) (Clinical Drug Metabolism; Merck Research Laboratories, West Point, PA, unpublished data). All patients who received study medication were included in the analysis of tolerability. Patients were evaluated for the occurrence of adverse events at each study visit. Laboratory monitoring included a complete blood cell count with differential and platelets and a full chemistry panel, including liver function tests, blood urea nitrogen (BUN), creatinine, amylase, lipase, electrolytes, and a fasting lipid profile. All safety laboratory results obtained and adverse events that occurred while subjects were on study therapy or within 14 days after discontinuation of study therapy were included.
Statistical Analyses
Antiretroviral Activity

The study hypothesis tested whether MK-0518 given twice daily for 10 days at the specified doses has superior antiviral activity compared with placebo, as measured by differences from baseline to day 10 in plasma HIV-1 RNA level (log10 copies/mL). If the difference of change from baseline in HIV RNA on day 10 between the MK-0518 groups and the placebo group is at least 1.5 log10, with a sample size of more than 6 patients per treatment group, it would give a power of >99.3% to claim that MK-0518 is superior to placebo. Plasma HIV-1 RNA changes were calculated based on levels measured by the AMPLICOR HIV-1 Monitor Standard Assay (version 1.5) with an LoQ of 400 copies/mL. Baseline measurements were defined as the randomization/day 1 value before dosing for each patient. HIV-1 RNA values less than the LoQ were imputed as LoQ (400 copies/mL) if a signal was detected or as 0.5 times the LoQ (200 copies/mL) if no signal was detected. Two-sided 95% confidence intervals (CIs) for the difference in changes from baseline in plasma HIV-1 RNA (log10 copies/mL) at each time point between each dose of MK-0518 and placebo were estimated using the t-distribution. The proportion of patients achieving HIV-1 RNA levels less than the LoQ of the AMPLICOR HIV-1 Monitor Standard Assay (400 copies/mL), the proportion of patients achieving HIV-1 RNA levels less than the LoQ of the UltraSensitive HIV-1 Monitor Assay (50 copies/mL), and change from baseline in CD4 cell counts were also summarized.
Steady-State Pharmacokinetics
Plasma concentrations in molar units (nM) and nominal sampling times were used to determine PK parameters for each subject. The area under the plasma concentration curve over the dosing interval (AUC0-12h) was calculated using the linear trapezoidal method for ascending concentrations and the log trapezoidal method for descending concentrations. Maximum plasma concentrations (Cmax), time to Cmax (Tmax), and the plasma concentration at the end of the dosing interval (C12h, trough) were obtained by inspection of the plasma concentration data. For the PK data, summary statistics for the PK parameters C12h, AUC0-12h, Cmax, and Tmax are presented by dose group.
Adverse Events
All clinical and laboratory adverse experiences were summarized by treatment group. The maximum intensity of clinical adverse experiences was reported according to the following criteria: mild (awareness of sign or symptom but easily tolerated), moderate (discomfort enough to cause interference with usual activity), and severe (incapacitating with inability to work or do usual activity). Safety laboratory values during treatment and follow-up were examined according to the 1992 Division of AIDS (DAIDS) toxicity guidelines for adults (available at: ) as well. Formal statistical testing was neither prespecified nor performed. Because this study is currently ongoing in the blind combination therapy phase, these data are presented as combined across the MK-0518 groups to avoid unblinding of the treatment assignments.
Study Subjects

Of the 35 patients enrolled, 94% were male, 63% were white, and the mean age was 40 years (Table 1). Twenty-eight patients received MK-0518 (7 on 100 mg twice daily, 7 on 200 mg twice daily, 6 on 400 mg twice daily, and 8 on 600 mg twice daily) and 7 received a placebo twice daily. All patients completed the 10-day monotherapy treatment period. The mean baseline log10 HIV RNA levels were 4.65, 4.53, 4.58, and 4.97 log10 copies/mL for the 4 MK-0518 dose groups, respectively, and 4.77 log10 copies/mL for the placebo group (see Table 1).
Antiretroviral Activity and Pharmacokinetics
All treated subjects responded to MK-0518 (Fig. 1). The viral decay rates were similar among all MK groups, and each was significantly greater compared with placebo (P < 0.001). There were no differences in the slope of HIV RNA decline (log10 copies/mL/d) from day 1 to day 10 for patients by stratification variable of entry HIV RNA level > or <50,000 copies/mL. Nevertheless, a greater decline from baseline at day 10 was observed in those with higher baseline RNA values, whereas patients with lower baseline RNA values more frequently achieved RNA levels <400 copies/mL by day 10. By day 10, mean decreases in log10 HIV RNA level of 1.93, 1.98, 1.66 and 2.16 copies/mL were observed for MK-0518 administered at doses of 100, 200, 400, and 600 mg twice daily, respectively, and all were significantly greater than that observed for the placebo group (P < 0.001 for all groups) (Fig. 2; Table 2). There was no apparent dose response, and no statistically significant differences were observed among the MK-0518 dose groups. By day 10, the proportions of patients achieving HIV RNA levels <400 copies/mL were 57% (4 of 7 patients), 57% (4 of 7 patients), 50% (3 of 6 patients), and 50% (4 of 8 patients) for groups administered MK-0518 at doses of 100, 200, 400, and 600 mg twice daily, respectively. None of the placebo recipients achieved HIV RNA levels <400 copies/mL. Plasma HIV RNA levels <50 copies/mL by UltraSensitive assay were also observed by day 10 for at least 1 patient in each MK-0518 group (see Table 2). Numeric increases in CD4 cell count were observed on day 10 for all MK-0518 dose groups, but these changes were not statistically significant (data not shown).


On day 10, a PK evaluation was performed on all subjects as detailed previously. Geometric mean plasma concentrations of MK-0518 at trough (C12h) were lowest in the 100-mg dose group and increased with dose. Geometric mean values for Cmax and AUC0-12h increased up to the 400-mg dose and were similar for the 400 and 600 mg regimens (Table 3). Because of the close spacing between these doses and fairly large intersubject variability in the PK profiles, it is not clear if this represents a true lack of dose proportionality or is just a reflection of the variability and small number of patients in each dose group. Half-life values could not be accurately estimated in this study, but the data seem to be generally consistent with the plasma concentration profile shape previously observed in healthy volunteers, where MK-0518 concentrations declined from Cmax in a biexponential manner with an initial half-life of approximately 1 hour and a terminal half-life of approximately 7 to 12 hours (Fig. 3).13 The C12h plasma concentrations (geometric mean) in all dosing groups exceeded 33 nM, the mean in vitro IC95 of MK-0518 for wild-type HIV-1 in the presence of 50% normal human serum. Although 3 of 6 individuals in the 100-mg dosing group had MK-0518 C12h levels less than the IC95 of 33 nM, these 3 patients achieved HIV RNA values <400 copies/mL or a >2 log10 decline in HIV RNA by day 10.


Tolerability of MK-0518
Overall, MK-0518 was generally well tolerated. There were no serious adverse experiences and no discontinuations because of adverse experiences. Clinical adverse experiences, irrespective of drug relation, were reported in 19 of 35 patients; these were generally transient and mild to moderate in severity. Headache and dizziness were most commonly reported across the treatment groups, including the placebo group. Drug-related clinical adverse experiences were reported in 8 patients among the 4 MK-0518 treatment groups and in 2 patients in the placebo group and included constipation, flatulence, stomach discomfort, chills, fatigue, malaise, anorexia, dizziness, headache, disorientation, increased heart rate, and hyperhidrosis; all were mild or moderate in intensity (Table 4). There were no apparent dose-related toxicities.
One laboratory adverse experience in the MK-0518 100-mg group of increased ALT was reported on day 5 (grade 1 per DAIDS criteria) and was considered to be drug related. This adverse experience resolved by day 10 without interruption of therapy. No other laboratory adverse experiences were reported. No grade 3 or 4 laboratory toxicities were observed.
This first study of MK-0518 in HIV-1-infected individuals unequivocally demonstrates its robust antiretroviral activity, favorable PK profile, and short-term tolerability when given twice daily at 100, 200, 400, and 600 mg dosing levels. PK parameters were in a similar range as those reported for HIV-1-uninfected subjects.13 Geometric mean values for C12h exceeded the IC95 in 50% human serum at all doses, which is consistent with twice-daily dosing. The approximately 2-fold log reduction in HIV-1 plasma viral load over 10 days is comparable to that observed with potent antiretroviral agents that target HIV-1 reverse transcriptase or protease and to the antiretroviral effect seen when combinations of at least 3 antiretroviral agents are used.14-16 The antiretroviral activity was comparably robust at all doses tested, with at least half of patients reaching plasma HIV-1 RNA levels <400 copies/mL by day 10 of monotherapy. There was no evidence to show a PK/pharmacodynamic relation, because all MK-0518 groups responded well (ie, the entire range of PK parameter values observed in this study was associated with pharmacodynamic efficacy). Based on these results, the second phase of this study has been initiated, during which MK-0518 at the 4 doses studied is to be compared with efavirenz dosed once daily, all coadministered with once-daily tenofovir and lamivudine.
Certain properties of MK-0518 are important considerations for its clinical use. It is primarily metabolized by the liver via glucuronidation and is neither an inducer nor an inhibitor of CYP3A4.17,18 This should clearly reduce potential drug interactions with other commonly used antiretroviral agents, especially the currently available protease inhibitors and nonnucleoside reverse transcriptase inhibitors. Specifically, there is no potential or need for boosting with CYP3A4 inhibitors such as ritonavir. Thus, use in salvage regimens, where the need is most acute, should be less complicated. Of note, there are no immediate changes in triglyceride or cholesterol levels (data not shown) such as may be seen with ritonavir and other protease inhibitors. Larger scale testing in various HIV-1-infected populations is currently underway and, ultimately, should better define the complete side effect profile of MK-0518. The introduction of a clinically relevant inhibitor of HIV-1 integrase represents a major advance in basic and clinical science. Efforts to target all 3 constitutive virally encoded enzymes required for viral replication have been accomplished successfully. How these compounds may ultimately be incorporated into the antiretroviral arsenal remains to be defined. Interim results from phase 2 trials in treatment-naive and treatment-experienced HIV-1-infected subjects harboring multidrug-resistant HIV-1 in combination regimens and at doses similar to those used in this study demonstrated that after 16 to 24 weeks, MK-0518 has sustained antiretroviral activity without substantial toxicity.19,20 If this observation is confirmed in the phase 3 studies now underway, MK-0518 should clearly be a welcome addition to the existing treatment options for those persons infected with HIV-1.
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