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Antiviral activity, safety, and pharmacokinetics/pharmacodynamics of dolutegravir as 10-day monotherapy in HIV-1-infected adults
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AIDS:
10 September 2011
"On average, plasma steady-state Cτ was three and 13 times higher than the in-vitro protein-adjusted IC90 of viral suppression (0.064 μg/ml) at doses of 10 and 50 mg, respectively.....Monotherapy with DTG once daily was associated with potent antiretroviral activity in a phase IIa trial, with a 2.5 log10 mean decline in HIV-1 RNA after 10 days of treatment with a 50-mg dose [18-26]. At the 10-mg dose, observed antiviral responses (2.0 log10 mean decline in HIV-1 RNA) were similar to or higher than those seen in short-term studies of other antiretrovirals, including INIs [8,9]. The majority of patients who received the two highest doses (10 or 50 mg) achieved plasma HIV-1 RNA levels less than 400 copies/ml on day 11 (10 mg, five of nine or 56%; 50 mg, nine of 10 or 90%) despite not receiving any other antiretroviral. In addition, seven of 10 patients (70%) in the 50-mg dose group achieved an HIV-1 RNA level less than 50 copies/ml during the study. Importantly, a sustained virologic response was also observed from day 11 to 14 among patients receiving the 50-mg dose, without continued dosing of DTG. On the basis of the observed half-life of DTG and modeled pharmacokinetic exposures between day 11 and 14 (data on file, GlaxoSmithKline, Research Triangle Park, North Carolina, USA), the likely explanation is that DTG exposures remained above the protein-adjusted IC50 (0.016 μg/ml) through day 14.......Monotherapy with DTG once daily was associated with potent antiretroviral activity in a phase IIa trial, with a 2.5 log10 mean decline in HIV-1 RNA after 10 days of treatment with a 50-mg dose [18-26]. At the 10-mg dose, observed antiviral responses (2.0 log10 mean decline in HIV-1 RNA) were similar to or higher than those seen in short-term studies of other antiretrovirals, including INIs [8,9]. The majority of patients who received the two highest doses (10 or 50 mg) achieved plasma HIV-1 RNA levels less than 400 copies/ml on day 11 (10 mg, five of nine or 56%; 50 mg, nine of 10 or 90%) despite not receiving any other antiretroviral. In addition, seven of 10 patients (70%) in the 50-mg dose group achieved an HIV-1 RNA level less than 50 copies/ml during the study. Importantly, a sustained virologic response was also observed from day 11 to 14 among patients receiving the 50-mg dose, without continued dosing of DTG. On the basis of the observed half-life of DTG and modeled pharmacokinetic exposures between day 11 and 14 (data on file, GlaxoSmithKline, Research Triangle Park, North Carolina, USA), the likely explanation is that DTG exposures remained above the protein-adjusted IC50 (0.016 μg/ml) through day 14."
Min, Sherenea; Sloan, Louisb; DeJesus, Edwinc; Hawkins, Trevord; McCurdy, Lewise; Song, Ivya; Stroder, Richarda; Chen, Shuguanga; Underwood, Marka; Fujiwara, Tamiof; Piscitelli, Stephena; Lalezari, Jayg bNorth Texas Infectious Disease Consultants PA, Dallas, TexasaGlaxoSmithKline, Research Triangle Park, North Carolina cOrlando Immunology Center, Orlando, Florida dSouthwest CARE Center, Santa Fe, New Mexico eID Consultants PA, Charlotte, North Carolina, USA fShionogi & Co. Ltd, Osaka, Japan gQuest Clinical Research, San Francisco, California, USA. Correspondence to Sherene Min, MD, MPH, GlaxoSmithKline, Infectious Diseases, 5 Moore Drive, Research Triangle Park, NC 27709, USA. Tel: +1 919 483 7203; fax: +1 919 315 5814; e-mail: sherene.s.min@gsk.com
Abstract
Objective: To evaluate the antiviral activity, safety, pharmacokinetics, and pharmacokinetics/pharmacodynamics of dolutegravir (DTG), a next-generation HIV integrase inhibitor (INI), as short-term monotherapy.
Design: A phase IIa, randomized, double-blind, dose-ranging study.
Methods: In this study, INI-naive, HIV-1-infected adults currently off antiretroviral therapy were randomized to receive DTG (2, 10, or 50 mg) or placebo once daily for 10 days in an eight active and two placebo randomization scheme per DTG dose. Placebo patients were pooled for the purpose of analysis.
Results: Thirty-five patients (n = 9 for DTG 2 and 10 mg, n = 10 for DTG 50 mg, and n = 7 for placebo) were enrolled. Baseline characteristics were similar across dose groups. Significant reductions in plasma HIV-1 RNA from baseline to day 11 were observed for all DTG dose groups compared with placebo (P < 0.001), with a mean decrease of 1.51-2.46 log10 copies/ml. In addition, a well characterized dose-response relationship was observed for viral load decrease. Most patients (seven of 10, 70%) receiving DTG 50 mg achieved plasma HIV-1 RNA less than 50 copies/ml. The pharmacokinetic variability was low (coefficient of variation, range 25-50%). Plasma HIV-1 RNA reduction was best predicted by Cτ using an Emax model. The most common adverse events were diarrhea, fatigue, and headache; the majority of adverse events were mild or moderate in severity.
Conclusion: Dolutegravir demonstrated potent antiviral activity, good short-term tolerability, low pharmacokinetic variability, and a predictable pharmacokinetics/pharmacodynamics relationship, which support once-daily dosing without a pharmacokinetic booster in integrase-naive patients in future studies.
Introduction
With the application of highly active antiretroviral therapy (ART) using antiretrovirals with improved potency, tolerability, and resistance profiles, people with HIV are living longer and receiving longer-term care [1,2]. However, there is still a need for additional treatment options that enhance adherence and have better tolerability, higher barriers to resistance, distinct resistance profiles, and fewer drug-drug interactions. These principles have been guiding the development of new agents that are not only focused on traditional targets but also on novel therapeutic targets. The newest class of drugs in HIV treatment is the integrase inhibitor (INI) class.
At the time of this study, the only INI approved by Food and Drug Administration, raltegravir, had been shown to effectively reduce viral load when given twice daily in combination therapy in both ART-naive and ART-experienced patients with HIV-1 [3,4]. Treatment-emergent resistance, however, has emerged in patients who fail first-generation, INI-containing regimens [5]. Additionally, cross-resistance exists between first-generation INIs; patients experiencing virologic failure with elvitegravir-resistant virus did not adequately respond to raltegravir treatment [6]. To meet the evolving needs of people with HIV, the next generation of INIs should have the following characteristics: improved convenience (once-daily dosing), enhanced potency with a higher genetic barrier to resistance, and a low risk of cross-resistance [1]. Dolutegravir (DTG), discovered by a Shionogi and GlaxoSmithKline research collaboration, is a novel HIV-1 integrase strand transfer inhibitor selected for its activity against INI resistance and its potential for higher genetic barrier to resistance in vitro, in addition to its favorable pharmacokinetic properties [7,8]. Early clinical data in healthy individuals demonstrated low pharmacokinetic variability and concentration-time profiles, supporting a once-daily, low-dose regimen without a pharmacokinetic booster [9]. The half-life of DTG was approximately 15 h and the trough concentration for the 50-mg suspension dose was approximately 25-fold above the protein-adjusted 90% inhibitory concentration (IC90) for HIV-1. The objective of this study was to evaluate the antiretroviral activity, safety, pharmacokinetic, and pharmacokinetic/pharmacodynamics of a range of DTG doses (2-50 mg) in short-term monotherapy with DTG in approximately 30 HIV-1-infected patients.
Discussion
Monotherapy with DTG once daily was associated with potent antiretroviral activity in a phase IIa trial, with a 2.5 log10 mean decline in HIV-1 RNA after 10 days of treatment with a 50-mg dose [18-26]. At the 10-mg dose, observed antiviral responses (2.0 log10 mean decline in HIV-1 RNA) were similar to or higher than those seen in short-term studies of other antiretrovirals, including INIs [8,9]. The majority of patients who received the two highest doses (10 or 50 mg) achieved plasma HIV-1 RNA levels less than 400 copies/ml on day 11 (10 mg, five of nine or 56%; 50 mg, nine of 10 or 90%) despite not receiving any other antiretroviral. In addition, seven of 10 patients (70%) in the 50-mg dose group achieved an HIV-1 RNA level less than 50 copies/ml during the study. Importantly, a sustained virologic response was also observed from day 11 to 14 among patients receiving the 50-mg dose, without continued dosing of DTG. On the basis of the observed half-life of DTG and modeled pharmacokinetic exposures between day 11 and 14 (data on file, GlaxoSmithKline, Research Triangle Park, North Carolina, USA), the likely explanation is that DTG exposures remained above the protein-adjusted IC50 (0.016 μg/ml) through day 14. In addition to the antiviral activity observed, patients who received DTG had median increases in CD4+ cell counts on day 11 compared with decreases in those receiving placebo.
No clinically significant genotypic or phenotypic changes to DTG or other INIs were observed in patients receiving DTG or placebo. Observed missing resistance data were typically associated with low plasma viral RNA levels on day 11. In cases wherein assays failed and plasma RNA levels met assay recommendations (e.g., as occurred in one of seven placebo virus examples), assay failure causes may have included reduced viral fitness or compromised sample processing. No patients had raltegravir-associated or elvitegravir-associated resistance mutations, with the exception of one patient virus. For that patient virus, the HIV-1 RNA result on day 11 was below the limit of detection, which limits the reliability of the genotype result; the change was at a nonsignature position for raltegravir (position 74) and not associated with a change in susceptibility to DTG. No resistance mutations identified in DTG in-vitro passage studies were observed in any patient virus. Similar numbers of genotypic changes were observed in patients receiving DTG and placebo. Additionally, no clinically significant changes in DTG susceptibility were observed. One placebo patient had a minor change in susceptibility (1.36-fold) to DTG, which is consistent with the approximately two-fold variability in DTG susceptibility of the integrase phenotype assay (data on file, GlaxoSmithKline, Research Triangle Park, North Carolina, USA). Therefore, there was no evidence of genotypic or phenotypic resistance to DTG in patients receiving DTG or placebo.
DTG tablets are dosed once daily without the need for a pharmacokinetic booster, supported by a half-life of approximately 12 h and exposures with the 10 and 50 mg doses that remain well above the protein-adjusted IC90 (0.064 μg/ml) throughout the dosing interval. The inhibitory quotient (Cτ divided by protein-adjusted IC90) for the 10 and 50 mg doses was 3 and 13, respectively, which suggests that DTG will have good activity in longer term combination treatment studies. A well characterized exposure-response relationship was demonstrated; levels of antiviral activity increased with increasing doses of DTG. The finding that Cτ was the pharmacokinetic parameter that best predicted a reduction in plasma viral load from baseline to day 11 is consistent with the observation that antiviral activity is associated with the maintenance of therapeutic plasma concentrations throughout the dosing interval, as was also observed in a trial with the boosted INI elvitegravir [19]. However, the current study with DTG did not differentiate among pharmacokinetic parameters (AUC0-τ, Cmax, and Cτ), given that all treatments were administered once daily. This well described exposure-response relationship distinguishes DTG from raltegravir in which plasma exposure has not been shown to correlate with clinical outcome [14]. The low interpatient pharmacokinetic variability and predictable pharmacokinetic/pharmacodynamic relationship of DTG provide greater confidence that the doses selected for dose-ranging phase IIb trials will demonstrate potent antiviral activity.
In this short-term monotherapy study, DTG was generally well tolerated in HIV-infected adult patients and no major safety issues or dose-related trends were identified. Overall, the safety profile observed in HIV-1-infected patients was similar to that previously observed in both single-dose and short-term repeat-dose studies of DTG suspension in healthy adult individuals [9].
These results support expanded evaluation of DTG in larger and longer term phase IIb dose-ranging studies of HIV-1-infected patients; these ongoing clinical studies will assess the long-term efficacy of DTG in combination with other antiretroviral agents. Given its potent antiviral activity, distinct resistance profile, predictable exposure-response relationship, and unboosted, low-dose, once-daily dosing profile, DTG has considerable promise as a next-generation INI, with the potential to deliver benefits for HIV-infected patients across the treatment spectrum.
Results
Patients
The planned sample size was 30 patients. Due to rapid screening and enrollment, a total of 35 patients (28 in the DTG treatment arms and seven in the placebo group) were randomized to dose groups and completed all study visits between 25 June 2008 and 26 August 2008. Demographics and baseline characteristics were similar among the four dose groups (Table 1). Approximately one-third (10/35, 29%) of all patients had received ART before study entry: a nucleoside or nucleotide reverse transcriptase inhibitor for 10 of 35 (29%) and a nonnucleoside reverse transcriptase or protease inhibitor for five (14%). For patients who had received antiretroviral treatment in the past, adequate treatment options to construct HIV therapy with at least three active antiretrovirals for future treatment were verified prior to enrollment, based on review and agreement by the investigator and the GlaxoSmithKline medical monitor.
Efficacy
Patients in all DTG dose groups demonstrated a statistically significant reduction in plasma HIV-1 RNA from baseline to day 11 compared with placebo (P < 0.001; Table 2). In addition, a well characterized dose-response relationship was observed (Fig. 1). In patients receiving DTG 50 mg once daily, antiviral response was sustained between day 11 and 14 despite dosing discontinuation on day 10 (Fig. 1). Furthermore, a higher proportion of patients who received DTG 50 mg had less than 400 or less than 50 copies/ml of plasma HIV-1 RNA at nadir compared with those who received DTG 2 or 10 mg (Table 2). Patients receiving DTG 50 mg had the most rapid HIV-1 RNA decline (Fig. 1). Numeric increases in CD4+ cell counts were observed for patients in all DTG dose groups on day 11 (median change, +15 to +106 cells/μl), but CD4+ cell counts tended to decrease in patients receiving placebo (median change -28.5). No patients experienced a new or recurrent HIV-associated condition or disease progression during the study.
Pharmacokinetics
Although all 28 patients in the DTG dose groups provided blood samples for pharmacokinetic analysis, two patients in the 10-mg dose group were not included in the pharmacokinetic summary population because of protocol deviations in dosing (one patient received 20 mg of DTG on day 1 and one patient missed a 10-mg dose on day 7). All patients receiving DTG had detectable concentrations on day 1 (after dosing commenced) and day 10. DTG was readily absorbed, with the maximum concentration achieved at a median of approximately 1.5-2.5 h after dosing and a mean t1/2 of 11.1-12.0 h (Table 3). Plasma concentrations of DTG reached steady state by day 7 of dosing. After 10 days of dosing, the accumulation ratios for AUC0-τ, Cmax, and Cτ were estimated to be 1.25-1.43, 1.23-1.40, and 1.27-1.42, respectively, across all dose levels. In addition, the increase in DTG exposure (AUC0-τ and Cmax) with increasing dose was slightly less than dose proportional after both single-dose (day 1) and repeat-dose administration (day 10). On average, plasma steady-state Cτ was three and 13 times higher than the in-vitro protein-adjusted IC90 of viral suppression (0.064 μg/ml) at doses of 10 and 50 mg, respectively.
Significant negative correlations between DTG exposure and change in plasma HIV-1 RNA from baseline to day 11 (i.e., greater antiviral activity with higher DTG plasma exposure) were observed. When relationships between various pharmacokinetic parameters and pharmacodynamic measure (HIV-1 RNA) were explored using linear and Emax models, the exposure-response relationship was best described by an Emax model with Emax fixed to 2.6, Hill factor fixed to 1, and pharmacokinetic parameter on the linear scale. Using this model, Cτ was the pharmacokinetic parameter that best predicted day 11 plasma viral load reduction from baseline or maximum plasma viral load reduction from baseline (Fig. 2).
Viral genotyping and phenotyping
Genotypic and phenotypic data were available at baseline and day 11 for six of seven patient viruses within the placebo group. Of the patients receiving DTG, genotypic and phenotypic data were available at baseline and on day 11 for 19 and 18 patient viruses, respectively. No raltegravir-associated or elvitegravir-associated resistance mutations at codons 92, 138, 140, 143, 148, or 155 [13,14], or other resistance-associated substitutions as listed in the Stanford HIV Drug Resistance Database [15,16], were observed during therapy, with the exception of one patient. In this patient receiving DTG 2 mg, a change at the nonsignature position 74 of L to mixture I/L/M was observed without a corresponding phenotypic change. This patient had a day 11 HIV-1 RNA less than 50 copies/ml. None of the currently identified mutations selected by DTG during in-vitro passage with wild-type HIV-1 (at codons 92, 153, and 193) [7,17] were observed.
The number and position of amino acid changes from day 1 to 11 were evaluated in placebo and DTG patients. Genotypic changes were common in evaluable patient viruses from the placebo (83%, five of six) and the DTG (85%, 17 of 20) groups between day 1 and 11. In placebo patients, the greatest number of genotypic changes was observed at position 196 (n = 2). For patients receiving DTG, genotypic changes for more than two patient viruses from day 1 to 11 were observed only at position 112 (n = 4), three in the 2-mg and one in the 50-mg dose groups.
Finally, there was no significant decrease in DTG susceptibility from day 1 to 11 for any patient. The largest decrease in susceptibility from day 1 to 11 was a 1.36-fold change in one patient in the placebo group.
Safety
DTG was generally well tolerated. There were no deaths, serious adverse events, or withdrawals during the study. Drug-related adverse events were reported by 16 of 35 patients (46%), and the proportion of patients who reported drug-related adverse events was similar across DTG dose groups (2 and 10 mg: three of nine, 33%; 50 mg: five of 10, 50%), although there was a higher percentage in the placebo group (five of seven, 71%). The most frequent drug-related adverse event was diarrhea (2 and 10 mg: one of nine, 11%; 50 mg: two of 10, 20%; placebo: three of seven, 43%). No drug-related adverse events occurred with greater frequency in a DTG dose group than in the placebo group, and no dose-related trends were observed for adverse events. Most adverse events were mild to moderate in severity, with the exception of four severe adverse events reported by one patient each: hypertriglyceridemia (10 mg), lipase increase (10 mg), migraine (50 mg), and night sweats (placebo).
There were no consistent or clinically significant changes in hematology, clinical chemistry, vital signs, or urinalysis values. Two patients had treatment-emergent, grade 3 laboratory abnormalities after receiving 10 mg of DTG. On the last day of dosing, one patient had an asymptomatic grade 3 lipase increase, which resolved by the end of follow-up (day 21). Another patient had an asymptomatic grade 3 triglyceride elevation, which resolved with continued dosing and was not considered drug related. No clinically significant electrocardiogram abnormalities or trends (i.e., no QTc >480 ms or QTc change >60 ms) were observed.
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