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.
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.
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 . 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 . 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 .
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.
All listed authors meet the criteria for authorship set forth by the International Committee for Medical Journal Editors. The authors wish to acknowledge the following individuals for their contribution to the study design, implementation and interpretation, or editorial assistance during the development of this manuscript: Julie Borland, Yu Lou, and Todd Parker.
S.M. was the clinical leader and GlaxoSmithKline medical monitor for the study, contributed to study design, protocol development, and data analysis, and was the primary author for the manuscript, with principal writing responsibilities.
L.S. was the investigator with primary management responsibilities in the study and provided critical review of the data and contributed to the editing/writing of the manuscript.
E.D.J. was the investigator with primary management responsibilities in the study and provided critical review of the data and contributed to the editing/writing of the manuscript.
T.H. was the investigator with primary management responsibilities in the study and provided critical review of the data and contributed to the editing/writing of the manuscript.
L.M.C. was the investigator with primary management responsibilities in the study and provided critical review of the data and contributed to the editing/writing of the manuscript.
I.S. was the pharmacokineticist for the study, contributed to study design, protocol development, and data analysis, and was the author for the pharmacokinetic sections of the manuscript.
R.S. was the study manager and contributed to study design, protocol development, data analysis, and writing/editing of the manuscript.
S.C. was the statistician and contributed to study design, protocol development, data analysis (developed statistical analysis plan), and writing/editing of the manuscript.
T.F. was the project leader and contributed to study design, protocol development, data analysis, and writing/editing of the manuscript.
M.U. was the virologist and contributed to study design, protocol development, data analysis (analyzed resistance data), and writing/editing of the manuscript.
S.P. was the clinical pharmacologist and contributed to study design, protocol development, data analysis, and writing/editing of the manuscript.
J.L. was the investigator with primary management responsibilities in the study and provided critical review of the data and contributed to the editing/writing of the manuscript.
Conflicts of interest
Funding for this study was provided by Shionogi-GlaxoSmithKline Pharmaceuticals LLC. E.D.J. has received research support from Abbott Laboratories, Achillion, Avexa, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Hoffman LaRoche Laboratories, Merck, Pfizer, Schering Plough, Taimed, Tobira, Tibotec, and Vertex Pharmaceuticals. He is currently serving as a consultant or has received honoraria from Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck, Tibotec, and Vertex. He is on the Speakers Bureau at Gilead Sciences, Merck, Tibotec, and Virco. T.H. is currently serving as a consultant to Gilead Sciences, Merck, and Tibotec. He has previously served as a consultant to Bristol-Myers Squibb. He is on the Speakers Bureau at Bristol-Myers Squibb, Gilead Sciences, Merck, and Tibotec. He is currently receiving research support from Gilead Sciences, GlaxoSmithKline, Pfizer, Salix Pharmaceuticals, Tibotec, and ViiV Healthcare. He has previously received research support from Bristol-Myers Squibb, Merck, and Napo. S.M., I.S., J.B., R.S., S.C., Y.L., M.U., and S.P. are employees of GlaxoSmithKline and receive company stock as part of their incentive packages. T.F. is an employee of Shionogi & Co. Ltd. L.S. is currently serving on the Speakers Bureau at Pfizer and ViiV Healthcare.
J.L. and L.M.C. have no conflicts of interest.
1. Serrao E, Odde S, Ramkumar K, Neamati N. Raltegravir, elvitegravir, and metoogravir: the birth of ‘me-too’ HIV-1 integrase inhibitors.Retrovirology
. [Accessed 11 June 2010]
2. Hawkins T. Understanding and managing the adverse effects of antiretroviral therapy
. Antiviral Res
3. Markowitz M, Nguyen B-Y, Gotuzzo E, Mendo F, Ratanasuwan W, Kovacs C, et al.
, and the Protocol 004 Part II Study Team. 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
4. Steigbigel RT, Cooper DA, Kumar PN, Eron JE, Schechter M, Markowitz M, et al.
, for the BENCHMRK Study Teams. Raltegravir with optimized background therapy for resistant HIV-1 infection.N Engl J Med
5. Cooper DA, Steigbigel RT, Gatell JM, Rockstroh JK, Katlama C, Yeni P, et al.
, for the BENCHMRK Study Teams. Subgroup and resistance analyses of raltegravir for resistant HIV-1 infection.N Engl J Med
6. DeJesus E, Cohen C, Elion R, Ortiz R, Maroldo L, Franson S, et al.
, for the 183–0101 Study Team. First report of raltegravir (RAL, MK-0518) use after virologic rebound on elvitegravir (EVT, GS 9137) [abstract TUPEB032].Presented at the 4th IAS Conference on HIV Pathogenesis, Treatment and Prevention
; 22–25 July 2007; Sydney, Australia.
7. Sato A, Kobayashi M, Yoshinaga T, Fujiwara T, Underwood M, Johns B, et al.S/GSK1349572 is a potent next generation HIV integrase inhibitor.Poster presented at the 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention
; 19–22 July 2009; Cape Town, South Africa.
8. Underwood M, Johns B, Sato A, Fujiwara T, Spreen W. S/GSK1349572: a next generation integrase inhibitor with activity against integrase inhibitor-resistant clinical isolates from patients experiencing virologic failure while on raltegravir therapy.Poster presented at the 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention
; 19–22 July 2009; Cape Town, South Africa.
9. Min S, Song I, Borland J, Chen S, Lou Y, Fujiwara T, et al.Pharmacokinetics (PK) and safety in healthy subjects of S/GSK1349572, a next generation, once-daily HIV integrase inhibitor (INI).Poster presented at the 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention
; 19–22 July 2009; Cape Town, South Africa.
10. Fransen S, Gupta S, Paxinos EE, Huang W, Parkin N, Miller M, et al.Integrase inhibitor (IN) susceptibility can be measured using recombinant viruses that express patient virus IN alone, or in combination with protease (PR) and reverse transcriptase (RT).Poster presented at the 12th Conference on Retroviruses and Opportunistic Infections
; 22–25 February 2005; Boston, MA.
12. Akaike H. A new look at the statistical model identification
. IEEE Trans Automat Contr
13. Hazuda DJ, Miller MD, Nguyen BY, Zhao J., for the P005 Study Team. Resistance to the HIV-integrase inhibitor raltegravir: analysis of protocol 005, a Phase II study in patients with triple-class resistant HIV-1 infection.Antivir Ther
14. McColl DJ, Fransen S, Gupta S, Parkin N, Margot N, Chuck S, et al. Resistance and cross-resistance to first generation integrase inhibitors: insights from a Phase II study of elvitegravir (GS-9137)
. Antivir Ther
16. Shafer RW. Rationale and uses of a public HIV drug-resistance database
. J Infect Dis
2006; 194 (Suppl 1):S51–S58.
17. Sato A, Seki T, Kobayashi M, Yoshinaga T, Fujiwara T, Underwood M, et al.In vitro passage of drug resistant HIV-1 against a next generation integrase inhibitor (INI), S/GSK1349572.Poster presented at the 49th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy Meeting
; 12–15 September 2009; San Francisco, CA.
18. Markowitz M, Morales-Ramirez JO, Nguyen B-Y, Kovacs CM, Steigbigel RT, Cooper DA, et al.
, and the Protocol 004 Study Team. 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
19. DeJesus E, Berger D, Markowitz M, Cohen C, Hawkins T, Ruane P, et al. for the 183-0101 Study TeamAntiviral activity, pharmacokinetics, and dose response of the HIV-1 integrase inhibitor GS-9137 (JTK-303) in treatment-naive and treatment-experienced patients
. J Acquir Immune Defic Syndr
20. Goebel F, Yakovlev A, Pozniak AL, Vinogradova E, Boogaerts G, Hoetelmans R, et al. Short-term antiviral activity of TMC278 – a novel NNRTI – in treatment-naive HIV-1-infected subjects
21. Gruzdev B, Rakhmanova A, Doubovskaya E, Yakovlev A, Peeters M, Rinehart A, et al. A randomized, double-blind, placebo-controlled trial of TMC125 as 7-day monotherapy in antiretroviral naive, HIV-1 infected subjects
22. Fätkenheuer G, Staszewski S, Plettenburg A, Hackman F, Layton G, McFadyen L, et al.Short-term monotherapy with UK-453
061, a novel NNRTI, reduces viral load in HIV infected patients [abstract WESS202].Presented at the 4th IAS Conference on HIV Pathogenesis, Treatment and Prevention
; 22–25 July 2007; Sydney, Australia.
23. Adkins JC, Noble S. Efavirenz.Drugs
:1055–1064; discussion 1065–1056.
24. Kilby JM, Hopkins S, Venetta TM, DiMassimo B, Cloud GA, Lee JY, et al. Potent suppression of HIV-1 replication in humans by T-20, a peptide inhibitor of gp41-mediated virus entry
. Nat Med
25. Murphy RL, Brun S, Hicks C, Eron JJ, Gulick R, King M, et al. ABT-378/ritonavir plus stavudine and lamivudine for the treatment of antiretroviral-naive adults with HIV-1 infection: 48-week results
26. Pozniak AL, Fatkenheuer G, Johnson M, Hopelman IM, Rockstroh J, Goebel F, et al.Effect of short-term monotherapy with UK-427
857 on viral load in HIV-infected patients.Slides presented at the 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy
; 14–17 September 2003; Chicago, IL.
Keywords:© 2011 Lippincott Williams & Wilkins, Inc.
antiretroviral therapy; dose response; integrase inhibitor; pharmacodynamics; pharmacokinetics