Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Antivirals for systemic use, other antivirals, ATC code: J05AJ03 
Mechanism of action

Dolutegravir inhibits HIV integrase by binding to the integrase active site and blocking the strand transfer step of retroviral Deoxyribonucleic acid (DNA) integration which is essential for the HIV replication cycle.
Pharmacodynamic effects

Antiviral activity in cell culture
The IC50 for dolutegravir in various labstrains using PBMC was 0.5 nM, and when using MT-4 cells it ranged from 0.7-2 nM. Similar IC50s were seen for clinical isolates without any major difference between subtypes; in a panel of 24 HIV-1 isolates of clades A, B, C, D, E, F and G and group O the mean IC50 value was 0.2 nM (range 0.02-2.14). The mean IC50 for 3 HIV-2 isolates was 0.18 nM (range 0.09-0.61).

Antiviral activity in combination with other antiviral agents
No antagonistic effects in vitro were seen with dolutegravir and other antiretrovirals tested: stavudine, abacavir, efavirenz, nevirapine, lopinavir, amprenavir, enfuvirtide, maraviroc and raltegravir. In addition, no antagonistic effects were seen for dolutegravir and adefovir, and ribavirin had no apparent effect on dolutegravir activity.

Effect of human serum
In 100% human serum, the mean protein fold shift was 75 fold, resulting in protein adjusted IC90 of 0.064 µg/mL.

Resistance

Resistance in vitro
Serial passage is used to study resistance evolution in vitro. When using the lab-strain HIV-1 IIIB during passage over 112 days, mutations selected appeared slowly, with substitutions at positions S153Y and F, resulting in a maximal fold change in susceptibility of 4 (range 2-4). These mutations were not selected in patients treated with dolutegravir in the clinical studies. Using strain NL432, mutations E92Q (FC 3) and G193E (also FC 3) were selected. The E92Q mutation has been selected in patients with pre-existing raltegravir resistance who were then treated with dolutegravir (listed as a secondary mutation for dolutegravir).

In further selection experiments using clinical isolates of subtype B, mutation R263K was seen in all five isolates (after 20 weeks and onwards). In subtype C (n=2) and A/G (n=2) isolates the integrase substitution R263K was selected in one isolate, and G118R in two isolates. R263K was reported from two ART experienced, INI naive individual patients with subtypes B and C in the clinical program, but without effects on dolutegravir susceptibility in vitro. G118R lowers the susceptibility to dolutegravir in site directed mutants (FC 10), but was not detected in patients receiving dolutegravir in the Phase III program.

Primary mutations for raltegravir/elvitegravir (Q148H/R/K, N155H, Y143R/H/C, E92Q and T66I) do not affect the in vitro susceptibility of dolutegravir as single mutations. When mutations listed as secondary integrase inhibitor associated mutations (for raltegravir/elvitegravir) are added to these primary mutations in experiments with site directed mutants, dolutegravir susceptibility is still unchanged (FC <2 vs wild type virus), except in the case of Q148-mutations, where a FC of 5-10 or higher is seen with combinations of certain secondary mutations. The effect by the Q148-mutations (H/R/K) was also verified in passage experiments with site directed mutants. In serial passage with strain NL432, starting with site directed mutants harbouring N155H or E92Q, no further selection of resistance was seen (FC unchanged around 1).
In contrast, starting with mutants harbouring mutation Q148H (FC 1), a variety of secondary mutations were seen with a consequent increase of FC to values >10.

A clinically relevant phenotypic cut-off value (FC vs wild type virus) has not been determined; genotypic resistance was a better predictor for outcome.

Seven hundred and five raltegravir resistant isolates from raltegravir experienced patients were analyzed for susceptibility to dolutegravir. Dolutegravir has a less than or equal to 10 FC against 94% of the 705 clinical isolates.


Resistance in vivo
In previously untreated patients receiving dolutegravir + 2 NRTIs in Phase IIb and Phase III, no development of resistance to the integrase class, or to the NRTI class was seen (n=1118 follow-up of 48-96 weeks). In previously untreated patients receiving dolutegravir + lamivudine in the GEMINI studies through week 144 (n=716), no development of resistance to the integrase class, or to the NRTI class was seen.

In patients with prior failed therapies, but naïve to the integrase class (SAILING study), integrase inhibitor substitutions were observed in 4/354 patients (follow-up 48 weeks) treated with dolutegravir, which was given in combination with an investigator selected background regimen (BR). Of these four, two subjects had a unique R263K integrase substitution, with a maximum FC of 1.93, one subject had a polymorphic V151V/I integrase substitution, with maximum FC of 0.92, and one subject had pre-existing integrase mutations and is assumed to have been integrase experienced or infected with integrase resistant virus by transmission. The R263K mutation was also selected in vitro (see above).

In the presence of integrase class-resistance (VIKING-3 study) the following mutations were selected in 32 patients with protocol defined virological failure (PDVF) through Week 24 and with paired genotypes (all treated with a 50 mg dose of dolutegravir film-coated tablets twice daily + optimized background agents): L74L/M (n=1), E92Q (n=2), T97A (n=9), E138K/A/T (n=8), G140S (n=2), Y143H (n=1), S147G (n=1), Q148H/K/R (n=4), and N155H (n=1) and E157E/Q (n=1). Treatment emergent integrase resistance typically appeared in patients with a history of the Q148-mutation (baseline or historic). Five further subjects experienced PDVF between weeks 24 and 48, and 2 of these 5 had treatment emergent mutations.
Treatment-emergent mutations or mixtures of mutations observed were L74I (n=1), N155H (n=2).

The VIKING-4 study examined dolutegravir (plus optimized background therapy) in subjects with primary genotypic resistance to INIs at Screening in 30 subjects. Treatment-emergent mutations observed were consistent with those observed in the VIKING-3 study.

In paediatric patients with prior failed therapies, but naïve to the integrase class, the integrase inhibitor substitution G118R was observed in 5/159 patients treated with dolutegravir, given in combination with an investigator selected background regimen. Of these five, 4 participants had additional integrase associated substitutions as follows: L74M, E138E/K, E92E/Q and T66I. Four of the 5 participants with emergent G118R had phenotypic data available. Dolutegravir FC (fold change as compared to wildtype virus) for these four participants ranged from 6 to 25-fold.

Effects on electrocardiogram

No relevant effects were seen on the QTc interval with doses exceeding the clinical dose by approximately three fold.

Clinical efficacy and safety

Previously untreated patients
The efficacy of dolutegravir in HIV-infected, therapy naïve subjects is based on the analyses of 96-week data from two randomized, international, double-blind, active-controlled trials, SPRING-2 (ING113086) and SINGLE (ING114467). This is supported by 96 week data from an open-label, randomized and active- controlled study FLAMINGO (ING114915) and additional data from the open-label phase of SINGLE to 144 weeks. The efficacy of dolutegravir in combination with lamivudine in adults is supported by 144-week data from two identical 148-week, randomised, multicentre, double-blind, non-inferiority studies GEMINI-1 (204861) and GEMINI-2 (205543).

In SPRING-2, 822 adults were randomized and received at least one dose of either dolutegravir 50 mg film- coated tablets once daily or raltegravir (RAL) 400 mg twice daily, both administered with either ABC/3TC or TDF/FTC. At baseline, median patient age was 36 years, 14% were female, 15% non-white, 11% had hepatitis B and/or C co-infection and 2% were CDC Class C, these characteristics were similar between treatment groups.


In SINGLE, 833 subjects were randomized and received at least one dose of either dolutegravir 50 mg film- coated tablets once daily with fixed-dose abacavir-lamivudine (Dolutegravir + ABC/3TC) or fixed-dose efavirenz-tenofovir-emtricitabine (EFV/TDF/FTC). At baseline, median patient age was 35 years, 16% were female, 32% non-white, 7% had hepatitis C co-infection and 4% were CDC Class C, these characteristics were similar between treatment groups.

The primary endpoint and other week 48 outcomes (including outcomes by key baseline covariates) for SPRING-2 and SINGLE are shown in Table 5.

Table 5 Response in SPRING-2 and SINGLE at 48 Weeks (Snapshot algorithm, <50 copies/mL) SPRING-2                              SINGLE
Dolutegravir     RAL 400 mg          Dolutegravir    EFV/TDF/FTC
50 mg Once      Twice Daily + 2         50 mg +         Once Daily
Daily + 2 NRTI          NRTI         ABC/3TC Once            N=419
N=411            N=411                Daily
N=414
HIV-1 RNA <50 copies/mL                    88%              85%                 88%               81% Treatment Difference*                 2.5% (95% CI: -2.2%, 7.1%)            7.4% (95% CI: 2.5%, 12.3%) Virologic non-response†                     5%               8%                  5%                6% HIV-1 RNA <50 copies/mL by baseline covariates
Baseline Viral Load
(cps/mL)
100,000                           267 / 297 (90%) 264 / 295 (89%) 253 / 280 (90%) 238 / 288 (83%) >100,000                            94 / 114 (82%)   87 / 116 (75%) 111 / 134 (83%) 100 / 131 (76%) Baseline CD4+ (cells/ mm3)
<200                                43 / 55 (78%)     34 / 50 (68%)       45 / 57 (79%)     48 / 62 (77%) 200 to <350                        128 / 144 (89%) 118 / 139 (85%) 143 / 163 (88%) 126 / 159 (79%)
350                               190 / 212 (90%) 199 / 222 (90%) 176 / 194 (91%) 164 / 198 (83%) NRTI backbone
ABC/3TC                            145 / 169 (86%) 142 / 164 (87%)             N/A               N/A TDF/FTC                            216 / 242 (89%) 209 / 247 (85%)             N/A               N/A Gender
Male                               308 / 348 (89%) 305 / 355 (86%) 307 / 347 (88%) 291 / 356 (82%) Female                              53 / 63 (84%)     46 / 56 (82%)       57 / 67 (85%)     47 / 63 (75%) Race
White                              306 / 346 (88%) 301 / 352 (86%) 255 / 284 (90%) 238 /285 (84%) African-America/African
55 / 65 (85%)     50 / 59 (85%)     109 / 130 (84%) 99 / 133 (74%)
Heritage/Other
Age (years)
<50                                 324/370 (88%)    312/365 (85%)       319/361 (88%)     302/375 (81%) 50                                  37/41 (90%)       39/46 (85%)         45/53 (85%)       36/44 (82%) Median CD4 change from
230              230                 246‡              187‡ baseline
* Adjusted for baseline stratification factors.
† Includes subjects who changed BR to new class or changed BR not permitted per protocol or due to lack of efficacy prior to Week 48 (for SPRING-2 only), subjects who discontinued prior to Week 48 for lack or loss of efficacy and subjects who are 50 copies in the 48 week window.
‡ Adjusted mean treatment difference was statistically significant (p<0.001) 
At week 48, dolutegravir was non-inferior to raltegravir in the SPRING-2 study, and in the SINGLE study dolutegravir + ABC/3TC was superior to efavirenz/TDF/FTC (p=0.003), table 5 above. In SINGLE, the median time to viral suppression was shorter in the dolutegravir treated patients (28 vs 84 days, (p<0.0001, analysis pre-specified and adjusted for multiplicity).

At week 96, results were consistent with those seen at week 48. In SPRING-2, dolutegravir was still non- 
inferior to raltegravir (viral suppression in 81% vs 76% of patients), and with a median change in CD4 count of 276 vs 264 cells/mm3, respectively. In SINGLE, dolutegravir + ABC/3TC was still superior to EFV/TDF/FTC (viral suppression in 80% vs 72%, treatment difference 8.0% (2.3, 13.8), p=0.006, and with an adjusted mean change in CD4 count of 325 vs 281 cells/ mm3, respectively. At 144 weeks in the open- label phase of SINGLE, virologic suppression was maintained, the dolutegravir + ABC/3TC arm (71%) was superior to the EFV/TDF/FTC arm (63%), treatment difference was 8.3% (2.0, 14.6).

In FLAMINGO (ING114915), an open-label, randomised and active-controlled study, 484 HIV-1 infected antiretroviral naïve adults received one dose of either dolutegravir 50 mg film-coated tablets once daily (n=242) or darunavir/ritonavir (DRV/r) 800 mg/100 mg once daily (n=242), both administered with either ABC/3TC or TDF/FTC. At baseline, median patient age was 34 years, 15% were female, 28% non-white, 10% had hepatitis B and/or C co-infection, and 3% were CDC Class C; these characteristics were similar between treatment groups. Virologic suppression (HIV-1 RNA <50 copies/mL) in the dolutegravir group (90%) was superior to the DRV/r group (83%) at 48 weeks. The adjusted difference in proportion and 95% CI were 7.1% (0.9, 13.2), p=0.025. At 96 weeks, virologic suppression in the dolutegravir group (80%) was superior to the DRV/r group (68%), (adjusted treatment difference [Dolutegravir-(DRV+RTV)]: 12.4%; 95% CI: [4.7, 20.2].

In GEMINI-1 (204861) and GEMINI-2 (205543), identical 148-week, randomised, double-blind studies, 1433 adult HIV-1 infected antiretroviral naïve subjects were randomised to either a two-drug regimen of dolutegravir 50 mg film-coated tablets plus lamivudine 300 mg once daily, or to a three-drug regimen of dolutegravir 50 mg film-coated tablets once daily with fixed dose TDF/FTC. Subjects were enrolled with a screening plasma HIV-1 RNA of 1000 c/mL to ≤500,000 c/mL. At baseline, in the pooled analysis, median patient age was 33 years, 15% were female, 31% non-white, 6% had hepatitis C co-infection and 9% were CDC Stage 3. Approximately one third of the patients were infected with an HIV non-B subtype; these characteristics were similar between treatment groups. Virologic suppression (HIV-1 RNA <50 copies/mL) in the dolutegravir plus lamivudine group was non-inferior to the dolutegravir plus TDF/FTC group at 48 weeks, as shown in Table 6. The results of the pooled analysis were in line with those of the individual studies, for which the primary endpoint (difference in proportion <50 copies/mL plasma HIV-1 RNA at week 48 based on the Snapshot algorithm) was met. The adjusted difference was -2.6% (95% CI: -6.7; 1.5) for GEMINI-1 and -0.7% (95% CI: -4.3; 2.9) for GEMINI-2 with a prespecified non-inferiority margin of 10%.

Table 6 Response (<50 cps/ml, snapshot) in GEMINI 1 + 2, pooled data at Week 48.
Dolutegravir + 3TC             Dolutegravir +
(N=716)                      TDF/FTC n/N (%)                       (N=717) n/N (%)
All patients                                    655/716 (91)                669/717 (93) adjusted diff -1.7% (CI95-4.4, 1.1) a
By BL HIV-1 RNA
≤100,000 cps/mL                             526/576 (91)                531/564 (94) >100,000 cps/mL                             129/140 (92)                138/153 (90) By CD4+
≤200 c/ mm3                                    50/63 (79)                  51/55 (93) >200 c/ mm3                                 605/653 (93)                618/662 (93) By HIV-1 subtype
B                                           424/467 (91)                452/488 (93) Non-B                                       231/249 (93)                217/229 (95) 
Rebound up to week 48 b                                    6 (<1)                     4 (<1) 
Mean change in CD4 count from
224                      217 baseline at Week 48, c/ mm3



a adjusted for BL stratification factors: Plasma HIV-1 RNA (≤100,000 cps/mL vs. >100,000 cps/mL) and CD4+ cell count (≤200 cells/mm3 vs. >200 cells/mm3).
b
Confirmed plasma HIV-1 RNA levels to ≥200 cps/mL after prior confirmed suppression to <200 cps/mL.

At 96 weeks and at 144 weeks in the GEMINI studies, the lower bound of the 95% confidence interval for the adjusted treatment difference of proportion of subjects with HIV-1 RNA <50 copies/mL (snapshot) was greater than the non-inferiority margin of -10%, for the individual studies as well as pooled analysis, see Table 7.

Table 7 Virologic Outcomes (snapshot algorithm) in GEMINI 1 + 2, pooled data at Weeks 96 and 144 GEMINI-1 and GEMINI-2 Pooled Data*
DTG +        DTG +      DTG +        DTG +
3TC       TDF/FTC       3TC       TDF/FTC
N=716        N=717      N=716        N=717
Week 96                Week 144
HIV-1 RNA <50 copies/mL                      86%           90%       82%           84% Treatment Difference†
-3.4% (-6.7, 0.0)       -1.8% (-5.8; 2.1)
(95% confidence intervals)
Virologic non response                        3%            2%        3%            3% Reasons
Data in window, ≥50 cps/mL                 <1%           <1%       <1%           <1% Discontinued, lack of efficacy              1%           <1%        1%           <1% Discontinued, other reasons, ≥50 cps/mL    <1%           <1%       <1%            2% Change in ART                              <1%           <1%       <1%           <1% No virologic data at Week 96/Week 144        11%            9%       15%           14% window
Reasons
Discontinued study due to AE or death       3%            3%        4%            4% Discontinued study for other reasons        8%            5%       11%            9% Loss to follow-up                         3%            1%        3%            3% Withdrew consent                          3%            2%        4%            3% Protocol deviations                       1%            1%        2%            1% Physicians decision                       1%           <1%        2%            1% Missing data in window, on study            0%           <1%       <1%           <1% DTG=Dolutegravir
* The results of the pooled analysis are in line with those of the individual studies.
† Based on CMH-stratified analysis adjusting for the following baseline stratification factors: Plasma HIV-1 RNA (≤100,000 c/mL vs. >100,000 c/mL) and CD4+ cell count (≤200 cells/mm3 vs. >200 cells/mm3).
Pooled analysis also stratified by study. Assessed using a non-inferiority margin of 10%.
N = Number of subjects in each treatment group


The mean increase in CD4+ T-cell counts through week 144 was 302 cells/mm3 in the dolutegravir plus lamivudine arm and 300 cells/mm3 in the dolutegravir plus tenofovir/emtricitabine arm.

Treatment emergent resistance in previously untreated patients failing therapy Through 96 weeks in SPRING-2 and FLAMINGO and 144 weeks in SINGLE, no cases of treatment emergent primary resistance to the integrase- or NRTI-class were seen in the dolutegravir-containing arms.
For the comparator arms, the same lack of treatment emergent resistance was also the case for patients treated with darunavir/r in FLAMINGO. In SPRING-2, four patients in the RAL-arm failed with major NRTI mutations and one with raltegravir resistance; in SINGLE, six patients in the EFV/TDF/FTC-arm failed with mutations associated with NNRTI resistance, and one developed a major NRTI mutation.
Through 144 weeks in the GEMINI-1 and GEMINI-2 studies, no cases of emergent resistance to the integrase- or NRTI-class were seen in either the Dolutegravir+3TC or comparator Dolutegravir+TDF/FTC arms.

Patients with prior treatment failure, but not exposed to the integrase class In the international multicentre, double-blind SAILING study (ING111762), 719 HIV-1 infected, antiretroviral therapy (ART)-experienced adults were randomized and received either dolutegravir 50 mg film-coated tablets once daily or raltegravir 400 mg twice daily with investigator selected background regimen consisting of up to 2 agents (including at least one fully active agent). At baseline, median patient age was 43 years, 32% were female, 50% non-white, 16% had hepatitis B and/or C co-infection, and 46% were CDC Class C. All patients had at least two class ART resistance, and 49% of subjects had at least 3- class ART resistance at baseline.

Week 48 outcomes (including outcomes by key baseline covariates) for SAILING are shown in Table 8.

Table 8 Response in SAILING at 48 Weeks (Snapshot algorithm, <50 copies/mL) Dolutegravir 50 mg       RAL 400 mg Twice
Once Daily + BR             Daily + BR
N=354§                   N=361§
HIV-1 RNA <50 copies/mL                                            71%                     64% Adjusted treatment difference‡                                    7.4% (95% CI: 0.7%, 14.2%) Virologic non-response                                             20%                     28% HIV-1 RNA <50 copies/mL by baseline covariates
Baseline Viral Load (copies/mL)
50,000 copies/mL                                          186 / 249 (75%)          180 / 254 (71%) >50,000 copies/mL                                           65 / 105 (62%)          50 / 107 (47%) Baseline CD4+ (cells/ mm3)
<50                                                          33 / 62 (53%)           30 / 59 (51%) 50 to <200                                                  77 / 111 (69%)          76 / 125 (61%) 200 to <350                                                  64 / 82 (78%)           53 / 79 (67%)
350                                                         77 / 99 (78%)           71 / 98 (72%) Background Regimen
Genotypic Susceptibility Score* <2                         155 / 216 (72%)          129 / 192 (67%) Genotypic Susceptibility Score* =2                          96 / 138 (70%)          101 / 169 (60%) Use of DRV in background regimen
No DRV use                                               143 / 214 (67%)          126 / 209 (60%) DRV use with primary PI mutations                          58 / 68 (85%)           50 / 75 (67%) DRV use without primary PI mutations                       50 / 72 (69%)           54 / 77 (70%) Gender
Male                                                       172 / 247 (70%)          156 / 238 (66%) Female                                                      79 / 107 (74%)          74 / 123 (60%) Race
White                                                      133 / 178 (75%)          125 / 175 (71%) African-America/African Heritage/Other                     118 / 175 (67%)          105 / 185 (57%) Age (years)
<50                                                        196 / 269 (73%)          172 / 277 (62%) 50                                                          55 / 85 (65%)           58 / 84 (69%) HIV sub type
Clade B                                                    173 / 241 (72%)          159 / 246 (65%) Clade C                                                      34 / 55 (62%)           29 / 48 (60%) Other†                                                       43 / 57 (75%)           42 / 67 (63%) 3
Mean increase in CD4+ T cell (cells/mm )                            162                    153 ‡ Adjusted for baseline stratification factors.
§ 4 subjects were excluded from the efficacy analysis due to data integrity at one study site *The Genotypic Susceptibility Score (GSS) was defined as the total number of ARTs in BR to which a subject’s viral isolate showed susceptibility at baseline based upon genotypic resistance tests.
†Other clades included: Complex (43), F1 (32), A1 (18), BF (14), all others <10.


In the SAILING study, virologic suppression (HIV-1 RNA <50 copies/mL) in the Tivicay arm (71%) was statistically superior to the raltegravir arm (64%), at Week 48 (p=0.03).

Statistically fewer subjects failed therapy with treatment-emergent integrase resistance on Tivicay (4/354, 1%) than on raltegravir (17/361, 5%) (p=0.003) (refer to section ‘Resistance in vivo’ above for details).

Patients with prior treatment failure that included an integrase inhibitor (and integrase class resistance) In the multicentre, open-label, single arm VIKING-3 study (ING112574), HIV-1 infected, ART-experienced adults with virological failure and current or historical evidence of raltegravir and/or elvitegravir resistance received a 50 mg dose of Tivicay film-coated tablets twice daily with the current failing background regimen for 7 days but with optimised background ART from Day 8. The study enrolled 183 patients, 133 with INI- resistance at Screening and 50 with only historical evidence of resistance (and not at Screening).
Raltegravir/elvitegravir was part of the current failing regimen in 98/183 patients (part of prior failing therapies in the others). At baseline, median patient age was 48 years, 23% were female, 29% non-white, and 20% had hepatitis B and/or C co-infection. Median baseline CD4+ was 140 cells/mm3, median duration of prior ART was 14 years, and 56% were CDC Class C. Subjects showed multiple class ART resistance at baseline: 79% had ≥2 NRTI, 75% ≥1 NNRTI, and 71% ≥2 PI major mutations; 62% had non-R5 virus.

Mean change from baseline in HIV RNA at day 8 (primary endpoint) was -1.4log10 copies/mL (95% CI -1.3 – -1.5log10, p<0.001). Response was associated with baseline INI mutation pathway, as shown in Table 9.

Table 9 Virologic response (day 8) after 7 days of functional monotherapy, in patients with RAL/EVG as part of current failing regimen, VIKING 3
Baseline parameters                                     Dolutegravir 50 mg BID N=88* n        Mean (SD) Plasma HIV-              Median
1 RNA log10 c/mL
Derived IN mutation group at
Baseline with ongoing RAL/EVG
Primary mutation other than             48              -1.59 (0.47)                  -1.64 Q148H/K/Ra
Q148+1 secondary mutationb              26              -1.14 (0.61)                  -1.08 b        14              -0.75 (0.84)                  -0.45
Q148+2 secondary mutations
*
Of 98 on RAL/EVG as part of current failing regimen, 88 had detectable primary INI mutations at Baseline and a Day 8 Plasma HIV-1 RNA outcome for evaluation a
Included primary IN resistance mutations N155H, Y143C/H/R, T66A, E92Q b
Secondary mutations from G140A/C/S, E138A/K/T, L74I.

In patients without a primary mutation detected at baseline (N=60) (i.e. RAL/EVG not part of current failing therapy) there was a 1.63 log10 reduction in viral load at day 8.

After the functional monotherapy phase, subjects had the opportunity to re-optimize their background regimen when possible. The overall response rate through 24 weeks of therapy, 69% (126/183), was generally sustained through 48 weeks with 116/183 (63%) of patients with HIV-1 RNA <50c/mL (ITT-E, Snapshot algorithm). When excluding patients who stopped therapy for non-efficacy reasons, and those with major protocol deviations (incorrect dolutegravir dosing, intake of prohibited co-medication), namely, “the Virological Outcome (VO)-population)”, the corresponding response rates were 75% (120/161, week 24) and 69% (111/160, week 48).

The response was lower when the Q148-mutation was present at baseline, and in particular in the presence of ≥2 secondary mutations, Table 10. The overall susceptibility score (OSS) of the optimised background regimen (OBR) was not associated with Week 24 response, nor with the week 48 response.


Table 10 Response by baseline Resistance, VIKING-3. VO Population (HIV-1 RNA <50 c/mL, Snapshot algorithm)
Week 48
Week 24 (N=161)
(N=160)
Derived IN Mutation                                                                          Total Group                          OSS=0         OSS=1           OSS=2    OSS>2       Total No primary IN mutation1                                                           45/55      38/55 2/2 (100%) 15/20 (75%) 19/21 (90%) 9/12 (75%)       (82%)      (69%)
Primary mutation other                                                            51/59      50/58 2 than Q148H/K/R               2/2 (100%) 20/20 (100%) 21/27 (78%) 8/10 (80%)      (86%)      (86%) Q148 + 1 secondary                                                                20/31      19/31 mutation3                    2/2 (100%) 8/12 (67%) 10/17 (59%)          -        (65%)      (61%) Q148 +≥2 secondary
4/16 (25%) mutations 3                   1/2 (50%) 2/11 (18%)          1/3 (33%)   -      4/16 (25%) 1
Historical or phenotypic evidence of INI resistance only.
2
N155H, Y143C/H/R, T66A, E92Q
3
G140A/C/S, E138A/K/T, L74I
OSS: combined genotypic and phenotypic resistance (Monogram Biosciences Net Assessment) 
The median change in CD4+ T cell count from baseline for VIKING-3 based on observed data was 61 cells/mm3 at Week 24 and 110 cells/mm3 at Week 48.

In the double blind, placebo controlled VIKING-4 study (ING116529), 30 HIV-1 infected, ART-experienced adults with primary genotypic resistance to INIs at Screening, were randomised to receive either dolutegravir 50 mg film-coated twice daily or placebo with the current failing regimen for 7 days followed by an open label phase with all subjects receiving dolutegravir. At baseline, median patient age was 49 years, 20% were female, 58% non-white, and 23% had hepatitis B and/or C co-infection. Median baseline CD4+ was 160 cells/mm3, median duration of prior ART was 13 years, and 63% were CDC Class C. Subjects showed multiple class ART resistance at baseline: 80% had 2 NRTI, 73% 1 NNRTI, and 67% 2 PI major mutations; 83% had non-R5 virus. Sixteen of 30 subjects (53%) harboured Q148 virus at baseline. The primary endpoint at Day 8 showed that dolutegravir 50 mg film-coated tablets twice daily was superior to placebo, with an adjusted mean treatment difference for the change from Baseline in Plasma HIV-1 RNA of -1.2 log10 copies/mL (95% CI -1.5 - -0.8log10 copies/mL, p<0.001). The day 8 responses in this placebo controlled study were fully in line with those seen in VIKING-3 (not placebo controlled), including by baseline integrase resistance categories. At week 48, 12/30 (40%) subjects had HIV-1 RNA <50 copies/mL (ITT-E, Snapshot algorithm).

In a combined analysis of VIKING-3 and VIKING-4 (n=186, VO population), the proportion of subjects with HIV RNA <50 copies/mL at Week 48 was 123/186 (66%). The proportion of subjects with HIV RNA <50 copies/mL was 96/126 (76%) for No Q148 mutations, 22/41 (54%) for Q148+1 and 5/19 (26%) for Q148+2 secondary mutations.

Paediatric population

In an ongoing Phase I/II 48 week multicentre, open-label study (P1093/ING112578), the pharmacokinetic parameters, safety, tolerability and efficacy of dolutegravir following once daily dosing were evaluated in combination regimens in HIV-1 infected infants, children and adolescents aged ≥ 4 weeks to < 18 years, the majority of whom were treatment-experienced.

The efficacy results (Table 11) include participants who received the recommended once daily doses of either dispersible tablets or film-coated tablets.



Table 11 Antiviral and Immunological Activity Through Week 24 and Week 48 in Paediatric Patients Week 24                           Week 48
N=75                               N=66 n/N       % (95% CI)              n/N        % (95% CI)
Proportion of participants with HIV                              56                                65.2 42/75                             43/66
RNA <50 c/mLa, b                                             (44.1, 67.5)                       (52.4, 76.5) Proportion of participants with HIV                             82.7                               80.3 62/75                             53/66
RNA <400 c/mLb                                               (72.2, 90.4)                       (68.7, 89.1) Median (n)      (Q1, Q3)          Median (n)       (Q1, Q3)
Change from baseline in CD4+ cell
145 (72)        (-64, 489)    184 (62)        (-179, 665) count (cells/mm3)
Change from baseline in CD4+
6 (72)          (2.5, 10)      8 (62)           (0.4, 11) percent
Q1, Q3= First and third quartiles, respectively.
a
Results of <200 c/mL from HIV-1 RNA testing using an LLOD of 200 c/mL were censored to >50 c/mL in this analysis b
Snapshot algorithm was used in the analyses


In participants experiencing virologic failure, 5/36 acquired integrase inhibitor substitution G118R. Of these five, 4 participants had additional integrase associated substitutions as follows: L74M, E138E/K, E92E/Q and T66I. Four of the 5 participants with emergent G118R had phenotypic data available. Dolutegravir FC (fold change as compared to wildtype virus) for these four participants ranged from 6 to 25-fold.

There are no data available on the use of dolutegravir plus lamivudine as a two-drug regimen in paediatric patients.

Pharmacokinetic Properties

5.2      Pharmacokinetic properties

Dolutegravir pharmacokinetics are similar between healthy and HIV-infected subjects. The PK variability of dolutegravir is low to moderate. In Phase I studies in healthy subjects, between-subject CVb% for AUC and Cmax ranged from ~20 to 40% and C from 30 to 65% across studies. The between-subject PK variability of dolutegravir was higher in HIV-infected subjects than healthy subjects. Within-subject variability (CVw%) is lower than between-subject variability.

Dispersible tablets and film-coated tablets do not have the same bioavailability. The relative bioavailability of dispersible tablets is approximately 1.6-fold higher as compared to film-coated tablets. Thus, a 30 mg dolutegravir dose administered as six 5 mg dispersible tablets will have similar exposure to a 50 mg dolutegravir dose administered as film-coated tablet(s). Similarly, a 25 mg dolutegravir dose administered as five 5 mg dispersible tablets, will provide comparable exposure to a 40 mg dolutegravir dose administered as four 10 mg film-coated tablets.

Absorption

Dolutegravir is rapidly absorbed following oral administration, with median Tmax at 1 to 3 hours post dose for film-coated tablet or dispersible tablet formulations.

Food increased the extent and slowed the rate of absorption of dolutegravir. Bioavailability of dolutegravir depends on meal content: low, moderate, and high fat meals increased dolutegravir AUC(0-) by 33%, 41%, and 66%, increased Cmax by 46%, 52%, and 67%, prolonged Tmax to 3, 4, and 5 hours from 2 hours under fasted conditions, respectively for the film-coated tablet. These increases may be clinically relevant in the presence of certain integrase class resistance. Therefore, Tivicay is recommended to be taken with food by patients infected with HIV with integrase class resistance (see section 4.2). No formal food effect studies were conducted for dispersible tablets. However, based on the available data, a higher food effect is not expected for the dispersible tablet compared to the film-coated tablet.

The absolute bioavailability of dolutegravir has not been established.

Distribution
Dolutegravir is highly bound (>99%) to human plasma proteins based on in vitro data. The apparent volume of distribution is 17 L to 20 L in HIV-infected patients, based on a population pharmacokinetic analysis.
Binding of dolutegravir to plasma proteins is independent of dolutegravir concentration. Total blood and plasma drug-related radioactivity concentration ratios averaged between 0.441 to 0.535, indicating minimal association of radioactivity with blood cellular components. The unbound fraction of dolutegravir in plasma is increased at low levels of serum albumin (<35 g/L) as seen in subjects with moderate hepatic impairment.

Dolutegravir is present in cerebrospinal fluid (CSF). In 13 treatment-naïve subjects on a stable dolutegravir plus abacavir/lamivudine regimen, dolutegravir concentration in CSF averaged 18 ng/mL (comparable to unbound plasma concentration, and above the IC50).

Dolutegravir is present in the female and male genital tract. AUC in cervicovaginal fluid, cervical tissue and vaginal tissue were 6-10% of those in corresponding plasma at steady state. AUC in semen was 7% and 17% in rectal tissue of those in corresponding plasma at steady state.

Biotransformation

Dolutegravir is primarily metabolized through glucuronidation via UGT1A1 with a minor CYP3A component. Dolutegravir is the predominant circulating compound in plasma; renal elimination of unchanged active substance is low (< 1% of the dose). Fifty-three percent of total oral dose is excreted unchanged in the faeces. It is unknown if all or part of this is due to unabsorbed active substance or biliary excretion of the glucuronidate conjugate, which can be further degraded to form the parent compound in the gut lumen. Thirty-two percent of the total oral dose is excreted in the urine, represented by ether glucuronide of dolutegravir (18.9% of total dose), N-dealkylation metabolite (3.6% of total dose), and a metabolite formed by oxidation at the benzylic carbon (3.0% of total dose).

Drug interactions

In vitro, dolutegravir demonstrated no direct, or weak inhibition (IC50>50 μM) of the enzymes cytochrome P450 (CYP)1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP3A, uridine diphosphate glucuronosyl transferase (UGT)1A1 or UGT2B7, or the transporters Pgp, BCRP, BSEP, OATP1B1, OATP1B3, OCT1, MATE2-K, MRP2 or MRP4. In vitro, dolutegravir did not induce CYP1A2, CYP2B6 or CYP3A4. Based on this data, dolutegravir is not expected to affect the pharmacokinetics of medicinal products that are substrates of major enzymes or transporters (see section 4.5).

In vitro, dolutegravir was not a substrate of human OATP 1B1, OATP 1B3 or OCT 1.

Elimination
Dolutegravir has a terminal half-life of ~14 hours. The apparent oral clearance (CL/F) is approximately 1L/hr in HIV-infected patients based on a population pharmacokinetic analysis.

Linearity/non-linearity

The linearity of dolutegravir pharmacokinetics is dependent on dose and formulation. Following oral administration of film-coated tablet formulations, in general, dolutegravir exhibited nonlinear pharmacokinetics with less than dose-proportional increases in plasma exposure from 2 to 100 mg; however increase in dolutegravir exposure appears dose proportional from 25 mg to 50 mg for the film-coated tablet formulation. With 50 mg film-coated tablet twice daily, the exposure over 24 hours was approximately doubled compared to 50 mg film-coated tablet once daily.


Pharmacokinetic/pharmacodynamic relationship(s)
In a randomized, dose-ranging trial, HIV-1–infected subjects treated with dolutegravir monotherapy (ING111521) demonstrated rapid and dose-dependent antiviral activity, with mean decline in HIV-1 RNA of 2.5 log10 at day 11 for 50 mg film-coated tablet dose. This antiviral response was maintained for 3 to 4 days after the last dose in the 50 mg film-coated tablet group.

PK/PD modelling using pooled data from clinical studies in integrase resistant patients suggest that increasing the dose from 50 mg film-coated tablet twice daily to 100 mg film-coated tablet twice daily may increase the effectiveness of dolutegravir in patients with integrase resistance and limited treatment options due to advanced multi class resistance. The proportion of responders (HIV-1 RNA <50 c/mL) at week 24 was predicted to increase around 4-18% in the subjects with Q148 + 2 secondary mutations from G140A/C/S, E138A/K/T, L74I. Although these simulated results have not been confirmed in clinical trials, this high dose may be considered in the presence of the Q148 + 2 secondary mutations from G140A/C/S, E138A/K/T, L74I in patients with overall limited treatment options due to advanced multi class resistance.
There is no clinical data on the safety or efficacy of the 100 mg film-coated tablet twice daily dose. Co- treatment with atazanavir increases the exposure of dolutegravir markedly, and should not be used in combination with this high dose, since safety with the resulting dolutegravir exposure has not been established.

Special patient populations

Children
The pharmacokinetics of dolutegravir given once daily as dispersible and film-coated tablets in HIV-1 infected infants, children and adolescents aged ≥ 4 weeks to < 18 years were evaluated in two on-going studies (P1093/ING112578 and ODYSSEY/201296). Steady state simulated plasma exposure at once daily weight band doses is summarized in Table 12.



Table 12 Summary of Simulated Dolutegravir PK Parameters at Once Daily Doses by Weight Band in Paediatric HIV-1 Infected Subjects
PK Parameter
Dolutegravir                     Geometric  Mean (90% CI)
Weight Band                   Once Daily
Dosage
(kg)                      Dose (mg)     Cmax        AUC0-24h          C24h Forma
(g/mL)      (g*h/mL)       (ng/mL)
4.02           49.4          1070
3 to <6            DT                5
(2.12, 7.96)    (21.6, 115)   (247, 3830)
5.90           67.4          1240
6 to <10b           DT                10
(3.23, 10.9)    (30.4, 151)   (257, 4580)
6.67           68.4          964
6 to <10c           DT                15
(3.75, 12.1)    (30.6, 154)   (158, 4150)
6.61           63.1          719
10 to <14           DT                20
(3.80, 11.5)    (28.9, 136)   (102, 3340)
7.17           69.5          824
DT                25
(4.10, 12.6)    (32.1, 151)   (122, 3780)
14 to <20
6.96           72.6          972
FCT               40
(3.83, 12.5)    (33.7, 156)   (150, 4260)
7.37           72.0           881
DT                30
(4.24, 12.9)    (33.3, 156)   (137, 3960)
20 to <25
7.43           78.6          1080
FCT               50
(4.13, 13.3)    (36.8, 171)   (178, 4690)
6.74           71.4          997
25 to <30           FCT               50
(3.73, 12.1)    (33.2, 154)   (162, 4250)
6.20           66.6          944
30 to <35           FCT               50
(3.45, 11.1)    (30.5, 141)   (154, 4020)
4.93           54.0          814
≥35               FCT               50
(2.66, 9.08)    (24.4, 118)   (142, 3310)
995 (697-
Target: Geometric Mean                           46 (37-134)
2260)
DT=dispersible tablet
FCT=film-coated tablet a. The bioavailability of dolutegravir DT is ~1.6-fold dolutegravir FCT.
a. <6 months of age b. ≥6 months of age



Steady state simulated plasma exposure at alternative twice daily weight band doses is summarized in Table 13. In contrast to once daily dosing, simulated data for alternative twice daily dosing have not been confirmed in clinical trials.

Table 13 Summary of Simulated Dolutegravir PK Parameters at Alternative Twice Daily Doses by Weight Band in Paediatric HIV-1 Infected Subjects

PK Parameter
Dolutegravir       Twice                  Geometric Mean (90% CI)
Weight Band
Dosage         Daily Dose
(kg)                                               Cmax          AUC0-12h         C12h Forma           (mg)
(g/mL)        (g*h/mL)       (ng/mL)
4.28            31.6           1760
6 to <10b            DT                5
(2.10, 9.01)     (14.6, 71.4)   (509, 5330)
6.19            43.6           2190
6 to <10c            DT               10
(3.15, 12.6)     (19.4, 96.9)   (565, 6960)
4.40            30.0           1400
10 to <14            DT               10
(2.27, 8.68)     (13.5, 66.0)   (351, 4480)
5.78            39.6           1890
DT               15
(2.97, 11.4)     (17.6, 86.3)   (482, 6070)
14 to <20
4.98            35.9           1840
FCT               20
(2.55, 9.96)     (16.5, 77.4)   (496, 5650)
5.01             34.7          1690
DT               15
(2.61, 9.99)     (15.8, 76.5)   (455, 5360)
20 to <25
5.38             39.2          2040
FCT               25
(2.73, 10.8)     (18.1, 85.4)   (567, 6250)
4.57            32.0           1580
DT               15
(2.37, 9.05)     (14.6, 69.1)   (414, 4930)
25 to <30
4.93            35.9           1910
FCT               25
(2.50, 9.85)     (16.4, 77.4)   (530, 5760)
4.54            33.3           1770
30 to <35           FCT               25
(2.31, 9.10)     (15.3, 72.4)   (494, 5400)
3.59            26.8           1470
≥35              FCT               25
(1.76, 7.36)     (12.1, 58.3)   (425, 4400)
DT=dispersible tablet
FCT=film-coated tablet a. The bioavailability of dolutegravir DT is ~1.6-fold dolutegravir FCT.
b. <6 months of age c. ≥6 months of age



Elderly
Population pharmacokinetic analysis of dolutegravir using data in HIV-1 infected adults showed that there was no clinically relevant effect of age on dolutegravir exposure.

Pharmacokinetic data for dolutegravir in subjects >65 years of age are limited.

Renal impairment
Renal clearance of unchanged active substance is a minor pathway of elimination for dolutegravir. A study of the pharmacokinetics of a single 50 mg dose of dolutegravir film-coated tablets was performed in subjects with severe renal impairment (CLcr <30 mL/min) and matched healthy controls. The exposure to dolutegravir was decreased by approximately 40% in subjects with severe renal impairment. The mechanism for the decrease is unknown. No dosage adjustment is considered necessary for patients with renal impairment. Tivicay has not been studied in patients on dialysis.

Hepatic impairment
Dolutegravir is primarily metabolized and eliminated by the liver. A single 50 mg dose of dolutegravir film- coated tablets was administered to 8 subjects with moderate hepatic impairment (Child-Pugh class B) and to 8 matched healthy adult controls. While the total dolutegravir concentration in plasma was similar, a 1.5- to 2-fold increase in unbound exposure to dolutegravir was observed in subjects with moderate hepatic impairment compared to healthy controls. No dosage adjustment is considered necessary for patients with mild to moderate hepatic impairment. The effect of severe hepatic impairment on the pharmacokinetics of Tivicay has not been studied.

Polymorphisms in drug metabolising enzymes
There is no evidence that common polymorphisms in drug metabolising enzymes alter dolutegravir pharmacokinetics to a clinically meaningful extent. In a meta-analysis using pharmacogenomics samples collected in clinical studies in healthy subjects, subjects with UGT1A1 (n=7) genotypes conferring poor dolutegravir metabolism had a 32% lower clearance of dolutegravir and 46% higher AUC compared with subjects with genotypes associated with normal metabolism via UGT1A1 (n=41).

Gender
Population PK analyses using pooled pharmacokinetic data from Phase IIb and Phase III adult trials revealed no clinically relevant effect of gender on the exposure of dolutegravir.

Race
Population PK analyses using pooled pharmacokinetic data from Phase IIb and Phase III adult trials revealed no clinically relevant effect of race on the exposure of dolutegravir. The pharmacokinetics of dolutegravir following single dose oral administration to Japanese subjects appear similar to observed parameters in Western (US) subjects.

Co-infection with Hepatitis B or C
Population pharmacokinetic analysis indicated that hepatitis C virus co-infection had no clinically relevant effect on the exposure to dolutegravir. There are limited data on subjects with hepatitis B co-infection.