Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Antivirals for systemic use, antivirals for treatment of HIV infections, combinations. ATC code: J05AR13

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.

Abacavir and lamivudine are potent selective inhibitors of HIV-1 and HIV-2. Both abacavir and lamivudine are metabolised sequentially by intracellular kinases to the respective 5'-triphosphates (TP) which are the active moieties with extended intracellular half-lives supporting once daily dosing (see section 5.2). Lamivudine-TP (an analogue for cytidine) and carbovir-TP (the active triphosphate form of abacavir, an analogue for guanosine) are substrates for and competitive inhibitors of HIV reverse transcriptase (RT). However, their main antiviral activity is through incorporation of the monophosphate form into the viral DNA chain, resulting in chain termination. Abacavir and lamivudine triphosphates show significantly less affinity for host cell DNA polymerases.

Pharmacodynamic effects

Antiviral activity in vitro
Dolutegravir, abacavir and lamivudine have been shown to inhibit replication of lab-strains and clinical isolates of HIV in a number of cell types, including transformed T cell lines, monocyte/macrophage derived lines and primary cultures of activated peripheral blood mononuclear cells (PMBCs) and monocyte/macrophages. The concentration of active substance necessary to effect viral replication by 50% (IC50 - half maximal inhibitory concentration) varied according to virus and host cell type.

The IC50 for dolutegravir in various lab-strains 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).

The mean IC50 for abacavir against lab-strains of HIV-1IIIB and HIV-1HXB2 ranged from 1.4 to 5.8 M.
The median or mean IC50 values for lamivudine against lab-strains of HIV-1 ranged from 0.007 to 2.3 M. The mean IC50 against lab-strains of HIV-2 (LAV2 and EHO) ranged from 1.57 to 7.5 M for abacavir and from 0.16 to 0.51 M for lamivudine.

The IC50 values of abacavir against HIV-1 Group M subtypes (A-G) ranged from 0.002 to 1.179 M, against Group O from 0.022 to 1.21 M, and against HIV-2 isolates, from 0.024 to 0.49 M. For lamivudine, the IC50 values against HIV-1 subtypes (A-G) ranged from 0.001 to 0.170 M, against Group O from 0.030 to 0.160 M and against HIV-2 isolates from 0.002 to 0.120 M in peripheral blood mononuclear cells.


HIV-1 isolates (CRF01_AE, n=12; CRF02_AG, n=12; and Subtype C or CRF_AC, n=13) from 37 untreated patients in Africa and Asia were susceptible to abacavir (IC50 fold changes < 2.5), and lamivudine (IC50 fold changes < 3.0), except for two CRF02_AG isolates with fold changes of 2.9 and 3.4 for abacavir. Group O isolates from antiviral naïve patients tested for lamivudine activity were highly sensitive.

The combination of abacavir and lamivudine has demonstrated antiviral activity in cell culture against non-subtype B isolates and HIV-2 isolates with equivalent antiviral activity as for subtype B isolates.

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

The antiviral activity of abacavir in cell culture was not antagonized when combined with the nucleoside reverse transcriptase inhibitors (NRTIs) didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine or zidovudine, the non-nucleoside reverse transcriptase inhibitor (NNRTI) nevirapine, or the protease inhibitor (PI) amprenavir.

No antagonistic effects in vitro were seen with lamivudine and other antiretrovirals (tested agents: abacavir, didanosine, nevirapine, zalcitabine, and zidovudine).

Effect of human serum
In 100% human serum, the mean fold shift for dolutegravir activity was 75-fold, resulting in protein adjusted IC90 of 0.064 ug/mL. Plasma protein binding studies in vitro indicate that abacavir binds only low to moderately (~49%) to human plasma proteins at therapeutic concentrations. Lamivudine exhibits linear pharmacokinetics over the therapeutic dose range and displays low plasma protein binding (less than 36%).

Resistance

Resistance in vitro: (dolutegravir)
Serial passage is used to study resistance evolution in vitro. When using the lab-strain HIVIII during passage over 112 days, mutations selected appeared slowly, with substitutions at positions S153Y and F.
These mutations were not selected in patients treated with dolutegravir in the clinical studies. Using strain NL432 mutations E92Q (fold change 3) and G193E (fold change 3) were selected. These mutations have been selected in patients with pre-existing raltegravir resistance and who were then treated with dolutegravir (listed as secondary mutations 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 individual patients with subtype B and subtype C in the clinical program for ART experienced, INI naive subjects, but without effects on dolutegravir susceptibility in vitro. G118R lowers the susceptibility to dolutegravir in site directed mutants (fold change 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, 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 primary mutations (excluding at Q148) in experiments with site directed mutants, dolutegravir susceptibility remains at or near wildtype level. In the case of the Q148-mutation viruses, increasing dolutegravir fold change is seen as the number of secondary mutations increase. The effect of the Q148-based mutations (H/R/K) was also consistent with in vitro passage experiments with site directed mutants. In serial passage with strain NL432-based site directed mutants at N155H or E92Q, no further selection of resistance was seen (fold change unchanged around 1). In contrast, starting passage with mutants with mutation Q148H (fold change 1), a variety of raltegravir associated secondary mutations accumulated with a consequent increase of fold change to values >10.
A clinically relevant phenotypic cut-off value (fold change 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 <10-fold change against 94% of the 705 clinical isolates.

Resistance in vivo: (dolutegravir)
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=876, follow-up of 48- 96 weeks).

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 fold change of 1.93, one subject had a polymorphic V151V/I integrase substitution, with maximum fold change 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).

Resistance in vitro and in vivo: (abacavir and lamivudine)
Abacavir-resistant isolates of HIV-1 have been selected in vitro and in vivo and are associated with specific genotypic changes in the RT codon region (codons M184V, K65R, L74V and Y115F). During in vitro abacavir selection the M184V mutation occurred first and resulted in about a 2-fold increase in IC50, below the abacavir clinical cut-off of 4.5-fold change. Continued passage in increasing concentrations of drug resulted in selection for double RT mutants 65R/184V and 74V/184V or triple RT mutant 74V/115Y/184V. Two mutations conferred a 7 to 8-fold change in abacavir susceptibility and combinations of three mutations were required to confer more than an 8-fold change in susceptibility.

HIV-1 resistance to lamivudine involves the development of a M184I or M184V amino acid change close to the active site of the viral RT. This variant arises both in vitro and in HIV-1 infected patients treated with lamivudine-containing antiretroviral therapy. M184V mutants display greatly reduced susceptibility to lamivudine and show diminished viral replicative capacity in vitro. M184V is associated with about a 2-fold increase in abacavir resistance but does not confer clinical resistance for abacavir.

Isolates resistant to abacavir may also show reduced sensitivity to lamivudine. The combination of abacavir/lamivudine has demonstrated decreased susceptibility to viruses with the substitutions K65R with or without the M184V/I substitution, and to viruses with L74V plus the M184V/I substitution.

Cross-resistance between dolutegravir or abacavir or lamivudine and antiretrovirals from other classes e.g. PIs or NNRTIs is unlikely.

Effects on electrocardiogram

No relevant effects were seen on the QTc interval, with doses of dolutegravir exceeding the clinical dose by approximately 3-fold. Similar studies were not conducted with either abacavir or lamivudine.

Clinical efficacy and safety

The efficacy of Triumeq in HIV-infected, therapy naive subjects is based on the analyses of data from a number of trials. The analyses included two randomised, international, double-blind, active-controlled trials, SINGLE (ING114467) and SPRING-2 (ING113086), the international, open-label, active- controlled trial FLAMINGO (ING114915), and the randomised, open-label, active-controlled, multicentre, non-inferiority study ARIA (ING117172).

The STRIIVING study (201147), was a randomised, open-label, active-controlled, multicentre, non- inferiority switch study in virologically suppressed subjects with no documented history of resistance to any class.

In SINGLE, 833 patients were treated with dolutegravir 50 mg film-coated tablets once daily plus fixed- dose abacavir-lamivudine (DTG + 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. Week 48 outcomes (including outcomes by key baseline covariates) are shown in Table 3.

Table 3:     Virologic Outcomes of Randomised Treatment of SINGLE at 48 Weeks (Snapshot algorithm)
48 weeks
DTG 50 mg + ABC/3TC                  EFV/TDF/FTC once daily                        once daily
N=414                             N=419
HIV-1 RNA <50 copies/mL                    88%                               81% Treatment Difference*                          7.4% (95% CI: 2.5%, 12.3%) Virologic non response†                     5%                                6% No virologic data at Weeks
7%                               13%
48 window
Reasons
Discontinued study/study medicinal product due to                    2%                               10% adverse event or death‡
Discontinued study/study medicinal product for other                 5%                                3% reasons§
Missing data during window
0                               <1% but on study
HIV-1 RNA <50 copies/mL by baseline covariates
Baseline Plasma Viral n / N (%)                         n / N (%)
Load (copies/mL)
100,000                            253 / 280 (90%)                238 / 288 (83%) >100,000                            111 / 134 (83%)                100 / 131 (76%) Baseline CD4+ (cells/ mm3)
<200                                 45 / 57 (79%)                   48 / 62 (77%) 200 to <350                         143 / 163 (88%)                126 / 159 (79%)
350                                176 / 194 (91%)                164 / 198 (83%) Gender
Male                                307 / 347 (88%)                291 / 356 (82%) Female                               57 / 67 (85%)                   47 / 63 (75%) Race
White                               255 / 284 (90%)                238 /285 (84%) African-American/African
109 / 130 (84%)                 99 / 133 (74%)
Heritage/Other
Age (years)
<50                                 319 / 361 (88%)                302 / 375 (81%) 50                                  45 / 53 (85%)                   36 / 44 (82%) 
* Adjusted for baseline stratification factors.
† Includes subjects who discontinued prior to Week 48 for lack or loss of efficacy and subjects who are 50 copies in the 48 week window.
‡ Includes subjects who discontinued due to an adverse event or death at any time point from Day 1 through the Week 48 analysis window if this resulted in no virologic data on treatment during the analysis window.
§ Includes reasons such as withdrew consent, loss to follow-up, moved, protocol deviation.
Notes: ABC/3TC = abacavir 600 mg, lamivudine 300 mg in the form of Kivexa/Epzicom fixed dose combination (FDC)
EFV/TDF/FTC = efavirenz 600 mg, tenofovir disoproxil 245 mg, emtricitabine 200 mg in the form of Atripla FDC.


In the primary 48 weeks analysis, the proportion of patients with virologic suppression in the dolutegravir + ABC/3TC arm, was superior to the EFV/TDF/FTC arm, p=0.003, the same treatment difference was observed in subjects defined by baseline HIV RNA level (< or > 100,000 copies/mL). The median time to viral suppression was shorter with ABC/3TC + DTG (28 vs 84 days, p<0.0001). The adjusted mean change in CD4+ T cell count from baseline were 267 cells versus 208 cells/mm3, respectively (p<0.001).
Both the time to viral suppression and change from baseline analyses were pre-specified and adjusted for multiplicity. At 96 weeks, the response was 80% vs 72%, respectively. The difference in the endpoint remained statistically significant (p=0.006). The statistically higher responses on DTG+ABC/3TC were driven by a higher rate of withdrawals due to AEs in the EFV/TDF/FTC arm, irrespective of viral load strata. Overall treatment differences at Week 96 are applicable to patients with high and low Baseline viral loads. At 144 weeks in the open-label phase of SINGLE, virologic suppression was maintained, the DTG +ABC/3TC arm (71%) was superior to the EFV/TDF/FTC arm (63%), treatment difference was 8.3% (2.0, 14.6).

In SPRING-2, 822 patients were treated with either dolutegravir 50 mg film-coated tablets once daily or raltegravir 400 mg twice daily (blinded), both with fixed-dose ABC/3TC (around 40%) or TDF/FTC (around 60%), given open label. Baseline demographics and outcomes are summarised in Table 4.
Dolutegravir was non-inferior to raltegravir, including within the subset of patients with the abacavir/lamivudine background regimen.


Table 4: Demographics and virologic outcomes of randomised treatment of SPRING-2 (snapshot algorithm)
DTG 50 mg       RAL 400mg once daily      twice daily
+ 2 NRTI       + 2 NRTI
N=411           N=411
Demographics
Median Age (years)                                                           37             35 Female                                                                      15%            14% Non-white                                                                   16%            14% Hepatitis B and/or C                                                        13%            11% CDC class C                                                                  2%             2% ABC/3TC backbone                                                            41%            40% Week 48 efficacy results
HIV-1 RNA <50 copies/mL                                                        88%            85% Treatment difference*                                                      2.5% (95% CI: -2.2%, 7.1%) Virologic non response†                                                      5%             8% No virologic data at Weeks 48 window                                         7%             7% Reasons
Discontinued study/study medicinal product due to adverse
2%             1% event or death‡
Discontinued study/study medicinal product for other
5%             6% reasons§
HIV-1 RNA <50 copies/mL for those on ABC/3TC                                   86%            87% Week 96 efficacy results
HIV-1 RNA <50 copies/mL                                                        81%            76% Treatment difference*                                                     4.5% (95% CI: -1.1%, 10.0%) HIV-1 RNA <50 copies/mL for those on ABC/3TC                                 74%            76% * Adjusted for baseline stratification factors.
† Includes subjects who discontinued prior to Week 48 for lack or loss of efficacy and subjects who are 50 copies in the 48 week window.
‡ Includes subjects who discontinued due to an adverse event or death at any time point from Day 1 through the Week 48 analysis window if this resulted in no virologic data on treatment during the analysis window.
§ Includes reasons such as protocol deviation, lost to follow up, and withdrew consent.
Notes: DTG = dolutegravir, RAL = raltegravir.


In FLAMINGO, 485 patients were treated with dolutegravir 50 mg film-coated tablets once daily or darunavir/ritonavir (DRV/r) 800 mg/100 mg once daily, both with ABC/3TC (around 33%) or TDF/FTC (around 67%). All treatments were given open-label. Main demographics and outcomes are summarised in Table 5.

Table 5: Demographics and Week 48 virologic outcomes of randomised treatment of FLAMINGO 

(snapshot algorithm)
DTG 50 mg          DRV+RTV once daily       800mg + 100mg
+ 2 NRTI          once daily
+2 NRTI
N=242             N=242
Demographics
Median Age (years)                                                       34                  34 Female                                                                  13%                17% Non-white                                                               28%                27% Hepatitis B and/or C                                                    11%                 8% CDC class C                                                              4%                 2% ABC/3TC backbone                                                        33%                33% Week 48 Efficacy Results
HIV-1 RNA <50 copies/mL                                                    90%                83% Treatment Difference*                                                   7.1% (95% CI: 0.9%, 13.2%) Virologic non response†                                                 6%                 7% No virologic data at Weeks 48 window                                    4%                10% Reasons
Discontinued study/study medicinal product due to adverse
1%                 4% event or death‡
Discontinued study/study medicinal product for other
2%                 5% reasons§
Missing data during window but on study                             <1%                 2% HIV-1 RNA <50copies/mL for those on ABC/3TC                                90%                85% Median time to viral suppression**                                       28 days             85 days * Adjusted for baseline stratification factors, p=0.025.
† Includes subjects who discontinued prior to Week 48 for lack or loss of efficacy and subjects who are 50 copies in the 48 week window.
‡ Includes subjects who discontinued due to an adverse event or death at any time point from Day 1 through the Week 48 analysis window if this resulted in no virologic data on treatment during the analysis window.
§ Includes reasons such as withdrew consent, loss to follow-up, protocol deviation.
** p<0.001.
Notes: DRV+RTV = darunavir + ritonavir, DTG = dolutegravir.

At 96 weeks, virologic suppression in the dolutegravir group (80%) was superior to the DRV/r group (68%), (adjusted treatment difference [DTG-(DRV+RTV)]: 12.4%; 95% CI: [4.7, 20.2]). Response rates at 96 weeks were 82% for DTG+ABC/3TC and 75% for DRV/r+ABC/3TC.

In ARIA (ING117172), a randomised, open-label, active-controlled, multicenter, parallel group, non- inferiority study; 499 HIV-1 infected ART naïve adult women were randomised 1:1 to receive either; DTG/ABC/3TC FDC film-coated tablets 50 mg/600 mg/300 mg; or atazanavir 300 mg plus ritonavir 100 mg plus tenofovir disproxil / emtricitabine 245 mg/200 mg (ATV+RTV+TDF/FTC FDC), all administered once daily.


Table 6: Demographics and Week 48 virologic outcomes of randomised treatment of ARIA (snapshot algorithm)

DTG/ABC/3TC           ATV+RTV+TDF/FTC
FDC                     FDC
N=248                   N=247
Demographics
Median Age (years)                                          37                        37 Female                                                    100 %                     100 % Non-white                                                  54 %                     57 % Hepatitis B and/ or C                                       6%                       9% CDC class C                                                 4%                       4% Week 48 Efficacy Results
HIV-1 RNA <50 copies/mL                                     82 %                     71 % Treatment difference                                          10.5 (3.1% to 17.8%) [p=0.005].
Virologic Failure                                           6%                      14 % Reasons
Data in window not below 50 c/mL threshold                2%                        6% Discontinued for lack of efficacy                         2%                       <1 % Discontinued for other reason while not                   3%                        7% below threshold
No Virologic Data                                           12 %                      15 % Discontinued due to AE or death                      4%                      7% Discontinued for other reasons                       6%                      6% Missing data during window but on study              2%                      2% AE = Adverse event.
HIV-1 - human immunodeficiency virus type 1
DTG/ABC/3TC FDC - abacavir/dolutegravir/lamivudine fixed-dose combination ATV+RTV+TDF/FTC FDC -atazanavir plus ritonavir plus tenofovir disproxil/emtricitabine fixed- dose combination


STRIIVING (201147) is a 48-week, randomised, open-label, active controlled, multicenter, non- inferiority study in patients without any prior treatment failure, and without any documented resistance to any class. Virologically suppressed (HIV-1 RNA <50 c/mL) subjects were randomly assigned (1:1) to continue their current ART regimen (2 NRTIs plus either a PI, NNRTI, or INI), or switch to ABC/DTG/3TC FDC film-coated tablets once daily (Early Switch). Hepatitis B co-infection was one of the main exclusion criteria.
Patients were mainly white (66%) or black (28%) of male sex (87%). Main prior transmission routes were homosexual (73%) or heterosexual (29%) contact. The proportion with a positive HCV serology was 7%. The median time from first starting ART was around 4.5 years.


Table 7: Outcomes of randomised treatment of STRIIVING (snapshot algorithm) 
Study Outcomes (Plasma HIV-1 RNA <50 c/mL) at Week 24 and Week 48 – Snapshot Analysis (ITT-E Population)
ABC/DTG/3TC         Current ART          Early Switch        Late Switch FDC                              ABC/DTG/3TC ABC/DTG/3TC
N=275             N=278                 FDC                FDC n (%)             n (%)               N=275              N=244 n (%)              n (%)
Outcome Time Point                  Day 1 to W 24      Day 1 to W 24       Day 1 to W48         W24 to W48 Virologic Success                        85 %              88 %                 83 %               92 % Virologic Failure                         1%                1%                  <1 %                1% Reasons
Data in window not below               1%                1%                  <1 %                1% threshold
No Virologic Data                        14 %              10 %                 17 %                7% Discontinued due to AE or               4%                 0%                  4%                 2% death
Discontinued for other                  9%                10 %                12 %                3% reasons
Missing data during                     1%                <1 %                 2%                 2% window but on study
ABC/DTG/3TC FDC = abacavir/dolutegravir/lamivudine fixed-dose combination; AE = adverse event; ART = antiretroviral therapy; HIV-1 = human immunodeficiency virus type 1; ITT-E = intent-to-treat exposed; W = week.
Virologic suppression (HIV-1 RNA <50 copies/mL) in the ABC/DTG/3TC FDC group (85%) was statistically non-inferior to the current ART groups (88%) at 24 weeks. The adjusted difference in proportion and 95% CI [ABC/DTG/3TC vs current ART] were 3.4%; 95% CI: [-9.1, 2.4]. After 24 weeks all remaining subjects switched to ABC/DTG/3TC FDC (Late Switch). Similar levels of virologic suppression were maintained in both the Early and Late Switch groups at 48 weeks.

De novo resistance in patients failing therapy in SINGLE, SPRING-2 and FLAMINGO 
De novo resistance was not detected to the integrase class or the NRTI class in any patients who were treated with dolutegravir + abacavir/lamivudine in the three studies mentioned.
For the comparators typical resistance was detected with TDF/FTC/EFV (SINGLE; six with NNRTI associated resistance and one with major NRTI resistance) and with 2 NRTIs + raltegravir (SPRING-2; four with major NRTI resistance and one with raltegravir resistance), while no de novo resistance was detected in patients treated with 2 NRTIs + DRV/RTV (FLAMINGO).

Paediatric population

In a Phase I/II 48 week multicentre, open-label study (P1093/ING112578), the pharmacokinetic parameters, safety, tolerability and efficacy of dolutegravir was evaluated in combination regimens in HIV-1 infected infants, children and adolescents.

At 24 weeks, 16 of 23 (69%) adolescents (12 to 17 years of age) treated with dolutegravir once daily (35 mg n=4; 50 mg n=19) plus OBR achieved viral load less than 50 copies/mL.
Twenty out of 23 children and adolescents (87%) had >1 log10 c/mL decrease from Baseline in HIV-1 RNA or HIV-1 RNA <400 c/mL at Week 24. Four subjects had virologic failure none of which had INI resistance at the time of virologic failure.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties
Triumeq film-coated tablet has been shown to be bioequivalent to dolutegravir single entity film-coated tablet and abacavir/lamivudine fixed-dose combination tablet (ABC/3TC FDC) administered separately.
This was demonstrated in a single dose, 2-way crossover bioequivalence study of Triumeq (fasted) versus 1 x 50 mg dolutegravir tablet, plus 1 x 600mg abacavir/300 mg lamivudine tablet (fasted) in healthy subjects (n=66). The effect of a high fat meal on the Triumeq tablet was evaluated in a subgroup of subjects in this study (n=12). Plasma Cmax and AUC of dolutegravir following administration of Triumeq with a high fat meal were 37% and 48% higher, respectively, than those following administration of Triumeq in the fasted state. This is not considered clinically significant (see Absorption). The effect of food on plasma exposures of abacavir and lamivudine following administration of Triumeq with a high fat meal were very similar to prior food effects observed with ABC/3TC FDC. These results indicate that Triumeq can be taken with or without food.

The pharmacokinetic properties of dolutegravir, lamivudine and abacavir are described below.

Absorption
Dolutegravir, abacavir and lamivudine are rapidly absorbed following oral administration. The absolute bioavailability of dolutegravir has not been established. The absolute bioavailability of oral abacavir and lamivudine in adults is about 83% and 80-85% respectively. The mean time to maximal serum concentrations (tmax) is about 2 to 3 hours (post dose for tablet formulation), 1.5 hours and 1.0 hour for dolutegravir, abacavir and lamivudine, respectively.

Exposure to dolutegravir was generally similar between healthy subjects and HIV-1–infected subjects. In HIV-1–infected adult subjects following dolutegravir 50 mg film-coated tablets once daily, the steady-state pharmacokinetic parameters (geometric mean [%CV]) based on population pharmacokinetic analyses were AUC(0-24) = 53.6 (27) g.h/mL, Cmax = 3.67 (20) g/mL, and Cmin = 1.11 (46) g/mL. Following a single dose of 600 mg of abacavir, the mean (CV) Cmax is 4.26 µg/ml (28%) and the mean (CV) AUC is 11.95 µg.h/ml (21%). Following multiple-dose oral administration of lamivudine 300 mg once daily for seven days, the mean (CV) steady-state Cmax is 2.04 µg/ml (26%) and the mean (CV) AUC24 is 8.87 µg.h/ml (21%).

The effect of a high fat meal on Triumeq film-coated tablet was evaluated in a subgroup of subjects (n=12) of the single dose, 2-way crossover bioequivalence study. Plasma Cmax and AUC of dolutegravir following administration of Triumeq film-coated tablets with a high fat meal were 37% and 48% higher, respectively, than those following administration of Triumeq film-coated tablets in the fasted state. For abacavir there was a decrease in Cmax with 23% and AUC was unchanged. The exposure of lamivudine was similar with and without food. These results indicate that Triumeq film-coated tablets can be taken with or without food.

Distribution

The apparent volume of distribution of dolutegravir (following oral administration of suspension formulation, Vd/F) is estimated at 12.5 L. Intravenous studies with abacavir and lamivudine showed that the mean apparent volume of distribution is 0.8 and 1.3 l/kg respectively.

Dolutegravir is highly bound (> 99%) to human plasma proteins based on in vitro data. 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. Plasma protein binding studies in vitro indicate that abacavir binds only low to moderately (~49%) to human plasma proteins at therapeutic concentrations. Lamivudine exhibits linear 

pharmacokinetics over the therapeutic dose range and displays limited plasma protein binding in vitro (< 36%).

Dolutegravir, abacavir and lamivudine are 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). Studies with abacavir demonstrate a CSF to plasma AUC ratio of between 30 to 44%. The observed values of the peak concentrations are 9-fold greater than the IC50 of abacavir of 0.08 µg/ml or 0.26 µM when abacavir is given at 600 mg twice daily. The mean ratio of CSF/serum lamivudine concentrations 2-4 hours after oral administration was approximately 12%. The true extent of CNS penetration of lamivudine and its relationship with any clinical efficacy is unknown.

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 metabolised via UGT1A1 with a minor CYP3A component (9.7% of total dose administered in a human mass balance study). 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).

Abacavir is primarily metabolised by the liver with approximately 2% of the administered dose being renally excreted, as unchanged compound. The primary pathways of metabolism in man are by alcohol dehydrogenase and by glucuronidation to produce the 5’-carboxylic acid and 5’-glucuronide which account for about 66% of the administered dose. These metabolites are excreted in the urine.

Metabolism of lamivudine is a minor route of elimination. Lamivudine is predominately cleared by renal excretion of unchanged lamivudine. The likelihood of metabolic drug interactions with lamivudine is low due to the small extent of hepatic metabolism (5-10%).

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, UGT1A1 or UGT2B7, or the transporters Pgp, BCRP, BSEP, organic anion transporting polypeptide 1B1 (OATP1B1), OATP1B3, OCT1, MATE2-K, multidrug resistance-associated protein 2 (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.

In vitro, abacavir did not inhibit or induce CYP enzymes (other than CY1A1 and CYP3A4 [limited potential], see section 4.5) and demonstrates no or weak inhibition of OATP1B1, OAT1B3, OCT1, OCT2, BCRP and P-gp or MATE2-K. Abacavir is therefore not expected to affect the plasma concentrations of medicinal products that are substrates of these enzymes or transporters.


Abacavir was not significantly metabolised by CYP enzymes. In vitro, abacavir was not a substrate of OATP1B1, OATP1B3, OCT1, OCT2, OAT1, MATE1, MATE2-K, MRP2 or MRP4 therefore medicinal products that modulate these transporters are not expected to affect abacavir plasma concentrations.

In vitro, lamivudine did not inhibit or induce CYP enzymes (such as CYP3A4, CYP2C9 or CYP2D6) and demonstrated no or weak inhibition of OATP1B1, OAT1B3, OCT3, BCRP, P-gp, MATE1 or MATE2-K.
Lamivudine is therefore not expected to affect the plasma concentrations of medicinal products that are substrates of these enzymes or transporters.

Lamivudine was not significantly metabolised by CYP enzymes.

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

The mean half-life of abacavir is about 1.5 hours. The geometric mean terminal half-life of intracellular active moiety carbovirtriphosphate (TP) at steady-state is 20.6 hours. Following multiple oral doses of abacavir 300 mg twice a day there is no significant accumulation of abacavir. Elimination of abacavir is via hepatic metabolism with subsequent excretion of metabolites primarily in the urine. The metabolites and unchanged abacavir account for about 83% of the administered abacavir dose in the urine. The remainder is eliminated in the faeces.

The observed lamivudine half-life of elimination is 18 to 19 hours. For patients receiving lamivudine 300 mg once daily, the terminal intracellular half-life of lamivudine-TP was 16 to 19 hours. The mean systemic clearance of lamivudine is approximately 0.32 L/h/kg, predominantly by renal clearance (> 70%) via the organic cationic transport system. Studies in patients with renal impairment show lamivudine elimination is affected by renal dysfunction. Dose reduction is required for patients with creatinine clearance < 50 ml/min (see section 4.2).

Pharmacokinetic/pharmacodynamic relationship(s)

In a randomised, 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 dose. This antiviral response was maintained for 3 to 4 days after the last dose in the 50 mg group.

Intracellular pharmacokinetics

The geometric mean terminal carbovir-TP intracellular half-life at steady-state was 20.6 hours, compared to the geometric mean abacavir plasma half-life of 2.6 hours. The terminal intracellular half-life of lamivudine-TP was prolonged to 16-19 hours, supporting once daily dosing of ABC and 3TC.

Special populations

Hepatic impairment
Pharmacokinetic data has been obtained for dolutegravir, abacavir and lamivudine separately.
Dolutegravir is primarily metabolised and eliminated by the liver. A single dose of 50 mg of dolutegravir 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 dose adjustment is considered necessary for patients with mild to moderate hepatic impairment. The effect of severe hepatic impairment on the pharmacokinetics of dolutegravir has not been studied.
Abacavir is metabolised primarily by the liver. The pharmacokinetics of abacavir have been studied in patients with mild hepatic impairment (Child-Pugh score 5-6) receiving a single 600 mg dose. The results showed that there was a mean increase of 1.89-fold [1.32; 2.70] in the abacavir AUC, and 1.58 [1.22; 2.04] fold in the elimination half-life. No recommendation on dose reduction is possible in patients with mild hepatic impairment due to substantial variability of abacavir exposure.

Data obtained in patients with moderate to severe hepatic impairment show that lamivudine pharmacokinetics are not significantly affected by hepatic dysfunction.

Based on data obtained for abacavir, Triumeq is not recommended in patients with moderate or severe hepatic impairment.

Renal impairment
Pharmacokinetic data have been obtained for dolutegravir, lamivudine and abacavir separately.

Renal clearance of unchanged active substance is a minor pathway of elimination for dolutegravir. A study of the pharmacokinetics of dolutegravir was performed in subjects with severe renal impairment (CrCl <30 mL/min). No clinically important pharmacokinetic differences between subjects with severe renal impairment (CrCl <30 mL/min) and matching healthy subjects were observed. Dolutegravir has not been studied in patients on dialysis, though differences in exposure are not expected.

Abacavir is primarily metabolised by the liver with approximately 2% of abacavir excreted unchanged in the urine. The pharmacokinetics of abacavir in patients with end-stage renal disease is similar to patients with normal renal function.

Studies with lamivudine show that plasma concentrations (AUC) are increased in patients with renal dysfunction due to decreased clearance.

Based on the lamivudine data, Triumeq is not recommended for patients with creatinine clearance of < 50 ml/min.

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

Pharmacokinetic data for dolutegravir, abacavir and lamivudine in subjects >65 years of age are limited.

Paediatric population
The pharmacokinetics of dolutegravir in 10 antiretroviral treatment-experienced HIV-1 infected adolescents (12 to 17 years) showed that dolutegravir 50 mg once daily dosage resulted in dolutegravir exposure comparable to that observed in adults who received dolutegravir 50 mg once daily.

Limited data are available in adolescents receiving a daily dose of 600 mg of abacavir and 300 mg of lamivudine. Pharmacokinetic parameters are comparable to those reported in adults.

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. There is no evidence that a dose adjustment of dolutegravir, abacavir or lamivudine would be required based on the effects of gender on PK parameters.

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. There is no evidence that a dose adjustment of dolutegravir, abacavir or lamivudine would be required based on the effects of race on PK parameters.

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 pharmacokinetic data on subjects with hepatitis B co-infection (see section 4.4).