July 30, 2016
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Tivicay

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Tivicay

CLINICAL PHARMACOLOGY

Mechanism Of Action

Dolutegravir is an HIV-1 antiviral agent [see Microbiology].

Pharmacodynamics

In a randomized, dose-ranging trial, HIV-1-infected subjects treated with dolutegravir monotherapy demonstrated rapid and dose-dependent antiviral activity with mean declines from baseline to Day 11 in HIV-1 RNA of 1.5, 2.0, and 2.5 log10 for dolutegravir 2 mg, 10 mg, and 50 mg once daily, respectively. This antiviral response was maintained for 3 to 4 days after the last dose in the 50-mg group.

Effects On Electrocardiogram

In a randomized, placebo-controlled, cross-over trial, 42 healthy subjects received single-dose oral administrations of placebo, dolutegravir 250-mg suspension (exposures approximately 3– fold of the 50-mg once-daily dose at steady state), and moxifloxacin 400 mg (active control) in random sequence. After baseline and placebo adjustment, the maximum mean QTc change based on Fridericia correction method (QTcF) for dolutegravir was 2.4 msec (1-sided 95% upper CI: 4.9 msec). TIVICAY did not prolong the QTc interval over 24 hours postdose.

Effects On Renal Function

The effect of dolutegravir on renal function was evaluated in an open-label, randomized, 3-arm, parallel, placebo-controlled trial in healthy subjects (n = 37) who received dolutegravir 50 mg once daily (n = 12), dolutegravir 50 mg twice daily (n = 13), or placebo once daily (n = 12) for 14 days. A decrease in creatinine clearance, as determined by 24-hour urine collection, was observed with both doses of dolutegravir after 14 days of treatment in subjects who received 50 mg once daily (9% decrease) and 50 mg twice daily (13% decrease). Neither dose of dolutegravir had a significant effect on the actual glomerular filtration rate (determined by the clearance of probe drug, iohexol) or effective renal plasma flow (determined by the clearance of probe drug, para-amino hippurate) compared with the placebo.

Pharmacokinetics

The pharmacokinetic properties of dolutegravir have been evaluated in healthy adult subjects and HIV-1-infected adult subjects. Exposure to dolutegravir was generally similar between healthy subjects and HIV-1-infected subjects. The non-linear exposure of dolutegravir following 50 mg twice daily compared with 50 mg once daily in HIV-1-infected subjects (Table 7) was attributed to the use of metabolic inducers in the background antiretroviral regimens of subjects receiving dolutegravir 50 mg twice daily in clinical trials. TIVICAY was administered without regard to food in these trials.

Table 7: Dolutegravir Steady-State Pharmacokinetic Parameter Estimates in HIV–1– Infected Adults

Parameter 50 mg Once Daily Geometric Meana (%CV) 50 mg Twice Daily Geometric Meanb (%CV)
AUC(0-24) (mcg.h/mL) 53.6 (27) 75.1 (35)
Cmax (mcg/mL) 3.67 (20) 4.15 (29)
Cmin (mcg/mL) 1.11 (46) 2.12 (47)
a Based on population pharmacokinetic analyses using data from SPRING-1 and SPRING-2.
b Based on population pharmacokinetic analyses using data from VIKING (ING112961) and VIKING-3.

Absorption

Following oral administration of dolutegravir, peak plasma concentrations were observed 2 to 3 hours postdose. With once-daily dosing, pharmacokinetic steady state is achieved within approximately 5 days with average accumulation ratios for AUC, Cmax, and C24 h ranging from 1.2 to 1.5.

Dolutegravir plasma concentrations increased in a less than dose-proportional manner above 50 mg. Dolutegravir is a P-gp substrate in vitro. The absolute bioavailability of dolutegravir has not been established.

Effects Of Food On Oral Absorption

TIVICAY may be taken with or without food. Food increased the extent of absorption and slowed the rate of absorption of dolutegravir. Low-, moderate-, and high-fat meals increased dolutegravir AUC(0-∞) by 33%, 41%, and 66%; increased Cmax by 46%, 52%, and 67%; and prolonged Tmax to 3, 4, and 5 hours from 2 hours under fasted conditions, respectively.

Distribution

Dolutegravir is highly bound (greater than or equal to 98.9%) to human plasma proteins based on in vivo data and binding is independent of plasma concentration of dolutegravir. The apparent volume of distribution (Vd/F) following 50-mg once-daily administration is estimated at 17.4 L based on a population pharmacokinetic analysis.

Cerebrospinal Fluid (CSF): In 12 treatment-na´ve subjects on dolutegravir 50 mg daily plus abacavir/lamivudine, the median dolutegravir concentration in CSF was 13.2 ng per mL (range: 3.74 ng per mL to 18.3 ng per mL) 2 to 6 hours postdose after 16 weeks of treatment. The clinical relevance of this finding has not been established.

Metabolism And Elimination

Dolutegravir is primarily metabolized via UGT1A1 with some contribution from CYP3A. After a single oral dose of [14C] dolutegravir, 53% of the total oral dose was excreted unchanged in feces. Thirty-one percent of the total oral dose was excreted in urine, represented by an ether glucuronide of dolutegravir (18.9% of total dose), a metabolite formed by oxidation at the benzylic carbon (3.0% of total dose), and its hydrolytic N-dealkylation product (3.6% of total dose). Renal elimination of unchanged drug was low (less than 1% of the dose).

Dolutegravir has a terminal half-life of approximately 14 hours and an apparent clearance (CL/F) of 1.0 L per hour based on population pharmacokinetic analyses.

Polymorphisms in Drug-Metabolizing Enzymes: In a meta-analysis of healthy subject trials, 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).

Specific Populations

Hepatic Impairment: Dolutegravir is primarily metabolized and eliminated by the liver. In a trial comparing 8 subjects with moderate hepatic impairment (Child-Pugh Score B) with 8 matched healthy controls, exposure of dolutegravir from a single 50-mg dose was similar between the 2 groups. No dosage adjustment is necessary for patients with mild to moderate hepatic impairment (Child-Pugh Score A or B). The effect of severe hepatic impairment (Child-Pugh Score C) on the pharmacokinetics of dolutegravir has not been studied. Therefore, TIVICAY is not recommended for use in patients with severe hepatic impairment.

HBV/HCV Co-infection: Population analyses using pooled pharmacokinetic data from adult trials indicated no clinically relevant effect of HCV co-infection on the pharmacokinetics of dolutegravir. There were limited data on HBV co-infection.

Renal Impairment: Renal clearance of unchanged drug is a minor pathway of elimination for dolutegravir. In a trial comparing 8 subjects with severe renal impairment (CrCl less than 30 mL per min) with 8 matched healthy controls, AUC, Cmax, and C24 of dolutegravir were decreased by 40%, 23%, and 43%, respectively, compared with those in matched healthy subjects. The cause of this decrease is unknown. Population pharmacokinetic analysis using data from SAILING and VIKING-3 trials indicated that mild and moderate renal impairment had no clinically relevant effect on the exposure of dolutegravir. No dosage adjustment is necessary for treatment-na´ve or treatment-experienced and INSTI-na´ve patients with mild, moderate, or severe renal impairment or for INSTI-experienced patients (with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance) with mild or moderate renal impairment. Caution is warranted for INSTI-experienced patients (with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance [see Microbiology]) with severe renal impairment, as the decrease in dolutegravir concentrations may result in loss of therapeutic effect and development of resistance to TIVICAY or other coadministered antiretroviral agents. Dolutegravir has not been studied in patients requiring dialysis.

Gender: Population analyses using pooled pharmacokinetic data from adult trials indicated gender had no clinically relevant effect on the exposure of dolutegravir.

Race: Population analyses using pooled pharmacokinetic data from adult trials indicated race had no clinically relevant effect on the pharmacokinetics of dolutegravir.

Geriatric Patients: Population analyses using pooled pharmacokinetic data from adult trials indicated age had no clinically relevant effect on the pharmacokinetics of dolutegravir.

Pediatric Patients: The pharmacokinetics of dolutegravir in HIV-1-infected children (n = 17) weighing at least 30 kg were similar to those observed in HIV-1-infected adults who received dolutegravir 50 mg once daily (Table 8) [see Clinical Studies].

Table 8: Dolutegravir Steady-State Pharmacokinetic Parameters in Pediatric Subjects

Weight (n) Dose of TIVICAYa Dolutegravir Pharmacokinetic Parameter Estimates Geometric Mean (%CV)
Cmax (mcg/mL) AUC(0-24) (mcg•h/mL) C24 (mcg/mL)
≥ 40 kg (n = 14) 50 mg once daily 3.89 (43) 50.1 (53) 0.99 (66)
≥ 30 to < 40 kg (n=3) 35 mg once daily 4.40 (54) 64.6 (64) 1.33 (93)

Population pharmacokinetic analyses demonstrate comparable exposures in children, at least 30 kg, dosed by weight-bands (35 mg or 50 mg of dolutegravir) to that observed in adults.

Drug Interactions

Drug interaction trials were performed with TIVICAY and other drugs likely to be coadministered or commonly used as probes for pharmacokinetic interactions. As dolutegravir is not expected to affect the pharmacokinetics of other drugs dependent on hepatic metabolism (Table 9) [see DRUG INTERACTIONS], the primary focus of these drug interaction trials was to evaluate the effect of coadministered drug on dolutegravir (Table 10).

Dosing or regimen recommendations as a result of established and other potentially significant drug-drug interactions with TIVICAY are provided in Table 6 [see DOSAGE AND ADMINISTRATION, DRUG INTERACTIONS].

Table 9: Summary of Effect of Dolutegravir on the Pharmacokinetics of Coadministered Drugs

Coadministered Drug(s) and Dose(s) Dose of TIVICAY n Geometric Mean Ratio (90% CI) of Pharmacokinetic Parameters of Coadministered Drug with/without Dolutegravir No Effect = 1.00
Cmax AUC Cτ or C24
Daclatasvir 60 mg once daily 50 mg once daily 12 1.03
(0.84 to 1.25)
0.98
(0.83 to 1.15)
1.06
(0.88 to 1.29)
Ethinyl estradiol 0.035 mg 50 mg twice daily 15 0.99
(0.91 to 1.08)
1.03
(0.96 to 1.11)
1.02
(0.93 to 1.11)
Metformin 500 mg twice daily 50 mg once daily 15a 1.66
(1.53 to 1.81)
1.79
(1.65 to 1.93)
-
Metformin 500 mg twice daily 50 mg twice daily 15a 2.11
(1.91 to 2.33)
2.45
(2.25 to 2.66)
-
Methadone 16 to 150 mg 50 mg twice daily 11 1.00
(0. 94 to 1.06)
0.98
(0.91 to 1.06)
0.99
(0.91 to 1.07)
Midazolam 3 mg 25 mg once daily 10 - 0.95
(0.79 to 1.15)
-
Norelgestromin 0.25 mg 50 mg twice daily 15 0.89
(0.82 to 0.97)
0.98
(0.91 to 1.04)
0.93
(0.85 to 1.03)
Rilpivirine 25 mg once daily 50 mg once daily 16 1.10
(0.99 to 1.22)
1.06
(0.98 to 1.16)
1.21
(1.07 to 1.38)
Tenofovir disoproxil fumarate 300 mg once daily 50 mg once daily 15 1.09
(0.97 to 1.23)
1.12
(1.01 to 1.24)
1.19
(1.04 to 1.35)
a The number of subjects represents the maximum number of subjects that were evaluated.

Table 10: Summary of Effect of Coadministered Drugs on the Pharmacokinetics of Dolutegravir

Coadministered Drug(s) and Dose(s) Dose of TIVICAY n Geometri Dolutegravir with/witho : Mean Ratio (90% CI) of Pharmacokinetic Parameters ut Coadministered Drugs No Effect = 1.00
Cmax AUC Cτ or C24
Atazanavir 400 mg once daily 30 mg once daily 12 1.50
(1.40 to 1.59)
1.91
(1.80 to 2.03)
2.80
(2.52 to 3.11)
Atazanavir/ritonavir 300/100 mg once daily 30 mg once daily 12 1.34
(1.25 to 1.42)
1.62
(1.50 to 1.74)
2.21
(1.97 to 2.47)
Darunavir/ritonavir 600/100 mg twice daily 30 mg once daily 15 0.89
(0.83 to 0.97)
0.78
(0.72 to 0.85)
0.62
(0.56 to 0.69)
Efavirenz 600 mg once daily 50 mg once daily 12 0.61
(0.51 to 0.73)
0.43
(0.35 to 0.54)
0.25
(0.18 to 0.34)
Etravirine 200 mg twice daily 50 mg once daily 16 0.48
(0.43 to 0.54)
0.29
(0.26 to 0.34)
0.12
(0.09 to 0.16)
Etravirine + darunavir/ritonavir 200 mg + 600/100 mg twice daily 50 mg once daily 9 0.88
(0.78 to 1.00)
0.75
(0.69 to 0.81)
0.63
(0.52 to 0.76)
Etravirine + lopinavir/ritonavir 200 mg + 400/100 mg twice daily 50 mg once daily 8 1.07
(1.02 to 1.13)
1.11
(1.02 to 1.20)
1.28
(1.13 to 1.45)
Fosamprenavir/ritonavir 700 mg/100 mg twice daily 50 mg once daily 12 0.76
(0.63 to 0.92)
0.65
(0.54 to 0.78)
0.51
(0.41 to 0.63)
Lopinavir/ritonavir 400/100 mg twice daily 30 mg once daily 15 1.00
(0.94 to 1.07)
0.97
(0.91 to 1.04)
0.94
(0.85 to 1.05)
Rilpivirine 25 mg once daily 50 mg once daily 16 1.13
(1.06 to 1.21)
1.12
(1.05 to 1.19)
1.22
(1.15 to 1.30)
Tenofovir 300 mg once daily 50 mg once daily 15 0.97
(0.87 to 1.08)
1.01
(0.91 to 1.11)
0.92
(0.82 to 1.04)
Tipranavir/ritonavir 500/200 mg twice daily 50 mg once daily 14 0.54
(0.50 to 0.57)
0.41
(0.38 to 0.44)
0.24
(0.21 to 0.27)
Antacid (Maalox®) simultaneous administration 50 mg single dose 16 0.28
(0.23 to 0.33)
0.26
(0.22 to 0.32)
0.26
(0.21 to 0.31)
Antacid (Maalox®) 2 h after dolutegravir 50 mg single dose 16 0.82
(0.69 to 0.98)
0.74
(0.62 to 0.90)
0.70
(0.58 to 0.85)
Boceprevir 800 mg every 8 hours 50 mg once daily 13 1.05
(0.96 to 1.15)
1.07
(0.95 to 1.20)
1.08
(0.91 to 1.28)
Calcium carbonate 1,200 mg simultaneous administration (fasted) 50 mg single dose 12 0.63
(0.50 to 0.81)
0.61
(0.47 to 0.80)
0.61
(0.47 to 0.80)
Calcium carbonate 1,200 mg simultaneous administration (fed) 50 mg single dose 11 1.07
(0.83 to 1.38)
1.09
(0.84 to 1.43)
1.08
(0.81 to 1.42)
Calcium carbonate 1,200 mg 2 h after dolutegravir 50 mg single dose 11 1.00
(0.78 to 1.29)
0.94
(0.72 to 1.23)
0.90
(0.68 to 1.19)
Carbamazepine 300 mg twice daily 50 mg once daily 16c 0.67
(0.61 to 0.73)
0.51
(0.48 to 0.55)
0.27
(0.24 to 0.31)
Daclatasvir 60 mg once daily 50 mg once daily 12 1.29
(1.07 to 1.57)
1.33
(1.11 to 1.59)
1.45
(1.25 to 1.68)
Ferrous fumarate 324 mg simultaneous administration
(fasted)
50 mg single dose 11 0.43
(0.35 to 0.52)
0.46
(0.38 to 0.56)
0.44
(0.36 to 0.54)
Ferrous fumarate 324 mg simultaneous administration (fed) 50 mg single dose 11 1.03
(0.84 to 1.26)
0.98
(0.81 to 1.20)
1.00
(0.81 to 1.23)
Ferrous fumarate 324 mg 2 h after dolutegravir 50 mg single dose 10 0.99
(0.81 to 1.21)
0.95
(0.77 to 1.15)
0.92
(0.74 to 1.13)
Multivitamin (One-A-Day®) simultaneous administration 50 mg single dose 16 0.65
(0.54 to 0.77)
0.67
(0.55 to 0.81)
0.68
(0.56 to 0.82)
Omeprazole 40 mg once daily 50 mg single dose 12 0.92
(0.75 to 1.11)
0.97
(0.78 to 1.20)
0.95
(0.75 to 1.21)
Prednisone 60 mg once daily with taper 50 mg once daily 12 1.06
(0.99 to 1.14)
1.11
(1.03 to 1.20)
1.17
(1.06 to 1.28)
Rifampina 600 mg once daily 50 mg twice daily 11 0.57
(0.49 to 0.65)
0.46
(0.38 to 0.55)
0.28
(0.23 to 0.34)
Rifampinb 600 mg once daily 50 mg twice daily 11 1.18
(1.03 to 1.37)
1.33
(1.15 to 1.53)
1.22
(1.01 to 1.48)
Rifabutin 300 mg once daily 50 mg once daily 9 1.16
(0.98 to 1.37)
0.95
(0.82 to 1.10)
0.70
(0.57 to 0.87)
a Comparison is rifampin taken with dolutegravir 50 mg twice daily compared with dolutegravir 50 mg twice daily.
b Comparison is rifampin taken with dolutegravir 50 mg twice daily compared with dolutegravir 50 mg once daily.
c The number of subjects represents the maximum number of subjects that were evaluated.

Microbiology

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. Strand transfer biochemical assays using purified HIV-1 integrase and pre-processed substrate DNA resulted in IC50 values of 2.7 nM and 12.6 nM.

Antiviral Activity In Cell Culture

Dolutegravir exhibited antiviral activity against laboratory strains of wild-type HIV-1 with mean EC50 values of 0.5 nM (0.21 ng per mL) to 2.1 nM (0.85 ng per mL) in peripheral blood mononuclear cells (PBMCs) and MT-4 cells. Dolutegravir exhibited antiviral activity against 13 clinically diverse clade B isolates with a mean EC50 value of 0.52 nM in a viral integrase susceptibility assay using the integrase coding region from clinical isolates. Dolutegravir demonstrated antiviral activity in cell culture against a panel of HIV-1 clinical isolates (3 in each group of M clades A, B, C, D, E, F, and G, and 3 in group O) with EC50 values ranging from 0.02 nM to 2.14 nM for HIV-1. Dolutegravir EC50 values against 3 HIV-2 clinical isolates in PBMC assays ranged from 0.09 nM to 0.61 nM.

Antiviral Activity In Combination with Other Antiviral Agents

The antiviral activity of dolutegravir was not antagonistic when combined with the INSTI, raltegravir; non-nucleoside reverse transcriptase inhibitors (NNRTIs), efavirenz or nevirapine; the nucleoside reverse transcriptase inhibitors (NRTIs), abacavir or stavudine; the protease inhibitors (PIs), amprenavir or lopinavir; the CCR5 co-receptor antagonist, maraviroc; or the fusion inhibitor, enfuvirtide. Dolutegravir antiviral activity was not antagonistic when combined with the HBV reverse transcriptase inhibitor, adefovir, or inhibited by the antiviral, ribavirin.

Resistance

Cell Culture: Dolutegravir-resistant viruses were selected in cell culture starting from different wild-type HIV-1 strains and clades. Amino acid substitutions E92Q, G118R, S153F or Y, G193E or R263K emerged in different passages and conferred decreased susceptibility to dolutegravir of up to 4-fold. Passage of mutant viruses containing the Q148R or Q148H substitutions selected for additional substitutions in integrase that conferred decreased susceptibility to dolutegravir (fold-change increase of 13 to 46). The additional integrase substitutions included T97A, E138K, G140S, and M154I. Passage of mutant viruses containing both G140S and Q148H selected for L74M, E92Q, and N155H.

Treatment-Na´ve Subjects: No subjects in the dolutegravir 50-mg once-daily treatment arms of treatment-na´ve trials SPRING-2 (96 weeks) and SINGLE (144 weeks) had a detectable decrease in susceptibility to dolutegravir or background NRTIs in the resistance analysis subset (n = 12 with HIV-1 RNA greater than 400 copies per mL at failure or last visit and having resistance data). Two virologic failure subjects in SINGLE had treatment-emergent G/D/E193D and G193G/E integrase substitutions at Week 84 and Week 108, respectively, and 1 subject with 275 copies per mL HIV-1 RNA had a treatment-emergent Q157Q/P integrase substitution detected at Week 24. None of these subjects had a corresponding decrease in dolutegravir susceptibility. No treatment-emergent genotypic resistance to the background regimen was observed in the dolutegravir arm in either the SPRING-2 or SINGLE trials. No treatment-emergent primary resistance substitutions were observed in either treatment group in the FLAMINGO trial through Week 96.

Treatment-Experienced, Integrase Strand Transfer Inhibitor-Na´ve Subjects: In the dolutegravir arm of the SAILING trial for treatment-experienced and INSTI-na´ve subjects (n = 354), treatment-emergent integrase substitutions were observed in 6 of 28 (21%) subjects who had virologic failure and resistance data. In 5 of the 6 subjects' isolates emergent INSTI substitutions included L74L/M/I, Q95Q/L, V151V/I (n = 1 each), and R263K (n = 2). The change in dolutegravir phenotypic susceptibility for these 5 subject isolates was less than 2-fold. One subject isolate had pre-existing raltegravir resistance substitutions E138A, G140S, and Q148H at baseline and had additional emergent INSTI-resistance substitutions T97A and E138A/T with a corresponding 148-fold reduction in dolutegravir susceptibility at failure. In the comparator raltegravir arm, 21 of 49 (43%) subjects with post-baseline resistance data had evidence of emergent INSTI-resistance substitutions (L74M, E92Q, T97A, E138Q, G140S/A, Y143R/C, Q148H/R, V151I, N155H, E157Q, and G163K/R) and raltegravir phenotypic resistance.

Treatment-Experienced, Integrase Strand Transfer Inhibitor-Experienced Subjects: VIKING-3 examined the efficacy of dolutegravir 50 mg twice daily plus optimized background therapy in subjects with prior or current virologic failure on an INSTI-(elvitegravir or raltegravir) containing regimen.

In VIKING-4 (ING116529), 30 subjects with current virological failure on an INSTI-containing regimen and genotypic evidence of INSTI-resistance substitutions at screening were randomized to receive either dolutegravir 50 mg twice daily or placebo with the current failing regimen for 7 days and then all subjects received open-label dolutegravir plus optimized background regimen from Day 8. Virologic responses at Week 48 by baseline genotypic and phenotypic INSTI-resistance categories and the INSTI resistance-associated substitutions that emerged on dolutegravir treatment in VIKING-4 were consistent with those seen in VIKING-3.

Response By Baseline Genotype

Of the 183 subjects with baseline data, 30% harbored virus with a substitution at Q148, and 33% had no primary INSTI-resistance substitutions (T66A/I/K, E92Q/V, Y143R/C/H, Q148H/R/K, and N155H) at baseline, but had historical genotypic evidence of INSTI-resistance substitutions, phenotypic evidence of elvitegravir or raltegravir resistance, or genotypic evidence of INSTI-resistance substitutions at screening.

Response rates by baseline genotype were analyzed in an “as-treated” analysis at Week 48 (n = 175) (Table 11). The response rate at Week 48 to dolutegravir-containing regimens was 47% (24 of 51) when Q148 substitutions were present at baseline; Q148 was always present with additional INSTI-resistance substitutions (see Table 11). In addition, a diminished virologic response of 40% (6 of 15) was observed when the substitution E157Q or K was present at baseline with other INSTI-resistance substitutions but without a Q148H or R substitution.

Table 11: Response by Baseline Integrase Genotype in Subjects with Prior Experience to an Integrase Strand Transfer Inhibitor in VIKING-3

Baseline Genotype Week 48 ( < 50 copies/mL)
n = 175
Overall Response 66% (116/175)
No Q148 substitutiona 74% (92/124)
Q148H/R + G140S/A/C without additional INSTI-resistance substitutionb 61% (17/28)
Q148H/R + ≥ 2 INSTI-resistance substitutionsc 29% (6/21)
a Includes INSTI-resistance substitutions Y143R/C/H and N155H.
b INSTI-resistance substitutions included T66A, L74I/M, E138A/K/T, G140S/A/C, Y143R/C/H, E157Q, G163S/E/K/Q, or G193E/R. Two additional subjects had baseline genotypes of Q148Q/R plus L74L/I/M (virologic failure) and Q148R plus E138K (responder).
c The most common pathway with Q148H/R + greater than or equal to 2 INSTI-resistance substitutions had Q148+G140+E138 substitutions (n = 16).

Response By Baseline Phenotype

Response rates by baseline phenotype were analyzed in an as-treated analysis using all subjects with available baseline phenotypes through Week 48 (n = 163) (see Table 12). These baseline phenotypic groups are based on subjects enrolled in VIKING-3 and are not meant to represent definitive clinical susceptibility cut points for dolutegravir. The data are provided to guide clinicians on the likelihood of virologic success based on pretreatment susceptibility to dolutegravir in INSTI-resistant patients.

Table 12: Response by Baseline Dolutegravir Phenotype (Fold-Change from Reference) in Subjects with Prior Experience to an Integrase Strand Transfer Inhibitor in VIKING-3

Baseline Dolutegravir Phenotype (Fold-Change from Reference) Response at Week 48 ( < 50 copies/mL) Subset
n = 163
Overall Response 64% (104/163)
< 3-fold change 72% (83/116)
3- < 10-fold change 53% (18/34)
≥ 10-fold change 23% (3/13)

Integrase Strand Transfer Inhibitor Treatment-Emergent Resistance

There were 50 subjects with virologic failure on the dolutegravir twice-daily regimen in VIKING-3 with HIV-1 RNA greater than 400 copies per mL at the failure timepoint, Week 48 or beyond, or the last timepoint on trial. Thirty-nine subjects with virologic failure had resistance data that were used in the Week 48 analysis. In the Week 48 resistance analysis 85% (33 of 39) of the subjects with virologic failure had treatment-emergent INSTI-resistance substitutions in their isolates. The most common treatment-emergent INSTI-resistance substitution was T97A. Other frequently emergent INSTI-resistance substitutions included L74M, I or V, E138K or A, G140S, Q148H, R or K, M154I, or N155H. Substitutions E92Q, Y143R or C/H, S147G, V151A, and E157E/Q each emerged in 1 to 3 subjects' isolates. At failure, the median dolutegravir fold-change from reference was 61-fold (range: 0.75 to 209) for isolates with emergent INSTI-resistance substitutions (n = 33).

Resistance to one or more background drugs in the dolutegravir twice-daily regimen also emerged in 49% (19 of 39) subjects in the Week 48 resistance analysis.

Cross-Resistance

Site-Directed Integrase Strand Transfer Inhibitor-Resistant Mutant HIV-1 and HIV-2 Strains: The susceptibility of dolutegravir was tested against 60 INSTI-resistant site-directed mutant HIV-1 viruses (28 with single substitutions and 32 with 2 or more substitutions) and 6 INSTI-resistant site-directed mutant HIV-2 viruses. The single INSTI-resistance substitutions T66K, I151L, and S153Y conferred a greater than 2-fold decrease in dolutegravir susceptibility (range: 2.3-fold to 3.6-fold from reference). Combinations of multiple substitutions T66K/L74M, E92Q/N155H, G140C/Q148R, G140S/Q148H, R or K, Q148R/N155H, T97A/G140S/Q148, and substitutions at E138/G140/Q148 showed a greater than 2-fold decrease in dolutegravir susceptibility (range: 2.5-fold to 21-fold from reference). In HIV-2 mutants, combinations of substitutions A153G/N155H/S163G and E92Q/T97A/N155H/S163D conferred 4-fold decreases in dolutegravir susceptibility, and E92Q/N155H and G140S/Q148R showed 8.5-fold and 17-fold decreases in dolutegravir susceptibility, respectively.

Reverse Transcriptase Inhibitor-and Protease Inhibitor-Resistant Strains: Dolutegravir demonstrated equivalent antiviral activity against 2 NNRTI-resistant, 3 NRTI-resistant, and 2 PI-resistant HIV-1 mutant clones compared with the wild-type strain.

Clinical Studies

The efficacy of TIVICAY is based on analyses of data from 3 trials, SPRING-2 (ING113086), SINGLE (ING114467), and FLAMINGO (ING114915), in treatment-na´ve, HIV-1-infected subjects (n = 2,125); one trial, SAILING (ING111762), in treatment-experienced, INSTI-na´ve HIV-1-infected subjects (n = 715); and from VIKING-3 (ING112574) trial in INSTI-experienced HIV-1-infected subjects (n = 183). The use of TIVICAY in pediatric patients aged 12 years and older is based on evaluation of safety, pharmacokinetics, and efficacy through 24 weeks in a multicenter, open-label trial in subjects (n = 23) without INSTI resistance.

Adult Subjects

Treatment-Na´ve Subjects

In SPRING-2, 822 subjects were randomized and received at least 1 dose of either TIVICAY 50 mg once daily or raltegravir 400 mg twice daily, both in combination with fixed-dose dual NRTI treatment (either abacavir sulfate and lamivudine [EPZICOM] or emtricitabine/tenofovir [TRUVADA]). There were 808 subjects included in the efficacy and safety analyses. At baseline, the median age of subjects was 36 years, 13% female, 15% non-white, 11% had hepatitis B and/or C virus co-infection, 2% were CDC Class C (AIDS), 28% had HIV-1 RNA greater than 100,000 copies per mL, 48% had CD4+ cell count less than 350 cells per mm³, and 39% received EPZICOM; these characteristics were similar between treatment groups.

In SINGLE, 833 subjects were randomized and received at least 1 dose of either TIVICAY 50 mg once daily with fixed-dose abacavir sulfate and lamivudine (EPZICOM) or fixed-dose efavirenz/emtricitabine/tenofovir (ATRIPLA). At baseline, the median age of subjects was 35 years, 16% female, 32% non-white, 7% had hepatitis C co-infection (hepatitis B virus coinfection was excluded), 4% were CDC Class C (AIDS), 32% had HIV-1 RNA greater than 100,000 copies per mL, and 53% had CD4+ cell count less than 350 cells per mm³; these characteristics were similar between treatment groups.

Outcomes for SPRING-2 (Week 96 analysis) and SINGLE (Week 144 open-label phase analysis which followed the Week 96 double-blind phase) are provided in Table 13. Side-by-side tabulation is to simplify presentation; direct comparisons across trials should not be made due to differing trial designs.

Table 13: Virologic Outcomes of Randomized Treatment in SPRING-2 at Week 96 and SINGLE at Week 144 (Snapshot Algorithm)

  SPRING-2 Week 96 SINGLE Week 144
TIVICAY 50 mg Once Daily + 2 NRTIs
(n = 403)
Raltegravir 400 mg Twice Daily + 2 NRTIs
(n = 405)
TIVICAY 50 mg + EPZICOM Once Daily
(n = 414)
ATRIPLA Once Daily
(n = 419)
HIV-1 RNA < 50 copies/mL 82% 78% 71% 63%
  Treatment differencea 4.9% (95% CI: -0.6%, 10.3%)d 8.3% (95% CI: 2.0%, 14.6%)e
Virologic nonresponse 5% 10% 10% 7%
  Data in window not < 50 copies/mL 1% 3% 4% < 1%
  Discontinued for lack of efficacy 2% 3% 3% 3%
  Discontinued for other reasons while not suppressed < 1% 3% 3% 4%
  Change in ART regimen < 1% < 1% 0 0
No virologic data 12% 12% 18% 30%
Reasons
  Discontinued study/study drug due to adverse event or deathb 2% 2% 4% 14%
  Discontinued study/study drug for other reasonsc 8% 9% 12% 13%
  Missing data during window but on study 2% < 1% 2% 3%
Proportion (%) of Subjects with HIV-1 RNA < 50 copies/mL by Baseline Category
Plasma viral load (copies/mL)
   ≤ 100,000 84% 83% 73% 64%
   > 100,000 79% 63% 69% 61%
Gender
  Male 84% 79% 72% 66%
  Female 70% 68% 69% 48%
Race
  White 83% 78% 72% 71%
  African-  American/African Heritage/Other 77% 75% 71% 47%
a Adjusted for pre-specified stratification factors.
b Includes subjects who discontinued due to an adverse event or death at any time point if this resulted in no virologic data on treatment during the analysis window.
c Other includes reasons such as withdrew consent, loss to follow-up, moved, and protocol deviation.
d The primary endpoint was assessed at Week 48 and the virologic success rate was 88% in the group receiving TIVICAY and 86% in the raltegravir group, with a treatment difference of 2.6% and 95% CI of (-1.9%, 7.2%).
e The primary endpoint was assessed at Week 48 and the virologic success rate was 88% in the group receiving TIVICAY and 81% in the ATRIPLA group, with a treatment difference of 7.4% and 95% CI of (2.5%, 12.3%). SPRING-2: Virologic outcomes were also comparable across baseline characteristics including CD4+ cell count, age, and use of EPZICOM or TRUVADA as NRTI background regimen. The median change in CD4+ cell counts from baseline were 276 cells per mm³ in the group receiving TIVICAY and 264 cells per mm³ for the raltegravir group at 96 weeks.

There was no treatment-emergent resistance to dolutegravir or to the NRTI background.

SINGLE: Treatment differences were maintained across baseline characteristics including baseline viral load, CD4+ cell count, age, gender, and race.

The adjusted mean changes in CD4+ cell counts from baseline were 378 cells per mm³in the group receiving TIVICAY + EPZICOM and 332 cells per mm³for the ATRIPLA group at 144 weeks. The adjusted difference between treatment arms and 95% CI was 46.9 cells per mm³(15.6 cells per mm³, 78.2 cells per mm³) (adjusted for pre-specified stratification factors: baseline HIV-1 RNA, and baseline CD4+ cell count).

There was no treatment-emergent resistance to dolutegravir, abacavir, or lamivudine.

FLAMINGO: In FLAMINGO, 485 subjects were randomized and received at least 1 dose of either TIVICAY 50 mg once daily (n = 243) or darunavir + ritonavir 800 mg/100 mg once daily (n = 242), both in combination with investigator-selected NRTI background regimen (either fixed-dose abacavir and lamivudine [EPZICOM] or fixed-dose emtricitabine/tenofovir disoproxil fumarate [TRUVADA]). There were 484 subjects included in the efficacy and safety analyses. At baseline, the median age of subjects was 34 years, 15% female, 28% non-white, 10% had hepatitis B and/or C virus co-infection, 3% were CDC Class C (AIDS), 25% had HIV-1 RNA greater than 100,000 copies per mL, and 35% had CD4+ cell count less than 350 cells per mm³; these characteristics were similar between treatment groups. Overall response rates by Snapshot algorithm through Week 96 were 80% for TIVICAY and 68% for darunavir/ritonavir. The proportion of subjects who were non-responders (HIV-1 RNA greater than or equal to 50 copies per mL) at Week 96 was 8% and 12% in the arms receiving TIVICAY and darunavir + ritonavir, respectively; no virologic data were available for 12% and 21% for subjects treated with TIVICAY and darunavir + ritonavir, respectively. The adjusted overall response rate difference in proportion and 95% CI was 12.4% (4.7%, 20.2%). No treatment-emergent primary resistance substitutions were observed in either treatment group.

Treatment-Experienced, Integrase Strand Transfer Inhibitor-Na´ve Subjects

In the international, multicenter, double-blind trial (SAILING), 719 HIV-1-infected, antiretroviral treatment-experienced adults were randomized and received either TIVICAY 50 mg once daily or raltegravir 400 mg twice daily with investigator-selected background regimen consisting of up to 2 agents, including at least 1 fully active agent. There were 715 subjects included in the efficacy and safety analyses. At baseline, the median age was 43 years, 32% were female, 50% non-white, 16% had hepatitis B and/or C virus co-infection, 46% were CDC Class C (AIDS), 20% had HIV-1 RNA greater than 100,000 copies per mL, and 72% had CD4+ cell count less than 350 cells per mm³; these characteristics were similar between treatment groups. All subjects had at least 2-class antiretroviral treatment resistance, and 49% of subjects had at least 3-class antiretroviral treatment resistance at baseline. Week 48 outcomes for SAILING are shown in Table 14.

Table 14: Virologic Outcomes of Randomized Treatment in SAILING at 48 Weeks (Snapshot Algorithm)

  TIVICAY 50 mgOnce Daily + BRa
(n = 354)
Raltegravir 400 mgTwice Daily + BRa
(n = 361)
HIV-1 RNA < 50 copies/mL 71% 64%
Adjustedb treatment difference 7.4% (95% CI: 0.7%, 14.2%)
Virologic nonresponse 20% 28%
No virologic data 9% 9%
Reasons
  Discontinued study/study drug due to adverse event or death 3% 4%
  Discontinued study/study drug for other reasonsc 5% 4%
  Missing data during window but on study 2% 1%
Proportion (%) with HIV-1 RNA < 50 copies/mL by Baseline Category
Plasma viral load (copies/mL)
   ≤ 50,000 copies/mL 75% 71%
   > 50,000 copies/mL 62% 47%
Background regimen
  No darunavir use 67% 60%
  Darunavir use with primary PI  substitutions 85% 67%
  Darunavir use without primary PI substitutions 69% 70%
Gender
  Male 70% 66%
  Female 74% 60%
Race 
  White 75% 71%
  Afri can-Ameri can/African Heritage/Other 67% 57%
a BR = Background regimen. Background regimen was restricted to less than or equal to 2 antiretroviral treatments with at least 1 fully active agent.
b Adjusted for pre-specified stratification factors.
c Other includes reasons such as withdrew consent, loss to follow-up, moved, and protocol deviation.

Treatment differences were maintained across the baseline characteristics including CD4+ cell count and age.

The mean changes in CD4+ cell counts from baseline were 162 cells per mm³in the group receiving TIVICAY and 153 cells per mm³in the raltegravir group.

Treatment-Experienced, Integrase Strand Transfer Inhibitor-Experienced Subjects

VIKING-3 examined the effect of TIVICAY 50 mg twice daily over 7 days of functional monotherapy, followed by optimized background therapy (OBT) with continued treatment of TIVICAY 50 mg twice daily.

In the multicenter, open-label, single-arm VIKING-3 trial, 183 HIV-1-infected, antiretroviral treatment-experienced adults with virological failure and current or historical evidence of raltegravir and/or elvitegravir resistance received TIVICAY 50 mg twice daily with the current failing background regimen for 7 days, then received TIVICAY with OBT from Day 8. A total of 183 subjects enrolled: 133 subjects with INSTI resistance at screening and 50 subjects with only historical evidence of resistance (and not at screening). At baseline, median age of subjects was 48 years; 23% were female, 29% non-white, and 20% had hepatitis B and/or C virus coinfection. Median baseline CD4+ cell count was 140 cells per mm³, median duration of prior antiretroviral treatment was 13 years, and 56% were CDC Class C. Subjects showed multiple-class antiretroviral treatment resistance at baseline: 79% had greater than or equal to 2 NRTI, 75% greater than or equal to 1 NNRTI, and 71% greater than or equal to 2 PI major substitutions; 62% had non-R5 virus.

Mean reduction from baseline in HIV-1 RNA at Day 8 (primary endpoint) was 1.4 log10 (95% CI: 1.3 log10, 1.5 log10). Response at Week 48 was affected by baseline INSTI substitutions [see Microbiology].

After the functional monotherapy phase, subjects had the opportunity to re-optimize their background regimen when possible. Week 48 virologic outcomes for VIKING-3 are shown in Table 15.

Table 15: Virologic Outcomes of Treatment of VIKING-3 at 48 Weeks (Snapshot Algorithm)

  TIVICAY 50 mg Twice Daily + OBT
(n = 183)
HIV-1 RNA < 50 copies/mL 63%
Virologic nonresponse 32%
No virologic data  
Reasons  
  Discontinued study/study drug due to adverse event or death 3%
Proportion (%) with HIV-1 RNA < 50 copies/mL by Baseline Category
Gender
  Male 63%
  Female 64%
Race
  White 63%
  African-Ameri can/African Heritage/Other 64%

Subjects harboring virus with Q148 and with additional Q148-associated secondary substitutions also had a reduced response at Week 48 in a stepwise fashion [see Microbiology].

The median change in CD4+ cell count from baseline was 80 cells per mm³at Week 48.

Pediatric Subjects

IMPAACT P1093 is a Phase ½, 48-week, multicenter, open-label trial to evaluate the pharmacokinetic parameters, safety, tolerability, and efficacy of TIVICAY in combination treatment regimens in HIV–1-infected infants, children, and adolescents. Subjects were stratified by age, enrolling adolescents first (Cohort 1: aged 12 to less than 18 years) and then younger children (Cohort 2A: aged 6 to less than 12 years). All subjects received a weight-based dose of TIVICAY [see DOSAGE AND ADMINISTRATION].

These 46 subjects had a mean age of 12 years (range: 6 to 17), were 54% female and 52% black. At baseline, mean plasma HIV-1 RNA was 4.6 log10 copies per mL, median CD4+ cell count was 639 cells per mm³(range: 9 to 1,700), and median CD4+% was 23% (range: 1% to 44%). Overall, 39% had baseline plasma HIV-1 RNA greater than 50,000 copies per mL and 33% had a CDC HIV clinical classification of category C. Most subjects had previously used at least 1 NNRTI (50%) or 1 PI (70%).

At Week 24, the proportion of subjects with HIV-1 RNA less than 50 copies per mL in Cohort 1 and Cohort 2A was 70% (16/23) and 61% (14/23), respectively. At Week 48, the proportion of subjects from Cohort 1 with HIV-1 RNA less than 50 copies per mL was 61% (14/23). Virologic outcomes were also evaluated based on body weight. Across both cohorts, virologic suppression (HIV-1 RNA less than 50 copies per mL) at Week 24 was achieved in 75% (18/24) of subjects weighing at least 40 kg and 55% (6/11) of subjects in the 30 to less than 40 kg weight-band. At

Week 48, 63% (12/19) of the subjects in Cohort 1 weighing at least 40 kg were virologically suppressed.

The median CD4+ cell count increase from baseline to Week 48 was 84 cells per mm³in Cohort 1. For Cohort 2A, the median CD4+ cell count increase from baseline to Week 24 was 209 cells per mm³.

Last reviewed on RxList: 6/17/2016
This monograph has been modified to include the generic and brand name in many instances.

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