12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

JULUCA is a fixed-dose combination of the HIV-1 antiretroviral agents, dolutegravir and rilpivirine [see Microbiology (12.4)].

12.2 Pharmacodynamics

Cardiac Electrophysiology

The effect of JULUCA on the QT interval has not been studied.

In a randomized, placebo-controlled, crossover trial, 42 healthy subjects received single-dose oral administration 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). Dolutegravir did not prolong the QTc interval over 24 hours postdose.

The effect of rilpivirine at the recommended dose of 25 mg once daily on the QTcF interval was evaluated in a randomized, placebo- and active- (moxifloxacin 400 mg once daily) controlled crossover study in 60 healthy adults, with 13 measurements over 24 hours at steady state. The maximum mean time-matched (95% upper confidence bound) differences in QTcF interval from placebo after baseline correction was 2.0 (5.0) milliseconds (i.e., below the threshold of clinical concern). When 75 mg and 300 mg once daily of rilpivirine (3 times and 12 times the recommended dosage in JULUCA, respectively) were studied in healthy adults, the maximum mean time-matched (95% upper confidence bound) differences in QTcF interval from placebo after baseline correction were 10.7 (15.3) and 23.3 (28.4) milliseconds, respectively. Steady-state administration of rilpivirine 75 mg once daily and 300 mg once daily resulted in a mean steady-state Cmax approximately 2.6-fold and 6.7-fold, respectively, higher than the mean Cmax observed with the recommended 25-mg once-daily dose of rilpivirine [see Drug Interactions (7.4)].

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.

12.3 Pharmacokinetics

Absorption, Distribution, Metabolism, and Excretion

The pharmacokinetic (PK) properties of the components of JULUCA are provided in Table 5. The multiple-dose pharmacokinetic parameters are provided in Table 6.

Table 5. Pharmacokinetic Properties of the Components of JULUCA
UGT = uridine diphosphate glucuronosyltransferase; CYP = Cytochrome P450.
a Geometric mean ratio (fed/fasted) in PK parameters and (90% confidence interval). High-calorie/high-fat meal = ~900 kcal, 56% fat. Moderate-fat meal = ~625 kcal, 32% fat. When rilpivirine was taken with only a protein-rich nutritional drink, exposures were 50% lower than when taken with a meal. b Dosing in mass balance studies: single-dose administration of [14C] dolutegravir or [14C] rilpivirine.
	Dolutegravir	Rilpivirine
Absorption
Tmax (h)	3	4
Effect of moderate-fat meal (relative to fasting)a	AUC Ratio 1.87 (1.54, 2.26)	AUC Ratio 1.57 (1.24, 1.98)
Effect of high-fat meal (relative to fasting)a	AUC Ratio 1.87 (1.53, 2.29)	AUC Ratio 1.72 (1.36, 2.16)
Distribution
% Bound to human plasma proteins	~99	~99
Source of protein binding data	in vitro	in vitro
Blood-to-plasma ratio	0.5	0.7
Metabolism
Primarily metabolized	UGT1A1 CYP3A (minor)	CYP3A
Elimination
Major route of elimination	Metabolism	Metabolism
t1/2 (h)	14	50
% of dose excreted as total 14C (unchanged drug) in urineb	31 (<1)	6.5 (<1)
% of dose excreted as total 14C (unchanged drug) in fecesb	64 (53)	85 (25)

Table 6. Multiple-Dose Pharmacokinetic Properties of the Components of JULUCA
a Based on population pharmacokinetic analyses using pooled data from ART treatment-naïve adults receiving 50 mg dolutegravir once daily or 25 mg rilpivirine once daily. b Observed Cmax in a pharmacokinetic substudy in ART treatment-naïve adults receiving 25 mg rilpivirine once daily.
Parameter Mean (CV%)	Dolutegravira	Rilpivirinea
Cmax (mcg/mL)	3.67 (20)	0.13 (54)b
AUCtau (mcg/h/mL)	53.6 (27)	2.2 (38)
Ctrough (mcg/mL)	1.11 (46)	0.08 (44)

Specific Populations

Pediatric Patients: The pharmacokinetics of dolutegravir plus rilpivirine has not been studied in pediatric subjects [see Use in Specific Populations (8.4)].

Geriatric Patients: Population pharmacokinetic analyses from studies with the individual components indicated age had no clinically relevant effect on the pharmacokinetics of dolutegravir or rilpivirine. Pharmacokinetic data in subjects 65 years of age and older are limited [see Use in Specific Populations (8.5)].

Patients with Renal Impairment: Population pharmacokinetic analyses indicated that mild and moderate renal impairment had no clinically relevant effect on the exposure of dolutegravir. Dolutegravir AUC, Cmax, and C24 were lower by 40%, 23%, and 43%, respectively, in subjects (n = 8) with severe renal impairment (creatinine clearance less than 30 mL/min) as compared with matched healthy controls. There is inadequate information to recommend appropriate dosing of dolutegravir in patients requiring dialysis [see Use in Specific Populations (8.6)].

Population pharmacokinetic analyses indicated that mild renal impairment had no clinically relevant effect on the exposure of rilpivirine. There is limited or no information regarding the pharmacokinetics of rilpivirine in patients with moderate or severe renal impairment, end-stage renal disease, or patients requiring dialysis.

Patients with Hepatic Impairment: Dolutegravir exposures were similar in subjects (n = 8) with moderate hepatic impairment (Child-Pugh Score B) as compared with matched healthy controls. The effect of severe hepatic impairment (Child-Pugh Score C) on the pharmacokinetics of dolutegravir has not been studied.

Rilpivirine exposure was 47% higher in subjects (n = 8) with mild hepatic impairment (Child-Pugh Score A) and 5% higher in subjects (n = 8) with moderate hepatic impairment (Child-Pugh Score B) compared with matched controls. The effect of severe hepatic impairment (Child-Pugh Score C) on the pharmacokinetics of rilpivirine has not been studied [see Use in Specific Populations (8.7)].

Patients with HBV/HCV Co-infection: Population pharmacokinetic analyses indicated that hepatitis C virus co-infection had no clinically relevant effect on the exposure of dolutegravir or rilpivirine. Subjects with hepatitis B co-infection were excluded from studies with dolutegravir plus rilpivirine.

Gender and Race: Population pharmacokinetic analyses from studies with the individual components revealed that gender and race had no clinically relevant effect on the pharmacokinetics of dolutegravir or rilpivirine.

Pregnancy and Postpartum: Rilpivirine: The exposure (C0h and AUC24h) to total rilpivirine after taking rilpivirine 25 mg once daily as part of an antiretroviral regimen was 30% to 40% lower during pregnancy (similar for the second and third trimesters) compared with postpartum (see Table 7). However, the exposure during pregnancy was not significantly different from exposures obtained in Phase 3 trials of rilpivirine-containing regimens. Based on the exposure-response relationship for rilpivirine, this decrease is not considered clinically relevant in patients who are virologically suppressed. The protein binding of rilpivirine was similar (>99%) during the second trimester, third trimester, and postpartum.

Table 7. Pharmacokinetic Results of Rilpivirine during the 2nd and 3rd Trimesters of Pregnancy and Postpartum Perioda
a Total rilpivirine exposure after administration of rilpivirine 25 mg once daily as part of an antiretroviral regimen.
Pharmacokinetics of Total Rilpivirine (mean ± SD)	Postpartum (6 to 12 Weeks) (n = 11)	2nd Trimester of Pregnancy (n = 15)	3rd Trimester of Pregnancy (n = 13)
C0h (ng/mL)	111 ± 69.2	65.0 ± 23.9	63.5 ± 26.2
Cmin (ng/mL)	84.0 ± 58.8	54.3 ± 25.8	52.9 ± 24.4
Cmax (ng/mL)	167 ± 101	121 ±45.9	123 ± 47.5
Tmax (h), median (range)	4.00 (2.03-25.08)	4.00 (1.00-9.00)	4.00 (2.00-24.93)
AUC24h (ng•h/mL)	2,714 ± 1,535	1,792 ± 711	1,762 ± 662

Drug Interaction Studies

Drug interaction trials were conducted with dolutegravir or rilpivirine as individual components and other drugs likely to be coadministered or commonly used as probes for pharmacokinetic interactions. In vitro, dolutegravir did not inhibit (IC50 greater than 50 microM) the following: CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A, UGT1A1, UGT2B7, P‑gp, BCRP, bile salt export pump (BSEP), organic anion transporter polypeptide (OATP)1B1, OATP1B3, OCT1, multidrug resistance protein (MRP)2, or MRP4. In vitro, dolutegravir did not induce CYP1A2, CYP2B6, or CYP3A4.

In vitro, dolutegravir inhibited the renal OCT2 (IC50 = 1.93 microM) and MATE1 (IC50 = 6.34 microM). In vivo, dolutegravir inhibits tubular secretion of creatinine by inhibiting OCT2 and potentially MATE1. Dolutegravir may increase plasma concentrations of drugs eliminated via OCT2 or MATE1 such as dofetilide, dalfampridine, and metformin [see Contraindications (4), Drug Interactions (7.4)].

In vitro, dolutegravir inhibited the basolateral renal transporters, organic anion transporter (OAT)1 (IC50 = 2.12 microM) and OAT3 (IC50 = 1.97 microM). However, in vivo, dolutegravir did not alter the plasma concentrations of tenofovir or para-amino hippurate, substrates of OAT1 and OAT3.

Dolutegravir is metabolized by UGT1A1 with some contribution from CYP3A. Dolutegravir is also a substrate of UGT1A3, UGT1A9, BCRP, and P-gp in vitro. In vitro, dolutegravir was not a substrate of OATP1B1 or OATP1B3.

Rilpivirine is primarily metabolized by CYP3A. Rilpivirine 25 mg once daily is not likely to have a clinically relevant effect on the exposure of medicinal products metabolized by CYP enzymes.

Dosing recommendations as a result of established and other potentially significant drug-drug interactions with dolutegravir or rilpivirine are provided in Table 4 [see Drug Interactions (7.4)].

Table 8. Summary of Effect of Dolutegravir on the Pharmacokinetics of Coadministered Drugs
a The number of subjects represents the maximum number of subjects that were evaluated.
Coadministered Drug(s) and Dose(s)	Dose of Dolutegravir	n	Geometric Mean Ratio (90% CI) of Pharmacokinetic Parameters of Coadministered Drug with/without Dolutegravir No Effect = 1.00
Coadministered Drug(s) and Dose(s)	Dose of Dolutegravir	n	Cmax	AUC	Cτ or C24
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)

Table 9. Summary of Effect of Coadministered Drugs on the Pharmacokinetics of Dolutegravir
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.
Coadministered Drug(s) and Dose(s)	Dose of Dolutegravir	n	Geometric Mean Ratio (90% CI) of Dolutegravir Pharmacokinetic Parameters with/without Coadministered Drugs No Effect = 1.00
Coadministered Drug(s) and Dose(s)	Dose of Dolutegravir	n	Cmax	AUC	Cτ or C24
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)
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)
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)

Table 10. Summary of Effect of Rilpivirine on the Pharmacokinetics of Coadministered Drugs
n = Maximum number of subjects with data; NA = Not available. a This interaction study has been performed with a dose higher than the recommended dose for rilpivirine (25 mg once daily) assessing the maximal effect on the coadministered drug. b N (maximum number of subjects with data) for AUC(0-∞) = 15. c AUC(0-last).
Coadministered Drug(s) and Dose(s)	Dose of Rilpivirine	n	Geometric Mean Ratio (90% CI) of Coadministered Drug Pharmacokinetic Parameters with/without EDURANT No Effect = 1.00
Coadministered Drug(s) and Dose(s)	Dose of Rilpivirine	n	Cmax	AUC	Cmin
Acetaminophen 500 mg single dose	150 mg once dailya	16	0.97 (0.86 to 1.10)	0.91 (0.86 to 0.97)	NA
Atorvastatin 40 mg once daily	150 mg once dailya	16	1.35 (1.08 to 1.68)	1.04 (0.97 to 1.12)	0.85 (0.69 to 1.03)
2-hydroxy-atorvastatin			1.58 (1.33 to 1.87)	1.39 (1.29 to 1.50)	1.32 (1.10 to 1.58)
4-hydroxy-atorvastatin			1.28 (1.15 to 1.43)	1.23 (1.13 to 1.33)	NA
Chlorzoxazone 500 mg single dose taken 2 hours after rilpivirine	150 mg once dailya	16	0.98 (0.85 to 1.13)	1.03 (0.95 to 1.13)	NA
Digoxin 0.5 mg single dose	25 mg once daily	22	1.06 (0.97 to 1.17)	0.98 (0.93 to 1.04)c	NA
Ethinylestradiol 0.035 mg once daily	25 mg once daily	17	1.17 (1.06 to 1.30)	1.14 (1.10 to 1.19)	1.09 (1.03 to 1.16)
Norethindrone 1 mg once daily			0.94 (0.83 to 1.06)	0.89 (0.84 to 0.94)	0.99 (0.90 to 1.08)
Ketoconazole 400 mg once daily	150 mg once dailya	14	0.85 (0.80 to 0.90)	0.76 (0.70 to 0.82)	0.34 (0.25 to 0.46)
Methadone 60-100 mg once daily, individualized dose	25 mg once daily	13
R(‑) methadone			0.86 (0.78 to 0.95)	0.84 (0.74 to 0.95)	0.78 (0.67 to 0.91)
S(+) methadone			0.87 (0.78 to 0.97)	0.84 (0.74 to 0.96)	0.79 (0.67 to 0.92)
Metformin 850 mg single dose	25 mg once daily	20	1.02 (0.95 to -1.10)	0.97 (0.90 to 1.06)b	NA
Omeprazole 20 mg once daily	150 mg once dailya	15	0.86 (0.68 to 1.09)	0.86 (0.76 to 0.97)	NA
Rifampin 600 mg once daily	150 mg once dailya	16	1.02 (0.93 to 1.12)	0.99 (0.92 to 1.07)	NA
25-desacetylrifampin			1.00 (0.87 to 1.15)	0.91 (0.77 to 1.07)	NA
Sildenafil 50 mg single dose	75 mg once dailya	16	0.93 (0.80 to 1.08)	0.97 (0.87 to 1.08)	NA
N-desmethyl-sildenafil			0.90 (0.80 to 1.02)	0.92 (0.85 to 0.99)c	NA
Simeprevir 150 mg once daily	25 mg once daily	21	1.10 (0.97 to 1.26)	1.06 (0.94 to 1.19)	0.96 (0.83 to 1.11)

Table 11. Summary of Effect of Coadministered Drugs on the Pharmacokinetics of Rilpivirine
n = Maximum number of subjects with data; NA = Not available; ↔ = No change. a This interaction study has been performed with a dose higher than the recommended dose for rilpivirine (25 mg once daily) assessing the maximal effect on the coadministered drug. b Comparison based on historic controls.
Coadministered Drug(s) and Dose(s)	Dose of Rilpivirine	n	Geometric Mean Ratio (90% CI) of Rilpivirine Pharmacokinetic Parameters with/without Coadministered Drugs No Effect = 1.00
Coadministered Drug(s) and Dose(s)	Dose of Rilpivirine	n	Cmax	AUC	Cmin
Acetaminophen 500 mg single dose	150 mg once dailya	16	1.09 (1.01 to 1.18)	1.16 (1.10 to 1.22)	1.26 (1.16 to 1.38)
Atorvastatin 40 mg once daily	150 mg once dailya	16	0.91 (0.79 to 1.06)	0.90 (0.81 to 0.99)	0.90 (0.84 to 0.96)
Chlorzoxazone 500 mg single dose taken 2 hours after rilpivirine	150 mg once dailya	16	1.17 (1.08 to 1.27)	1.25 (1.16 to 1.35)	1.18 (1.09 to 1.28)
Ethinylestradiol/ Norethindrone 0.035 mg once daily/ 1 mg once daily	25 mg once daily	15	↔b	↔b	↔b
Famotidine 40 mg single dose taken 12 hours before rilpivirine	150 mg single dosea	24	0.99 (0.84 to 1.16)	0.91 (0.78 to 1.07)	NA
Famotidine 40 mg single dose taken 2 hours before rilpivirine	150 mg single dosea	23	0.15 (0.12 to 0.19)	0.24 (0.20 to 0.28)	NA
Famotidine 40 mg single dose taken 4 hours after rilpivirine	150 mg single dosea	24	1.21 (1.06 to 1.39)	1.13 (1.01 to 1.27)	NA
Ketoconazole 400 mg once daily	150 mg once dailyb	15	1.30 (1.13 to 1.48)	1.49 (1.31 to 1.70)	1.76 (1.57 to 1.97)
Methadone 60-100 mg once daily, individualized dose	25 mg once daily	12	↔b	↔b	↔b
Omeprazole 20 mg once daily	150 mg once dailya	16	0.60 (0.48 to 0.73)	0.60 (0.51 to 0.71)	0.67 (0.58 to 0.78)
Rifabutin 300 mg once daily	25 mg once daily	18	0.69 (0.62 to 0.76)	0.58 (0.52 to 0.65)	0.52 (0.46 to 0.59)
Rifabutin 300 mg once daily	50 mg once daily	18	1.43 (1.30 to 1.56)	1.16 (1.06 to 1.26)	0.93 (0.85 to 1.01)
			(reference arm for comparison was 25-mg-once-daily rilpivirine administered alone)
Rifampin 600 mg once daily	150 mg once dailya	16	0.31 (0.27 to 0.36)	0.20 (0.18 to 0.23)	0.11 (0.10 to 0.13)
Sildenafil 50 mg single dose	75 mg once dailya	16	0.92 (0.85 to 0.99)	0.98 (0.92 to 1.05)	1.04 (0.98 to 1.09)
Simeprevir 150 mg once daily	25 mg once daily	23	1.04 (0.95 to 1.13)	1.12 (1.05 to 1.19)	1.25 (1.16 to 1.35)

12.4 Microbiology

Mechanism of Action

Dolutegravir inhibits HIV integrase by binding to the integrase active site and blocking the strand transfer step of retroviral 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.

Rilpivirine is a diarylpyrimidine NNRTI of HIV-1 and inhibits HIV-1 replication by non-competitive inhibition of HIV-1 reverse transcriptase (RT). Rilpivirine does not inhibit the human cellular DNA polymerases α, β, and γ.

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 to 2.1 nM (0.21 to 0.85 ng/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.

Rilpivirine exhibited activity against laboratory strains of wild-type HIV-1 in an acutely infected T-cell line with a median EC50 value for HIV-1IIIB of 0.73 nM (0.27 ng/mL). Rilpivirine demonstrated antiviral activity against a broad panel of HIV-1 group M (clades A, B, C, D, F, G, H) primary isolates with EC50 values ranging from 0.07 nM to 1.01 nM (0.03 to 0.37 ng/mL) and was less active against group O primary isolates with EC50 values ranging from 2.88 to 8.45 nM (1.06 to 3.10 ng/mL).

Antiviral Activity in Combination with Other Antiviral Agents

Neither dolutegravir nor rilpivirine were antagonistic to all tested anti-HIV agents or with each other when tested in combination.

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.

Rilpivirine-resistant strains were selected in cell culture starting from wild-type HIV-1 of different origins and clades as well as NNRTI-resistant HIV-1. The frequently observed amino acid substitutions that emerged and conferred decreased phenotypic susceptibility to rilpivirine included: L100I; K101E; V106I and A; V108I; E138K and G, Q, R; V179F and I; Y181C and I; V189I; G190E; H221Y; F227C; and M230I and L.

Virologically Suppressed Subjects: In the pooled SWORD-1 and SWORD-2 trials, 12 subjects (7 in SWORD-1 and 5 in SWORD-2) had confirmed virologic failure (HIV-1 RNA greater than 200 copies/mL) while receiving dolutegravir plus rilpivirine at any time through Week 148. Ten of the confirmed virologic failures had post-baseline resistance data, with 6 isolates showing evidence of rilpivirine resistance, and 2 with evidence of dolutegravir resistance substitutions. Six isolates showed genotypic and/or phenotypic resistance to rilpivirine with emergent NNRTI-resistance substitutions E138E/A (rilpivirine 1.6-fold change), M230M/L (rilpivirine 2-fold change), L100L/I, K101Q and E138A (rilpivirine 4.1-fold change), K101K/E (rilpivirine 1.2-fold change), K101K/E, M230M/L (rilpivirine 2-fold change), and L100L/V/M, M230M/L (rilpivirine 31-fold change). In addition, 1 virologic failure subject had NNRTI-resistance substitutions K103N and V179I at Week 88 with rilpivirine phenotypic fold change of 5.2 but had no baseline sample.

One virologic failure isolate had emergent INSTI-resistance substitution V151V/I present post-baseline with baseline INSTI-resistance substitutions N155N/H and G163G/R (by exploratory HIV proviral DNA archive sequencing); no integrase phenotypic data were available for this isolate at virologic failure. One other subject had the dolutegravir-resistance substitution G193E at baseline and virologic failure, but no detectable phenotypic resistance (fold change = 1.02) at Week 24.

No resistance-associated substitutions were observed for the 2 subjects meeting confirmed virologic failure in the comparative current antiretroviral regimen arms at Week 48.

Cross-Resistance

Dolutegravir: 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). 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).

Rilpivirine: Considering all of the available cell culture and clinical data, any of the following amino acid substitutions, when present at baseline, are likely to decrease the antiviral activity of rilpivirine: K101E or P; E138A, G, K, R, or Q; V179L; Y181C, I, or V; Y188L; H221Y; F227C; M230I or L.

Cross-resistance in site-directed mutant virus has been observed among NNRTIs. The single NNRTI substitutions K101P, Y181I, and Y181V conferred 52 times, 15 times, and 12 times decreased susceptibility to rilpivirine, respectively. The combination of E138K and M184I showed 6.7 times reduced susceptibility to rilpivirine compared with 2.8 times for E138K alone. The K103N substitution did not show reduced susceptibility to rilpivirine by itself. However, the combination of K103N and L100I resulted in a 7 times reduced susceptibility to rilpivirine. In another study, the Y188L substitution resulted in a reduced susceptibility to rilpivirine of 9 times for clinical isolates and 6 times for site-directed mutants. Combinations of 2 or 3 NNRTI resistance-associated substitutions gave decreased susceptibility to rilpivirine (fold-change range: 3.7 to 554) in 38% and 66% of mutants, respectively.

Cross-resistance to efavirenz, etravirine, and/or nevirapine is likely after virologic failure and development of rilpivirine resistance.