12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

CABENUVA contains 2 long-acting HIV-1 antiretroviral drugs, cabotegravir and rilpivirine [see Microbiology (12.4)].

12.2 Pharmacodynamics

Cardiac Electrophysiology

At a dose of cabotegravir 150 mg orally every 12 hours (10 times the recommended total daily oral lead-in dosage of CABENUVA), the QT interval is not prolonged to any clinically relevant extent. Administration of 3 doses of cabotegravir 150 mg orally every 12 hours resulted in a geometric mean Cmax approximately 2.8-, 5.4-, and 5.6-fold above the geometric mean steady-state Cmax associated with the recommended 30‑mg dose of oral cabotegravir, the recommended 400‑mg dose given monthly, and the recommended 600-mg dose given every 2 months of cabotegravir extended-release injectable suspension, respectively.

At the recommended dose of rilpivirine 25 mg orally once daily, the QT interval is not prolonged to any clinically relevant extent. The rilpivirine 25-mg once-daily mean steady-state Cmax was 247 ng/mL, which is 1.7-fold higher than the mean steady-state Cmax observed with the recommended 600-mg dose of rilpivirine extended-release injectable suspension given monthly and 1.6-fold higher than the mean steady-state Cmax observed with the recommended 900-mg dose of rilpivirine extended-release injectable suspension given every 2 months.

When rilpivirine 75-mg and 300-mg once-daily oral doses (3 and 12 times, respectively, the recommended oral lead-in dosage) were studied in healthy adults, the maximum mean time-matched (95% upper confidence bound) differences in QTcF interval were 10.7 (15.3) and 23.3 (28.4) msec, respectively, after baseline and placebo adjustment. Steady-state administration of rilpivirine 75 mg once daily and 300 mg once daily resulted in a mean steady-state Cmax approximately 4.4- and 11.6-fold, respectively, higher than the mean steady-state Cmax observed with the recommended 600-mg dose of rilpivirine extended-release injectable suspension given monthly and approximately 4.1- and 10.7-fold, respectively, higher than the mean steady-state Cmax observed with the recommended 900-mg dose of rilpivirine extended-release injectable suspension given every 2 months. The corresponding Cmax ratios are 2.6 and 6.7 when compared with the recommended oral rilpivirine dosage [see Warnings and Precautions (5.5)].

12.3 Pharmacokinetics

Absorption, Distribution, and Elimination

The pharmacokinetic properties of the components of CABENUVA are provided in Table 9. The multiple-dose pharmacokinetic parameters are provided in Table 10. For the pharmacokinetic properties of oral cabotegravir and oral rilpivirine, refer to the full prescribing information for VOCABRIA (cabotegravir) and EDURANT (rilpivirine), respectively.

Table 9. Pharmacokinetic Properties of the Components of CABENUVA
CSF = Cerebrospinal fluid, BLQ = Below limit of quantification.
a When taken orally with a high-fat meal versus fasted, the AUC(0-inf) (geometric mean ratio [90% CI] of cabotegravir and rilpivirine are 1.14 [1.02, 1.28] and 1.72 [1.36, 2.16]), respectively. b The clinical relevance of CSF-to-plasma concentration ratios is unknown. Concentrations were measured at steady-state 1 week after intramuscular administration of cabotegravir and rilpivirine extended-release injectable suspensions given monthly or every 2 months. c Elimination half-life driven by slow absorption rate from the intramuscular injection site. d Dosing in mass balance studies: single-dose oral administration of [14C] cabotegravir; single-dose oral administration of [14C] rilpivirine.
	Cabotegravir	Rilpivirine
Absorptiona
Tmax (days), median	7	3 to 4
Distribution
% Bound to human plasma proteins	>99.8	99.7
Blood-to-plasma ratio	0.52	0.7
CSF-to-plasma concentration ratio (median [range])b	0.003	0.01
	(0.002 to 0.004)	(BLQ to 0.02)
Elimination
t1/2 (weeks), meanc	5.6 to 11.5	13 to 28
Metabolism
Metabolic pathways	UGT1A1	CYP3A
	UGT1A9 (minor)
Excretion
Major route of elimination	Metabolism	Metabolism
% of dose excreted as total 14C (unchanged drug) in urined	27 (0)	6 (<1)
% of dose excreted as total 14C (unchanged drug) in fecesd	59 (47)	85 (26)

Table 10. Pharmacokinetic Parameters following Once-Daily Oral Cabotegravir and Rilpivirine and following Initiation and Monthly and Every-2-Month Continuation Intramuscular Injections of the Components of CABENUVA in Adults
IM = Intramuscular.
a Pharmacokinetic parameter values were based on individual post-hoc estimates from separate cabotegravir and rilpivirine population pharmacokinetic models (cabotegravir: pooled FLAIR and ATLAS for the oral, initial, and monthly injection dosing schedule and ATLAS-2M [participants with no prior exposure to cabotegravir plus rilpivirine] for the every-2-month injection dosing schedule; rilpivirine: pooled FLAIR, ATLAS, and ATLAS-2M [participants with no prior exposure], except for initial injection (direct to injection) [see footnote e] and for oral rilpivirine [see footnote g]). b tau is dosing interval: 24 hours for oral cabotegravir and rilpivirine, 1 month for cabotegravir and rilpivirine extended-release injectable suspensions given monthly, 2 months for cabotegravir and rilpivirine extended-release injectable suspensions given every 2 months. c Oral lead-in pharmacokinetic parameter values represent steady-state. d Initial injection Cmax values primarily reflect oral dosing because the initial injection was administered on the same day as the last oral dose; however, AUC(0-tau) and the Ctau values reflect the initial injections for cabotegravir and rilpivirine. e Pharmacokinetic parameters for initial injection (direct to injection) based on observed data from FLAIR Extension Phase (n = 110), AUC not calculated based on observed data, Cmax = 1 week following initial injection, Ctau = 1 month following initial injection. f Monthly and every-2-month injection pharmacokinetic parameter values represent Week 48 data. g Oral rilpivirine: AUC(0-tau) based on population pharmacokinetic estimates of rilpivirine 25 mg once daily from pooled Phase 3 trials with EDURANT (rilpivirine); Ctau based on observed data from FLAIR, ATLAS, and ATLAS-2M; Cmax based on observed data for rilpivirine 25 mg once daily from a pharmacokinetic substudy in pooled Phase 3 trials with EDURANT (rilpivirine).
Drug	Dosing Phase	Dosage Regimen	Geometric Mean (5th, 95th Percentile)a
Drug	Dosing Phase	Dosage Regimen	AUC(0-tau)b (mcg•h/mL)	Cmax (mcg/mL)	Ctaub (mcg/mL)
Cabotegravir	Oral lead-inc	30 mg once daily	145 (93.5, 224)	8.0 (5.3, 11.9)	4.6 (2.8, 7.5)
	Initial injection (after oral lead-in)d	600 mg IM initial dose	1,591 (714; 3,245)	8.0 (5.3, 11.9)	1.5 (0.65, 2.9)
	Initial injection (direct to injection)e	600 mg IM initial dose	—	1.89 (0.438, 5.69)	1.43 (0.403, 3.90)
	Monthly injectionf	400 mg IM monthly	2,415 (1,494; 3,645)	4.2 (2.5, 6.5)	2.8 (1.7, 4.6)
	Every-2-month injectionf	600 mg IM every 2 months	3,764 (2,431; 5,857)	4.0 (2.3, 6.8)	1.6 (0.8, 3.0)
Drug	Dosing Phase	Dosage Regimen	Geometric Mean (5th, 95th Percentile)a
Drug	Dosing Phase	Dosage Regimen	AUC(0-tau)b (ng•h/mL)	Cmax (ng/mL)	Ctaub (ng/mL)
Rilpivirine	Oral lead-inc,g	25 mg once daily	2,083 (1,125; 3,748)	116 (48.6, 244)	79.4 (31.8, 177)
	Initial injection (after oral lead-in)d	900 mg IM initial dose	44,842 (21,712; 87,575)	144 (93.9, 221)	41.9 (21.7, 78.9)
	Initial injection (direct to injection)e	900 mg IM initial dose	—	68 (27.5, 220)	48.9 (17.7, 138)
	Monthly injectionf	600 mg IM monthly	68,324 (39,042; 118,111)	121 (68.1, 210)	85.8 (49.6, 147)
	Every-2-month injectionf	900 mg IM every 2 months	132,450 (76,638; 221,783)	138 (80.6, 228)	68.9 (38.0, 119)

Specific Populations

No clinically significant differences in the pharmacokinetics of cabotegravir or rilpivirine were observed based on age, sex, race/ethnicity, BMI, or UGT1A1 polymorphisms.

Cabotegravir and rilpivirine concentrations in participants who were hepatitis C virus antibody positive at baseline were similar to those in the overall study population. The effect of hepatitis B virus co-infection on the pharmacokinetics of cabotegravir is unknown. No clinically relevant differences in the pharmacokinetics of oral rilpivirine have been observed with hepatitis B and/or C virus co-infection.

Patients with Renal Impairment: With oral cabotegravir, no clinically significant differences in the pharmacokinetics of cabotegravir are expected in patients with mild, moderate, or severe renal impairment. Cabotegravir has not been studied in patients with end-stage renal disease not on dialysis. As cabotegravir is >99% protein bound, dialysis is not expected to alter exposures of cabotegravir [see Use in Specific Populations (8.6)].

Population pharmacokinetic analyses indicated that mild renal impairment had no clinically relevant effect on the exposure of oral rilpivirine. There is limited or no information regarding the pharmacokinetics of rilpivirine in patients with moderate or severe renal impairment or end-stage renal disease not on dialysis. As rilpivirine is >99% protein bound, dialysis is not expected to alter exposures of rilpivirine [see Use in Specific Populations (8.6)].

Patients with Hepatic Impairment: No clinically significant differences in the pharmacokinetics of cabotegravir are expected in mild to moderate (Child-Pugh A or B) hepatic impairment. The effect of severe hepatic impairment (Child-Pugh C) on the pharmacokinetics of cabotegravir has not been studied [see Use in Specific Populations (8.7)].

No clinically significant differences in the pharmacokinetics of rilpivirine were observed in mild to moderate (Child-Pugh A or B) hepatic impairment. The effect of severe hepatic impairment (Child-Pugh C) has not been studied [see Use in Specific Populations (8.7)].

Geriatric Patients: The pharmacokinetics of cabotegravir (oral or injectable) and of injectable rilpivirine have not been studied and data are limited in participants aged 65 years or older [see Use in Specific Populations (8.5)].

Pediatric Patients: Population pharmacokinetic analyses revealed no clinically relevant differences in exposure between adolescent participants (weighing ≥35 kg and aged at least 12 years) and adult participants with and without HIV-1 from the cabotegravir or rilpivirine development program.

Table 11. Pharmacokinetic Parameters following Cabotegravir and Rilpivirine Orally Once Daily, and Initiation, Monthly, and Every-2-Months Continuation Intramuscular Injections in Adolescents Aged 12 to Younger than 18 Years (≥35 kg)
IM = intramuscular, PO = by mouth.
a Pharmacokinetic parameter values for cabotegravir were based on individual post-hoc estimates from population pharmacokinetic models in both adolescents with HIV-1 (n = 147) weighing 35.2 to 98.5 kg and adolescents without HIV-1 (n = 62) weighing 39.9 to 167 kg. Pharmacokinetic parameter values for rilpivirine were based on individual post-hoc estimates from a population pharmacokinetic model in adolescents with HIV-1 (n = 148) weighing 35.2 to 98.5 kg.
b tau is dosing interval: 24 hours for oral administration, 1 month for the initial injection and monthly intramuscular injections, and 2 months for every-2-months intramuscular injections of extended‑release injectable suspension.
c Oral lead-in pharmacokinetic parameter values represent steady-state.
d Initial injection Cmax values primarily reflect oral dosing because the initial injection was administered on the same day as the last oral dose; however, the AUC(0-tau) and Ctau values reflect the initial injection.
e Monthly and every-2-month injection pharmacokinetic parameter values represent Week 48 data.
Drug	Dosing Phase	Dosage Regimen	Geometric Mean (5th, 95th Percentile)a
Drug	Dosing Phase	Dosage Regimen	AUC(0-tau)b (mcg•h/mL)	Cmax (mcg/mL)	Ctaub (mcg/mL)
Cabotegravir	Oral lead-inc	30 mg once daily	203 (136, 320)	10.7 (7.36, 16.6)	6.43 (4.15, 10.5)
	Initial injectiond	600 mg IM initial dose	2,085 (1,056; 4,259)	10.8 (7.42, 16.6)	1.88 (0.801, 3.71)
	Every-1-month injectione	400 mg IM every 1 month	3,416 (2,303; 5,109)	5.73 (3.76, 8.90)	4.24 (2.74, 6.45)
	Every-2-months injectione	600 mg IM every 2 months	5,184 (3,511; 7,677)	5.10 (3.06, 8.24)	2.54 (1.25, 4.19)
Drug	Dosing Phase	Dosage Regimen	Geometric Mean (5th, 95th Percentile)a
Drug	Dosing Phase	Dosage Regimen	AUC(0-tau)b (ng•h/mL)	Cmax (ng/mL)	Ctaub (ng/mL)
Rilpivirine	Oral lead-inc	25 mg PO once daily	2,389 (1,259; 4,414)	144 (80.8, 234)	76.1 (27.9, 184)
	Initial injectiond	900 mg IM initial dose	35,259 (20,301; 63,047)	135 (85.8, 211)	36.5 (22.4, 59.4)
	Every-1-month injectione	600 mg IM every month	84,280 (49,444; 156,987)	146 (84.8, 269)	109 (64.8, 202)
	Every-2-months injectione	900 mg IM every 2 months	110,686 (78,480; 151,744)	108 (68.0, 164)	61.8 (44.5, 88.0)

Drug Interaction Studies

Cabotegravir is not a clinically relevant inhibitor of the following enzymes and transporters: CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4; UGT1A1, 1A3, 1A4, 1A6, 1A9, 2B4, 2B7, 2B15, and 2B17; P-glycoprotein (P‑gp); breast cancer resistance protein (BCRP); bile salt export pump (BSEP); organic cation transporter (OCT)1, OCT2; organic anion transporter polypeptide (OATP)1B1, OATP1B3; multidrug and toxin extrusion transporter (MATE) 1, MATE 2-K; and multidrug resistance protein (MRP)2 or MRP4.

In vitro, cabotegravir inhibited renal OAT1 (IC50 = 0.81 microM) and OAT3 (IC50 = 0.41 microM). Based on physiologically based pharmacokinetic (PBPK) modeling, cabotegravir may increase the AUC of OAT1/3 substrates up to approximately 80%.

In vitro, cabotegravir did not induce CYP1A2, CYP2B6, or CYP3A4.

‎Simulations using PBPK modeling show that no clinically significant interaction is expected during coadministration of cabotegravir with drugs that inhibit UGT1A1.

In vitro, cabotegravir was not a substrate of OATP1B1, OATP1B3, OATP2B1, or OCT1.

Cabotegravir is a substrate of P-gp and BCRP in vitro; however, because of its high permeability, no alteration in cabotegravir absorption is expected with coadministration of P-gp or BCRP inhibitors.

Rilpivirine is not likely to have a clinically relevant effect on the exposure of drugs metabolized by CYP enzymes.

Drug interaction studies were not conducted with injectable cabotegravir or injectable rilpivirine. Drug interaction studies with oral cabotegravir or oral rilpivirine are summarized in Tables 12, 13, 14, and 15.

Table 12. Effect of Coadministered Drugs on the Pharmacokinetics of Cabotegravir
n = Maximum number of participants with data, CI = Confidence Interval.
Coadministered Drug(s) and Dose(s)	Dose of Cabotegravir	n	Geometric Mean Ratio (90% CI) of Cabotegravir Pharmacokinetic Parameters with/without Coadministered Drugs No Effect = 1.00
Coadministered Drug(s) and Dose(s)	Dose of Cabotegravir	n	Cmax	AUC	Ctau or C24
Etravirine	30 mg	12	1.04	1.01	1.00
200 mg twice daily	once daily		(0.99, 1.09)	(0.96, 1.06)	(0.94, 1.06)
Rifabutin	30 mg	12	0.83	0.79	0.74
300 mg once daily	once daily		(0.76, 0.90)	(0.74, 0.83)	(0.70, 0.78)
Rifampin	30-mg	15	0.94	0.41	0.50
600 mg once daily	single dose		(0.87, 1.02)	(0.36, 0.46)	(0.44, 0.57)
Rilpivirine	30 mg	11	1.05	1.12	1.14
25 mg once daily	once daily		(0.96, 1.15)	(1.05, 1.19)	(1.04, 1.24)

Table 13. Effect of Coadministered Drugs on the Pharmacokinetics of Rilpivirine
n = Maximum number of participants with data, CI = Confidence Interval, ↔ = 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	150 mg	16	1.09	1.16	1.26
500-mg single dose	once dailya		(1.01 to 1.18)	(1.10 to 1.22)	(1.16 to 1.38)
Atorvastatin	150 mg	16	0.91	0.90	0.90
40 mg once daily	once dailya		(0.79 to 1.06)	(0.81 to 0.99)	(0.84 to 0.96)
Chlorzoxazone	150 mg	16	1.17	1.25	1.18
500-mg single dose taken 2 hours after rilpivirine	once dailya		(1.08 to 1.27)	(1.16 to 1.35)	(1.09 to 1.28)
Darunavir/ritonavir	150 mg	14	1.79	2.30	2.78
800/100 mg once daily	once dailya		(1.56 to 2.06)	(1.98 to 2.67)	(2.39 to 3.24)
Didanosine	150 mg	21	1.00	1.00	1.00
400 mg once daily delayed-release capsules taken 2 hours before rilpivirine	once dailya		(0.90 to 1.10)	(0.95 to 1.06)	(0.92 to 1.09)
Ethinyl estradiol/ norethindrone	25 mg once daily	15	↔b	↔b	↔b
0.035 mg once daily/1 mg once daily
Ketoconazole	150 mg	15	1.30	1.49	1.76
400 mg once daily	once dailyb		(1.13 to 1.48)	(1.31 to 1.70)	(1.57 to 1.97)
Lopinavir/ritonavir	150 mg	15	1.29	1.52	1.74
400/100 mg twice daily (soft gel capsule)	once dailya		(1.18 to 1.40)	(1.36 to 1.70)	(1.46 to 2.08)
Methadone	25 mg	12	↔b	↔b	↔b
60 to 100 mg once daily, individualized dose	once daily
Raltegravir	25 mg	23	1.12	1.12	1.03
400 mg twice daily	once daily		(1.04 to 1.20)	(1.05 to 1.19)	(0.96 to 1.12)
Rifabutin	25 mg	18	0.69	0.58	0.52
300 mg once daily	once daily		(0.62 to 0.76)	(0.52 to 0.65)	(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	150 mg	16	0.31	0.20	0.11
600 mg once daily	once dailya		(0.27 to 0.36)	(0.18 to 0.23)	(0.10 to 0.13)
Sildenafil	75 mg	16	0.92	0.98	1.04
50-mg single dose	once dailya		(0.85 to 0.99)	(0.92 to 1.05)	(0.98 to 1.09)
Tenofovir disoproxil fumarate	150 mg	16	0.96	1.01	0.99
300 mg once daily	once dailya		(0.81 to 1.13)	(0.87 to 1.18)	(0.83 to 1.16)

Table 14. Effect of Cabotegravir on the Pharmacokinetics of Coadministered Drugs
n = Maximum number of participants with data, CI = Confidence Interval, NA = Not available.
Coadministered Drug(s) and Dose(s)	Dose of Cabotegravir	n	Geometric Mean Ratio (90% CI) of Pharmacokinetic Parameters of Coadministered Drug with/without Cabotegravir No Effect = 1.00
Coadministered Drug(s) and Dose(s)	Dose of Cabotegravir	n	Cmax	AUC	Ctau or C24
Ethinyl estradiol	30 mg	19	0.92	1.02	1.00
0.03 mg once daily	once daily		(0.83, 1.03)	(0.97, 1.08)	(0.92, 1.10)
Levonorgestrel	30 mg	19	1.05	1.12	1.07
0.15 mg once daily	once daily		(0.96, 1.15)	(1.07, 1.18)	(1.01, 1.15)
Midazolam	30 mg	12	1.09	1.10	NA
3 mg	once daily		(0.94, 1.26)	(0.95, 1.26)
Rilpivirine	30 mg	11	0.96	0.99	0.92
25 mg once daily	once daily		(0.85, 1.09)	(0.89, 1.09)	(0.79, 1.07)

Table 15. Effect of Rilpivirine on the Pharmacokinetics of Coadministered Drugs
n = Maximum number of participants with data, CI = Confidence Interval, 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 AUC(0-last) c n = (maximum number of participants with data) for AUC(0-∞) = 15.
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	150 mg	16	0.97	0.91	NA
500-mg single dose	once dailya		(0.86 to 1.10)	(0.86 to 0.97)
Atorvastatin	150 mg	16	1.35	1.04	0.85
40 mg once daily	once dailya		(1.08 to 1.68)	(0.97 to 1.12)	(0.69 to 1.03)
2-hydroxy-atorvastatin			1.58	1.39	1.32
			(1.33 to 1.87)	(1.29 to 1.50)	(1.10 to 1.58)
4-hydroxy-atorvastatin			1.28	1.23	NA
			(1.15 to 1.43)	(1.13 to 1.33)
Chlorzoxazone	150 mg	16	0.98	1.03	NA
500-mg single dose taken 2 hours after rilpivirine	once dailya		(0.85 to 1.13)	(0.95 to 1.13)
Darunavir/ritonavir	150 mg	15	0.90	0.89	0.89
800/100 mg once daily	once dailya		(0.81 to 1.00)	(0.81 to 0.99)	(0.68 to 1.16)
Didanosine	150 mg	13	0.96	1.12	NA
400 mg once daily delayed-release capsules taken 2 hours before rilpivirine	once dailya		(0.80 to 1.14)	(0.99 to 1.27)
Digoxin	25 mg	22	1.06	0.98	NA
0.5-mg single dose	once daily		(0.97 to 1.17)	(0.93 to 1.04)b
Ethinyl estradiol	25 mg	17	1.17	1.14	1.09
0.035 mg once daily	once daily		(1.06 to 1.30)	(1.10 to 1.19)	(1.03 to 1.16)
Norethindrone			0.94	0.89	0.99
1 mg once daily			(0.83 to 1.06)	(0.84 to 0.94)	(0.90 to 1.08)
Ketoconazole	150 mg	14	0.85	0.76	0.34
400 mg once daily	once dailya		(0.80 to 0.90)	(0.70 to 0.82)	(0.25 to 0.46)
Lopinavir/ritonavir	150 mg	15	0.96	0.99	0.89
400/100 mg twice daily (soft gel capsule)	once dailya		(0.88 to 1.05)	(0.89 to 1.10)	(0.73 to 1.08)
Methadone	25 mg	13
60 to 100 mg once daily, individualized dose	once daily
R(‑) methadone			0.86	0.84	0.78
			(0.78 to 0.95)	(0.74 to 0.95)	(0.67 to 0.91)
S(+) methadone			0.87	0.84	0.79
			(0.78 to 0.97)	(0.74 to 0.96)	(0.67 to 0.92)
Metformin	25 mg	20	1.02	0.97	NA
850-mg single dose	once daily		(0.95 to -1.10)	(0.90 to 1.06)c
Raltegravir	25 mg	23	1.10	1.09	1.27
400 mg twice daily	once daily		(0.77 to 1.58)	(0.81 to 1.47)	(1.01 to 1.60)
Rifampin	150 mg	16	1.02	0.99	NA
600 mg once daily	once dailya		(0.93 to 1.12)	(0.92 to 1.07)
25-desacetylrifampin			1.00	0.91	NA
			(0.87 to 1.15)	(0.77 to 1.07)
Sildenafil	75 mg	16	0.93	0.97	NA
50-mg single dose	once dailya		(0.80 to 1.08)	(0.87 to 1.08)
N-desmethyl-sildenafil			0.90	0.92	NA
			(0.80 to 1.02)	(0.85 to 0.99)b
Tenofovir disoproxil fumarate	150 mg	16	1.19	1.23	1.24
300 mg once daily	once dailya		(1.06 to 1.34)	(1.16 to 1.31)	(1.10 to 1.38)

12.4 Microbiology

Mechanism of Action

Cabotegravir inhibits HIV integrase by binding to the integrase active site and blocking the strand transfer step of retroviral deoxyribonucleic acid (DNA) integration that is essential for the HIV replication cycle. The mean 50% inhibitory concentration (IC50) value of cabotegravir in a strand transfer assay using purified recombinant HIV-1 integrase was 3.0 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

Cabotegravir exhibited antiviral activity against laboratory strains of HIV-1 (subtype B, n = 4) with mean 50 percent effective concentration (EC50) values of 0.22 to 1.7 nM in peripheral blood mononuclear cells (PBMCs) and 293 cells. Cabotegravir demonstrated antiviral activity in PBMCs against a panel of 24 HIV-1 clinical isolates (3 in each of group M subtypes A, B, C, D, E, F, and G and 3 in group O) with a median EC50 value of 0.19 nM (range: 0.02 to 1.06 nM, n = 24). The median EC50 value against subtype B clinical isolates was 0.05 nM (range: 0.02 to 0.50 nM, n = 3). Against clinical HIV-2 isolates, the median EC50 value was 0.12 nM (range: 0.10 to 0.14 nM, n = 3).

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 (subtypes A, B, C, D, F, G, and 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 nM to 8.45 nM (1.06 to 3.10 ng/mL).

In cell culture, cabotegravir was not antagonistic in combination with the NNRTI rilpivirine, or the nucleoside reverse transcriptase inhibitors (NRTIs) emtricitabine (FTC), lamivudine (3TC), or tenofovir disoproxil fumarate (TDF).

The antiviral activity of rilpivirine was not antagonistic when combined with the NNRTIs efavirenz, etravirine, or nevirapine; the NRTIs abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, or zidovudine; the protease inhibitors amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, or tipranavir; the fusion inhibitor enfuvirtide; the CCR5 co-receptor antagonist maraviroc, or the INSTI raltegravir.

Resistance

Cell Culture: Cabotegravir-resistant viruses were selected during passage of HIV-1 strain IIIB in MT-2 cells in the presence of cabotegravir. Amino acid substitutions in integrase that emerged and conferred decreased susceptibility to cabotegravir included Q146L (fold change: 1.3 to 4.6), S153Y (fold change: 2.8 to 8.4), and I162M (fold change: 2.8). The integrase substitution T124A also emerged alone (fold change: 1.1 to 7.4 in cabotegravir susceptibility), in combination with S153Y (fold change: 3.6 to 6.6 in cabotegravir susceptibility) or I162M (2.8-fold change in cabotegravir susceptibility). Cell culture passage of virus harboring integrase substitutions Q148H, Q148K, or Q148R selected for additional substitutions (C56S, V72I, L74M, V75A, T122N, E138K, G140S, G149A, and M154I), with substituted viruses having reduced susceptibility to cabotegravir of 2.0- to 410-fold change. The combinations of E138K+Q148K and V72I+E138K+Q148K conferred the greatest reductions of 53- to 260‑fold change and 410-fold change, respectively.

Rilpivirine-resistant strains were selected in cell culture starting from wild-type HIV-1 of different origins and subtypes 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.

Clinical Trials: In the pooled Phase 3 FLAIR (Week 124) and ATLAS (Week 96) analysis, there were 8 confirmed virologic failures (2 consecutive HIV-1 RNA ≥200 copies/mL) on cabotegravir plus rilpivirine (8/591, 1.4%) and 8 confirmed virologic failures on current antiretroviral regimen (8/591, 1.4%). Of the 8 confirmed virologic failures in the cabotegravir plus rilpivirine arm, 7 (88%) had treatment-emergent NNRTI resistance-associated substitutions K101E, V106V/A, V108I, E138A, E138G, E138K, H221H/L, or M230L in reverse transcriptase, and 6 of them showed reduced phenotypic susceptibility to rilpivirine (range: 2- to 27-fold). One additional participant in the ATLAS Extension Switch on cabotegravir plus rilpivirine had emergent NNRTI resistance substitution E138A at Week 80 with HIV-1 RNA >50 copies/mL and <200 copies/mL.

Additionally, 5 of the 8 (63%) cabotegravir plus rilpivirine confirmed virologic failures had treatment-emergent INSTI resistance-associated substitutions and reduced phenotypic susceptibility to cabotegravir: Q148R (n = 2; 5- and 9-fold decreased susceptibility to cabotegravir), G140R (n = 1; 7-fold decreased susceptibility to cabotegravir), N155H (n = 1; 3‑fold decreased susceptibility to cabotegravir), or N155H+R263K (n = 1; 9-fold decreased susceptibility to cabotegravir).

There was another confirmed virologic failure participant at Week 112 in FLAIR who had switched to cabotegravir plus rilpivirine direct to injection at Week 100; there were no INSTI resistance‑associated substitutions detected at failure.

In comparison, in the current antiretroviral regimen arm with 8 confirmed virologic failures, 2 of 7 (29%) who had post-baseline resistance data had treatment-emergent resistance substitutions and phenotypic resistance to their antiretroviral drugs; both had treatment-emergent NRTI substitutions, M184V or I, which conferred resistance to emtricitabine or lamivudine in their regimen, and one of them also had the treatment-emergent NNRTI resistance substitution G190S, which conferred resistance to efavirenz in their regimen.

In the ATLAS-2M trial, there were 11 confirmed virologic failures (2 consecutive HIV-1 RNA ≥200 copies/mL) through Week 48: 9 participants (1.7%) in the every-2-month treatment arm and 2 participants (0.4%) in the monthly treatment arm. Of note, 8 of the 11 (73%) participants met confirmed virologic failure criteria at or before the Week 24 injection visit.

Four of the 9 confirmed virologic failure participants in the every-2-month arm transitioned from the oral current antiretroviral regimen arm of ATLAS into this trial.

In the every-2-month treatment arm, 8 of 9 (89%) confirmed virologic failure participants had NNRTI resistance-associated substitutions (E138E/K+V179V/I, K101E+E138A, A98G+K103N, E138K, V179I+Y188L+P225H, Y188L, K103N+E138A, or K101E) at virologic failure. Decreases in rilpivirine susceptibility for these 8 participant isolates ranged from 2- to 30-fold. Six of the 8 participants with NNRTI resistance-associated substitutions also had INSTI resistance-associated substitutions (L74I+Q148Q/R+N155N/H (n = 2), L74I+T97A+N155H, L74I+N155H, N155H, or L74I+Q148R) at failure with cabotegravir fold changes ranging from 1- to 9-fold. The INSTI polymorphism L74I was detected at baseline in 5 of the virologic failure participants by a HIV-1 proviral DNA assay.

In the monthly treatment arm, both of the confirmed virologic failure participants had NNRTI resistance-associated substitutions (K101E+M230L or Y188F+G190Q) at virologic failure with decreased susceptibility to rilpivirine of 17- and >119.2-fold, respectively. Both participants also had INSTI resistance-associated substitutions (N155N/H or Q148R+E138E/K) at failure with decreased susceptibility to cabotegravir of 2- and 5-fold, respectively. Neither participant had the L74I integrase polymorphism at baseline.

Genotypic Baseline Factors Associated with Virologic Failure

An increased risk of cabotegravir plus rilpivirine confirmed virologic failure is associated with baseline virological factors: HIV-1 subtype A1, the presence of baseline integrase L74I polymorphism, and archived NNRTI resistance-associated substitutions.

Association of Subtype A1 and Baseline L74I Polymorphism in Integrase with Cabotegravir plus Rilpivirine Virologic Failure

Eight of the 18 (44%) cabotegravir plus rilpivirine confirmed virologic failures in FLAIR, ATLAS, and ATLAS-2M had HIV‑1 subtype A1 with 7 of the 8 subtype A1 failures having the integrase polymorphism L74I detected at baseline and failure timepoints (Table 16). There was no detectable phenotypic resistance to cabotegravir conferred by the presence of L74I at baseline. Subtype A1 is uncommon in the U.S.

The presence of the integrase polymorphism L74I in subtype B commonly seen in the U.S. was not associated with virologic failure. In contrast to FLAIR and ATLAS, where all virologic failures were subtype A, A1, or AG, subtypes of the cabotegravir plus rilpivirine virologic failures in ATLAS-2M included A (n = 1), A1 (n = 3), B (n = 4), C (n = 2), and complex/A1 (n = 1).

Association of Archived Baseline NNRTI Substitutions with Cabotegravir plus Rilpivirine Virologic Failure

The presence of archived NNRTI resistance-associated substitutions at baseline detected using an exploratory HIV-1 proviral DNA assay was associated with a higher virologic failure rate in the every-2-month arm of ATLAS-2M and in the cabotegravir plus rilpivirine arm (monthly) of ATLAS compared to without archived NNRTI resistance-associated substitutions (Table 16). However, in clinical practice, it is unlikely baseline resistance testing will be performed on virologically suppressed patients (HIV-1 RNA <50 copies/mL). Thus, in patients with an incomplete or uncertain NNRTI treatment history, consideration should be given before starting cabotegravir plus rilpivirine treatment.

Table 16. Rate of Confirmed Virologic Failure in FLAIR, ATLAS, and ATLAS-2M: Baselinea Analysis (Subtype Al, Presence of lntegrase Polymorphism L74I, and Presence of Archived NNRTI Resistance-Associated Substitutions)
NNRTI = Non-Nucleoside Reverse Transcriptase Inhibitor, CAB+RPV = Cabotegravir + Rilpivirine, CAR = Current Antiretroviral Regimen, RAS = Resistance-Associated Substitutions, NA = Not available. a Baseline and/or Screening result used. b Per Standard Monogram Nomenclature Reports. Based on June 2020 Los Alamos National Library panel, the majority of HIV-1 subtype A1 was reclassified as HIV-1 subtype A6. c L74I and L74L/I mixture. d Baseline/Screening NNRTI substitutions at L100, K101, K103, V106, V108, E138, V179, Y181, Y188, G190, H221, P225, M230.
	FLAIR CAB+RPV N = 283	FLAIR CAR N = 283	ATLAS CAB+RPV N = 308	ATLAS CAR N = 308	ATLAS-2M Q4W N = 523	ATLAS-2M Q8W N = 522
Total confirmed virologic failures	5	4	3	4	2	9
Subtype A1b	4/8 (50%)	1/4 (25%)	1/17 (6%)	0/21 (0%)	0/30 (0%)	4/31 (13%)
+L74Ic	4/5 (80%)	1/3 (33%)	1/16 (6%)	0/19 (0%)	2/28 (0%)	3/26 (12%)
-L74I	0/3 (0%)	0/1 (0%)	0/1 (0%)	0/2 (0%)	0/2 (0%)	1/5 (20%)
Other subtypes	2/268 (0.7%)	3/272 (1%)	2/240 (0.8%)	4/252 (1.6%)	2/409 (0.5%)	5/415 (1.2%)
+L74Ic	0/49 (0%)	1/43 (2.3%)	1/29 (3%)	1/39 (2.6%)	0/42 (0%)	2/48 (4%)
-L74I	0/219 (2.5%)	2/229 (0.9%)	1/211 (0.5%)	3/213 (1.4%)	2/367 (0.5%)	3/367 (0.8%)
Missing data	7	7	51	35	84	76
With NNRTI RASd	NA	NA	3/78 (4%)	2/83 (2%)	1/128 (0.8%)	7/117 (6%)
Without NNRTI RAS	NA	NA	0/179 (0%)	2/190 (1%)	1/310 (0.3%)	2/327 (0.6%)
Missing data	NA	NA	51	35	84	76

Cross-Resistance

Virologic failure isolates from cabotegravir plus rilpivirine treatment in FLAIR, ATLAS, and ATLAS-2M exhibited cross-resistance to INSTIs and NNRTIs. All confirmed virologic isolates with genotypic evidence of cabotegravir resistance had cross-resistance to elvitegravir and raltegravir but retained phenotypic susceptibility to dolutegravir and when tested bictegravir. Virologic failure isolates with rilpivirine resistance had cross-resistance with NNRTIs delavirdine, doravirine, efavirenz, etravirine, and nevirapine.

Cabotegravir: Cross-resistance has been observed among INSTIs. Cabotegravir had reduced susceptibility (>5-fold change) to recombinant HIV-1 strain NL432 viruses harboring the following integrase amino acid substitutions: G118R, Q148K, Q148R, T66K+L74M, E92Q+N155H, E138A+Q148R, E138K+Q148K/R, G140C+Q148R, G140S+Q148H/K/R, Y143H+N155H, and Q148R+N155H (range: 5.1- to 81-fold). The substitutions E138K+Q148K and Q148R+N155H conferred the greatest reductions in susceptibility of 81- and 61-fold, respectively.

Cabotegravir was active against viruses harboring the NNRTI substitutions K103N or Y188L, or the NRTI substitutions M184V, D67N/K70R/T215Y, or V75I/F77L/F116Y/Q151M.

Rilpivirine: Cross-resistance has been observed among NNRTIs. The single NNRTI substitutions K101P, Y181I, and Y181V conferred 52-, 15-, and 12-times fold change to rilpivirine, respectively. The K103N substitution did not show reduced susceptibility to rilpivirine by itself. Combinations of 2 or 3 NNRTI resistance-associated substitutions gave 3.7- to 554-fold change to rilpivirine in 38% and 66% of substitutions, respectively. Considering all 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 and P; E138A, G, K, R, and Q; V179L; Y181C, I, and V; Y188L; H221Y; F227C; M230I and L, and the combination of L100I/K103N.