VOCABRIA Film-coated tablet Ref.[10736] Active ingredients: Cabotegravir

Cardiac Electrophysiology

At a dose of cabotegravir 150 mg orally every 12 hours (10 times the recommended total daily oral lead-in dosage of VOCABRIA) 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 C_max approximately 2.8-fold above the geometric mean steady-state C_max associated with the recommended 30-mg dose of oral cabotegravir. For additional QT information related to the injectable formulations of cabotegravir and rilpivirine (CABENUVA) and the oral formulation of rilpivirine (EDURANT), refer to the prescribing information for CABENUVA and EDURANT.

Absorption, Distribution, Metabolism, and Excretion

The pharmacokinetic properties of cabotegravir are provided in Table 2. The multiple-dose pharmacokinetic parameters are provided in Table 3.

Table 2. Pharmacokinetic Properties of Cabotegravir:

^a Geometric mean ratio (fed/fasted) in pharmacokinetic parameters and 90% confidence interval. High‑ calorie/high-fat meal = 870 kcal, 53% fat.
^b The clinical relevance of CSF-to-plasma concentration ratios is unknown. Concentrations were measured at steady-state one week after administration of cabotegravir extended-release injectable suspensions given monthly or every 2 months.
^c Dosing in mass balance studies: single-dose oral administration of [¹⁴C] cabotegravir.

Table 3. Multiple-Dose Pharmacokinetic Parameters of Oral Cabotegravir:

^a Pharmacokinetic parameter values were based on individual post-hoc estimates from the final population pharmacokinetic model for subjects receiving 30 mg of oral cabotegravir once daily in FLAIR and ATLAS trials.

Specific Populations

No clinically significant differences in the pharmacokinetics of cabotegravir were observed based on age, sex, race/ethnicity, body mass index, or UGT1A1 polymorphisms. The effect of hepatitis B and C virus co-infection on the pharmacokinetics of cabotegravir is unknown. The pharmacokinetics of cabotegravir has not been studied in pediatric patients and data are limited in subjects aged 65 years or older [see Use in Specific Populations (8.4, 8.5)].

Patients with Renal Impairment

No clinically significant differences in the pharmacokinetics of cabotegravir are expected 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 greater than 99% protein bound, dialysis is not expected to alter exposures of cabotegravir [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)].

Drug Interaction Studies

Cabotegravir is not a clinically relevant inhibitor of the following enzymes and transporters: cytochrome P450 (CYP)1A2, 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; 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, 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.

The effects of coadministered drugs on the exposure of cabotegravir are summarized in Table 4 and the effects of cabotegravir on the exposure of coadministered drugs are summarized in Table 5

Table 4. Effect of Coadministered Drugs on the Pharmacokinetics of Cabotegravir:

CI = Confidence Interval; n = Maximum number of subjects with data; NA = Not available.

Table 5. Effect of Cabotegravir on the Pharmacokinetics of Coadministered Drugs:

CI = Confidence Interval; n = Maximum number of subjects with data; NA = Not available.

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 which 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.

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 nM 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 nM 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 nM to 0.14 nM, n=4).

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

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 which 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-fold to 410-fold change. The combinations of E138K+Q148K and V72I+E138K+Q148K conferred the greatest reductions of 53-fold to 260-fold change and 410-fold change, respectively.

Clinical Trials

In the pooled Phase 3 FLAIR and ATLAS trials, there were 7 confirmed virologic failures (2 consecutive HIV-1 RNA greater than or equal to 200 copies/mL) on cabotegravir plus rilpivirine (7/591, 1.2%) and 7 confirmed virologic failures on current antiretroviral regimen (7/591, 1.2%). Of the 7 virologic failures in the cabotegravir plus rilpivirine arm, 6 had post-baseline resistance data. All 6 had treatment-emergent NNRTI resistance-associated substitutions K101E, V108I, E138A, E138K, or H221H/L in reverse transcriptase, and 5 of them showed reduced phenotypic susceptibility to rilpivirine (range: 2.4-fold to 7.1‑fold).

Additionally, 4 of the 6 (67%) cabotegravir plus rilpivirine virologic failures with post-baseline resistance data had treatment-emergent INSTI resistance-associated substitutions and reduced phenotypic susceptibility to cabotegravir (Q148R [n=2; 5-fold and 9-fold decreased susceptibility to cabotegravir], G140R [n=1; 7-fold decreased susceptibility to cabotegravir], or N155H [n=1; 3-fold decreased susceptibility to cabotegravir]).

In comparison, 2 of the 7 (29%) virologic failures in the current antiretroviral regimen arm 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, conferring resistance to efavirenz in their regimen.

In other Phase 2 and 3 clinical trials (207966, LATTE and LATTE-2), virologic failures on cabotegravir plus rilpivirine also showed emergent genotypic and phenotypic cabotegravir and rilpivirine resistance (with emergent INSTI resistance-associated substitutions Q148R, N155H, E138K+Q148R, E138K+G140A+Q148R, G140S+Q148R, Q148R+N155H, and NNRTI resistance-associated substitutions K101E, K101E+E138A or K, K101E+M230L, K103N+K238T, K103N+E138G+K238T, E138K or Q, and Y188L).

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

Five of the 7 cabotegravir plus rilpivirine virologic failures in FLAIR and ATLAS had HIV-1 subtype A1 and the integrase substitution L74I detected at baseline and failure timepoints. Subjects with subtype A1 infection whose virus did not have L74I at baseline did not experience virologic failure (Table 6). In addition, there was no detectable phenotypic resistance to cabotegravir conferred by the presence of L74I at baseline.

The other 2 virologic failures had subtype AG and did not have the integrase substitution L74I at baseline or at failure. Six of the virologic failures with subtype A1 and AG were from Russia where the prevalence of subtypes A, A1 and AG are high. Subtypes A, A1, and AG are uncommon in the United States.

The presence of the integrase substitution L74I in other subtypes, such as subtype B commonly seen in the United States, was not associated with virologic failure (Table 6). In contrast to the Phase 3 trials where all virologic failures were subtype A1 or AG, subtypes of the cabotegravir plus rilpivirine virologic failures in Phase 2 clinical trials included A1, A, B, and C.

Table 6. Rate of Virologic Failure in FLAIR Trial: Baseline Analysis (Subtypes A1 and B, and Presence of Integrase Substitution L74I):

^a There were 4 virologic failures in the cabotegravir arm. One virologic failure in the cabotegravir arm had subtype AG.
^b There were 3 virologic failures in the current antiretroviral regimen arm. Two virologic failures in the current antiretroviral regimen arm had subtype B.

Cross-Resistance

Cross-resistance has been observed among INSTIs. Cabotegravir had reduced susceptibility (greater than 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-fold to 81-fold). The substitutions E138K+Q148K and Q148R+N155H conferred the greatest reductions in susceptibility of 81-fold 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.

Carcinogenesis

Two-year carcinogenicity studies in mice and rats were conducted with cabotegravir. In mice, no drug-related increases in tumor incidence were observed at cabotegravir exposures (AUC) up to approximately 8 times (males) and 7 times (females) higher than those in humans at the RHD. In rats, no drug-related increases in tumor incidence were observed at cabotegravir exposures up to approximately 26 times higher than those in humans at the RHD.

Mutagenesis

Cabotegravir was not genotoxic in the bacterial reverse mutation assay, mouse lymphoma assay, or in the in vivo rodent micronucleus assay.

Impairment of Fertility

In rats, no effects on fertility were observed at cabotegravir exposures (AUC) greater than 20 times (male) and 28 times (female) the exposure in humans at the RHD.

14.1 Clinical Trials in Adults

The use of VOCABRIA in combination with EDURANT (rilpivirine) as an oral lead-in and in patients who miss planned injections with CABENUVA (cabotegravir; rilpivirine) extended-release injectable suspensions was evaluated in two Phase 3 randomized, multicenter, active-controlled, parallel-arm, open-label, non-inferiority trials (Trial 201584: FLAIR [NCT02938520] and Trial 201585: ATLAS [NCT02951052]) in subjects who were virologically suppressed (HIV-1 RNA less than 50 copies/mL). Please refer to the CABENUVA prescribing information for additional information.