Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties
Pharmacotherapeutic group: Antiviral for systemic use, integrase inhibitor, ATC code: J05AJ04.

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.

Pharmacodynamic effects

Antiviral activity in cell culture
Cabotegravir exhibited antiviral activity against laboratory strains of wild-type HIV-1 with mean concentration of cabotegravir necessary to reduce viral replication by 50 percent (EC50) values of 0.22 nM in peripheral blood mononuclear cells (PBMCs), 0.74 nM in 293T cells and 0.57 nM in MT-4 cells. Cabotegravir demonstrated antiviral activity in cell culture against a panel of 24 HIV-1 clinical isolates (three 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 1.06 nM for HIV-1. Cabotegravir EC50 values against three HIV-2 clinical isolates ranged from 0.10 nM to 0.14 nM. No clinical data is available in patients with HIV-2.

Antiviral Activity in combination with other medicinal products
No medicines with inherent anti-HIV activity were antagonistic to cabotegravir’s antiretroviral activity (in vitro assessments were conducted in combination with rilpivirine, lamivudine, tenofovir and emtricitabine).

Resistance in vitro
Isolation from wild-type HIV-1 and activity against resistant strains: Viruses with >10-fold increase in cabotegravir EC50 were not observed during the 112-day passage of strain IIIB. The following integrase (IN) mutations emerged after passaging wild type HIV-1 (with T124A polymorphism) in the presence of cabotegravir: Q146L (fold-change [FC] range 1.3-4.6), S153Y (FC range 2.8-8.4), and I162M (FC = 2.8). As noted above, the detection of T124A is selection of a pre-existing minority variant that does not have differential susceptibility to cabotegravir. No amino acid substitutions in the integrase region were selected when passaging the wild-type HIV-1 NL-432 in the presence of 6.4 nM of cabotegravir through Day 56.

Among the multiple mutants, the highest FC was observed with mutants containing Q148K or Q148R.
E138K/Q148H resulted in a 0.92-fold decrease in susceptibility to cabotegravir but E138K/Q148R resulted in a 12-fold decrease in susceptibility and E138K/Q148K resulted in an 81-fold decrease in susceptibility to cabotegravir. G140C/Q148R and G140S/Q148R resulted in a 22- and 12-fold decrease in susceptibility to cabotegravir, respectively. While N155H did not alter susceptibility to cabotegravir, N155H/Q148R resulted in a 61-fold decrease in susceptibility to cabotegravir. Other multiple mutants, which resulted in a FC between 5 and 10, are: T66K/L74M (FC=6.3), G140S/Q148K (FC=5.6), G140S/Q148H (FC=6.1) and E92Q/N155H (FC=5.3).

Resistance in vivo
The number of subjects who met Confirmed Virologic Failure (CVF) criteria was low across the pooled FLAIR and ATLAS trials. In the pooled analysis, there were 7 CVFs on cabotegravir plus rilpivirine (7/591, 1.2%) and 7 CVFs on current antiretroviral regimen (7/591, 1.2%). The three CVFs on cabotegravir plus rilpivirine in FLAIR with resistance data had Subtype A1. In addition, 2 of the 3 CVFs had treatment-emergent integrase inhibitor resistance associated substitution Q148R while one of the three had G140R with reduced phenotypic susceptibility to cabotegravir. All 3 CVFs carried one rilpivirine resistance-associated substitution: K101E, E138E/A/K/T or E138K, and two of the three 
showed reduced phenotypic susceptibility to rilpivirine. The 3 CVFs in ATLAS had subtype A, A1 and AG. One of the three CVFs carried the INI resistance-associated substitution N155H at failure with reduced cabotegravir phenotype susceptibility. All three CVFs carried one rilpivirine resistance- associated substitution at failure: E138A, E138E/K or E138K, and showed reduced phenotypic susceptibility to rilpivirine. In two of these three CVFs, the rilpivirine resistance-associated substitutions observed at failure were also observed at baseline in PBMC HIV-1 DNA. The seventh CVF (FLAIR) never received an injection.

The substitutions associated with resistance to long-acting cabotegravir injection, observed in the pooled ATLAS and FLAIR trials were G140R (n=1), Q148R (n=2), and N155H (n=1).

In the ATLAS-2M study 10 subjects met CVF criteria through Week 48: 8 subjects (1.5%) in the Q8W arm and 2 subjects (0.4%) in the Q4W arm. Eight subjects met CVF criteria at or before the Week 24 timepoint.

At Baseline in the Q8W arm, 5 subjects had rilpivirine resistance-associated mutations of Y181Y/C + H221H/Y, Y188Y/F/H/L, Y188L, E138A or E138E/A and 1 subject contained cabotegravir resistance mutation, G140G/R (in addition to the above Y188Y/F/H/L rilpivirine resistance-associated mutation).
At the suspected virologic failure (SVF) timepoint in the Q8W arm, 6 subjects had rilpivirine resistance-associated mutations with 2 subjects having an addition of K101E and 1 subject having an addition of E138E/K from Baseline to SVF timepoint. Rilpivirine FC was above the biological cut-off for 7 subjects and ranged from 2.4 to 15. Five of the 6 subjects with rilpivirine resistance-associated substitution, also had INSTI resistance-associated substitutions, N155H (n=2); Q148R; Q148Q/R+N155N/H (n=2). INSTI substitution, L74I, was seen in 4/7 subjects. The Integrase genotype and phenotype assay failed for one subject and cabotegravir phenotype was unavailable for another.
FCs for the Q8W subjects ranged from 0.6 to 9.1 for cabotegravir, 0.8 to 2.2 for dolutegravir and 0.8 to 1.7 for bictegravir.

In the Q4W arm, neither subject had any rilpivirine or INSTI resistance-associated substitutions at Baseline. One subject had the NNRTI substitution, G190Q, in combination with the NNRTI polymorphism, V189I. At SVF timepoint, one subject had on-treatment rilpivirine resistance- associated mutations, K101E + M230L and the other retained the G190Q + V189I NNRTI substitutions with the addition of V179V/I. Both subjects showed reduced phenotypic susceptibility to rilpivirine. Both subjects also had INSTI resistance-associated mutations, either Q148R + E138E/K or N155N/H at SVF and 1 subject had reduced susceptibility to cabotegravir. Neither subject had the INSTI substitution, L74I. FCs for the Q4W subjects were 1.8 and 4.6 for cabotegravir, 1.0 and 1.4 for dolutegravir and 1.1 and 1.5 for bictegravir.

Clinical efficacy and safety

The efficacy of Vocabria plus rilpivirine has been evaluated in two Phase III randomised, multicentre, active-controlled, parallel-arm, open-label, non-inferiority studies, FLAIR (study 201584) and ATLAS (study 201585). The primary analysis was conducted after all subjects completed their Week 48 visit or discontinued the study prematurely.

Patients virologically suppressed (on prior dolutegravir based regimen for 20 weeks) In FLAIR, 629 HIV-1-infected, antiretroviral treatment (ART)-naive subjects received a dolutegravir integrase strand transfer inhibitor (INSTI) containing regimen for 20 weeks (either dolutegravir/abacavir/lamivudine or dolutegravir plus 2 other nucleoside reverse transcriptase inhibitors if subjects were HLA-B*5701 positive). Subjects who were virologically suppressed (HIV-1 RNA <50 copies per mL, n=566) were then randomised (1:1) to receive either the Vocabria plus rilpivirine regimen or remain on the current antiretroviral (CAR) regimen. Subjects randomised to receive the Vocabria plus rilpivirine regimen, initiated treatment with oral lead-in dosing with one 30 mg Vocabria tablet plus one 25 mg rilpivirine tablet, daily, for at least 4 weeks, followed by treatment with Vocabria injection (month 1: 600 mg injection, month 2 onwards: 400 mg injection) plus rilpivirine injection (month 1: 900 mg injection, month 2 onwards: 600 mg injection) every month for an additional 44 weeks. This study was extended to 96 weeks.
Patients virologically suppressed (stable on prior ARV therapy for at least 6 months) In ATLAS, 616 HIV-1-infected, ART-experienced, virologically-suppressed (for at least 6 months) subjects (HIV-1 RNA <50 copies per mL) were randomised (1:1) and received either the Vocabria plus rilpivirine regimen or remained on the CAR regimen. Subjects randomised to receive the Vocabria plus rilpivirine regimen, initiated treatment with oral lead-in dosing with one 30 mg Vocabria tablet plus one 25 mg rilpivirine tablet, daily for at least 4 weeks, followed by treatment with Vocabria injection (month 1: 600 mg injection, month 2 onwards: 400 mg injection) plus rilpivirine injection (month 1: 900 mg injection, month 2 onwards: 600 mg injection) every month for an additional 44 weeks. In ATLAS, 50%, 17%, and 33% of subjects received an NNRTI, PI, or INI (respectively) as their baseline third treatment medicine class prior to randomisation and this was similar between treatment arms.

Pooled data
At baseline, in the pooled analysis, for the Vocabria plus rilpivirine arm, the median age of subjects was 38 years, 27% were female, 27% were non-white, 1% were  65 years and 7% had CD4+ cell count less than 350 cells per mm3; these characteristics were similar between treatment arms.

The primary endpoint of both studies was the proportion of subjects with plasma HIV-1 RNA ≥50 copies/mL at week 48 (snapshot algorithm for the ITT-E population).

In a pooled analysis of the two pivotal studies, Vocabria plus rilpivirine was non-inferior to CAR on the proportion of subjects having plasma HIV-1 RNA ≥50 c/mL (1.9% and 1.7% respectively) at Week 48. The adjusted treatment difference between Vocabria plus rilpivirine and CAR (0.2; 95% CI: -1.4, 1.7) for the pooled analysis met the non-inferiority criterion (upper bound of the 95% CI below 4%).

The primary endpoint and other week 48 outcomes, including outcomes by key baseline factors, for FLAIR and ATLAS are shown in Tables 8 and 9.



Table 8           Virologic outcomes of randomised treatment of FLAIR and ATLAS at 48 Weeks (Snapshot analysis)

FLAIR                        ATLAS                      Pooled Data
Vocabria    CAR              Vocabria    CAR              Vocabria      CAR + RPV     N=283              + RPV     N=308              +RPV        N=591 N=283                        N=308                        N=591
HIV-1 RNA≥50
6 (2.1)         7 (2.5)     5 (1.6)         3 (1.0)     11 (1.9)         10 (1.7) copies/mL† (%)
Treatment
Difference %                   -0.4 (-2.8,2.1)             0.7 (-1.2, 2.5)              0.2 (-1.4, 1.7) (95% CI)*
HIV-1 RNA <50           265 (93.6)       264 (93.3)  285 (92.5)     294 (95.5)    550 (93.1)       558 (94.4) copies/mL (%)
Treatment                0.4 (-3.7, 4.5)                  -3.0 (-6.7, 0.7)             -1.4 (-4.1, 1.4) Difference %
(95% CI)*
No virologic data at Week 48                12 (4.2)        12 (4.2)    18 (5.8)        11 (3.6)     30 (5.1)         23 (3.9) window (%)
Reasons
Discontinued study/study drug
8 (2.8)         2 (0.7)    11 (3.6)         5 (1.6)     19 (3.2)          7 (1.2) due to adverse event or death (%)
Discontinued study/study drug
4 (1.4)        10 (3.5)     7 (2.3)         6 (1.9)     11 (1.9)         16 (2.7) for other reasons
(%)
Missing data during window but on                 0               0           0               0           0                 0 study (%)
* Adjusted for baseline stratification factors.
† Includes subjects who discontinued for lack of efficacy, discontinued while not supressed.
N = Number of subjects in each treatment group, CI = confidence interval, CAR = current antiviral regimen.

Table 9          Proportion of subjects with plasma HIV-1 RNA ≥50 copies/mL at Week 48 for key baseline factors (Snapshot Outcomes).

Pooled Data from FLAIR and ATLAS
Vocabria+RPV                  CAR
Baseline factors
N=591                    N=591 n/N (%)                  n/N (%)
Baseline CD4+        <350                                    0/42                  2/54 (3.7) (cells/ mm3)         350 to <500                         5/120 (4.2)                 0/117 500                                 6/429 (1.4)             8 / 420 (1.9) Gender               Male                                 6/429 (1.4)              9/423 (2.1) Female                                5/162 (3.1)                       1/168 (0.6) Race                 White                                 9/430 (2.1)                       7/408 (1.7) Black
2/109 (1.8)                       3/133 (2.3)
African/American
Asian/Other                              0/52                              0/48 BMI                  <30 kg/m2                             6/491 (1.2)                       8/488 (1.6) ≥30 kg/m2                             5/100 (5.0)                       2/103 (1.9) 


Age (years)         <50                                 9/492 (1.8)                 8/466 (1.7) 50                                 2/99 (2.0)                  2/125 (1.6) Baseline            PI                                  1/51 (2.0)                     0/54 antiviral           INI                                 6/385 (1.6)                 9/382 (2.4) therapy at randomisation       NNRTIs                              4/155 (2.6)                 1/155 (0.6) BMI= body mass index
PI= Protease inhibitor
INI= Integrase inhibitor
NNRTI= non-nucleoside reverse transcriptase inhibitor
In the FLAIR and ATLAS studies, treatment differences across baseline characteristics (CD4+ count, gender, race, BMI, age, baseline third medicine treatment class) were comparable.

Week 96 FLAIR
In the FLAIR study at 96 Weeks, the results remained consistent with the results at 48 Weeks. The proportion of subjects having plasma HIV-1 RNA ≥50 c/mL in Vocabria plus rilpivirine (n=283) and CAR (n=283) was 3.2% and 3.2% respectively (adjusted treatment difference between Vocabria plus rilpivirine and CAR [0.0; 95% CI: -2.9, 2.9]). The proportion of subjects having plasma HIV-1 RNA <50 c/mL in Vocabria plus rilpivirine and CAR was 87% and 89%, respectively (adjusted treatment difference between Vocabria plus rilpivirine and CAR [-2.8; 95% CI: -8.2, 2.5]).

Week 124 FLAIR Direct to Injection vs Oral Lead-in.
In the FLAIR study, an evaluation of safety and efficacy was performed at Week 124 for patients electing to switch (at Week 100) from abacavir/dolutegravir/lamivudine to Vocabria plus rilpivirine in the Extension Phase. Subjects were given the option to switch with or without an oral lead-in phase, creating an oral lead-in (OLI) group (n=121) and a direct to injection (DTI) group (n=111).

At Week 124, the proportion of subjects with HIV-1 RNA ≥50 copies/mL was 0.8% and 0.9% for the oral lead-in and direct to injection groups, respectively. The rates of virologic suppression (HIV-1 RNA <50 c/mL) were similar in both OLI (93.4%) and DTI (99.1%) groups.

Every 2 month dosing
Patients virologically suppressed (stable on prior ARV therapy for at least 6 months) The efficacy and safety of Vocabria injection given every 2 months, has been evaluated in one Phase IIIb randomised, multicentre, parallel-arm, open-label, non-inferiority study, ATLAS-2M (207966).
The primary analysis was conducted after all subjects completed their Week 48 visit or discontinued the study prematurely.

In ATLAS-2M, 1045 HIV-1 infected, ART experienced, virologically suppressed subjects were randomised (1:1) and received a Vocabria plus rilpivirine injection regimen administered either every 2 months or monthly. Subjects initially on non-cabotegravir/rilpivirine treatment received oral lead-in treatment comprising one 30 mg Vocabria tablet plus one 25 mg rilpivirine tablet, daily, for at least 4 weeks. Subjects randomised to monthly Vocabria injections (month 1: 600 mg injection, month 2 onwards: 400 mg injection) and rilpivirine injections (month 1: 900 mg injection, month 2 onwards: 600 mg injection) received treatment for an additional 44 weeks. Subjects randomised to every 2 month Vocabria injections (600 mg injection at months 1, 2, 4 and every 2 months thereafter) and rilpivirine injections (900 mg injection at months 1, 2, 4 and every 2 months thereafter) received treatment for an additional 44 weeks. Prior to randomisation, 63%, 13% and 24% of subjects received Vocabria plus rilpivirine for 0 weeks, 1 to 24 weeks and >24 weeks, respectively.

At baseline, the median age of subjects was 42 years, 27% were female, 27% were non-white, 4% were  65 years and 6% had a CD4+ cell count less than 350 cells per mm3; these characteristics were similar between the treatment arms.



The primary endpoint in ATLAS-2M was the proportion of subjects with a plasma HIV-1 RNA 50 c/mL at Week 48 (snapshot algorithm for the ITT-E population).

In ATLAS-2M, Vocabria and rilpivirine administered every 2 months was non-inferior to Vocabria and rilpivirine administered every month on the proportion of subjects having plasma HIV-1 RNA ≥50 c/mL (1.7% and 1.0% respectively) at Week 48. The adjusted treatment difference between Vocabria and rilpivirine administered every 2 months and every month (0.8; 95% CI: -0.6, 2.2) met the non- inferiority criterion (upper bound of the 95% CI below 4%).

Table 10      Virologic outcomes of randomised treatment of ATLAS-2M at 48 Weeks (Snapshot analysis)

2 month Dosing (Q8W)      Monthly Dosing (Q4W)
N=522 (%)                   N=523 (%)
HIV-1 RNA≥50 copies/mL† (%)                      9 (1.7)                     5 (1.0) Treatment Difference % (95%                                0.8 (-0.6, 2.2) CI)*
HIV-1 RNA <50 copies/mL (%)                       492 (94.3)                       489 (93.5) Treatment Difference % (95% CI)*                                 0.8 (-2.1, 3.7) No virologic data at week 48                       21 (4.0)                         29 (5.5) window
Reasons:
Discontinued study due to AE or                   9 (1.7)                         13 (2.5) death (%)
Discontinued study for other                     12 (2.3)                         16 (3.1) reasons (%)
On study but missing data in                           0                             0 window (%)
* Adjusted for baseline stratification factors.
† Includes subjects who discontinued for lack of efficacy, discontinued while not suppressed.
N = Number of subjects in each treatment group, CI = confidence interval, CAR = current antiviral regimen.

Table 11         Proportion of subjects with Plasma HIV-1 RNA ≥50 copies/mL at Week 48 for key baseline factors (Snapshot Outcomes).

Baseline factors                    Number of HIV-1 RNA ≥50 c/mL/Total Assessed (%)
2 Month Dosing     Monthly dosing
(Q8W)              (Q4W)
Baseline CD4+ cell          <350                   1/ 35 (2.9)               1/ 27 (3.7) count (cells/mm3)
350 to <500            1/ 96 (1.0)                             0/ 89

≥500                   7/391 (1.8)                        4/407 (1.0) 
Gender                      Male                   4/385 (1.0)                        5/380 (1.3) 
Female                 5/137 (3.5)                             0/143

Race                        White                  5/370 (1.4)                        5/393 (1.3) 
Non-White              4/152 (2.6)                             0/130

Black/African          4/101 (4.0)                             0/ 90
American
Baseline factors                 Number of HIV-1 RNA ≥50 c/mL/Total Assessed (%)
2 Month Dosing     Monthly dosing
(Q8W)              (Q4W)
Non-                 5/421 (1.2)              5/421 (1.2)
Black/African
American
BMI                       <30 kg/m2            3/409 (0.7)                   3/425 (0.7) 
≥30 kg/m2            6/113 (5.3)                    2/98 (2.0)

Age (years)               <35                  4/137 (2.9)                   1/145 (0.7) 
35 to <50            3/242 (1.2)                   2/239 (0.8)

50                  2/143 (1.4)                   2/139 (1.4)
Prior exposure            None                 5/327 (1.5)                   5/327 (1.5) CAB/RPV
1-24 weeks           3/69 (4.3)                        0/68

>24 weeks            1/126 (0.8)                      0/128

BMI= body mass index
In the ATLAS-2M study, treatment differences on the primary endpoint across baseline characteristics (CD4+ lymphocyte count, gender, race, BMI, age and prior exposure to cabotegravir/rilpivirine) were not clinically meaningful.

The efficacy results at Week 96 are consistent with the results of the primary endpoint at Week 48.
Vocabria plus rilpivirine injections administered every 2 months is non-inferior to Vocabria and rilpivirine administered every month. The proportion of subjects having plasma HIV-1 RNA ≥50 c/mL at Week 96 in Vocabria plus rilpivirine every 2 months dosing (n=522) and Vocabria plus rilpivirine monthly dosing (n=523) was 2.1% and 1.1% respectively (adjusted treatment difference between Vocabria plus rilpivirine every 2 months dosing and monthly dosing [1.0; 95% CI: -0.6, 2.5]). The proportion of subjects having plasma HIV-1 RNA <50 c/mL at Week 96 in Vocabria plus rilpivirine every 2 months dosing and Vocabria plus rilpivirine monthly dosing was 91% and 90.2% respectively (adjusted treatment difference between Vocabria plus rilpivirine every 2 months dosing and monthly dosing [0.8; 95% CI: -2.8, 4.3]).

The efficacy results at Week 152 are consistent with the results of the primary endpoint at Week 48 and at Week 96. Vocabria plus rilpivirine injections administered every 2 months is non-inferior to Vocabria and rilpivirine administered every month. In an ITT analysis, the proportion of subjects having plasma HIV-1 RNA ≥50 c/mL at Week 152 in Vocabria plus rilpivirine every 2 months dosing (n=522) and Vocabria plus rilpivirine monthly dosing (n=523) was 2.7% and 1.0% respectively (adjusted treatment difference between Vocabria plus rilpivirine every 2 months dosing and monthly dosing [1.7; 95% CI: 0.1, 3.3]). In an ITT analysis, the proportion of subjects having plasma HIV-1 RNA <50 c/mL at Week 152 in Vocabria plus rilpivirine every 2 months dosing and Vocabria plus rilpivirine monthly dosing was 87% and 86% respectively (adjusted treatment difference between Vocabria plus rilpivirine every 2 months dosing and monthly dosing [1.5; 95% CI: -2.6, 5.6]).

Post-hoc analyses
Multivariable analyses of pooled phase 3 studies (ATLAS through 96 weeks, FLAIR through 124 weeks and ATLAS-2M through 152 weeks) examined the influence of various factors on the risk of CVF. The baseline factors analysis (BFA) examined baseline viral and participant characteristics and dosing regimen; and the multivariable analysis (MVA) included the baseline factors and incorporated 
post-baseline predicted plasma drug concentrations on CVF using regression modelling with a variable selection procedure. Following a total of 4291 person-years, the unadjusted CVF incidence rate was 0.54 per 100 person-years; 23 CVFs were reported (1.4% of 1651 individuals in these studies).

The BFA demonstrated rilpivirine resistance mutations (incidence rate ratio IRR=21.65, p<0.0001), HIV-1 subtype A6/A1 (IRR=12.87, p<0.0001), and body mass index (IRR=1.09 per 1 unit increase, p=0.04; IRR=3.97 of ≥30 kg/m2, p=0.01) were associated with CVF. Other variables including Q4W or Q8W dosing, female gender, or CAB/INSTI resistance mutations had no significant association with CVF. A combination of at least 2 of the following key baseline factors was associated with an increased risk of CVF: rilpivirine resistance mutations, HIV-1 subtype A6/A1, or BMI30 kg/m2 (see Table 12).

Table 12         Virologic outcomes by presence of key baseline factors of rilpivirine resistance mutations, Subtype A6/A11 and BMI ≥30 kg/m2

Baseline Factors (number)            Virologic Successes (%)2            Confirmed Virologic Failure (%)3
0                                    844/970 (87.0)                      4/970 (0.4) 1                                    343/404 (84.9)                      8/404 (2.0)4 2                                   44/57 (77.2)                        11/57 (19.3)5 TOTAL                                1231/1431 (86.0)                    23/1431 (1.6)6 (95% Confidence Interval)            (84.1%, 87.8%)                      (1.0%, 2.4%) 1
HIV-1 subtype A1 or A6 classification based on Los Alamos National Library panel from HIV Sequence database (June 2020)
2
Based on the FDA Snapshot algorithm of RNA <50 copies/mL at Week 48 for ATLAS, at Week 124 for FLAIR, at Week 152 for ATLAS-2M.
3
Defined as two consecutive measurements of HIV RNA ≥200 copies/mL.
4
Positive Predictive Value (PPV) <2%; Negative Predictive Value (NPV) 98.5%; sensitivity 34.8%; specificity 71.9%
5
PPV 19.3%; NPV 99.1%; sensitivity 47.8%; specificity 96.7%
6
Analysis dataset with all non-missing covariates for baseline factors (out of a total of 1651 individuals) 
In patients with at least two of these risk factors, the proportion of subjects who had a CVF was higher than observed in patients with none or one risk factor, with CVF identified in 6/24 patients [25.0%, 95%CI (9.8%, 46.7%)] treated with the every 2 months dosing regimen and 5/33 patients [15.2%, 95%CI (5.1%, 31.9%)] treated with the monthly dosing regimen.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties
Cabotegravir pharmacokinetics is similar between healthy and HIV-infected subjects. The PK variability of cabotegravir is moderate to high. In HIV-infected subjects participating in Phase III studies, between-subject CVb% for Ctau ranged from 39 to 48%. Higher between-subject variability ranging from 41% to 89% was observed with single dose administration of long-acting cabotegravir injection.



Table 13            Pharmacokinetic parameters following cabotegravir orally once daily, and initiation, monthly and every 2 month continuation intramuscular injections 
Geometric Mean (5th, 95th Percentile)a
Dosage              AUC(0-tau)b                 Cmax                       Ctau Dosing Phase         Regimen              (µg•h/mL)                 (µg/mL)                   (µg/mL) 30 mg                  145                      8.0                       4.6 Oral lead-inc once daily           (93.5, 224)              (5.3, 11.9)                (2.8, 7.5) Initial          600 mg IM                1 591                     8.0                       1.5 injectiond         Initial Dose         (714, 3 245)              (5.3, 11.9)               (0.65, 2.9) Monthly           400 mg IM                2 415                     4.2                       2.8 injectione           monthly           (1 494, 3 645)              (2.5, 6.5)                (1.7, 4.6) Every 2-                                   3,764                     4.0                       1.6 600 mg IM month                                (2 431, 5 857)              (2.3, 6.8)                (0.8, 3.0) Every 2-month injectione a
Pharmacokinetic (PK) parameter values were based on individual post-hoc estimates from population PK models for patients in FLAIR and ATLAS for the monthly regimen and in ATLAS-2M for the every 2 month regimen.
b tau is dosing interval: 24 hours for oral administration; 1 month for monthly and 2 months for every 2 month IM 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. When administered without OLI (DTI n=110), observed geometric mean (5 th, 95th percentile) CAB Cmax (1 week post initial injection) was 1.89 g/mL (0.438, 5.69) and CAB Ctau was 1.43 g/mL (0.403, 3.90).
e
Monthly and every 2 month injection pharmacokinetic parameter values represent Week◦48 data.

Absorption

Cabotegravir injection exhibits absorption-limited (flip-flop) kinetics resulting from slow absorption from the gluteal muscle into the systemic circulation resulting in sustained plasma concentrations.
Following a single intramuscular dose, plasma cabotegravir concentrations are detectable on the first day and gradually rise to reach maximum plasma concentration with a median Tmax of 7 days.
Cabotegravir has been detected in plasma up to 52 weeks or longer after administration of a single injection. Pharmacokinetic steady-state is achieved by 44 weeks.
Plasma cabotegravir exposure increases in proportion or slightly less than in proportion to dose following single and repeat IM injection of doses ranging from 100 to 800 mg.

Distribution

Cabotegravir is highly bound (>99%) to human plasma proteins, based on in vitro data. Following administration of oral tablets, the mean apparent oral volume of distribution (Vz/F) in plasma was 12.3 L. In humans, the estimate of plasma cabotegravir Vc/F was 5.27 L and Vp/F was 2.43 L. These volume estimates, along with the assumption of high bioavailability, suggest some distribution of cabotegravir to the extracellular space.

Cabotegravir is present in the female and male genital tract. Median cervical and vaginal tissue:plasma ratios ranged from 0.16 to 0.28 and median rectal tissue:plasma ratios were 0.08 following a single 400 mg intramuscular injection (IM) at 4, 8, and 12 weeks after dosing.

Cabotegravir is present in cerebrospinal fluid (CSF). In HIV-infected subjects receiving a regimen of cabotegravir injection plus rilpivirine injection, the cabotegravir CSF to plasma concentration ratio [median (range)] (n=16) was 0.003(range: 0.002 to 0.004) one week following a steady-state long acting cabotegravir (Q4W or Q8W) injection. Consistent with therapeutic cabotegravir concentrations in the CSF, CSF HIV-1 RNA (n=16) was <50 c/mL in 100% and <2 c/mL in 15/16 (94%) of subjects.


At the same time point, plasma HIV-1 RNA (n=18) was <50 c/mL in 100% and <2 c/mL in 12/18 (66.7%) of subjects.

In vitro, cabotegravir was not a substrate of organic anion transporting polypeptide (OATP) 1B1, OATP2B1, OATP1B3 or organic cation transporter (OCT1).

Biotransformation

Cabotegravir is primarily metabolised by UGT1A1 with a minor UGT1A9 component. Cabotegravir is the predominant circulating compound in plasma, representing > 90% of plasma total radiocarbon.
Following oral administration in humans, cabotegravir is primarily eliminated through metabolism; renal elimination of unchanged cabotegravir is low (<1% of the dose). Forty-seven percent of the total oral dose is excreted as unchanged cabotegravir in the faeces. It is unknown if all or part of this is due to unabsorbed drug or biliary excretion of the glucuronide conjugate, which can be further degraded to form the parent compound in the gut lumen. Cabotegravir was observed to be present in duodenal bile samples. The glucuronide metabolite was also present in some, but not all, of the duodenal bile samples. Twenty-seven percent of the total oral dose is excreted in the urine, primarily as a glucuronide metabolite (75% of urine radioactivity, 20% of total dose).

Cabotegravir is not a clinically relevant inhibitor of the following enzymes and transporters: CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B4, UGT2B7, UGT2B15, and UGT2B17, P-gp, BCRP, Bile salt export pump (BSEP), OCT1, OCT2, OATP1B1, OATP1B3, multidrug and toxin extrusion transporter (MATE) 1, MATE 2-K, multidrug resistance protein (MRP) 2 or MRP4.

Elimination

Cabotegravir mean apparent terminal phase half-life is absorption-rate limited and is estimated to be 5.6 to 11.5 weeks after a single dose IM injection. The significantly longer apparent half-life compared to oral reflects elimination from the injection site into the systemic circulation. The apparent CL/F was 0.151 L/h.

Linearity/non-linearity

Plasma CAB exposure increases in proportion or slightly less than in proportion to dose following single and repeat IM injection of doses ranging from 100 to 800 mg.

Polymorphisms

In a meta-analysis of healthy and HIV-infected subject trials, HIV-infected subjects with UGT1A1 genotypes conferring poor cabotegravir metabolism had a 1.2-fold mean increase in steady-state cabotegravir AUC, Cmax, and Ctau following long acting injection administration compared with subjects with genotypes associated with normal metabolism via UGT1A1. These differences are not considered clinically relevant. No dose adjustment is required in subjects with UGT1A1 polymorphisms.

Special patient populations

Gender
Population pharmacokinetic analyses revealed no clinically relevant effect of gender on the exposure of cabotegravir, therefore no dose adjustment is required on the basis of gender.

Race
Population pharmacokinetic analyses revealed no clinically relevant effect of race on the exposure of cabotegravir, therefore no dosage adjustment is required on the basis of race.


Body Mass Index (BMI)
Population pharmacokinetic analyses revealed no clinically relevant effect of BMI on the exposure of cabotegravir, therefore no dose adjustment is required on the basis of BMI.

Elderly
Population pharmacokinetic analysis of cabotegravir revealed no clinically relevant effect of age on cabotegravir exposure. Pharmacokinetic data for cabotegravir in subjects of >65 years old are limited.

Renal impairment
No clinically important pharmacokinetic differences between subjects with severe renal impairment (CrCL <30 mL/min and not on dialysis) and matching healthy subjects were observed. No dosage adjustment is necessary for patients with mild to severe renal impairment (not on dialysis).
Cabotegravir has not been studied in patients on dialysis.

Hepatic impairment
No clinically important pharmacokinetic differences between subjects with moderate hepatic impairment and matching healthy subjects were observed. 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 cabotegravir has not been studied.