Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Antivirals for systemic use, antivirals for treatment of HIV infections, combinations. ATC code: J05AR21

Mechanism of action

Dolutegravir inhibits HIV integrase by binding to the integrase active site and blocking the strand transfer step of retroviral Deoxyribonucleic acid (DNA) integration which is essential for the HIV replication cycle.

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

Pharmacodynamic effects
Antiviral activity in cell culture
The IC50 for dolutegravir against various laboratory strains using PBMC was 0.5 nM, and when using MT-4 cells it ranged from 0.7-2 nM. Similar IC50s were seen for clinical isolates without any major difference between subtypes; in a panel of 24 HIV-1 isolates of clades A, B, C, D, E, F and G and group O the mean IC50 value was 0.2 nM (range 0.02-2.14). The mean IC50 for 3 HIV-2 isolates was 0.18 nM (range 0.09-0.61).



Rilpivirine exhibited activity against laboratory strains of wild-type HIV-1 in an acutely infected T-cell line with a median IC50 value for HIV-1/IIIB of 0.73 nM (0.27 ng/mL). Rilpivirine demonstrated limited in vitro activity against HIV-2 with IC50 values ranging from 2 510 to 10 830 nM.

Rilpivirine also demonstrated antiviral activity against a broad panel of HIV-1 group M (clades A, B, C, D, F, G, H) primary isolates with IC50 values ranging from 0.07 to 1.01 nM and group O primary isolates with EC50 values ranging from 2.88 to 8.45 nM.

Effect of human serum and serum proteins
In 100% human serum, the dolutegravir mean protein fold shift was 75 fold, resulting in protein adjusted IC90 of 0.064 g/mL.

A reduction in the antiviral activity of rilpivirine was observed in the presence of 1 mg/mL alpha-1-acid glycoprotein, 45 mg/mL human serum albumin, and 50% human serum as demonstrated by median IC50 rates of 1.8, 39.2 and 18.5, respectively.

Resistance

Resistance in vitro
Serial passage is used to study resistance evolution in vitro. For dolutegravir, when using the laboratory strain HIV-1 IIIB during passage over 112 days, mutations selected appeared slowly, with substitutions at positions S153Y and F; these mutations were not selected in patients treated with dolutegravir in the clinical studies. Using strain NL432, integrase mutations E92Q (fold change [FC] 3) and G193E (FC 3) were selected. These mutations have been selected in patients with pre-existing raltegravir resistance and who were then treated with dolutegravir (listed as secondary mutations for dolutegravir).

In further selection experiments using clinical isolates of subtype B, mutation R263K was seen in all five isolates (after 20 weeks and onwards). In subtype C (n=2) and A/G (n=2) isolates the integrase substitution R263K was selected in one isolate, and G118R in two isolates. R263K was reported from two individual patients with subtype B and subtype C in the Phase III clinical program for ART experienced, INI naive subjects, but without effects on dolutegravir susceptibility in vitro. G118R lowers the susceptibility to dolutegravir in site directed mutants (FC 10), but was not detected in patients receiving dolutegravir in the Phase III program.

Primary mutations for raltegravir/elvitegravir (Q148H/R/K, N155H, Y143R/H/C, E92Q, T66I) do not affect the in vitro susceptibility of dolutegravir as single mutations. When mutations listed as secondary integrase inhibitor associated mutations (for raltegravir/elvitegravir) are added to primary mutations (excluding at Q148) in experiments with site directed mutants, dolutegravir susceptibility remains at or near wildtype level. In the case of the Q148-mutation viruses, increasing dolutegravir FC is seen as the number of secondary mutations increase. The effect of the Q148-based mutations (H/R/K) was also consistent with in vitro passage experiments with site directed mutants. In serial passage with strain NL432-based site directed mutants at N155H or E92Q, no further selection of resistance was seen (FC unchanged around 1). In contrast, starting passage with mutants with mutation Q148H (FC 1), a variety of raltegravir associated secondary mutations accumulated with a consequent increase of FC to values >10.

A clinically relevant phenotypic cut-off value (FC vs wild type virus) has not been determined; genotypic resistance was a better predictor for outcome.

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 most commonly observed amino acid substitutions that emerged included: L100I, K101E, V108I, E138K, V179F, Y181C, H221Y, F227C and M230I. Resistance to rilpivirine was considered present when FC in EC50 value was above the biological cut-off (BCO) of the assay.

Resistance in vivo
Through 48 Weeks with comparative data two subjects receiving dolutegravir plus rilpivirine and two subjects continuing their current antiretroviral regimen (CAR) experienced confirmed virologic failure leading to withdrawal (CVW) criteria across the pooled SWORD-1 (201636) and SWORD-2 (201637) studies. Overall eleven subjects receiving dolutegravir plus rilpivirine met CVW through Week 148, see Table 3. The NNRTI-associated substitutions E138E/A and M230M/L were detected in three and two subjects at time of withdrawal.

Table 3:        Summary of resistance by drug class for subjects with confirmed virologic withdrawal in early and late switch phases of the SWORD studies


Regimen /                                                        Mutation by Drug Class HIV-1 RNA (c/mL)                             mutation (FC)***
Treatment                (time point) exposure                                                       INI                       NNRTI (weeks)*
SVW             CVW**              BL             VW          BL             VW DTG+RPV /             88              466                             G193E G193E                       none           none
36               (Wk24)         (Wk24UNS)                          (1.02) DTG+RPV /         1,059,771           1018                                                    K101K/E none           none        none
47              (Wk36)          (Wk36UNS)                                                   (0.75)
DTG+RPV /            162              217
L74I            NR        V108I           NR
21              (Wk64)            (Wk76)
DTG+RPV /            833              1174          N155N/H           V151V/I none           none
17              (Wk64)          (Wk64UNS)        G163G/R            (NR) DTG+RPV /            278              2571                                                    E138E/A none           none        none
88               (Wk76)           (Wk88)                                                    (1.61) DTG+RPV /            147              289                                                      K103N ND             none        NR
92               (Wk88)         (Wk88UNS)                                                   (5.24) DTG+RPV /            280               225 none           none        none           none
105              (Wk88)           (Wk100)
K101E,
DTG+RPV /            651             1105                                        K101E,        E138A, G193E            NR
105             (Wk100)        (Wk100UNS)                                     E138A        M230M/L (31)
E157Q          E157Q,
DTG+RPV /            118              230                                                     M230M/L G193E,         G193E        none
120             (Wk112)        (Wk112UNS)                                                    (2) T97T/A          (1.47)
E138A,
DTG+RPV /           4294             7247
NR              NR         NR            L100L/I
101             (Wk136)        (Wk136UNS)
(4.14)
* The resistance testing at virologic failure time failed for one subject, therefore, details are not included in this table.
** CVW was met with 2 consecutive viral loads after Day 1 ≥50 c/mL, with the second one being >200 c/mL.
*** The baseline assay only provides genotypic data, and not phenotypic data.

CAR = current antiretroviral regimen; DTG+RPV = dolutegravir plus rilpivirine SVW = suspected virologic withdrawal criteria; CVW = confirmatory virologic withdrawal criteria; BL = baseline resistance testing results; VW = resistance testing results when CVW criteria have been met; Wk = week; UNS = unscheduled visit; “ND” Baseline testing was not performed as PBMC/Whole blood samples were note collected; “none” indicates no resistance observed; "NR" indicates data are not reported due to assay failure or sample unavailability.

In previously untreated patients receiving dolutegravir + 2 NRTIs in Phase IIb and Phase III, no development of resistance to the integrase class, or to the NRTI class was seen (n=876, follow-up of 48-96 weeks).


In patients with prior failed therapies, but naïve to the integrase class (SAILING study), integrase inhibitor substitutions were observed in 4/354 patients (follow-up 48 weeks) treated with dolutegravir, which was given in combination with an investigator selected background regimen (BR). Of these four, two subjects had a unique R263K integrase substitution, with a maximum FC of 1.93, one subject had a polymorphic V151V/I integrase substitution, with maximum FC of 0.92, and one subject had pre-existing integrase mutations and is assumed to have been integrase inhibitor experienced or infected with integrase inhibitor resistant virus by transmission. The R263K mutation was also selected in vitro (see above).

From rilpivirine Phase IIIstudies, in the week 48 pooled resistance analysis conducted with previously untreated patients, 62 (of a total of 72) virologic failures in the rilpivirine arm had resistance data at baseline and time of failure. In this analysis, the resistance-associated mutations (RAMs) associated with NNRTI resistance that developed in at least 2 rilpivirine virologic failures were: V90I, K101E, E138K, E138Q, V179I, Y181C, V189I, H221Y, and F227C. In the studies, the presence of the mutations V90I and V189I, at baseline, did not affect response. The E138K substitution emerged most frequently during rilpivirine treatment, commonly in combination with the M184I substitution. In the week 48 analysis, 31 out of 62 of rilpivirine virologic failures had concomitant NNRTI and NRTI RAMs; 17 of those 31 had the combination of E138K and M184I. The most common mutations were the same in the week 48 and week 96 analyses.
From the week 48 to the week 96 analysis, 24 (3.5%) and 14 (2.1%) additional virologic failures occurred in the rilpivirine and efavirenz arm, respectively.

Cross-resistance

Site-directed INI mutant virus
Dolutegravir activity was determined against a panel of 60 INI-resistant site-directed mutant HIV-1 viruses (28 with single substitutions and 32 with 2 or more substitutions). The single INI-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).

Site-directed NNRTI mutant virus
In a panel of 67 HIV-1 recombinant laboratory strains with one amino acid substitution at RT positions associated with NNRTI resistance, including the most commonly found K103N and Y181C, rilpivirine showed antiviral activity (FC≤BCO) against 64 (96%) of these strains. The single amino acid substitutions associated with a loss of susceptibility to rilpivirine were: K101P, Y181I and Y181V. The K103N substitution did not result in reduced susceptibility to rilpivirine by itself, but the combination of K103N and L100I resulted in a 7-fold reduced susceptibility to rilpivirine.
Considering all of the available in vitro and in vivo data, the following amino acid substitutions, when present at baseline, are likely to affect the activity of rilpivirine: K101E, K101P, E138A, E138G, E138K, E138R, E138Q, V179L, Y181C, Y181I, Y181V, Y188L, H221Y, F227C, M230I or M230L.

Recombinant clinical isolates
Seven hundred and five raltegravir resistant isolates from raltegravir experienced patients were analysed for susceptibility to dolutegravir. Dolutegravir had a <10 FC against 94% of the 705 clinical isolates.

Rilpivirine retained sensitivity (FC ≤ BCO) against 62% of 4786 HIV-1 recombinant clinical isolates resistant to efavirenz and/or nevirapine.

Previously untreated HIV-1 infected adult patients
In a Week 96 pooled analyses of virologic failures with baseline viral load ≤100,000 copies/mL and resistance to rilpivirine (n = 5), subjects had cross-resistance to efavirenz (n = 3), etravirine (n = 4), and nevirapine (n = 1).

Effects on electrocardiogram

The effect of rilpivirine at the recommended dose of 25 mg once daily on the QTcF interval was evaluated in a randomised, placebo and active (moxifloxacin 400 mg once daily) controlled crossover study in 60 healthy adults, with 13 measurements over 24 hours at steady-state. Rilpivirine at the recommended dose of 25 mg once daily is not associated with a clinically relevant effect on QTc.

When supratherapeutic doses of 75 mg once daily and 300 mg once daily of rilpivirine 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) ms, respectively. Steady- state administration of rilpivirine 75 mg once daily and 300 mg once daily resulted in a mean Cmax approximately 2.6-fold and 6.7-fold, respectively, higher than the mean steady-state Cmax observed with the recommended 25 mg once daily dose of rilpivirine (see section 4.4).

No relevant effects were seen with dolutegravir on the QTc interval, with doses exceeding the clinical dose by approximately three fold.

Clinical efficacy and safety

The efficacy and safety of switching from an antiretroviral regimen (containing 2 NRTIs plus either an INI, an NNRTI, or a PI) to a dual regimen of dolutegravir 50 mg and rilpivirine 25 mg was evaluated in 2 identical 148-week, randomised, open-label, multicentre, parallel-group, non-inferiority studies SWORD-1 (201636) and SWORD-2 (201637). Subjects were enrolled if they were on their first or second antiretroviral regimen with no history of virological failure, had no suspected or known resistance to any antiretroviral and had been stably suppressed (HIV-1 RNA < 50 copies/mL) for at least 6 months prior to screening. Subjects were randomised 1:1 to continue their CAR or be switched to a two-agent regimen dolutegravir plus rilpivirine administered once daily. The primary efficacy endpoint for the SWORD studies was the proportion of subjects with plasma HIV-1 RNA <50 copies/mL at Week 48 (Snapshot algorithm for the ITT- E population).

At baseline, in the pooled analysis, characteristics were similar between treatment arms with the median age of subjects of 43 years (28%, 50 years of age or older; 3%, 65 years of age or older), 22% female, 20% non- white and 77% were CDC Class A. Median CD+cell count was about 600 cells per mm3 with 11% having CD4+ cell count less than 350 cells per mm3. In the pooled analysis, 54%, 26%, and 20% of subjects were receiving an NNRTI, PI, or INI (respectively) as their baseline third treatment agent class prior to randomisation.

The pooled primary analysis demonstrated that dolutegravir plus rilpivirine is non-inferior to CAR, with 95% of subjects in both arms achieving the primary endpoint of <50 copies/mL plasma HIV-1 RNA at Week 48 based on the Snapshot algorithm (Table 4).

The primary endpoint and other outcomes (including outcomes by key baseline covariates) for the pooled SWORD-1 and SWORD-2 studies are shown in Table 4.

Table 4:        Virologic outcomes of randomised treatment at week 48 (Snapshot algorithm) 
SWORD-1 and SWORD-2 Pooled
Data***
DTG + RPV                 CAR
N=513                 N=511 n (%)                  n (%)
HIV-1 RNA <50 copies/mL                                     486 (95%)             485 (95%) Treatment Difference*                                               -0.2 (-3.0, 2.5) Virologic non response**                                     3 (<1%)                6 (1%) Reasons
Data in window not <50 copies/mL                                0                 2 (<1%) Discontinued for lack of efficacy                           2 (<1%)               2 (<1%) 

Discontinued for other reasons while not <50
1 (<1%)               1 (<1%) copies/mL
Change in ART                                                    0                 1 (<1%) No virologic data at Week 48 window                            24 (5%)                20 (4%) Reasons
Discontinued study/study agent due to adverse
17 (3%)               3 (<1%) event or death
Discontinued study/study agent for other reasons              7 (1%)                16 (3%) Missing data during window but on study                          0                 1 (<1%) HIV-1 RNA <50 copies/mL by baseline covariates n/N (%)                n/N (%)
Baseline CD4+ (cells/ mm3)
<350                                                       51 / 58 (88%)          46 / 52 (88%) 350                                                      435 / 455 (96%)       439 / 459 (96%) Baseline Third Treatment Agent Class
INI                                                       99 / 105 (94%)          92 / 97 (95%) NNRTI                                                     263 / 275 (96%)       265 / 278 (95%) PI                                                        124 / 133 (93%)       128 / 136 (94%) Gender
Male                                                      375 / 393 (95%)       387 / 403 (96%) Female                                                    111 / 120 (93%)        98 / 108 (91%) Race
White                                                     395 / 421 (94%)       380 / 400 (95%) African-America/African Heritage/Other                     91 / 92 (99%)        105 / 111 (95%) Age (years)
<50                                                       350 / 366 (96%)       348 / 369 (94%) 50                                                       136 / 147 (93%)       137 / 142 (96%) * Adjusted for baseline stratification factors and assessed using a non-inferiority margin of - 8%.
** Non-inferiority of dolutegravir plus rilpivirine to CAR, in the proportion of subjects classified as virologic non-responders, was demonstrated using a non-inferiority margin of 4%.
Adjusted difference (95% CI) -0.6 (-1.7, 0.6).
*** The results of the pooled analysis are in line with those of the individual studies, for which differences in proportions meeting the primary endpoint of <50 copies/mL plasma HIV-1 RNA at Week 48 (based on the Snapshot algorithm) for DTG+RPV versus CAR were -0.6 (95% CI: -4.3; 3.0) for SWORD-1 and 0.2 (95% CI: -3.9; 4.2) for SWORD-2 with a preset non- inferiority margin of -10%.
N = Number of subjects in each treatment arm
CAR = current antiretroviral regimen; DTG+RPV = dolutegravir plus rilpivirine; INI = Integrase inhibitor; NNRTI = Non-nucleoside reverse transcriptase inhibitor; PI = Protease Inhibitor

At Week 148 in the pooled SWORD-1 and SWORD-2 studies, 84% of subjects who received dolutegravir plus rilpivirine as of study start had plasma HIV-1 RNA < 50 copies/mL based on the Snapshot algorithm. In subjects who initially remained on their CAR and switched to dolutegravir plus rilpivirine at Week 52, 90% had plasma HIV-1 RNA < 50 copies/mL at Week 148 based on the Snapshot algorithm, which was comparable to the response rate (89%) observed at Week 100 (similar exposure duration) in subjects receiving dolutegravir plus rilpivirine as of study start.

Effects on bone
In a DEXA substudy mean bone mineral density (BMD) increased from Baseline to Week 48 in subjects who switched to dolutegravir plus rilpivirine (1.34% total hip and 1.46% lumbar spine) compared with those who continued on treatment with a TDF-containing antiretroviral regimen (0.05% total hip and 0.15% lumbar spine. Any beneficial effect on fracture rate was not studied.

Pregnancy

No efficacy and safety data are available for the combination of dolutegravir and rilpivirine in pregnancy.
Rilpivirine in combination with a background regimen was evaluated in a clinical study of 19 pregnant women during the second and third trimesters, and postpartum. The pharmacokinetic data demonstrate that total exposure (AUC) to rilpivirine as a part of an antiretroviral regimen was approximately 30% lower during pregnancy compared with postpartum (6-12 weeks). Of the 12 subjects that completed the study, 10 subjects were suppressed at the end of the study; in the other 2 subjects an increase in viral load was observed postpartum, for 1 subject due to suspected suboptimal adherence. No mother to child transmission occurred in all 10 infants born to the mothers who completed the study and for whom the HIV status was available. There were no new safety findings compared with the known safety profile of rilpivirine in HIV-1 infected adults.

In limited data from small numbers of women who received dolutegravir 50 mg once daily in combination with a background regimen, the total exposure (AUC) to dolutegravir was 37% lower during the 2nd trimester of pregnancy, and 29% lower during the 3rd trimester of pregnancy, compared with postpartum (6- 12 weeks). Of the 29 subjects that completed the study, 27 subjects were suppressed at the end of the study.
No mother to child transmission was identified. While 24 infants were confirmed to be uninfected, 5 were indeterminate due to incomplete testing, see section 5.2.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties
Juluca is bioequivalent to a dolutegravir 50 mg tablet and a rilpivirine 25 mg tablet administered together with a meal.

Dolutegravir pharmacokinetics are similar between healthy and HIV-infected subjects. The PK variability of dolutegravir is low to moderate. In Phase I studies in healthy subjects, between-subject CVb% for AUC and Cmax ranged from ~20 to 40% and C from 30 to 65% across studies. The between-subject PK variability of dolutegravir was higher in HIV-infected subjects than healthy subjects. Within-subject variability (CVw%) is lower than between-subject variability.

The pharmacokinetic properties of rilpivirine have been evaluated in adult healthy subjects and in adult antiretroviral treatment-naïve HIV-1 infected patients. Systemic exposure to rilpivirine was generally lower in HIV-1 infected patients than in healthy subjects.

Absorption

Dolutegravir is rapidly absorbed following oral administration, with median Tmax at 2 to 3 hours post dose for tablet formulation. After oral administration, the maximum plasma concentration of rilpivirine is generally achieved within 4-5 hours.

Juluca must be taken with a meal to obtain optimal absorption of rilpivirine (see section 4.2). When Juluca was taken with a meal, the absorption of both dolutegravir and rilpivirine was increased. Moderate and high fat meals increased the dolutegravir AUC(0-) by approximately 87% and Cmax by approximately 75%.
Rilpivirine AUC(0-) was increased by 57% and 72% and Cmax by 89% and 117%, with moderate and high fat meals respectively, compared to fasted conditions. Taking Juluca in fasted condition or with only a protein-rich nutritional drink may result in decreased plasma concentrations of rilpivirine, which could potentially reduce the therapeutic effect of Juluca.

The absolute bioavailability of dolutegravir or rilpivirine has not been established.

Distribution
Dolutegravir is highly bound (>99%) to human plasma proteins based on in vitro data. The apparent volume of distribution is 17 L to 20 L in HIV-infected patients, based on a population pharmacokinetic analysis.
Binding of dolutegravir to plasma proteins is independent of dolutegravir concentration. Total blood and 
plasma drug-related radioactivity concentration ratios averaged between 0.441 to 0.535, indicating minimal association of radioactivity with blood cellular components. The unbound fraction of dolutegravir in plasma is increased at low levels of serum albumin (<35 g/L) as seen in subjects with moderate hepatic impairment.

Dolutegravir is present in cerebrospinal fluid (CSF). In 13 treatment-naïve subjects on a stable dolutegravir plus abacavir/lamivudine regimen, dolutegravir concentration in CSF averaged 18 ng/mL (comparable to unbound plasma concentration, and above the IC50).

Dolutegravir is present in the female and male genital tract. AUC in cervicovaginal fluid, cervical tissue and vaginal tissue were 6-10% of those in corresponding plasma at steady state. AUC in semen was 7% and 17% in rectal tissue of those in corresponding plasma at steady state.

Rilpivirine is approximately 99.7% bound to plasma proteins in vitro, primarily to albumin. The distribution of rilpivirine into compartments other than plasma (e.g., cerebrospinal fluid, genital tract secretions) has not been evaluated in humans.

Biotransformation

Dolutegravir is primarily metabolised through glucuronidation via UGT1A1 with a minor CYP3A component. Dolutegravir is the predominant circulating compound in plasma; renal elimination of unchanged active substance is low (< 1% of the dose). Fifty-three percent of total oral dose is excreted unchanged in the faeces. It is unknown if all or part of this is due to unabsorbed active substance or biliary excretion of the glucuronidate conjugate, which can be further degraded to form the parent compound in the gut lumen. Thirty-two percent of the total oral dose is excreted in the urine, mainly represented by ether glucuronide of dolutegravir (18.9% of total dose), N-dealkylation metabolite (3.6% of total dose), and a metabolite formed by oxidation at the benzylic carbon (3.0% of total dose).

In vitro experiments indicate that rilpivirine primarily undergoes oxidative metabolism mediated by the CYP3A system.

Drug interactions

In vitro, dolutegravir demonstrated no direct, or weak inhibition (IC50>50 μM) of the enzymes cytochrome P450 (CYP)1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP3A, uridine diphosphate glucuronosyl transferase (UGT)1A1 or UGT2B7, or the transporters Pgp, BCRP, BSEP, OATP1B1, OATP1B3, OCT1, MATE2-K, MRP2 or MRP4. In vitro, dolutegravir did not induce CYP1A2, CYP2B6 or CYP3A4. Based on this data, dolutegravir is not expected to affect the pharmacokinetics of medicinal products that are substrates of major enzymes or transporters (see section 4.5).

In vitro, dolutegravir was not a substrate of human OATP 1B1, OATP 1B3 or OCT 1.

Elimination
Dolutegravir has a terminal half-life of ~14 hours. The apparent oral clearance (CL/F) is approximately 1L/hr in HIV-infected patients based on a population pharmacokinetic analysis.

The terminal elimination half-life of rilpivirine is approximately 45 hours. After single dose oral administration of 14C-rilpivirine, on average 85% and 6.1% of the radioactivity could be retrieved in faeces and urine, respectively. In faeces, unchanged rilpivirine accounted for on average 25% of the administered dose. Only trace amounts of unchanged rilpivirine (< 1% of dose) were detected in urine.

Special patient populations



Elderly
Population pharmacokinetic analysis using data in HIV-1 infected adults showed that there was no clinically relevant effect of age on dolutegravir or rilpivirine exposures. Pharmacokinetic data in subjects >65 years old are very limited.

Renal impairment
Renal clearance of unchanged active substance is a minor pathway of elimination for dolutegravir. A study of the pharmacokinetics of dolutegravir was performed in subjects with severe renal impairment (CLcr <30 mL/min) and matched healthy controls. The exposure to dolutegravir was decreased by approximately 40% in subjects with severe renal impairment. The mechanism for the decrease is unknown. The pharmacokinetics of rilpivirine have not been studied in patients with renal insufficiency.

Renal elimination of rilpivirine is negligible. No dose adjustment is needed for patients with mild or moderate renal impairment. In patients with severe renal impairment or end-stage renal disease, dolutegravir/rilpivirine should be used with caution, as rilpivirine plasma concentrations may be increased due to alteration of drug absorption, distribution and/or metabolism secondary to renal dysfunction. In patients with severe renal impairment or end-stage renal disease, the combination of dolutegravir/rilpivirine with a strong CYP3A inhibitor should only be used if the benefit outweighs the risk. Dolutegravir/rilpivirine has not been studied in patients on dialysis. As dolutegravir and rilpivirine are highly bound to plasma proteins, it is unlikely that they will be significantly removed by haemodialysis or peritoneal dialysis (see section 4.2).

Hepatic impairment
Dolutegravir and rilpivirine are both primarily metabolised and eliminated by the liver. A single dose of 50 mg of dolutegravir was administered to 8 subjects with moderate hepatic impairment (Child-Pugh score B) and to 8 matched healthy adult controls. While the total dolutegravir concentration in plasma was similar, a 1.5- to 2-fold increase in unbound exposure to dolutegravir was observed in subjects with moderate hepatic impairment compared to healthy controls.

In a rilpivirine study comparing 8 patients with mild hepatic impairment (Child-Pugh score A) to 8 matched controls, and 8 patients with moderate hepatic impairment (Child-Pugh score B) to 8 matched controls, the multiple dose exposure of rilpivirine was 47% higher in patients with mild hepatic impairment and 5% higher in patients with moderate hepatic impairment. However, it may not be excluded that the pharmacologically active, unbound, rilpivirine exposure is significantly increased in moderate hepatic impairment.

No dose adjustment is considered necessary for patients with mild to moderate hepatic impairment (Child- Pugh score A or B). Dolutegravir/rilpivirine should be used with caution in patients with moderate hepatic impairment. The effect of severe hepatic impairment (Child-Pugh score C) on the pharmacokinetics of dolutegravir or rilpivirine has not been studied, therefore dolutegravir/rilpivirine is not recommended in these patients.

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

Race
No clinically important pharmacokinetic differences of dolutegravir or rilpivirine due to race have been identified.

Co-infection with Hepatitis B or C
Population pharmacokinetic analysis indicated that hepatitis C virus co-infection had no clinically relevant effect on the exposure to dolutegravir or rilpivirine. Subjects with hepatitis B co-infection or hepatitis C infection in need of anti-HCV therapy were excluded from studies with the dual combination of dolutegravir and rilpivirine.


Pregnancy and postpartum
No pharmacokinetic data are available for the combination of dolutegravir and rilpivirine in pregnancy. In limited data from small numbers of women in study IMPAACT P1026 who received dolutegravir 50 mg once daily during the 2nd trimester of pregnancy, mean intra-individual values for total dolutegravir Cmax, AUC24h and C24h values were, respectively, 26%, 37% and 51% lower as compared to postpartum; during the 3rd trimester of pregnancy, Cmax, AUC24h and Cmin values were, respectively, 25%, 29% and 34% lower as compared to postpartum (see section 4.6).

In women receiving rilpivirine 25 mg once daily during the 2nd trimester of pregnancy, mean intra- individual values for total rilpivirine Cmax, AUC24h and Cmin values were, respectively, 21%, 29% and 35% lower as compared to postpartum; during the 3rd trimester of pregnancy, Cmax, AUC24h and Cmin values were, respectively, 20%, 31% and 42% lower as compared to postpartum (see section 4.6).