Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Antivirals for systemic use, direct acting antivirals, ATC code: J05AB16 
Mechanism of action

Remdesivir is an adenosine nucleotide prodrug that is metabolized within host cells to form the pharmacologically active nucleoside triphosphate metabolite. Remdesivir triphosphate acts as an analog of adenosine triphosphate (ATP) and competes with the natural ATP substrate for incorporation into nascent RNA chains by the SARS-CoV-2 RNA-dependent RNA polymerase, which results in delayed chain termination during replication of the viral RNA. As an additional mechanism, remdesivir triphosphate can also inhibit viral RNA synthesis following its incorporation into the template viral RNA as a result of read- through by the viral polymerase that may occur in the presence of higher nucleotide concentrations. When 
remdesivir nucleotide is present in the viral RNA template, the efficiency of incorporation of the complementary natural nucleotide is compromised, thereby inhibiting viral RNA synthesis.

Antiviral activity

Remdesivir exhibited in vitro activity against a clinical isolate of SARS-CoV-2 in primary human airway epithelial cells with a 50% effective concentration (EC50) of 9.9 nM after 48 hours of treatment. Remdesivir inhibited the replication of SARS-CoV-2 in the continuous human lung epithelial cell lines Calu-3 and A549- hACE2 with EC50 values of 280 nM after 72 hours of treatment and 115 nM after 48 hours of treatment, respectively. The EC50 values of remdesivir against SARS-CoV-2 in Vero cells were 137 nM at 24 hours and 750 nM at 48 hours post-treatment.

The antiviral activity of remdesivir was antagonised by chloroquine phosphate in a dose-dependent manner when the two drugs were co-incubated at clinically relevant concentrations in HEp-2 cells infected with respiratory syncytial virus (RSV). Higher remdesivir EC50 values were observed with increasing concentrations of chloroquine phosphate. Increasing concentrations of chloroquine phosphate reduced formation of remdesivir triphosphate in A549-hACE2, HEp-2 and normal human bronchial epithelial cells.

Based on in vitro testing, remdesivir retained similar antiviral activity ( EC50 fold change values below the in vitro susceptibility change cutoff of 2.8-fold ) against clinical isolates of SARS-CoV-2 variants compared to an earlier lineage SARS-CoV-2 (lineage A) isolate, including Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), Epsilon (B.1.429), Zeta (P.2), Iota (B.1.526), Kappa (B.1.617.1), Lambda (C.37), and Omicron variants (including B.1.1.529/BA.1, BA.2, BA.2.12.1, BA.2.75, BA.4, BA.4.6, BA.5, BF.5, BF.7, BQ.1, BQ.1.1 , CH.1.1, EG.1.2, EG.5.1, FL.22, XBB, XBB.1.5, XBB.1.16, XBB.2.3.2 and XBF). For these variants, the EC50 fold change values ranged between 0.2 to 2.3 compared to an earlier lineage SARS-CoV-2 (lineage A) isolate. Using the SARS-CoV-2 replicon system, remdesivir retained similar antiviral activity ( EC50 fold change values below the in vitro susceptibility change cutoff of 2.5-fold) against Omicron subvariants BA.2.86 and XBB.1.9.2 compared to the wildtype reference replicon (lineage B).

Resistance

In Cell Culture
SARS-CoV-2 isolates with reduced susceptibility to remdesivir have been selected in cell culture. In one selection with GS-441524, the parent nucleoside of remdesivir, virus pools emerged expressing combinations of amino acid substitutions at V166A, N198S, S759A, V792I, C799F, and C799R in the viral RNA-dependent RNA polymerase, conferring EC50 fold-changes of 2.7 up to 10.4. When individually introduced into a wild- type recombinant virus by site-directed mutagenesis, 1.7- to 3.5-fold reduced susceptibility to remdesivir was observed. In a second selection with remdesivir using a SARS-CoV-2 isolate containing the P323L substitution in the viral polymerase, a single amino acid substitution at V166L emerged. Recombinant viruses with substitutions at P323L alone or P323L+V166L in combination exhibited 1.3- and 1.5-fold changes in remdesivir susceptibility, respectively.

Cell culture resistance profiling of remdesivir using the rodent CoV murine hepatitis virus identified two substitutions (F476L and V553L) in the viral RNA-dependent RNA polymerase at residues conserved across CoVs that conferred 5.6-fold reduced susceptibility to remdesivir. Introduction of the corresponding substitutions (F480L and V557L) into SARS-CoV resulted in 6-fold reduced susceptibility to remdesivir in cell culture and attenuated SARS-CoV pathogenesis in a mouse model. When individually introduced into a SARS-CoV-2 recombinant virus, the corresponding substitutions at F480L and V557L each conferred 2-fold reduced susceptibility to remdesivir.

In Clinical Trials
In NIAID ACTT-1 Study (CO-US-540-5776), among 61 patients with baseline and post-baseline sequencing data available, the rate of emerging substitutions in the viral RNA-dependent RNA polymerase was similar in patients treated with remdesivir compared to placebo. In 2 patients treated with remdesivir, substitutions in the RNA-dependent RNA polymerase previously identified in resistance selection experiments (V792I or C799F) and associated with low fold change in remdesivir susceptibility (≤3.4-fold) were observed. No other RNA- 
dependent RNA polymerase substitutions observed in patients treated with remdesivir were associated with resistance to remdesivir.

In Study GS-US-540-5773, among 19 patients treated with remdesivir who had baseline and post-baseline sequencing data available, substitutions in the viral RNA-dependent RNA polymerase (nsp12) were observed in 4 patients. The substitutions T76I, A526V, A554V and C697F were not associated with resistance to remdesivir (≤ 1.45-fold change in susceptibility). The effect of substitution E665K on susceptibility to remdesivir could not be determined due to lack of replication.

In GS-US-540-9012 Study, among 244 patients with baseline and post-baseline sequencing data available, the rate of emerging substitutions in the viral RNA-dependent RNA polymerase was similar in patients treated with remdesivir compared to placebo. In one patient treated with remdesivir, one substitution in the RNA- dependent RNA polymerase (A376V) emerged and was associated with a decrease in remdesivir susceptibility in vitro (12.6-fold). No other substitutions in the RNA-dependent RNA polymerase or other proteins of the replication-transcription complex observed in patients treated with remdesivir were associated with resistance to remdesivir.

In Study GS-US-540-5823, among patients with baseline and post-baseline sequencing data available, substitutions in the viral RNA-dependent RNA polymerase (A656P and G670V) were observed in one of 23 patients treated with remdesivir. The substitutions observed have not been associated with resistance to remdesivir.

Clinical efficacy and safety

Clinical trials in patients with COVID-19
NIAID ACTT-1 Study (CO-US-540-5776)
A randomised, double-blind, placebo-controlled clinical trial evaluated remdesivir 200 mg once daily for 1 day followed by remdesivir 100 mg once daily for up to 9 days (for a total of up to 10 days of intravenously administered therapy) in hospitalised adult patients with COVID-19 with evidence of lower respiratory tract involvement. The trial enrolled 1,062 hospitalised patients: 159 (15%) patients with mild/moderate disease (15% in both treatment groups) and 903 (85%) patients with severe disease (85% in both treatment groups).
Mild/moderate disease was defined as SpO2 > 94% and respiratory rate < 24 breaths/minute without supplemental oxygen; severe disease was defined as SpO2 ≤ 94% on room air, a respiratory rate ≥ 24 breaths/min, and an oxygen requirement, or a requirement for mechanical ventilation. A total of 285 patients (26.8%) (n=131 received remdesivir) were on mechanical ventilation/Extracorporeal Membrane Oxygenation (ECMO). Patients were randomised 1:1, stratified by disease severity at enrolment, to receive remdesivir (n=541) or placebo (n=521), plus standard of care.

The baseline mean age was 59 years and 36% of patients were aged 65 or older. Sixty-four percent were male, 53% were White, 21% were Black, 13% were Asian. The most common comorbidities were hypertension (51%), obesity (45%) and type 2 diabetes mellitus (31%); the distribution of comorbidities was similar between the two treatment groups.

Approximately 38.4% (208/541) of the patients received a 10-day treatment course with remdesivir.

The primary clinical endpoint was time to recovery within 29 days after randomisation, defined as either discharged from hospital (with or without limitations of activity and with or without home oxygen requirements) or hospitalised but not requiring supplemental oxygen and no longer requiring ongoing medical care. The median time to recovery was 10 days in the remdesivir group compared to 15 days in the placebo group (recovery rate ratio 1.29; [95% CI 1.12 to 1.49], p < 0.001).

No difference in time to recovery was seen in the stratum of patients with mild-moderate disease at enrolment (n=159). The median time to recovery was 5 days in the remdesivir and 7 days in the placebo groups (recovery rate ratio 1.10; [95% CI 0.8 to 1.53]); the odds of improvement in the ordinal scale in the remdesivir 

group at Day 15 when compared to the placebo group were as follows: odds ratio, 1.2; [95% CI 0.7 to 2.2, p = 0.562].

Among patients with severe disease at enrolment (n=903), the median time to recovery was 12 days in the remdesivir group compared to 19 days in the placebo group (recovery rate ratio, 1.34; [95% CI 1.14 to 1.58]; p < 0.001); the odds of improvement in the ordinal scale in the remdesivir group at Day 15 when compared to the placebo group were as follows: odds ratio, 1.6; [95% CI 1.3 to 2.0].

Overall, the odds of improvement in the ordinal scale were higher in the remdesivir group at Day 15 when compared to the placebo group (odds ratio, 1.6; [95% CI 1.3 to 1.9], p < 0.001).

The 29-day mortality in the overall population was 11.6% for the remdesivir group vs 15.4% for the placebo group (hazard ratio, 0.73; [95% CI 0.52 to 1.03]; p=0.07). A post-hoc analysis of 29-day mortality by ordinal scale is reported in Table 7.

Table 7:        29-Day mortality outcomes by ordinal scalea at baseline—NIAID ACTT-1 trial Ordinal Score at Baseline
5                                           6
Requiring low-flow oxygen             Requiring high-flow oxygen or non- invasive mechanical ventilation
Remdesivir             Placebo            Remdesivir               Placebo (N=232)               (N=203)               (N=95)                (N=98) 29-day mortality                        4.1                   12.8                 21.8                   20.6
Hazard ratiob (95% CI)                      0.30 (0.14, 0.64)                           1.02 (0.54, 1.91) a    Not a pre-specified analysis.
b    Hazard ratios for baseline ordinal score subgroups are from unstratified Cox proportional hazards models.

Study GS-US-540-5773 in Patients with Severe COVID-19
A randomised, open-label multi-centre clinical trial (Study 5773) of patients at least 12 years of age with confirmed SARS-CoV-2 infection, oxygen saturation of ≤ 94% on room air, and radiological evidence of pneumonia compared 200 patients who received remdesivir for 5 days with 197 patients who received remdesivir for 10 days. All patients received 200 mg of remdesivir on Day 1 and 100 mg once daily on subsequent days, plus standard of care. The primary endpoint was clinical status on Day 14 assessed on a 7- point ordinal scale ranging from hospital discharge to increasing levels of oxygen and ventilatory support to death.

The odds of improvement at Day 14 for patients randomized to a 10-day course of remdesivir compared with those randomized to a 5-day course was 0.67 (odds ratio); [95% CI 0.46 to 0.98]. Statistically significant imbalances in baseline clinical status were observed in this study. After adjusting for between-group differences at baseline, the odds of improvement at Day 14 was 0.75 (odds ratio); [95% CI 0.51 to 1.12]. In addition, there were no statistically significant differences in recovery rates or mortality rates in the 5-day and 10-day groups once adjusted for between group differences at baseline. All-cause 28-day mortality was 12% vs 14% in the 5- and 10-day treatment groups, respectively.

Study GS-US-540-9012 in patients with confirmed COVID-19 at increased risk for disease progression A randomised, double-blind, placebo-controlled, multi-centre clinical trial to evaluate treatment with remdesivir in an outpatient setting in 562 patients with confirmed COVID-19 and at least one risk factor for disease progression to hospitalisation. Risk factors for disease progression were: aged ≥ 60 years, chronic lung disease, hypertension, cardiovascular or cerebrovascular disease, diabetes mellitus, obesity, immunocompromised state, chronic mild or moderate kidney disease, chronic liver disease, current cancer, or sickle cell disease. Vaccinated patients were excluded from the study.

Patients treated with remdesivir received 200 mg on Day 1 and 100 mg once daily on subsequent days for a total of 3 days of intravenously administered therapy. Patients were randomized in a 1:1 manner, stratified by residence in a skilled nursing facility (yes/no), age (< 60 vs ≥ 60 years), and region (US vs ex-US) to receive remdesivir (n=279) or placebo (n=283), plus standard of care.


At baseline, mean age was 50 years (with 30% of patients aged 60 or older); 52% were male, 80% were White, 8% were Black, 2% were Asian, 44% were Hispanic or Latino; median body mass index was 30.7 kg/m2. The most common comorbidities were diabetes mellitus (62%), obesity (56%), and hypertension (48%). Median (Q1, Q3) duration of symptoms prior to treatment was 5 (3,6) days; median viral load was 6.3 log10 copies/mL at baseline. The baseline demographics and disease characteristics were balanced across the remdesivir and placebo treatment groups. Post-hoc exploratory analysis of optional biomarker samples showed 14.8% of patients were serological positive at baseline and 37.7% were serological negative (47.5% did not consent to optional biomarker collection).

The primary endpoint was the proportion of patients with COVID-19 related hospitalisation (defined as at least 24 hours of acute care) or all-cause 28-day mortality. Events (COVID-19-related hospitalisation or all- cause 28-day mortality) occurred in 2 (0.7%) patients treated with remdesivir compared to 15 (5.3%) patients concurrently randomized to placebo, demonstrating an 87% reduction in COVID-19-related hospitalisation or all-cause mortality compared to placebo (hazard ratio, 0.134 [95% CI, 0.031 to 0.586]; p=0.0076). The absolute risk reduction was 4.6% (95% CI, 1.8% to 7.5%). No deaths were observed at Day 28. Six of the 17 hospitalisation events occurred in participants with known baseline serostatus (serological positive: n=0 in remdesivir group and n=2 in placebo group; serological negative: n=2 in remdesivir group and n=2 in placebo group). Eleven of the 17 hospitalisation events occurred in participants with unknown baseline serostatus in placebo group and none in the remdesivir group. No conclusion can be made on efficacy in the subgroups stratified by serostatus due to the small number of patients with known serostatus and overall low event rates.

QT

Current non-clinical and clinical data do not suggest a risk of QT prolongation, but QT prolongation has not been fully evaluated in humans.

Paediatric population

Study GS-US-540-5823 is a single-arm, open-label study where the pharmacokinetics and safety of remdesivir in paediatric patients at least 28 days of age and weighing at least 3 kg with COVID-19 (n=53) was assessed. Efficacy endpoints were secondary and descriptively analysed and therefore these should be interpreted with caution. The study is ongoing.

Patients weighing ≥ 40 kg received 200 mg of remdesivir on Day 1 followed by remdesivir 100 mg once daily on subsequent days (i.e., the adult dose); patients weighing ≥ 3 kg to < 40 kg received remdesivir 5 mg/kg on Day 1 followed by remdesivir 2.5 mg/kg once daily on subsequent days. Median (range) exposure to remdesivir was 5 (1, 10) days.

At baseline, median age was 7 years (range: 0.1 to 17 years); 57% were female; median weight was 24.6 kg (range: 4 kg to 192 kg). A total of 19 patients (37%) were obese (BMI-for-age ≥ 95th percentile); 7 (58%), 2 (17%), 3 (27%), 3 (27%), and 4 (80%) patients in Cohorts 1, 2, 3, 4 and 8 respectively. A total of 12 patients (23%) were on invasive mechanical ventilation (score of 2 in a 7-point ordinal scale), 18 (34%) were on non- invasive ventilation or high-flow oxygen (score of 3); 10 (19%) were on low-flow oxygen (score of 4); and 13 (25%) were on room air (score of 5), at baseline. The overall median (Q1, Q3) duration of symptoms and hospitalisation prior to first dose of remdesivir was 5 (3, 7) days and 1 (1, 3) day, respectively.

In the overall population of the study, the median (Q1, Q3) change from baseline in clinical status (assessed on a 7-point ordinal scale ranging from death [score of 1] to hospital discharge [score of 7]) was +2.0 (1.0, 4.0) points on Day 10. Among those with an ordinal score of ≤ 5 points at baseline, the proportion who had a
≥ 2-point improvement in clinical status on Day 10 was 75.0% (39/52); median (Q1, Q3) time to recovery was 7 (5, 16) days. Overall, 60% of patients were discharged by Day 10. Most patients 92% (49/53) received at least 1 concomitant medication other than remdesivir for the treatment of COVID-19 including immune modulator and anti-inflammatory agents. Three patients died during the study.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties
The pharmacokinetic properties of remdesivir have been investigated in healthy volunteers and patients with COVID-19.

Absorption

The pharmacokinetic properties of remdesivir and the predominant circulating metabolite GS-441524 have been evaluated in healthy adult subjects. Following intravenous administration of remdesivir adult dosage regimen, peak plasma concentration was observed at end of infusion, regardless of dose level, and declined rapidly thereafter with a half-life of approximately 1 hour. Peak plasma concentrations of GS-441524 were observed at 1.5 to 2.0 hours post start of a 30 minutes infusion.

Distribution

Remdesivir is approximately 93% bound to human plasma proteins (ex-vivo data) with free fraction ranging from 6.4% to 7.4%. The binding is independent of drug concentration over the range of 1 to 10 μM, with no evidence for saturation of remdesivir binding. After a single 150 mg dose of [14C]-remdesivir in healthy subjects, the blood to plasma ratio of [14C]-radioactivity was approximately 0.68 at 15 minutes from start of infusion, increased over time reaching ratio of 1.0 at 5 hours, indicating differential distribution of remdesivir and its metabolites to plasma or cellular components of blood.

Biotransformation

Remdesivir is extensively metabolized to the pharmacologically active nucleoside analog triphosphate GS-443902 (formed intracellularly). The metabolic activation pathway involves hydrolysis by esterases, which leads to the formation of the intermediate metabolite, GS-704277. In the liver, carboxylesterase 1 and cathepsin A are the esterases responsible for 80% and 10% of remdesivir metabolism, respectively.
Phosphoramidate cleavage followed by phosphorylation forms the active triphosphate, GS-443902.
Dephosphorylation of all phosphorylated metabolites can result in the formation of nucleoside metabolite GS-441524 that itself is not efficiently re-phosphorylated. Decyanation of remdesivir and/or its metabolites, followed by subsequent rhodanese mediated conversion generates thiocyanate anion. The levels of thiocyanate detected following administration of 100 mg and 200 mg remdesivir were observed to be significantly below endogenous levels in human plasma.

Elimination

Following a single 150 mg IV dose of [14C]-remdesivir, mean total recovery of the dose was 92%, consisting of approximately 74% and 18% recovered in urine and feces, respectively. The majority of the remdesivir dose recovered in urine was GS-441524 (49%), while 10% was recovered as remdesivir. These data indicate that renal clearance is the major elimination pathway for GS-441524. The median terminal half-lives of remdesivir and GS-441524 were approximately 1 and 27 hours, respectively.

Pharmacokinetics of remdesivir and metabolites in adults with COVID-19 
Pharmacokinetic exposures for remdesivir and its metabolites in adults with COVID-19 are provided in Table 8.


Table 8:         Multiple dose PK parametersa of remdesivir and metabolites (GS-441524 and GS-704277) following IV administration of remdesivir 100 mg to adults with COVID-19 Parameters
Remdesivir                     GS-441524                          GS-704277 Meanb (95%CI)
Cmax
2700 (2440, 2990)              143 (135, 152)                   198 (180, 218) (ng/mL)
AUCtau
1710 (1480, 1980)            2410 (2250, 2580)                  392 (348, 442) (ng•h/mL)
Ctau(ng/mL)                               ND                       61.5 (56.5, 66.8)                       ND CI=Confidence Interval; ND=Not detectable (at 24 hours post-dose) a. Population PK estimates for 30-minute IV infusion of remdesivir for 3 days (Study GS-US-540-9012, n=147).
b. Geometric mean estimates

Other special populations

Gender, race and age
Based on gender, race and age, pharmacokinetic differences on the exposures of remdesivir were evaluated using population pharmacokinetic analysis. Gender and race did not affect the pharmacokinetics of remdesivir and its metabolites (GS-704277 and GS-441524). Pharmacokinetic exposures of the GS-441524 metabolite were modestly increased in hospitalised COVID-19 patients ≥ 60 years of age, however no dose adjustment is needed in these patients.
Pregnancy
In CO-US-540-5961 (IMPAACT 2032) study, mean exposures (AUCtau, Cmax, and Ctau) of remdesivir and its metabolites (GS-441524 and GS-704277) were comparable between pregnant and non-pregnant women of child-bearing potential.

Paediatric patients
Population pharmacokinetic models for remdesivir and its circulating metabolites (GS-704277 and GS- 441524), developed using pooled data from studies in healthy subjects and in adult and paediatric patients with COVID-19, were used to predict pharmacokinetic exposures in 50 paediatric patients aged ≥ 28 days to < 18 years and weighing ≥ 3 kg (Study GS-US-540-5823) (Table 9). Geometric mean exposures (AUCtau, Cmax and Ctau) for these patients at the doses administered were higher for remdesivir (44% to 147%), GS-441524 (- 21% to 25%), and GS-704277 (7% to 91%) as compared to those in adult hospitalised patients with COVID-
19. The increases were not considered clinically significant.

Table 9:         Pharmacokinetic parametersa estimate of steady-state plasma remdesivir, GS-441524 and GS-704277 in paediatric and adult hospitalised COVID-19 patients
Parameters                                         Paediatric patients                                        Adult Meanb                     Cohort 1        Cohort 8     Cohort 2        Cohort 3            Cohort 4        hospitalised 12 to <18       <12 Years   28 Days to     28 Days to           28 Days to         patients Years and          and       <18 Years      <18 Years           <18 Years         (N=277) Weighing        Weighing        and            and                 and ≥40 kg          ≥40 kg      Weighing       Weighing            Weighing 3 (N=12)           (N=5)        20 to           12 to            to <12 kg <40 kg          <20 kg              (N=10)
(N=12)          (N=11)
Remdesivir
Cmax (ng/mL)                  3910           3920            5680             5530           4900             2650 AUCtau (h•ng/mL)              2470           2280            3500             3910           2930             1590 GS-441524
Cmax (ng/mL)                 197             162             181              158            202              170 AUCtau (h•ng/mL)             3460            2640            2870             2400           2770             3060 Ctau (ng/mL)                 98.3            76.2            73.8             69.4           78.4             78.4 GS-704277
Cmax (ng/mL)                  307             278             423              444            390              233 AUCtau (h•ng/mL)              815             537             754              734            691              501 a    PK parameters were simulated using PopPK modeling with 0.5 hour of duration for remdesivir infusions.
b    Geometric mean estimates.


Paediatric hospitalised patients are from Study GS-US-540-5823; patients received 200 mg on Day 1 followed by remdesivir 100 mg once daily on subsequent days (Cohort 1 and 8), or 5 mg/kg on Day 1 followed by remdesivir 2.5 mg/kg once daily on subsequent days (Cohort 2-4) for a total treatment duration of up to 10 days.
Adult hospitalised patients are from Study CO-US-540-5844 (a phase 3 randomised study to evaluate the safety and antiviral activity of remdesivir in patients with severe COVID-19); patients received 200 mg on Day 1 followed by remdesivir 100 mg once daily on subsequent days (10 days total treatment duration).

Renal impairment
The pharmacokinetics of remdesivir and GS-441524 in renal impairment have not been evaluated. Remdesivir is not cleared unchanged in urine to any substantial extent, but its main metabolite GS-441524 is renally cleared and the metabolite levels in plasma may theoretically increase in patients with impaired renal function.
The excipient betadex sulfobutyl ether sodium is renally cleared and accumulates in patients with decreased renal function. Veklury should not be used in patients with eGFR < 30 mL/min.

Hepatic impairment
The pharmacokinetics of remdesivir and GS-441524 in hepatic impairment have not been evaluated. The role of the liver in the metabolism of remdesivir is unknown.

Hospitalisation
Pharmacokinetic exposures for remdesivir in hospitalised patients with severe COVID-19 pneumonia were generally within the range of the exposures in non-hospitalised patients. The GS-704277 and GS-441524 metabolite levels were modestly increased.
Interactions
Remdesivir inhibited CYP3A4 in vitro (see section 4.5). At physiologically relevant concentrations (steady- state), remdesivir or its metabolites GS-441524 and GS-704277 did not inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, and 2D6 in vitro. Remdesivir is not a time-dependent inhibitor of CYP450 enzymes in vitro.

Remdesivir induced CYP1A2 and potentially CYP3A4, but not CYP2B6 in vitro (see section 4.5).

In vitro data indicates no clinically relevant inhibition of UGT1A3, 1A4, 1A6, 1A9 or 2B7 by remdesivir or its metabolites GS-441524 and GS-704277. Remdesivir, but not its metabolites, inhibited UGT1A1 in vitro.

For GS-441524 and GS-704277, the only enzyme for which metabolism could be detected was UGT1A3.

Remdesivir inhibited OAT3, MATE1, OCT1, OATP1B1 and OATP1B3 in vitro (see section 4.5).
At physiologically relevant concentrations, remdesivir and its metabolites did not inhibit P-gp and BCRP in vitro.