Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: ViiV Healthcare BV, Huis ter Heideweg 62, 3705 LZ Zeist, Netherlands
Pharmacotherapeutic group: Antivirals for systemic use, other antivirals
ATC code: J05AX09
Maraviroc is a member of a therapeutic class called CCR5 antagonists. Maraviroc selectively binds to the human chemokine receptor CCR5, preventing CCR5-tropic HIV-1 from entering cells.
Maraviroc has no antiviral activity in vitro against viruses which can use CXCR4 as their entry coreceptor (dual-tropic or CXCR4-tropic viruses, collectively termed ‘CXCR4-using’ virus below). The serum adjusted EC90 value in 43 primary HIV-1 clinical isolates was 0.57 (0.06-10.7) ng/mL without significant changes between different subtypes tested. The antiviral activity of maraviroc against HIV-2 has not been evaluated. For details please refer to the pharmacology section of the CELSENTRI European Public Assessment Report (EPAR) on the European Medicines Agency (EMA) website.
When used with other antiretroviral medicinal products in cell culture, the combination of maraviroc was not antagonistic with a range of NRTIs, NNRTIs, PIs or the HIV fusion inhibitor enfuvirtide.
Virologic escape from maraviroc can occur via 2 routes: the emergence of pre-existing virus which can use CXCR4 as its entry co-receptor (CXCR4-using virus) or the selection of virus that continues to use exclusively drug-bound CCR5 (CCR5-tropic virus).
HIV-1 variants with reduced susceptibility to maraviroc have been selected in vitro, following serial passage of two CCR5-tropic viruses (0 laboratory strains, 2 clinical isolates). The maravirocresistant viruses remained CCR5-tropic and there was no conversion from a CCR5-tropic virus to a CXCR4-using virus.
Concentration response curves for the maraviroc-resistant viruses were characterized phenotypically by curves that did not reach 100% inhibition in assays using serial dilutions of maraviroc (<100% maximal percentage inhibition (MPI)). Traditional IC50/IC90 fold-change was not a useful parameter to measure phenotypic resistance, as those values were sometimes unchanged despite significantly reduced sensitivity.
Mutations were found to accumulate in the gp120 envelope glycoprotein (the viral protein that binds to the CCR5 co-receptor). The position of these mutations was not consistent between different isolates. Hence, the relevance of these mutations to maraviroc susceptibility in other viruses is not known.
HIV-1 clinical isolates resistant to NRTIs, NNRTIs, PIs and enfuvirtide were all susceptible to maraviroc in cell culture. Maraviroc-resistant viruses that emerged in vitro remained sensitive to the fusion inhibitor enfuvirtide and the PI, saquinavir.
In the pivotal studies (MOTIVATE 1 and MOTIVATE 2), 7.6% of patients had a change in tropism result from CCR5-tropic to CXCR4-tropic or dual/mixed-tropic between screening and baseline (a period of 4-6 weeks).
CXCR4-using virus was detected at failure in approximately 60% of subjects who failed treatment on maraviroc, as compared to 6% of subjects who experienced treatment failure in the placebo + OBT arm. To investigate the likely origin of the on-treatment CXCR4-using virus, a detailed clonal analysis was conducted on virus from 20 representative subjects (16 subjects from the maraviroc arms and 4 subjects from the placebo + OBT arm) in whom CXCR4-using virus was detected at treatment failure. This analysis indicated that CXCR4-using virus emerged from a pre-existing CXCR4-using reservoir not detected at baseline, rather than from mutation of CCR5-tropic virus present at baseline. An analysis of tropism following failure of maraviroc therapy with CXCR4- using virus in patients with CCR5 virus at baseline, demonstrated that the virus population reverted back to CCR5 tropism in 33 of 36 patients with more than 35 days of follow-up.
At the time of failure with CXCR4-using virus, the resistance pattern to other antiretrovirals appears similar to that of the CCR5-tropic population at baseline, based on available data. Hence, in the selection of a treatment regimen, it should be assumed that viruses forming part of the previously undetected CXCR4 -using population (i.e. minor viral population) harbours the same resistance pattern as the CCR5-tropic population.
In patients with CCR5-tropic virus at time of treatment failure with maraviroc, 22 out of 58 patients had virus with reduced sensitivity to maraviroc. In the remaining 36 patients, there was no evidence of virus with reduced sensitivity as identified by exploratory virology analyses on a representative group. The latter group had markers correlating to low compliance (low and variable drug levels and often a calculated high residual sensitivity score of the OBT). In patients failing therapy with CCR5-tropic virus only, maraviroc might be considered still active if the MPI value is ≥95% (PhenoSense Entry assay). Residual activity in vivo for viruses with MPI-values <95% has not been determined.
A relatively small number of individuals receiving maraviroc-containing therapy have failed with phenotypic resistance (i.e. the ability to use drug-bound CCR5 with MPI <95%). To date, no signature mutation(s) have been identified. The gp120 amino acid substitutions identified so far are context dependent and inherently unpredictable with regards to maraviroc susceptibility.
In the Week 48 analysis (N=103), non-CCR5 tropic-virus was detected in 5/23 (22%) subjects at virologic failure. One additional subject had CCR5 tropic-virus with reduced susceptibility to maraviroc at virologic failure, although this was not retained at the end of treatment. Subjects with virologic failure generally appeared to have low compliance to both maraviroc and the background antiretroviral elements of their regimens. Overall, the mechanisms of resistance to maraviroc observed in this treatment-experienced paediatric population were similar to those observed in adult populations.
The clinical efficacy of maraviroc (in combination with other antiretroviral medicinal products) on plasma HIV RNA levels and CD4+ cell counts have been investigated in two pivotal randomized, double blind, multicentre studies (MOTIVATE 1 and MOTIVATE 2, n=1076) in patients infected with CCR5 tropic HIV-1 as determined by the Monogram Trofile Assay.
Patients who were eligible for these studies had prior exposure to at least 3 antiretroviral medicinal product classes [≥1 NRTIs, ≥1 NNRTIs, ≥2 PIs, and/or enfurvirtide] or documented resistance to at least one member of each class. Patients were randomised in a 2:2:1 ratio to maraviroc 300 mg (dose equivalence) once daily, twice daily or placebo in combination with an optimized background consisting of 3 to 6 antiretroviral medicinal products (excluding low-dose ritonavir). The OBT was selected on the basis of the subject’s prior treatment history and baseline genotypic and phenotypic viral resistance measurements.
Table 5. Demographic and baseline characteristics of patients (pooled studies MOTIVATE 1 and MOTIVATE 2):
Limited numbers of patients from ethnicities other than Caucasian were included in the pivotal clinical studies, therefore very limited data are available in these patient populations.
The mean increase in CD4+ cell count from baseline in patients who failed with a change in tropism result to dual/mixed tropic or CXCR4, in the maraviroc 300 mg twice daily + OBT (+56 cells/mm3) group was greater than that seen in patients failing placebo + OBT (+13.8 cells/mm3) regardless of tropism.
Table 6. Efficacy Outcomes at week 48 (pooled studies MOTIVATE 1 and MOTIVATE 2):
In a retrospective analysis of the MOTIVATE studies with a more sensitive assay for screening of tropism (Trofile ES), the response rates (<50 copies/mL at week 48) in patients with only CCR5-tropic virus detected at baseline was 48.2% in those treated with maraviroc + OBT (n=328), and 16.3% in those treated with placebo + OBT (n=178).
Maraviroc 300 mg twice daily + OBT was superior to placebo + OBT across all subgroups of patients analysed (see Table 7). Patients with very low CD4+ count at baseline (i.e. <50 cells/µL) had a less favourable outcome. This subgroup had a high degree of bad prognostic markers, i.e. extensive resistance and high baseline viral loads. However, a significant treatment benefit for maraviroc compared to placebo + OBT was still demonstrated (see Table 7).
Table 7. Proportion of patients achieving <50 copies/mL at Week 48 by subgroup (pooled Studies MOTIVATE 1 and MOTIVATE 2):
Study A4001029 was an exploratory study in patients infected with dual/mixed or CXCR4 tropic HIV-1 with a similar design as the studies MOTIVATE 1 and MOTIVATE 2. Use of maraviroc was not associated with a significant decrease in HIV 1 RNA compared with placebo in these subjects and no adverse effect on CD4+ cell count was noted.
A randomised, double-blinded study (MERIT), explored maraviroc versus efavirenz, both in combination with zidovudine/lamivudine (n=721, 1:1). After 48 weeks of treatment, maraviroc did not reach non-inferiority to efavirenz for the endpoint of HIV-1 RNA <50 copies/mL (65.3 vs. 69.3 % respectively, lower confidence bound -11.9%). More patients treated with maraviroc discontinued due to lack of efficacy (43 vs.15) and among patients with lack of efficacy, the proportion acquiring NRTI resistance (mainly lamivudine) was higher in the maraviroc arm. Fewer patients discontinued maraviroc due to adverse events (15 vs. 49).
The hepatic safety of maraviroc in combination with other antiretroviral agents in CCR5-tropic HIV-1-infected subjects with HIV RNA <50 copies/mL, co-infected with Hepatitis C and/or Hepatitis B Virus was evaluated in a multicentre, randomized, double blinded, placebo-controlled study. 70 subjects (Child-Pugh Class A, n=64; Child-Pugh Class B, n=6) were randomized to the maraviroc group and 67 subjects (Child-Pugh Class A, n=59; Child-Pugh Class B, n=8) were randomized to the placebo group.
The primary objective assessed the incidence of Grade 3 and 4 ALT abnormalities (>5x upper limit of normal (ULN) if baseline ALT ≤ULN; or >3.5x baseline if baseline ALT >ULN) at Week 48. One subject in each treatment arm met the primary endpoint by Week 48 (at Week 8 for placebo and Week 36 for the maraviroc arm).
Study A4001031 is an open-label, multicenter trial in paediatric patients (aged 2 years to less than 18 years) infected with CCR5-tropic HIV-1, determined by the enhanced-sensitivity Trofile assay. Subjects were required to have HIV-1 RNA greater than 1,000 copies per mL at Screening.
All subjects (n=103) received maraviroc twice daily and OBT. Maraviroc dosing was based on body surface area and doses were adjusted based on whether the subject was receiving potent CYP3A inhibitors and/or inducers.
In paediatric patients with a successful tropism test, dual mixed/CXCR4-tropic virus was detected in around 40% of screening samples (8/27, 30% in 2-6 year-olds, 31/81, 38% in 6-12 year-olds and 41/90, 46% in 12-18 year-olds), underscoring the importance of tropism testing also in the paediatric population.
The population was 52% female and 69% black, with mean age of 10 years (range: 2 years to 17 years). At baseline, mean plasma HIV-1 RNA was 4.3 log10 copies/mL (range 2.4 to 6.2 log10 copies per mL), mean CD4+ cell count was 551 cells/mm³ (range 1 to 1654 cells/mm³ ) and mean CD4+ % was 21% (range 0% to 42%).
At 48 weeks, using a missing, switch or discontinuation equals failure analysis, 48% of subjects treated with maraviroc and OBT achieved plasma HIV-1 RNA less than 48 copies/mL and 65% of subjects achieved plasma HIV-1 RNA less than 400 copies per mL. The mean CD4+ cell count (percent) increase from baseline to Week 48 was 247 cells/mm³ (5%).
The absorption of maraviroc is variable with multiple peaks. Median peak maraviroc plasma concentrations are attained at 2 hours (range 0.5-4 hours) following single oral doses of 300 mg commercial tablet administered to healthy volunteers. The pharmacokinetics of oral maraviroc are not dose proportional over the dose range. The absolute bioavailability of a 100 mg dose is 23% and is predicted to be 33% at 300 mg. Maraviroc is a substrate for the efflux transporter Pglycoprotein.
Co-administration of a 300 mg tablet with a high fat breakfast reduced maraviroc Cmax and AUC by 33% and co-administration of 75 mg of oral solution with a high fat breakfast reduced maraviroc AUC by 73% in adult healthy volunteers. Studies with the tablets demonstrated a reduced foodeffect at higher doses.
There were no food restrictions in the adult studies (using tablet formulations) or in the paediatric study (using both tablet and oral solution formulations). The results did not indicate any relevant efficacy or safety concern related to either fed or fasted dosing conditions. Therefore, maraviroc tablets and oral solution can be taken with or without food at the recommended doses in adults, adolescents and children aged 2 years and older and weighing at least 10 kg (see section 4.2).
Maraviroc is bound (approximately 76%) to human plasma proteins, and shows moderate affinity for albumin and alpha-1 acid glycoprotein. The volume of distribution of maraviroc is approximately 194 L.
Studies in humans and in vitro studies using human liver microsomes and expressed enzymes have demonstrated that maraviroc is principally metabolized by the cytochrome P450 system to metabolites that are essentially inactive against HIV-1. In vitro studies indicate that CYP3A4 is the major enzyme responsible for maraviroc metabolism. In vitro studies also indicate that polymorphic enzymes CYP2C9, CYP2D6 and CYP2C19 do not contribute significantly to the metabolism of maraviroc.
Maraviroc is the major circulating component (approximately 42% radioactivity) following a single oral dose of 300 mg. The most significant circulating metabolite in humans is a secondary amine (approximately 22% radioactivity) formed by N-dealkylation. This polar metabolite has no significant pharmacological activity. Other metabolites are products of mono-oxidation and are only minor components of plasma radioactivity.
A mass balance/excretion study was conducted using a single 300 mg dose of 14C-labeled maraviroc. Approximately 20% of the radiolabel was recovered in the urine and 76% was recovered in the faeces over 168 hours. Maraviroc was the major component present in urine (mean of 8% dose) and faeces (mean of 25% dose). The remainder was excreted as metabolites. After intravenous administration (30 mg), the half-life of maraviroc was 13.2 h, 22% of the dose was excreted unchanged in the urine and the values of total clearance and renal clearance were 44.0 L/h and 10.17 L/h respectively.
Intensive pharmacokinetics of maraviroc were evaluated in 50 treatment-experienced, CCR5- tropic, HIV-1 infected paediatric patients aged 2 to 18 years (weight 10.0 to 57.6 kg) in the dosefinding stage of clinical trial A4001031. Doses were given with food on intensive pharmacokinetic evaluation days and optimised to achieve an average concentration over the dosing interval (Cavg) of greater than 100 ng/mL; otherwise, maraviroc was given with or without food. The initial dose of maraviroc was scaled from adult doses using a body surface area (BSA) of 1.73 m² to children and adolescent BSA (m² )-based bands. In addition, dosing was based on whether subjects were receiving potent CYP3A inhibitors (38/50), potent CYP3A inducers (2/50) or other concomitant medicinal products that are not potent CYP3A inhibitors or potent CYP3A inducers (10/50) as part of OBT. Sparse pharmacokinetics were evaluated in all subjects including the additional 47 subjects receiving potent CYP3A inhibitors that did not take part in the dose-finding stage. The impact of potent CYP3A inhibitors and/or inducers on maraviroc pharmacokinetic parameters in paediatric patients was similar to that observed in adults.
BSA (m²)-based bands have been modified to weight (kg)-based bands to simplify dosing and reduce dosing errors (see section 4.2). Use of weight (kg)-based doses in treatment-experienced HIV-1-infected children and adolescents results in maraviroc exposures similar to those observed in treatment-experienced adults receiving recommended doses with concomitant medications. The pharmacokinetics of maraviroc in paediatric patients below 2 years of age have not been established (see section 4.2).
Population analysis of the Phase 1/2a and Phase 3 studies (16-65 years of age) has been conducted and no effect of age have been observed (see section 4.2).
A study compared the pharmacokinetics of a single 300 mg dose of maraviroc in subjects with severe renal impairment (CLcr < 30 mL/min, n=6) and end stage renal disease (ESRD) to healthy volunteers (n=6). The geometric mean AUCinf (CV%) for maraviroc was as follows: healthy volunteers (normal renal function) 1348.4 ng·h/mL (61%); severe renal impairment 4367.7 ng·h/mL (52%); ESRD (dosing after dialysis) 2677.4 ng·h/mL (40%); and ESRD (dosing before dialysis) 2805.5 ng·h/mL (45%). The C max (CV%) was 335.6 ng/mL (87%) in healthy volunteers (normal renal function); 801.2 ng/mL (56%) in severe renal impairment; 576.7 ng/mL (51%) in ESRD (dosing after dialysis) and 478.5 ng/mL (38%) in ESRD (dosing before dialysis). Dialysis had a minimal effect on exposure in subjects with ESRD. Exposures observed in subjects with severe renal impairment and ESRD were within the range observed in single maraviroc 300 mg dose studies in healthy volunteers with normal renal function. Therefore, no dose adjustment is necessary in patients with renal impairment receiving maraviroc without a potent CYP3A4 inhibitor (see sections 4.2, 4.4 and 4.5).
In addition, the study compared the pharmacokinetics of multiple dose maraviroc in combination with saquinavir/ritonavir 1000/100 mg BID (a potent CYP3A4 inhibitor) for 7 days in subjects with mild renal impairment (CLcr >50 and ≤80 mL/min, n=6) and moderate renal impairment (CLcr ≥30 and ≤50 mL/min, n=6) to healthy volunteers (n=6). Subjects received 150 mg of maraviroc at different dose frequencies (healthy volunteers – every 12 hours; mild renal impairment – every 24 hours; moderate renal impairment – every 48 hours). The average concentration (Cavg) of maraviroc over 24 hours was 445.1 ng/mL, 338.3 ng/mL, and 223.7 ng/mL for subjects with normal renal function, mild renal impairment, and moderate renal impairment, respectively. The Cavg of maraviroc from 24-48 hours for subjects with moderate renal impairment was low (Cavg: 32.8 ng/mL). Therefore, dosing frequencies of longer than 24 hours in subjects with renal impairment may result in inadequate exposures between 24-48 hours.
Dose adjustment is necessary in patients with renal impairment receiving maraviroc with potent CYP3A4 inhibitors (see sections 4.2 and 4.4 and 4.5).
Maraviroc is primarily metabolized and eliminated by the liver. A study compared the pharmacokinetics of a single 300 mg dose of maraviroc in patients with mild (Child-Pugh Class A, n=8), and moderate (Child-Pugh Class B, n=8) hepatic impairment compared to healthy subjects (n=8). Geometric mean ratios for Cmax and AUClast were 11% and 25% higher respectively for subjects with mild hepatic impairment, and 32% and 46% higher respectively for subjects with moderate hepatic impairment compared to subjects with normal hepatic function. The effects of moderate hepatic impairment may be underestimated due to limited data in patients with decreased metabolic capacity and higher renal clearance in these subjects. The results should therefore be interpreted with caution. The pharmacokinetics of maraviroc has not been studied in subjects with severe hepatic impairment (see sections 4.2 and 4.4).
No relevant difference between Caucasian, Asian and Black subjects has been observed. The pharmacokinetics in other races has not been evaluated.
No relevant differences in pharmacokinetics have been observed.
The pharmacokinetics of maraviroc is dependent on CYP3A5 activity and expression level, which can be modulated by genetic variation. Subjects with a functional CYP3A5 (CYP3A5*1 allele) have been shown to have a reduced exposure to maraviroc compared to subjects with defect CYP3A5 activity (e.g., CYP3A5*3, CYP3A5*6, and CYP3A5*7). The CYP3A5 allelic frequency depends on ethnicity: the majority of Caucasians (~90%) are poor metabolisers of CYP3A5 substrates (i.e., subjects with no copy of functional CYP3A5 alleles) while approximately 40% of African-Americans and 70% of Sub-Saharan Africans are extensive metabolisers (i.e., subjects with two copies of functional CYP3A5 alleles).
In a Phase 1 study conducted in healthy subjects, Blacks with a CYP3A5 genotype conferring extensive maraviroc metabolism (2 CYP3A5*1 alleles; n=12) had a 37% and 26% lower AUC when dosed with maraviroc 300 mg twice daily compared with Black (n=11) and Caucasian (n=12) subjects with CYP3A5 genotype conferring poor maraviroc metabolism (no CYP3A5*1 allele), respectively. The difference in maraviroc exposure between CYP3A5 extensive and poor metabolisers was reduced when maraviroc was administered together with a strong CYP3A inhibitor: extensive CYP3A5 metabolisers (n=12) had a 17% lower maraviroc AUC compared with poor CYP3A5 metabolisers (n=11) when dosed with maraviroc 150 mg once daily in the presence of darunavir/cobicistat (800/150 mg).
All subjects in the Phase 1 study achieved the Cavg concentrations that have been shown to be associated with near maximal virologic efficacy with maraviroc (75 ng/mL) in the Phase 3 study in treatment-naïve adult patients (MERIT). Therefore, despite differences in CYP3A5 genotype prevalence by race, the effect of CYP3A5 genotype on maraviroc exposure is not considered clinically significant and no maraviroc dose adjustment according to CYP3A5 genotype, race or ethnicity is needed.
Primary pharmacological activity (CCR5 receptor affinity) was present in the monkey (100% receptor occupancy) and limited in the mouse, rat, rabbit and dog. In mice and human beings that lack CCR5 receptors through genetic deletion, no significant adverse consequences have been reported.
In vitro and in vivo studies showed that maraviroc has a potential to increase QTc interval at supratherapeutic doses with no evidence of arrhythmia.
Repeated dose toxicity studies in rats identified the liver as the primary target organ for toxicity (increases in transaminases, bile duct hyperplasia, and necrosis).
Maraviroc was evaluated for carcinogenic potential by a 6 month transgenic mouse study and a 24 month study in rats. In mice, no statistically significant increase in the incidence of tumours was reported at systemic exposures from 7 to 39-times the human exposure (unbound AUC0-24h measurement) at a dose of 300 mg twice daily. In rats, administration of maraviroc at a systemic exposure 21-times the expected human exposure produced thyroid adenomas associated with adaptive liver changes. These findings are considered of low human relevance. In addition, cholangiocarcinomas (2/60 males at 900 mg/kg) and cholangioma (1/60 females at 500 mg/kg) were reported in the rat study at a systemic exposure at least 15-times the expected free human exposure.
Maraviroc was not mutagenic or genotoxic in a battery of in vitro and in vivo assays including bacterial reverse mutation, chromosome aberrations in human lymphocytes and mouse bone marrow micronucleus.
Maraviroc did not impair mating or fertility of male or female rats, and did not affect sperm of treated male rats up to 1000 mg/kg. The exposure at this dose level corresponded to 39-fold the estimated free clinical AUC for a 300 mg twice daily dose.
Embryofoetal development studies were conducted in rats and rabbits at doses up to 39- and 34- fold the estimated free clinical AUC for a 300 mg twice daily dose. In rabbit, 7 foetuses had external anomalies at maternally toxic doses and 1 foetus at the mid dose of 75 mg/kg.
Pre- and post-natal developmental studies were performed in rats at doses up to 27-fold the estimated free clinical AUC for a 300 mg twice daily dose. A slight increase in motor activity in high-dose male rats at both weaning and as adults was noted, while no effects were seen in females. Other developmental parameters of these offspring, including fertility and reproductive performance, were not affected by the maternal administration of maraviroc.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
