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Selzentry

CLINICAL PHARMACOLOGY

Mechanism Of Action

Maraviroc is an antiviral drug [see Microbiology].

Pharmacodynamics

Exposure-Response Relationship in Treatment-Experienced Subjects

The relationship between maraviroc, modeled plasma trough concentration (Cmin) (1 to 9 samples per subject taken on up to 7 visits), and virologic response was evaluated in 973 treatment-experienced HIV-1-infected subjects with varied optimized background antiretroviral regimens in Trials A4001027 and A4001028. The Cmin, baseline viral load, baseline CD4+ cell count, and overall sensitivity score (OSS) were found to be important predictors of virologic success (defined as viral load < 400 copies/mL at 24 weeks). Table 7 illustrates the proportions of subjects with virologic success (%) within each Cmin quartile for 150-mg twice-daily and 300-mg twice-daily groups.

Table 7:Treatment-Experienced Subjects With Virologic Success by Cmin Quartile (Q1-Q4)

  150 mg Twice Daily (With CYP3A Inhibitors) 300 mg Twice Daily (Without CYP3A Inhibitors)
N Median Cmin % Subjects With Virologic Success N Median Cmin % Subjects With Virologic Success
Placebo 160 - 30.6 35 - 28.6
Q1 78 33 52.6 22 13 50
Q2 77 87 63.6 22 29 68.2
Q3 78 166 78.2 22 46 63.6
Q4 78 279 74.4 22 97 68.2

Exposure-Response Relationship in Treatment-Naive Subjects

The relationship between maraviroc, modeled plasma trough concentration (Cmin) (1 to 12 samples per subject taken on up to 8 visits), and virologic response was evaluated in 294 treatment-naive HIV-1infected subjects receiving maraviroc 300 mg twice daily in combination with zidovudine/lamivudine in Trial A4001026. Table 8 illustrates the proportion (%) of subjects with virologic success < 50 copies/mL at 48 weeks within each Cmin quartile for the 300-mg twice-daily dose.

Table 8: Treatment-Naive Subjects With Virologic Success by Cmin Quartile (Q1-Q4)

  300 mg Twice Daily
N Median Cmin % Subjects With Virologic Success
Q1 75 23 57.3
Q2 72 39 72.2
Q3 73 56 74
Q4 74 81 83.8

Eighteen of 75 (24%) subjects in Q1 had no measurable maraviroc concentration on at least one occasion versus 1 of 73 and 1 of 74 in Q3 and Q4, respectively.

Effects on Electrocardiogram

A placebo-controlled, randomized, crossover trial to evaluate the effect on the QT interval of healthy male and female volunteers was conducted with 3 single oral doses of maraviroc and moxifloxacin. The placebo-adjusted mean maximum (upper 1-sided 95% CI) increases in QTc from baseline after 100, 300, and 900 mg of maraviroc were -2 (0), -1 (1), and 1 (3) msec, respectively, and 13 (15) msec for moxifloxacin 400 mg. No subject in any group had an increase in QTc of ≥ 60 msec from baseline. No subject experienced an interval exceeding the potentially clinically relevant threshold of 500 msec.

Pharmacokinetics

Table 9: Mean Maraviroc Pharmacokinetic Parameters

Patient Population Maraviroc Dose N AUC12 (ng•h/mL) Cmax (ng/mL) Cmin (ng/mL)
Healthy volunteers (Phase 1) 300 mg twice daily 64 2,908 888 43.1
Asymptomatic HIV subjects (Phase 2a) 300 mg twice daily 8 2,550 618 33.6
Treatment-experienced 300 mg twice daily 94 1,513 266 37.2
HIV subjects (Phase 3)a 150 mg twice daily (+ CYP3A inhibitor) 375 2,463 332 101
Treatment-naive HIV subjects (Phase 2b/3)a 300 mg twice daily 344 1,865 287 60
aThe estimated exposure is lower compared with other trials possibly due to sparse sampling, food effect, compliance, and concomitant medications.

Absorption

Peak maraviroc plasma concentrations are attained 0.5 to 4 hours following single oral doses of 1 to 1,200 mg administered to uninfected 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 P-gp.

Effect of Food on Oral Absorption

Coadministration of a 300-mg tablet with a high-fat breakfast reduced maraviroc Cmax and AUC by 33% in healthy volunteers. There were no food restrictions in the trials that demonstrated the efficacy and safety of maraviroc [see Clinical Studies]. Therefore, maraviroc can be taken with or without food at the recommended dose [see DOSAGE AND ADMINISTRATION].

Distribution

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.

Metabolism

Trials 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 CYP3A 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 (~42% drug-related radioactivity) following a single oral dose of 300 mg [14C]-maraviroc. The most significant circulating metabolite in humans is a secondary amine (~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 drug-related radioactivity.

Excretion

The terminal half-life of maraviroc following oral dosing to steady state in healthy subjects was 14 to 18 hours. A mass balance/excretion trial 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 feces over 168 hours. Maraviroc was the major component present in urine (mean of 8% dose) and feces (mean of 25% dose). The remainder was excreted as metabolites.

Hepatic Impairment

Maraviroc is primarily metabolized and eliminated by the liver. A trial compared the pharmacokinetics of a single 300-mg dose of SELZENTRY in subjects with mild (Child-Pugh Class A, n = 8), and moderate (Child-Pugh Class B, n = 8) hepatic impairment with pharmacokinetics in healthy subjects (n = 8). The mean Cmax and AUC 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 with subjects with normal hepatic function. These changes do not warrant a dose adjustment. Maraviroc concentrations are higher when SELZENTRY 150 mg is administered with a potent CYP3A inhibitor compared with following administration of 300 mg without a CYP3A inhibitor, so patients with moderate hepatic impairment who receive SELZENTRY 150 mg with a potent CYP3A inhibitor should be monitored closely for maraviroc-associated adverse events. The pharmacokinetics of maraviroc have not been studied in subjects with severe hepatic impairment [see WARNINGS AND PRECAUTIONS].

Renal Impairment

A trial compared the pharmacokinetics of a single 300-mg dose of SELZENTRY in subjects with severe renal impairment (CLcr < 30 mL/min, n = 6) and ESRD (n = 6) to healthy volunteers (n = 6). Geometric mean ratios for maraviroc Cmax and AUCinf were 2.4-fold and 3.2-fold higher, respectively, for subjects with severe renal impairment, and 1.7-fold and 2.0-fold higher, respectively, for subjects with ESRD as compared with subjects with normal renal function in this trial. Hemodialysis had a minimal effect on maraviroc clearance and exposure in subjects with ESRD. Exposures observed in subjects with severe renal impairment and ESRD were within the range observed in previous 300-mg single-dose trials of SELZENTRY in healthy volunteers with normal renal function. However, maraviroc exposures in the subjects with normal renal function in this trial were 50% lower than that observed in previous trials. Based on the results of this trial, no dose adjustment is recommended for patients with renal impairment receiving SELZENTRY without a potent CYP3A inhibitor or inducer. However, if patients with severe renal impairment or ESRD experience any symptoms of postural hypotension while taking SELZENTRY 300 mg twice daily, their dose should be reduced to 150 mg twice daily [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS].

In addition, the trial compared the pharmacokinetics of multiple-dose SELZENTRY in combination with saquinavir/ritonavir 1,000/100 mg twice daily (a potent CYP3A inhibitor combination) 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) with healthy volunteers with normal renal function (n = 6). Subjects received 150 mg of SELZENTRY at different dose frequencies (healthy volunteers – every 12 hours; mild renal impairment – every 24 hours; moderate renal impairment – every 48 hours). Compared with healthy volunteers (dosed every 12 hours), geometric mean ratios for maraviroc AUCtau, Cmax, and Cmin were 50% higher, 20% higher, and 43% lower, respectively, for subjects with mild renal impairment (dosed every 24 hours). Geometric mean ratios for maraviroc AUCtau, Cmax, and Cmin were 16% higher, 29% lower, and 85% lower, respectively, for subjects with moderate renal impairment (dosed every 48 hours) compared with healthy volunteers (dosed every 12 hours). Based on the data from this trial, no adjustment in dose is recommended for patients with mild or moderate renal impairment [see DOSAGE AND ADMINISTRATION].

Effect of Concomitant Drugs on the Pharmacokinetics of Maraviroc

Maraviroc is a substrate of CYP3A and P-gp and hence its pharmacokinetics are likely to be modulated by inhibitors and inducers of these enzymes/transporters. The CYP3A/P-gp inhibitors ketoconazole, telaprevir, boceprevir, lopinavir/ritonavir, ritonavir, darunavir/ritonavir, saquinavir/ritonavir, and atazanavir ± ritonavir all increased the Cmax and AUC of maraviroc (see Table 10). The CYP3A inducers rifampin, etravirine, and efavirenz decreased the Cmax and AUC of maraviroc (see Table 10).

Tipranavir/ritonavir (net CYP3A inhibitor/P-gp inducer) did not affect the steady-state pharmacokinetics of maraviroc (see Table 10). Cotrimoxazole and tenofovir did not affect the pharmacokinetics of maraviroc.

Table 10: Effect of Coadministered Agents on the Pharmacokinetics of Maraviroc

Coadministered Drug and Dose N Dose of SELZENTRY Ratio (90% CI) of Maraviroc Pharmacokinetic Parameters With/Without Coadministered Drug (No Effect = 1.00)
Cmin AUCtau Cmax
CYP3A and/or P-gp Inhibitors
Ketoconazole 400 mg q.d. 12 100 mg b.i.d. 3.75
(3.01, 4.69)
5.00
(3.98, 6.29)
3.38
(2.38, 4.78)
Ritonavir 100 mg b.i.d. 8 100 mg b.i.d. 4.55
(3.37, 6.13)
2.61
(1.92, 3.56)
1.28
(0.79, 2.09)
Saquinavir (soft gel capsules) /ritonavir 1,000 mg/100 mg b.i.d. 11 100 mg b.i.d. 11.3
(8.96, 14.1)
9.77
(7.87, 12.14)
4.78
(3.41, 6.71)
Lopinavir/ritonavir 400 mg/100 mg b.i.d. 11 300 mg b.i.d. 9.24
(7.98, 10.7)
3.95
(3.43, 4.56)
1.97
(1.66, 2.34)
Atazanavir 400 mg q.d. 12 300 mg b.i.d. 4.19
(3.65, 4.80)
3.57
(3.30, 3.87)
2.09
(1.72, 2.55)
Atazanavir/ritonavir 300 mg/100 mg q.d. 12 300 mg b.i.d. 6.67
(5.78, 7.70)
4.88
(4.40, 5.41)
2.67
(2.32, 3.08)
Darunavir/ritonavir 600 mg/100 mg b.i.d. 12 150 mg b.i.d. 8.00
(6.35, 10.1)
4.05 2.94, 5.59 2.29
(1.46, 3.59)
Boceprevir 800 mg t.i.d. 14 150 mg b.i.d. 2.78
(2.40, 3.23)
3.02
(2.53, 3.59)
3.33
(2.54, 4.36)
Telaprevir 750 mg t.i.d.b 13 150 mg b.i.d. 10.17
(8.73, 11.85)
9.49
(7.94, 11.34)
7.81
(5.92, 10.32)
CYP3A and/or P-gp Inducers
Efavirenz 600 mg q.d. 12 100 mg b.i.d. 0.55
(0.43, 0.72)
0.55
(0.49, 0.62)
0.49
(0.38, 0.63)
Efavirenz 600 mg q.d. 12 200 mg b.i.d. (+ efavirenz): 100 mg b.i.d.
(alone)
1.09
(0.89, 1.35)
1.15
(0.98, 1.35)
1.16
(0.87, 1.55)
Rifampicin 600 mg q.d. 12 100 mg b.i.d. 0.22
(0.17, 0.28)
0.37
(0.33, 0.41)
0.34
(0.26, 0.43)
Rifampicin 600 mg q.d. 12 200 mg b.i.d. (+ rifampicin): 100 mg b.i.d.
(alone)
0.66
(0.54, 0.82)
1.04
(0.89, 1.22)
0.97
(0.72, 1.29)
Etravirine 200 mg b.i.d. 14 300 mg b.i.d. 0.61
(0.53, 0.71)
0.47
(0.38, 0.58)
0.40
(0.28, 0.57)
Nevirapinea 200 mg b.i.d. (+ lamivudine 150 mg b.i.d., tenofovir 300 mg q.d.) 8 300 mg single dose - 1.01
(0.65, 1.55)
1.54
(0.94, 2.51)
CYP3A and/or P-gp Inhibitors and Inducers
Lopinavir/ritonavir +efavirenz 400 mg/100 mg b.i.d. + 600 mg q.d. 11 300 mg b.i.d. 6.29
(4.72, 8.39)
2.53
(2.24, 2.87)
1.25
(1.01, 1.55)
Saquinavir (soft gelcapsules) /ritonavir + efavirenz 1,000 mg/100 mg b.i.d. + 600 mg q.d. 11 100 mg b.i.d. 8.42
(6.46, 10.97)
5
(4.26, 5.87)
2.26
(1.64, 3.11)
Darunavir/ritonavir + etravirine 600 mg/100 mg b.i.d. + 200 mg b.i.d. 10 150 mg b.i.d. 5.27
(4.51, 6.15)
3.10
(2.57, 3.74)
1.77
(1.20, 2.60)
Fosamprenavir/ritonavir 700 mg/100 mg b.i.d. 14 300 mg b.i.d. 4.74
(4.03, 5.57)
2.49
(2.19, 2.82)
1.52
(1.27, 1.82)
Fosamprenavir/ritonavir 1,400 mg/100 mg q.d. 14 300 mg q.d. 1.80
(1.53, 2.13)
2.26
(1.99, 2.58)
1.45
(1.20, 1.74)
Tipranavir/ritonavir 500 mg/200 mg b.i.d. 12 150 mg b.i.d. 1.80
(1.55, 2.09)
1.02
(0.85, 1.23)
0.86
(0.61, 1.21)
Other
Raltegravir 400 mg b.i.d. 17 300 mg b.i.d. 0.90
(0.85, 0.96)
0.86
(0.80, 0.92)
0.79
(0.67, 0.94)
aCompared with historical data.
bConducted under fed conditions. The geometric mean Cmax of maraviroc is 858 ng/mL when maraviroc is coadministered with telaprevir.

Effect of Maraviroc on the Pharmacokinetics of Concomitant Drugs

Maraviroc is unlikely to inhibit the metabolism of coadministered drugs metabolized by the following cytochrome P enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP3A) because maraviroc did not inhibit activity of those enzymes at clinically relevant concentrations in vitro. Maraviroc does not induce CYP1A2 in vitro.

In vitro results suggest that maraviroc could inhibit P-gp in the gut. However, maraviroc did not significantly affect the pharmacokinetics of digoxin in vivo, indicating maraviroc may not significantly inhibit or induce P-gp clinically.

Drug interaction trials were performed with maraviroc and other drugs likely to be coadministered or commonly used as probes for pharmacokinetic interactions (see Table 10).

Coadministration of fosamprenavir 700 mg/ritonavir 100 mg twice daily and maraviroc 300 mg twice daily decreased the Cmin and AUC of amprenavir by 36% and 35%, respectively. Coadministration of fosamprenavir 1,400 mg/ritonavir 100 mg once daily and maraviroc 300 mg once daily decreased the Cmin and AUC by 15% and 30%, respectively. No dosage adjustment is necessary when SELZENTRY is dosed 150 mg twice daily in combination with fosamprenavir/ritonavir dosed once or twice daily. Fosamprenavir should be given with ritonavir when coadministered with SELZENTRY.

Maraviroc had no significant effect on the pharmacokinetics of boceprevir, telaprevir, zidovudine, or lamivudine. Maraviroc decreased the Cmin and AUC of raltegravir by 27% and 37%, respectively, which is not clinically significant. Maraviroc had no clinically relevant effect on the pharmacokinetics of midazolam, the oral contraceptives ethinylestradiol and levonorgestrel, no effect on the urinary 6β-hydroxycortisol/cortisol ratio, suggesting no induction of CYP3A in vivo. Maraviroc had no effect on the debrisoquine metabolic ratio (MR) at 300 mg twice daily or less in vivo and did not cause inhibition of CYP2D6 in vitro until concentrations > 100 μM. However, there was 234% increase in debrisoquine MR on treatment compared with baseline at 600 mg once daily, suggesting potential inhibition of CYP2D6 at higher dose.

Microbiology

Mechanism of Action

Maraviroc is a member of a therapeutic class called CCR5 coreceptor antagonists. Maraviroc selectively binds to the human chemokine receptor CCR5 present on the cell membrane, preventing the interaction of HIV-1 gp120 and CCR5 necessary for CCR5-tropic HIV-1 to enter cells. CXCR4-tropic and dual-tropic HIV-1 entry is not inhibited by maraviroc.

Antiviral Activity in Cell Culture

Maraviroc inhibits the replication of CCR5-tropic laboratory strains and primary isolates of HIV-1 in models of acute peripheral blood leukocyte infection. The mean EC50 value (50% effective concentration) for maraviroc against HIV-1 group M isolates (subtypes A to J and circulating recombinant form AE) and group O isolates ranged from 0.1 to 4.5 nM (0.05 to 2.3 ng/mL) in cell culture.

When used with other antiretroviral agents in cell culture, the combination of maraviroc was not antagonistic with NNRTIs (delavirdine, efavirenz, and nevirapine), NRTIs (abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine, and zidovudine), or protease inhibitors (amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, and tipranavir). Maraviroc was not antagonistic with the HIV fusion inhibitor enfuvirtide. Maraviroc was not active against CXCR4-tropic and dual-tropic viruses (EC50 value > 10 μM). The antiviral activity of maraviroc against HIV-2 has not been evaluated.

Resistance in Cell Culture: HIV-1 variants with reduced susceptibility to maraviroc have been selected in cell culture, following serial passage of 2 CCR5-tropic viruses (CCl/85 and RU570). The maraviroc-resistant viruses remained CCR5-tropic with no evidence of a change from a CCR5-tropic virus to a CXCR4-using virus. Two amino acid residue substitutions in the V3-loop region of the HIV-1 envelope glycoprotein (gp160), A316T, and I323V (HXB2 numbering), were shown to be necessary for the maraviroc-resistant phenotype in the HIV-1 isolate CCl/85. In the RU570 isolate a 3-amino acid residue deletion in the V3 loop, ΔQAI (HXB2 positions 315 to 317), was associated with maraviroc resistance. The relevance of the specific gp120 mutations observed in maraviroc-resistant isolates selected in cell culture to clinical maraviroc resistance is not known. Maraviroc-resistant viruses were characterized phenotypically by concentration-response curves that did not reach 100% inhibition in phenotypic drug assays, rather than increases in EC50 values.

Cross-Resistance in Cell Culture: Maraviroc had antiviral activity against HIV-1 clinical isolates resistant to NNRTIs, NRTIs, PIs, and the fusion inhibitor enfuvirtide in cell culture (EC50 values ranged from 0.7 to 8.9 nM (0.36 to 4.57 ng/mL). Maraviroc-resistant viruses that emerged in cell culture remained susceptible to the enfuvirtide and the protease inhibitor saquinavir.

Clinical Resistance: Virologic failure on maraviroc can result from genotypic and phenotypic resistance to maraviroc, through outgrowth of undetected CXCR4-using virus present before maraviroc treatment (see Tropism below), through resistance to background therapy drugs (Table 11), or due to low exposure to maraviroc [see CLINICAL PHARMACOLOGY].

Antiretroviral Treatment-Experienced Subjects (Trials A4001027 and A4001028): Week 48 data from treatment-experienced subjects failing maraviroc-containing regimens with CCR5-tropic virus (n = 58) have identified 22 viruses that had decreased susceptibility to maraviroc characterized in phenotypic drug assays by concentration-response curves that did not reach 100% inhibition. Additionally, CCR5-tropic virus from 2 of these treatment-failure subjects had ≥ 3-fold shifts in EC50 values for maraviroc at the time of failure.

Fifteen of these viruses were sequenced in the gp120 encoding region and multiple amino acid substitutions with unique patterns in the heterogeneous V3 loop region were detected. Changes at either amino acid position 308 or 323 (HXB2 numbering) were seen in the V3 loop in 7 of the subjects with decreased maraviroc susceptibility. Substitutions outside the V3 loop of gp120 may also contribute to reduced susceptibility to maraviroc.

Antiretroviral Treatment-Naive Subjects (Trial A4001026): Treatment-naive subjects receiving SELZENTRY had more virologic failures and more treatment-emergent resistance to the background regimen drugs compared with those receiving efavirenz (Table 11).

Table 11: Development of Resistance to Maraviroc or Efavirenz and Background Drugs in Antiretroviral Treatment-Naive Trial A4001026 for Patients with CCR5-Tropic Virus at Screening Using Enhanced Sensitivity TROFILE® Assay

  Maraviroc Efavirenz
Total N in dataset (as-treated) 273 241
Total virologic failures (as-treated) 85(31%) 56 (23%)
Evaluable virologic failures with post baseline genotypic and phenotypic data 73 43
  Lamivudine resistance 39 (53%) 13 (30%)
  Zidovudine resistance 2 (3%) 0
  Efavirenz resistance - 23 (53%)
  Phenotypic resistance to maraviroca 19 (26 % )
aIncludes subjects failing with CXCR4-or dual/mixed-tropism because these viruses are not intrinsically susceptible to maraviroc.

In an as-treated analysis of treatment-naive subjects at 96 weeks, 32 subjects failed a maraviroc-containing regimen with CCR5-tropic virus and had a tropism result at failure; 7 of these subjects had evidence of maraviroc phenotypic resistance defined as concentration-response curves that did not reach 95% inhibition. One additional subject had a ≥ 3-fold shift in the EC50 value for maraviroc at the time of failure. A clonal analysis of the V3 loop amino acid envelope sequences was performed from 6 of the 7 subjects. Changes in V3 loop amino acid sequence differed between each of these different subjects, even for those infected with the same virus clade suggesting that that there are multiple diverse pathways to maraviroc resistance. The subjects who failed with CCR5-tropic virus and without a detectable maraviroc shift in susceptibility were not evaluated for genotypic resistance.

Of the 32 maraviroc virologic failures failing with CCR5-tropic virus, 20 (63%) also had genotypic and/or phenotypic resistance to background drugs in the regimen (lamivudine, zidovudine).

Tropism: In both treatment-experienced and treatment-naive subjects, detection of CXCR4-using virus prior to initiation of therapy has been associated with a reduced virologic response to maraviroc.

Antiretroviral Treatment-Experienced Subjects: In the majority of cases, treatment failure on maraviroc was associated with detection of CXCR4-using virus (i.e., CXCR4-or dual/mixed-tropic) which was not detected by the tropism assay prior to treatment. CXCR4-using virus was detected at failure in approximately 55% of subjects who failed treatment on maraviroc by Week 48, as compared with 9% of subjects who experienced treatment failure in the placebo 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 arm) in whom CXCR4-using virus was detected at treatment failure. From analysis of amino acid sequence differences and phylogenetic data, it was determined that CXCR4-using virus in these subjects emerged from a low level of pre-existing CXCR4-using virus not detected by the tropism assay (which is population-based) prior to treatment rather than from a coreceptor switch from CCR5-tropic virus to CXCR4-using virus resulting from mutation in the virus.

Detection of CXCR4-using virus prior to initiation of therapy has been associated with a reduced virological response to maraviroc. Furthermore, subjects failing maraviroc twice daily at Week 48 with CXCR4-using virus had a lower median increase in CD4+ cell counts from baseline (+41 cells/mm³) than those subjects failing with CCR5-tropic virus (+162 cells/mm³). The median increase in CD4+ cell count in subjects failing in the placebo arm was +7 cells/mm³ .

Antiretroviral Treatment-Naive Subjects: In a 96-week trial of antiretroviral treatment-naive subjects, 14% (12/85) who had CCR5-tropic virus at screening with an enhanced sensitivity tropism assay (TROFILE) and failed therapy on maraviroc had CXCR4-using virus at the time of treatment failure. A detailed clonal analysis was conducted in 2 previously antiretroviral treatment-naive subjects enrolled in a Phase 2a monotherapy trial who had CXCR4-using virus detected after 10 days treatment with maraviroc. Consistent with the detailed clonal analysis conducted in treatment-experienced subjects, the CXCR4-using variants appear to emerge from outgrowth of a pre-existing undetected CXCR4-using virus. Screening with an enhanced sensitivity tropism assay reduced the number of maraviroc virologic failures with CXCR4-or dual/mixed-tropic virus at failure to 12 compared with 24 when screening with the original tropism assay. All but one (11/12; 92%) of the maraviroc failures failing with CXCR4or dual/mixed-tropic virus also had genotypic and phenotypic resistance to the background drug lamivudine at failure and 33% (4/12) developed zidovudine-associated resistance substitutions.

Subjects who had CCR5-tropic virus at baseline and failed maraviroc therapy with CXCR4-using virus had a median increase in CD4+ cell counts from baseline of +113 cells/mm³ while those subjects failing with CCR5-tropic virus had an increase of +135 cells/mm³. The median increase in CD4+ cell count in subjects failing in the efavirenz arm was + 95 cells/mm³ .

Clinical Studies

The clinical efficacy and safety of SELZENTRY are derived from analyses of data from 3 trials in adult subjects infected with CCR5-tropic HIV-1: A4001027 and A4001028 in antiretroviral treatment-experienced adult subjects and A4001026 in treatment-naive subjects. These trials were supported by a 48-week trial in antiretroviral treatment-experienced adult subjects infected with dual/mixed-tropic HIV-1, A4001029.

Trials In CCR5-Tropic, Treatment-Experienced Subjects

Trials A4001027 and A4001028 were double-blind, randomized, placebo-controlled, multicenter trials in subjects infected with CCR5-tropic HIV-1. Subjects were required to have an HIV-1 RNA greater than 5,000 copies/mL despite at least 6 months of prior therapy with at least 1 agent from 3 of the 4 antiretroviral drug classes ( ≥ 1 NRTI, ≥ 1 NNRTI, ≥ 2 PIs, and/or enfuvirtide) or documented resistance to at least 1 member of each class. All subjects received an optimized background regimen consisting of 3 to 6 antiretroviral agents (excluding low-dose ritonavir) selected on the basis of the subject's prior treatment history and baseline genotypic and phenotypic viral resistance measurements. In addition to the optimized background regimen, subjects were then randomized in a 2:2:1 ratio to SELZENTRY 300 mg once daily, SELZENTRY 300 mg twice daily, or placebo. Doses were adjusted based on background therapy as described in Dosing and Administration (2), Table 1.

In the pooled analysis for A4001027 and A4001028, the demographics and baseline characteristics of the treatment groups were comparable (Table 12). Of the 1,043 subjects with a CCR5-tropism result at screening, 7.6% had a dual/mixed-tropism result at the baseline visit 4 to 6 weeks later. This illustrates the background change from CCR5-to dual/mixed-tropism result over time in this treatment-experienced population, prior to a change in antiretroviral regimen or administration of a CCR5 co-receptor antagonist.

Table 12: Demographic and Baseline Characteristics of Subjects in Trials A4001027 and A4001028

  SELZENTRY Twice Daily
(N = 426)
Placebo
(N = 209)
Age (years)
  Mean (range) 46.3 (21-73) 45.7 (29-72)
Sex
  Male 382 (89.7%) 185 (88.5%)
  Female 44 (10.3%) 24 (11.5%)
Race
  White 363 (85.2%) 178 (85.2%)
  Black 51 (12.0%) 26 (12.4%)
  Other 12 (2.8%) 5 (2.4%)
Region
  U.S. 276 (64.8%) 135 (64.6%)
  Non-U.S. 150 (35.2%) 74 (35.4%)
Subjects with previous enfuvirtide use 142 (33.3%) 62 (29.7%)
Subjects with enfuvirtide as part of OBT 182 (42.7%) 91 (43.5%)
Baseline plasma HIV-1 RNA (log10 copies/mL) Mean (range) 4.85 (2.96-6.88) 4.86 (3.46-7.07)
Subjects with screening viral load ≥ 100,000 copies/mL 179 (42.0%) 84 (40.2%)
Baseline CD4+ cell count (cells/mm³) Median (range) 167 (2-820) 171 (1-675)
Subjects with baseline CD4+ cell count ≤ 200 cells/mm³) 250 (58.7%) 118 (56.5%)
Subjects with Overall Susceptibility Score (OSS):a
  0 57 (13.4%) 35 (16.7%)
  1 136 (31.9%) 44 (21.1%)
  2 104 (24.4%) 59 (28.2%)
   ≥ 3 125 (29.3%) 66 (31.6%)
Subjects with enfuvirtide resistance mutations 90 (21.2%) 45 (21.5%)
Median number of resistance-associated:b
  PI mutations 10 10
  NNRTI mutations 1 1
  NRTI mutations 6 6
aOSS -Sum of active drugs in OBT based on combined information from genotypic and phenotypic testing.
bResistance mutations based on IAS guidelines.1

The Week 48 results for the pooled Trials A4001027 and A4001028 are shown in Table 13.

Table 13: Outcomes of Randomized Treatment at Week 48 Trials A4001027 and A4001028

Outcome SELZENTRY Twice Daily
(N = 426)
Placebo
(N = 209)
Mean Difference
Mean change from Baseline to Week 48 in HIV-1 RNA (log10 copies/mL) -1.84 -0.78 -1.05
< 400 copies/mL at Week 48 239 (56%) 47 (22%) 34%
< 50 copies/mL at Week 48 194 (46%) 35 (17%) 29%
Discontinuations  
  Insufficient clinical response 97 (23%) 113 (54%)  
  Adverse events 19 (4%) 11 (5%)  
  Other 27 (6%) 18 (9%)  
Subjects with treatment-emergent CDC Category C events 22 (5%) 16 (8%)
Deaths (during trial or within 28 days of last dose) 9 (2%)a 1 (0.5%)
aOne additional subject died while receiving open-label therapy with SELZENTRY subsequent to discontinuing double-blind placebo due to insufficient response.

After 48 weeks of therapy, the proportions of subjects with HIV-1 RNA < 400 copies/mL receiving SELZENTRY compared with placebo were 56% and 22%, respectively. The mean changes in plasma HIV-1 RNA from baseline to Week 48 were –1.84 log10 copies/mL for subjects receiving SELZENTRY + OBT compared with –0.78 log10 copies/mL for subjects receiving OBT only. The mean increase in CD4+ cell count was higher on SELZENTRY twice daily + OBT (124 cells/mm³) than on placebo + OBT (60 cells/mm³).

Trial In Dual/Mixed-Tropic, Treatment-Experienced Subjects

Trial A4001029 was an exploratory, randomized, double-blind, multicenter trial to determine the safety and efficacy of SELZENTRY in subjects infected with dual/mixed coreceptor tropic HIV-1. The inclusion/exclusion criteria were similar to those for Trials A4001027 and A4001028 above and the subjects were randomized in a 1:1:1 ratio to SELZENTRY once daily, SELZENTRY twice daily, or placebo. No increased risk of infection or HIV disease progression was observed in the subjects who received SELZENTRY. Use of SELZENTRY 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.

Trial In Treatment-Naive Subjects

Trial A4001026 is an ongoing, randomized, double-blind, multicenter trial in subjects infected with CCR5-tropic HIV-1 classified by the original TROFILE tropism assay. Subjects were required to have plasma HIV-1 RNA ≥ 2,000 copies/mL and could not have: 1) previously received any antiretroviral therapy for > 14 days, 2) an active or recent opportunistic infection or a suspected primary HIV-1 infection, or 3) phenotypic or genotypic resistance to zidovudine, lamivudine, or efavirenz. Subjects were randomized in a 1:1:1 ratio to SELZENTRY 300 mg once daily, SELZENTRY 300 mg twice daily, or efavirenz 600 mg once daily, each in combination with zidovudine/lamivudine. The efficacy and safety of SELZENTRY are based on the comparison of SELZENTRY twice daily versus efavirenz. In a pre-planned interim analysis at 16 weeks, SELZENTRY 300 mg once daily failed to meet the pre-specified criteria for demonstrating non-inferiority and was discontinued.

The demographic and baseline characteristics of the maraviroc and efavirenz treatment groups were comparable (Table 14). Subjects were stratified by screening HIV-1 RNA levels and by geographic region. The median CD4+ cell counts and mean HIV-1 RNA at baseline were similar for both treatment groups.

Table 14: Demographic and Baseline Characteristics of Subjects in Trial A4001026

  SELZENTRY 300 mg Twice Daily + Zidovudine/ Lamivudine
(N = 360)
Efavirenz 600 mg Once Daily + Zidovudine/ Lamivudine
(N = 361)
Age (years)
  Mean 36.7 37.4
  Range 20-69 18-77
Female, n% 104 (29) 102 (28)
Race, n%
  White 204 (57) 198 (55)
  Black 123 (34) 133 (37)
  Asian 6 (2) 5 (1)
  Other 27 (8) 25 (7)
Median (range) CD4+ cell count (cells/μL) 241 (5-1,422) 254 (8-1,053)
Median (range) HIV-1 RNA (log10 copies/mL) 4.9 ( 3-7) 4.9 (3-7)

The treatment outcomes at 96 weeks for Trial A4001026 are shown in Table 15. Treatment outcomes are based on reanalysis of the screening samples using a more sensitive tropism assay, enhanced sensitivity TROFILE HIV tropism assay, which became available after the Week 48 analysis, approximately 15% of the subjects identified as CCR5-tropic in the original analysis had dual/mixed-or CXCR4-tropic virus. Screening with enhanced sensitivity version of the TROFILE tropism assay reduced the number of maraviroc virologic failures with CXCR4-or dual/mixed-tropic virus at failure to 12 compared with 24 when screening with the original TROFILE HIV tropism assay.

Table 15: Trial Outcome (Snapshot) at Week 96 Using Enhanced Sensitivity Assaya

Outcome at Week 96b SELZENTRY 300 mg Twice Daily + Zidovudine/ Lamivudine
N = 311
n (%)
Efavirenz 600 mg Once Daily + Zidovudine/ Lamivudine
N = 303
n (%)
Virologic Responders: (HIV-1 RNA < 400 copies/mL) 199 (64) 195 (64)
Virologic Failure:
   Non-sustained HIV-1 RNA suppression 39 (13) 22 (7)
   HIV-1 RNA never suppressed 9 (3) 1 ( < 1)
Virologic Responders: (HIV-1 RNA < 50 copies/mL) 183 (59) 190 (63)
Virologic Failure:
  Non-sustained HIV-1 RNA suppression 43 (14) 25 (8)
   HIV-1 RNA never suppressed 21 (7) 3 (1)
Discontinuations due to:
  Adverse events 19 (6) 47 (16)
  Death 2 (1) 2 (1)
  Otherc 43 (14) 36 (12)
aThe total number of subjects (Ns) in Table 15 represents the subjects who had a CCR5-tropic virus in the reanalysis of screening samples using the more sensitive tropism assay. This reanalysis reclassified approximately 15% of subjects shown in Table 14 as having dual/mixedor CXCR4-tropic virus. These numbers are different than those presented in Table 14 because the numbers in Table 14 reflect the subjects with CCR5-tropic virus according to the original tropism assay.
bWeek 48 results: Virologic responders ( < 400): 228/311 (73%) in SELZENTRY, 219/303 (72%) in efavirenz; Virologic responders ( < 50): 213/311 (69 %) in SELZENTRY, 207/303 (68%) in efavirenz.
cOther reasons for discontinuation include lost to follow-up, withdrawn, protocol violation, and other.

The median increase from baseline in CD4+ cell counts at Week 96 was 184 cells/mm³ for the arm receiving SELZENTRY compared with 155 cells/mm³ for the efavirenz arm.

REFERENCES

1. IAS-USA Drug Resistance Mutations Figures. http://www.iasusa.org/pub/topics/2006/issue3/125.pdf

Last reviewed on RxList: 4/11/2014
This monograph has been modified to include the generic and brand name in many instances.

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