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Zavesca

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Zavesca

Zavesca

CLINICAL PHARMACOLOGY

Mechanism Of Action

Type 1 Gaucher disease is caused by a functional deficiency of glucocerebrosidase, the enzyme that mediates the degradation of the glycosphingolipid glucosylceramide.

Miglustat functions as a competitive and reversible inhibitor of the enzyme glucosylceramide synthase, the initial enzyme in a series of reactions which results in the synthesis of most glycosphingolipids.

Zavesca helps reduce the rate of glycosphingolipid biosynthesis so that the amount of glycosphingolipid substrate is reduced to a level which allows the residual activity of the deficient glucocerebrosidase enzyme to be more effective (substrate reduction therapy). In vitro and in vivo studies have shown that miglustat can reduce the synthesis of glucosylceramidebased glycosphingolipids.

Pharmacokinetics

Absorption

After a 100 mg oral dose, the time to maximum observed plasma concentration of miglustat (tmax) ranged from 2 to 2.5 hours in Gaucher patients. Plasma concentrations show a biexponential decline, characterized by a short distribution phase and a longer elimination phase. The effective half-life of miglustat is approximately 6 to 7 hours, which predicts that steady-state will be achieved by 1.5 to 2 days following the start of three times daily dosing.

Miglustat, dosed at 50 and 100 mg three times daily in Gaucher patients, exhibits dose-proportional pharmacokinetics. The pharmacokinetics of miglustat were not altered after repeated dosing three times daily for up to 12 months.

In healthy subjects, co-administration of Zavesca with food results in a decrease in the rate of absorption of miglustat (maximum plasma concentration [Cmax] was decreased by 36% and tmax delayed 2 h) but had no statistically significant effect on the extent of absorption of miglustat (area-under-the-plasma-concentration time curve [AUC] was decreased by 14%). The mean oral bioavailability of a 100-mg miglustat capsule is about 97% relative to an oral solution administered under fasting conditions. The pharmacokinetics of miglustat were similar between adult type 1 Gaucher disease patients and healthy subjects after a single dose administration of miglustat 100 mg.

Distribution

Miglustat does not bind to plasma proteins. Mean apparent volume of distribution of miglustat is 83-105 liters in Gaucher patients. At steady state, the concentration of miglustat in cerebrospinal fluid of six non-Gaucher patients was 31.4-67.2% of that in plasma, indicating that miglustat crosses the blood brain barrier.

Metabolism and Excretion

The major route of excretion of miglustat is via kidney. Following administration of a single dose of 100 mg 14C-miglustat to healthy volunteers, 83% of the radioactivity was recovered in urine and 12% in feces. In healthy subjects, 67% of the administered dose was excreted unchanged in urine over 72 hours. The most abundant metabolite in urine was miglustat glucuronide accounting for 5% of the dose. The terminal half-life of radioactivity in plasma was 150 hours, suggesting the presence of one or more metabolites with a prolonged half-life. The metabolite accounting for this observation has not been identified, but may accumulate and reach concentrations exceeding those of miglustat at steady state.

Specific Populations

Gender: There was no statistically significant gender difference in miglustat pharmacokinetics, based on pooled data analysis.

Race: Ethnic differences in miglustat pharmacokinetics have not been evaluated in Gaucher patients. However, apparent oral clearance of miglustat in patients of Ashkenazi Jewish descent was not statistically different to that in others (1 Asian and 15 Caucasians), based on a cross-study analysis.

Hepatic Impairment: No studies have been performed to assess the pharmacokinetics of miglustat in patients with hepatic impairment.

Renal Impairment: Limited data in non-Gaucher patients with impaired renal function indicate that the apparent oral clearance (CL/F) of miglustat decreases with decreasing renal function. While the number of subjects with mild and moderate renal impairment was very small, the data suggest an approximate decrease in the apparent oral clearance of 40% and 60% respectively, in mild and moderate renal impairment, justifying the need to decrease the dosing of miglustat in such patients dependent upon creatinine clearance levels [see DOSAGE AND ADMINISTRATION].

Data in severe renal impairment are limited to two patients with creatinine clearances in the range 18-29 mL/min and cannot be extrapolated below this range. These data suggest a decrease in CL/F by at least 70% in patients with severe renal impairment [see DOSAGE AND ADMINISTRATION and Use In Specific Populations].

Drug Interaction Studies

Miglustat does not inhibit the metabolism of various substrates of cytochrome P450 enzymes including, CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4 and CYP4A11 in vitro; consequently significant interactions via inhibition of these enzymes are unlikely with drugs that are substrates of cytochrome P450 enzymes.

Drug interaction between Zavesca (miglustat 100 mg orally three times daily) and imiglucerase 7.5 or 15 U/kg/day was assessed in imiglucerase-stabilized patients after one month of coadministration. There was no significant effect of imiglucerase on the pharmacokinetics of miglustat, with the co-administration of imiglucerase and miglustat resulting in a 22% reduction in Cmax and a 14% reduction in the AUC for miglustat. While Zavesca appeared to increase the clearance of imiglucerase by 70%, these results are not conclusive because of the small number of subjects studied and because patients took variable doses of imiglucerase [see DRUG INTERACTIONS].

Concomitant therapy with loperamide during clinical trials did not appear to significantly alter the pharmacokinetics of miglustat.

Animal Toxicology And/Or Pharmacology

Histopathology findings in the absence of clinical signs in the central nervous system of the monkey (brain, spine) that included vascular mineralization, in addition to mineralization and necrosis of white matter were observed at > 750 mg/kg/day (4 times the human therapeutic systemic exposure based on area-under-the-plasma-concentration curve [AUC] comparisons) in a 52-week oral toxicity study using doses of 750 and 2000 mg/kg/d. Vacuolization of white matter was observed in rats dosed orally by gavage at ≥ 180 mg/kg/d (6 times the human therapeutic exposure based on surface area comparisons, mg/m²) in a 4-week study using doses of 180, 840, and 4200 mg/kg/d. Vacuolization can sometimes occur as an artifact of tissue processing. Findings in dogs included tremor and absent corneal reflexes at 105 mg/kg/day (10 times the human therapeutic systemic exposure, based on body surface area comparisons, mg/m²) after a 4-week oral gavage toxicity study using doses of 35, 70, 105, and 140 mg/kg/d. Ataxia, diminished/absent pupillary, palpebral, or patellar reflexes were observed in a dog at ≥ 495 mg/kg/day (50 times the human therapeutic systemic exposure based on body surface area comparisons, mg/m²), in a 2-week oral gavage toxicity study using doses of 85, 165, 495, and 825 mg/kg/d.

Cataracts were observed in rats at ≥ 180 mg/kg/day (4 times the human therapeutic systemic exposure, based on AUC) in a 52-week oral gavage toxicity study using doses of 180, 420, 840, and 1680 mg/kg/d.

Gastrointestinal necrosis, inflammation, and hemorrhage were observed in dogs at ≥ 85 mg/kg/day (9 times the human therapeutic systemic exposure based on body surface area comparisons, mg/m²) after a 2-week oral (capsule) toxicity study using doses of 85, 165, 495, and 825 mg/kg/d. Similar GI toxicity occurred in rats at 1200 mg/kg/day (7 times the human therapeutic systemic exposure, based on AUC) in a 26-week oral gavage toxicity study using doses of 300, 600, and 1200 mg/kg/d. In monkeys, similar GI toxicity occurred at ≥ 750 mg/kg/day (6 times the human therapeutic systemic exposure based on AUC) following a 52week oral gavage toxicity study using doses of 750 and 2000 mg/kg/d.

Clinical Studies

The efficacy of Zavesca in type 1 Gaucher disease has been investigated in two open-label, uncontrolled trials and one randomized, open-label, active-controlled trial with enzyme replacement given as imiglucerase. Patients who received Zavesca were treated with doses ranging from 100 to 600 mg a day, although the majority of patients were maintained on doses between 200 to 300 mg a day. Efficacy parameters included the evaluation of liver and spleen organ volume, hemoglobin concentration, and platelet count. A total of 80 patients were exposed to Zavesca during the three trials and their extension period.

Open-Label Uncontrolled Monotherapy Trials

In Study 1, Zavesca was administered at a starting dose of 100 mg three times daily for 12 months (dose range of 100 once-daily to 200 mg three times daily) to 28 adult patients with type 1 Gaucher disease, who were unable to receive enzyme replacement therapy and who had not taken enzyme replacement therapy in the preceding 6 months. Twenty-two patients completed the trial. After 12 months of treatment, the results showed significant mean percent reductions from baseline in liver volume of 12% and spleen volume of 19%, a non-significant increase from baseline in mean absolute hemoglobin concentration of 0.26 g/dL and a mean absolute increase from baseline in platelet counts of 8 x 109/L (See Tables 3-6).

In Study 2, Zavesca was administered at a dose of 50 mg three times daily for 6 months to 18 adult patients with type 1 Gaucher disease who were unable to receive enzyme replacement therapy and who had not taken enzyme replacement therapy in the preceding 6 months. Seventeen patients completed the trial. After 6 months of treatment, the results showed significant mean percent reductions from baseline in liver volume of 6% and spleen volume of 5%. There was a non-significant mean absolute decrease from baseline in hemoglobin concentration of 0.13 g/dL and a non-significant mean absolute increase from baseline in platelet counts of 5 x 109/L (See Tables 3-6).

Extension Period

Eighteen patients were enrolled in a 12-month extension to Study 1. A subset of patients continuing in the extension had larger mean baseline liver volumes, and lower mean baseline platelet counts and hemoglobin concentrations than the original study population (See Tables 3-6). After a total of 24 months of treatment, there were significant mean decreases from baseline in liver and spleen organ volumes of 15% and 27%, respectively, and significant mean absolute increases from baseline in hemoglobin concentration and platelet count of 0.9 g/dL and 14 x 109/L, respectively (See Tables 3-6).

Sixteen patients were enrolled in a 6-month extension to Study 2. After a total of 12 months of treatment, there was a mean decrease from baseline in spleen organ volume of 10%, whereas the mean percent decrease in liver organ volume remained at 6%. There were no significant changes in hemoglobin concentrations or platelet counts (See Tables 3-6).

Liver volume results from Studies 1 and 2 and their extensions are summarized in Table 3:

Table 3: Liver Volume Changes in Two Open-Label Uncontrolled Monotherapy Trials of Zavesca with Extension Period

  n Liver Volume
Absolute Mean (L) (2-sided 95% CI) Percent Mean (%) (2-sided 95% CI)
Study 1 (starting dose Zavesca 100 mg three times daily)
  Baseline (Month 0) 21 2.39  
  Month 12 Change from baseline -0.28 (-0.38, -0.18) -12.1% (-16.4, 7.9)
Study 1 Extension Phase
  Baseline (Month 0) 12 2.54
  Month 24 Change from baseline -0.36 (-0.48, -0.24) -14.5% (-19.3, 9.7)
Study 2 (Zavesca 50 mg three times daily)
  Baseline (Month 0) 17 2.45
  Month 6 Change from baseline -0.14 (-0.25, -0.03) -5.9% (-9.9, -1.9)
Study 2 Extension Phase
  Baseline (Month 0) 13 2.35
  Month 12 Change from baseline   -0.17 (-0.3, -0.0) -6.2% (-12.0, -0.5)

Spleen volume results from Studies 1 and 2 and their extensions are summarized in Table 4:

Table 4: Spleen Volume Changes in Two Open-Label Uncontrolled Monotherapy Trials of Zavesca with Extension Period

  n Spleen Volume
Absolute Mean (L) (2-sided 95% CI) Percent Mean (%) (2-sided 95% CI)
Study 1 (starting dose Zavesca 100 mg three times daily)
  Baseline (Month 0) 18 1.64
  Month 12 Change from baseline -0.32 (-0.42, -0.22) -19.0% (-23.7, -14.3)
Study 1 Extension Phase
  Baseline (Month 0) 10 1.56
  Month 24 Change from baseline -0.42 (-0.53, -0.30) -26.4% (-30.4, -22.4)
Study 2 (Zavesca 50 mg three times daily)
  Baseline (Month 0) 11 1.98
  Month 6 Change from baseline -0.09 (-0.18, -0.01) -4.5% (-8.2, -0.7)
Study 2 Extension Phase
  Baseline (Month 0) 9 1.98
  Month 12 Change from baseline -0.23 (-0.46, 0.00) -10.1% (-20.1, -0.1)

Hemoglobin concentration results from Studies 1 and 2 and their extensions are summarized in Table 5:

Table 5: Hemoglobin Concentration Changes in Two Open-Label Uncontrolled Monotherapy Trials of Zavesca with Extension Period

  n Hemoglobin Concentration
Absolute Mean (g/dL) (2-sided 95% CI) Percent Mean (%) (2-sided 95% CI)
Study 1 (starting dose Zavesca 100 mg three times daily)
  Baseline (Month 0) 22 11.94
  Month 12 Change from baseline 0.26 (-0.05, 0.57) 2.6% (-0.5, 5.7)
Study 1 Extension Phase
  Baseline (Month 0) 13 11.03
  Month 24 Change from baseline 0.91 (0.30, 1.53) 9.1% (2.9, 15.2)
Study 2 (Zavesca 50 mg three times daily)
  Baseline (Month 0) 17 11.6
  Month 6 Change from baseline -0.13 (-0.51, 0.24) -1.3% (-4.4, 1.8)
Study 2 Extension Phase
  Baseline (Month 0) 13 11.94
  Month 12 Change from baseline 0.06 (-0.73, 0.85) 1.2% (-5.2, 7.7)

Platelet count results from Studies 1 and 2 and their extensions are summarized in Table 6:

Table 6: Platelet Count Changes in Two Open-Label Uncontrolled Monotherapy Trials of Zavesca with Extension Period

  n Platelet Count
Absolute Mean (109/L) (2-sided 95% CI) Percent Mean (%) (2-sided 95% CI)
Study 1 (starting dose Zavesca 100 mg three times daily)
  Baseline (Month 0) 22 76.58
  Month 12 Change from baseline 8.28 (1.88, 14.69) 16.0% (-0.8, 32.8)
Study 1 Extension Phase
  Baseline (Month 0) 13 72.35
  Month 24 Change from baseline 13.58 (7.72, 19.43) 26.1% (14.7, 37.5)
Study 2 (Zavesca 50 mg three times daily)
  Baseline (Month 0) 17 116.47
  Month 6 Change from baseline 5.35 (-6.31, 17.02) 2.0% (-6.9, 10.8)
Study 2 Extension Phase
  Baseline (Month 0) 13 122.15
  Month 12 Change from baseline 14.0 (-3.4, 31.4) 14.7% (-1.4, 30.7)

Open-Label Active-Controlled Trial

Study 3 was an open-label, randomized, active-controlled study of 36 adult patients with type 1 Gaucher disease, who had been receiving enzyme replacement therapy with imiglucerase for a minimum of 2 years prior to study entry. Patients were randomized 1:1:1 to one of three treatment groups, as follows:

  • Zavesca 100 mg three times daily alone
  • imiglucerase (patient's usual dose) alone
  • Zavesca 100 mg three times daily and imiglucerase (usual dose)

Patients were treated for 6 months, and 33 patients completed the study. Because Zavesca is only indicated as monotherapy, the results for the monotherapy arms are described below. At Month 6, the results showed a decrease in mean percent change in liver volume in the Zavesca treatment group compared to the imiglucerase alone group. There were no significant differences between the groups for mean absolute changes in liver and spleen volume and hemoglobin concentration. However, there was a significant difference between the Zavesca alone and imiglucerase alone groups in platelet counts at Month 6, with the Zavesca alone group having a mean absolute decrease in platelet count of 21.6 x 109/L and the imiglucerase alone group having a mean absolute increase in platelet count of 10.1 x 109/L (See Tables 7-10).

Extension period

Twenty-nine patients were enrolled in a 6-month extension to Study 3. In the extension phase, all 29 patients had withdrawn from imiglucerase and received open-label Zavesca 100 mg three times daily monotherapy. At Month 12, the results showed non-significant decreases in platelet counts from baseline in all the treatment groups (by original randomization). There was a significant decrease in platelet counts from Month 6 to Month 12 in the group originally randomized to treatment with imiglucerase, and a continued decrease in platelet counts in the group originally randomized to Zavesca alone. There were no significant changes in any treatment group for liver volume, spleen volume, or hemoglobin concentration (See Tables 7-10).

Liver volume results from Study 3 and extension are summarized in Table 7:

Table 7: Liver Volume Changes from Study 3 and Extension Phase

  Imiglucerase alone Zavesca alone
Study 3 n=11 n=10
  Month 0 1.81 1.58
  Month 6 Change (L) 0.04 -0.05
  Month 6 % Change 3.6% -2.9%
  Adjusted mean Difference from Imiglucerase (95% CI)   -4.5% (-13.2, 4.2)
Extension Phase* n=10 n=8
  Month 0 1.94 1.60
  Month 12 Change (L) -0.05 -0.01
  Month 12 % Change -0.7% -0.8%
*All patients received Zavesca 100 mg three times daily monotherapy from Month 6 to Month 12.

Spleen volume results from Study 3 and extension are summarized in Table 8:

Table 8: Spleen Volume Changes from Study 3 and Extension Phase

  Imiglucerase alone Zavesca alone
Study 3 n=8 n=7
  Month 0 0.61 0.69
  Month 6 Change (L) -0.02 -0.03
  Month 6 % Change -2.1% -4.8%
  Adjusted % Difference from Imiglucerase (95% CI) -5.8% (-22.1, 10.5)
Extension Phase* n=7 n=6
  Month 0 0.83 0.57
  Month 12 Change (L) 0.04 -0.05
  Month 12 % Change 1.5% -6.1%
*All patients received Zavesca 100 mg three times daily monotherapy from Month 6 to Month 12. Hemoglobin concentration results from Study 3 and extension are summarized in Table 9:

Table 9: Hemoglobin Concentration Changes from Study 3 and Extension Phase

  Imiglucerase alone Zavesca alone
Study 3 n=12 n=10
  Month 0 13.18 12.44
  Month 6 Change (g/dL) -0.15 -0.31
  Month 6 % Change -1.2% -2.4%
  Adjusted % Difference from Imiglucerase (95% CI) -1.9% (-6.4, 2.6)
Extension Phase* n=10 n=9
  Month 0 13.39 12.46
  Month 12 Change (g/dL) -0.48 -0.13
  Month 12 % Change -3.1% -1.1%
*All patients received Zavesca 100 mg three times daily monotherapy from Month 6 to Month 12 . Platelet count results from Study 3 and extension are summarized in Table 10:

Table 10: Platelet Count Changes from Study 3 and Extension Phase

  Imiglucerase alone Zavesca alone
Study 3 n=12 n=101
  Month 0 165.75 70.55
  Month 6 Change (109/L) 15.29 -21.60
  Month 6 % Change 10.1% -9.6%
  Adjusted % Difference from Imiglucerase (95% CI) -17.1% (-32.9, -1.3)
Extension Phase* n=10 n=9
  Month 0 170.05 184.83
  Month 12 Change (109/L) -3.75 -27.39
  Month 12 % Change -3.2% -10.4%
*All patients received Zavesca 100 mg three times daily monotherapy from Month 6 to Month 12. Patients with platelet counts above 150 x 109/L at baseline who were randomized to Zavesca treatment had significant decreases in platelet counts at Month 12.

Last reviewed on RxList: 2/21/2014
This monograph has been modified to include the generic and brand name in many instances.

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