Zavesca® (miglustat capsules, 100mg) is an inhibitor of the enzyme glucosylceramide synthase, which is a glucosyl transferase enzyme responsible for the first step in the synthesis of most glycosphingolipids. Zavesca is an N-alkylated imino sugar, a synthetic analog of D-glucose.
The chemical name for miglustat is 1,5-(butylimino)-1,5-dideoxy-D-glucitol with the chemical formula C10H21NO4 and a molecular weight of 219.28.
Miglustat is a white to off-white crystalline solid and has a bitter taste. It is highly soluble in water (>1000mg/mL as a free base).
Zavesca is supplied in hard gelatin capsules each containing 100 mg miglustat for oral administration. Each Zavesca 100 mg capsule also contains sodium starch glycollate, povidone (K30), and magnesium stearate. Ingredients in the capsule shell include gelatin and titanium dioxide, and the shells are printed with edible ink consisting of black iron oxide and shellac.
Zavesca - Clinical Pharmacology
Background
Type 1 Gaucher disease is caused by a functional deficiency of glucocerebrosidase, the enzyme that mediates the degradation of the glycosphingolipid glucosylceramide. The failure to degrade glucosylceramide results in the lysosomal storage of this material within tissue macrophages leading to widespread pathology. Macrophages containing stored glucosylceramide are typically found in the liver, spleen, and bone marrow and occasionally in lung, kidney, and intestine. Secondary hematologic consequences include severe anemia and thrombocytopenia in addition to the characteristic progressive hepatosplenomegaly. Skeletal complications include osteonecrosis and osteopenia with secondary pathological fractures. Enzyme replacement therapy is the standard of care for most patients who require treatment for type 1 Gaucher disease.
Mode of Action
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. The goal of treatment with Zavesca is to 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 glucosylceramide-based glycosphingolipids. In clinical trials, Zavesca improved liver and spleen volume, as well as hemoglobin concentration and platelet count.
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 in Gaucher patients, exhibits dose proportional pharmacokinetics. Miglustat's pharmacokinetics were not altered after repeated dosing three times daily for up to 12 months.
Co-administration of Zavesca with food results in a decrease in the rate of absorption of miglustat (maximum serum concentration [Cmax] was decreased by 36% and tmax delayed 2 h) but has no statistically significant effect on the extent of absorption of miglustat (area-under-the-plasma-concentration 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.
Distribution
Miglustat does not bind to plasma proteins. Mean apparent volume of distribution of miglustat is 83-105 liters in Gaucher patients, indicating that miglustat distributes into extravascular tissues.
Elimination
The major route of excretion of miglustat is renal. Miglustat is excreted unchanged in the urine. Renal impairment has a significant effect on the pharmacokinetics of miglustat resulting in increased systemic exposure of miglustat in such patients. There is no evidence that miglustat is metabolized in humans.
Special 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 Insufficiency
No studies have been performed to assess the pharmacokinetics of miglustat in patients with hepatic impairment, since miglustat is not metabolized in the human liver.
Renal Insufficiency
Limited data in patients with Fabry disease and impaired renal function indicate that 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 CL/F 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. Treatment with miglustat in patients with severe renal impairment is therefore not recommended (see sections on PRECAUTIONS and DOSAGE AND ADMINISTRATION).
Drug Interactions
(See also PRECAUTIONS, Drug Interactions)
Miglustat does not inhibit or induce various substrates of cytochrome P450 enzymes; consequently significant interactions are unlikely with drugs that are substrates of cytochrome P450 enzymes.
Drug interaction between Zavesca (miglustat 100 mg orally three times daily) and Cerezyme® (imiglucerase; 7.5 or 15 U/kg/day) was assessed in Cerezyme stabilized patients after one month of co-administration. There was no significant effect of Cerezyme on pharmacokinetics of miglustat, with the co-administration of Cerezyme 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 Cerezyme (see PRECAUTIONS, Drug Interactions).
Concomitant therapy with loperamide during clinical trials did not appear to significantly alter the pharmacokinetics of miglustat.
Clinical Studies
The efficacy of Zavesca in type 1 Gaucher disease has been investigated in two open-label, uncontrolled studies and one randomized, open-label, active-controlled study with enzyme replacement given as Cerezyme. 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 studies and their extensions.
Open-Label Uncontrolled Monotherapy Studies
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 -200 mg three times daily) to 28 adult patients with type 1 Gaucher disease, who were unable or unwilling to take enzyme replacement therapy, and who had not taken enzyme replacement therapy in the preceding 6 months. Twenty-two patients completed the study. 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 × 109/L (See Tables 1-4).
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 or unwilling to take enzyme replacement therapy and who had not taken enzyme replacement therapy in the preceding 6 months. Seventeen patients completed the study. 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 × 109/L (See Tables 1-4).
Extension period
Eighteen patients were enrolled in a 12-month extension to Study 1. A subset of patients continuing in the extension had somewhat larger mean baseline liver volumes, and lower mean baseline platelet counts and hemoglobin concentrations than the original study population. After a total of 24 months of treatment, there were significant mean decreases from baseline in liver and spleen organ volume of 15% and 27%, respectively, and significant mean absolute increases from baseline in hemoglobin concentration and platelet counts of 0.9 g/L and 14 × 109/L, respectively (See Tables 1-4).
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 1-4).
Liver volume results from Studies 1 and 2 and their extensions are summarized in Table 1:
| 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 2:
| 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 3:
| 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 | 11.60 | |
| 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) | |
A more pronounced improvement in hemoglobin concentrations was seen at 18 and 24 months in patients with baseline (Month 0) hemoglobin concentrations <11.5 g/dL.
Platelet count results from Studies 1 and 2 and their extensions are summarized in Table 4:
| 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 Study
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 Cerezyme 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
- Cerezyme (patient's usual dose) alone
- Zavesca 100 mg three times daily + Cerezyme (usual dose)
Patients were treated for 6 months, and 33 patients completed the study. At Month 6, the results showed a significant decrease in mean percent change in liver volume in the combination treatment group compared to the Cerezyme 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 Cerezyme alone groups in platelet counts at Month 6, with the Zavesca alone group having a mean absolute decrease in platelet count of 21.6 × 109/L and the Cerezyme alone group having a mean absolute increase in platelet count of 10.1 × 109/L (see Tables 5-8).
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 Cerezyme 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 three treatment groups (by original randomization). There were significant decreases in platelet counts from Month 6 to Month 12 in the 2 groups originally randomized to treatment with Cerezyme and to combination therapy, 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 5-8).
Liver volume results from Study 3 and extension are summarized in Table 5:
| Cerezyme alone | Zavesca alone | Combination | |
|---|---|---|---|
| |||
| Study 3 | n=11 | n=10 | n=9 |
| Month 0 | 1.81 | 1.58 | 2.01 |
| Month 6 Change (L) | 0.04 | -0.05 | -0.09 |
| Month 6 % Change | 3.6% | -2.9% | -4.9% |
| Adjusted mean Difference from Cerezyme (95% CI) | -4.5% (-13.2, 4.2) | -8.4% (-16.6, -0.1) | |
| Extension Phase* | n=10 | n=8 | n=8 |
| Month 0 | 1.94 | 1.60 | 2.04 |
| Month 12 Change (L) | -0.05 | -0.01 | -0.08 |
| Month 12 % Change | -0.7% | -0.8% | -4.0% |
Spleen volume results from Study 3 and extension are summarized in Table 6:
| Cerezyme alone | Zavesca alone | Combination | |
|---|---|---|---|
| |||
| Study 3 | n=8 | n=7 | n=7 |
| Month 0 | 0.61 | 0.69 | 0.76 |
| Month 6 Change (L) | -0.02 | -0.03 | -0.08 |
| Month 6 % Change | -2.1% | -4.8% | -8.5% |
| Adjusted % Difference from Cerezyme (95% CI) | -5.8% (-22.1, 10.5) | -6.4% (-21.0, 8.2) | |
| Extension Phase* | n=7 | n=6 | n=6 |
| Month 0 | 0.83 | 0.57 | 0.84 |
| Month 12 Change (L) | 0.04 | -0.05 | -0.05 |
| Month 12 % Change | 1.5% | -6.1% | -4.8% |
Hemoglobin concentration results from Study 3 and extension are summarized in Table 7:
| Cerezyme alone | Zavesca alone | Combination | |
|---|---|---|---|
| |||
| Study 3 | n=12 | n=10 | n=11 |
| Month 0 | 13.18 | 12.44 | 12.38 |
| Month 6 Change (g/L) | -0.15 | -0.31 | -0.10 |
| Month 6 % Change | -1.2% | -2.4% | -0.5% |
| Adjusted % Difference from Cerezyme (95% CI) | -1.9% (-6.4, 2.6) | -0.6% (-4.8, 3.5) | |
| Extension Phase* | n=10 | n=9 | n=9 |
| Month 0 | 13.39 | 12.46 | 12.20 |
| Month 12 Change (g/L) | -0.48 | -0.13 | -0.13 |
| Month 12 % Change | -3.1% | -1.1% | -0.8% |
Platelet count results from Study 3 and extension are summarized in Table 8:
| Cerezyme alone | Zavesca alone | Combination | |
|---|---|---|---|
| |||
| Study 3 | n=12 | n=10 | n=11 |
| Month 0 | 165.75 | 170.55 | 152.14 |
| Month 6 Change (109/L) | 15.29 | -21.60 | 2.73 |
| Month 6 % Change | 10.1% | -9.6% | 3.2% |
| Adjusted % Difference from Cerezyme (95% CI) | -17.1% (-32.9, -1.3) | -4.6% (-19.9, 10.7) | |
| Extension Phase* | n=10 | n=9 | n=9 |
| Month 0 | 170.05 | 184.83 | 136.33 |
| Month 12 Change (109/L) | -3.75 | -27.39 | -12.22 |
| Month 12 % Change | -3.2% | -10.4% | -8.3% |
In patients with platelet counts above 150 × 109/L at baseline, there were significant decreases in platelet counts at Month 12 in patients randomized to Zavesca treatment.
Summary of clinical studies
Treatment with Zavesca as monotherapy at a starting dose of 100 mg three times daily (dosage range 100 mg once daily to 200 mg three times daily) in adult type 1 Gaucher disease patients who were either treatment naïve or who had not taken enzyme replacement therapy in the previous 6 months resulted in decreases in liver and spleen volume after 12 months of treatment, and increases in platelet counts and hemoglobin concentration after 24 months of treatment. However, in adult type I Gaucher disease patients who had been treated with enzyme replacement therapy for at least 2 years, switching to Zavesca as monotherapy was associated with decreases in platelet counts after discontinuation of enzyme replacement therapy. Platelet counts also declined after discontinuation of enzyme replacement therapy in patients treated with combination therapy.
The efficacy and safety of Zavesca has not been evaluated in patients with severe type 1 Gaucher disease, defined as a hemoglobin concentration below 9 g/dL or a platelet count below 50 × 109/L or active bone disease.
Indications and Usage for Zavesca
Zavesca is indicated for the treatment of adult patients with mild to moderate type 1 Gaucher disease for whom enzyme replacement therapy is not a therapeutic option (e.g. due to constraints such as allergy, hypersensitivity, or poor venous access).
Contraindications
Zavesca is contraindicated in patients who have demonstrated hypersensitivity to the active substance or any of the excipients.
Pregnancy Category X
Miglustat may cause fetal harm when administered to a pregnant woman. In female rats given miglustat by oral gavage at doses of 20, 60, 180 mg/kg/day beginning 14 days before mating and continuing through gestation day 17 (organogenesis), decreased live births including complete litter loss and decreased fetal weight was observed in the mid- and high-dose groups (systemic exposures ≥2 times the human therapeutic systemic exposure based on body surface area comparison). In pregnant rats given miglustat by oral gavage at doses of 20, 60, 180 mg/kg/day from gestation day 6 through lactation (postpartum day 20), dystocia and delayed parturition were observed in the mid- and high-dose groups (systemic exposures ≥2 times the human therapeutic systemic exposure, based on body surface area comparison), in addition decreased live births and pup body weights were observed at >20 mg/kg/day (systemic exposures less than the human therapeutic systemic exposure, based on body surface area comparison).
In pregnant rabbits given miglustat by oral gavage at doses of 15, 30, 45 mg/kg/day during gestation days 6-18 (organogenesis), maternal death and decreased body weight gain were observed at 15 mg/kg/day (systemic exposures less than the human therapeutic systemic exposure, based on body surface area comparisons).
Zavesca is contraindicated in women who are or may become pregnant. If this drug is administered to a woman with reproductive potential, the patient should be apprised of the potential hazard to a fetus.
Warnings
Peripheral Neuropathy
Cases of peripheral neuropathy have been reported in patients treated with Zavesca. All patients receiving Zavesca treatment should undergo baseline and repeat neurological evaluations at approximately 6-month intervals. Patients who develop symptoms such as numbness and tingling should have a careful re-assessment of the risk/benefit of Zavesca therapy and cessation of treatment may be considered.
Precautions
General
Therapy should be directed by physicians knowledgeable in the management of patients with Gaucher disease.
Tremor
Approximately 30% of patients have reported tremor or exacerbation of existing tremor on treatment. These tremors were described as an exaggerated physiological tremor of the hands. Tremor usually began within the first month of therapy and in many cases resolved between 1 to 3 months during treatment. Dose reduction may ameliorate the tremor usually within days but discontinuation with treatment may sometimes be required.
Diarrhea and Weight Loss
Diarrhea and weight loss were common in clinical studies of patients treated with Zavesca, with approximately 85% and up to 65% of treated patients, respectively, reporting these conditions. Diarrhea appears to be the result of the disaccharidase inhibitory activity of Zavesca, with a resultant osmotic diarrhea. It is unclear if weight loss results from the diarrhea and associated gastrointestinal complaints, a decrease in food intake, or a combination of these or other factors. The incidence of weight loss was most evident in the first 12 months of treatment. The incidence of diarrhea was noted to decrease over time with continued Zavesca treatment, and was noted to result in an increase in the use of anti-diarrheal medications, most commonly loperamide. Patients may be instructed to avoid high carbohydrate content foods during treatment with Zavesca if they present with diarrhea.
Patients with persistent gastrointestinal events that continue during treatment with Zavesca, and who do not respond to usual interventions (e.g. diet modification), should be evaluated to determine whether significant underlying gastrointestinal disease is present. The safety of treatment with Zavesca has not been evaluated in patients with significant gastrointestinal disease, such as inflammatory bowel disease, and continued treatment of these patients with Zavesca should occur only after consideration of the risks and benefits of continued treatment.
Reductions in Platelet Count
In a clinical trial evaluating the use of Zavesca for another indication, mild reductions in platelet counts without association with bleeding were observed in some patients; approximately 40% of patients in this trial had low platelet counts (defined as below 150 × 109/L) before starting treatment with Zavesca.
Male Fertility
Male patients should maintain reliable contraceptive methods while taking Zavesca. Studies in the rat have shown that miglustat adversely affects spermatogenesis and sperm parameters, thereby reducing fertility. Until further information is available, it is advised that before seeking to conceive, male patients should cease Zavesca and maintain reliable contraceptive methods for 3 months thereafter (see Carcinogenesis, Mutagenesis, and Impairment of Fertility).
Information for Patients
Patients should be informed of the potential risks and benefits of Zavesca and of alternative modes of therapy. Patients should be advised that diarrhea, gastrointestinal complaints, and weight loss are common side effects of Zavesca therapy, and to adhere to dietary instructions. Patients should also be advised to promptly report any numbness, pain, or burning in the hands and feet, and the development of tremor or worsening in an existing tremor.
Drug Interactions
While co-administration of Zavesca appeared to increase the clearance of Cerezyme by 70%, these results are not conclusive because of the small number of subjects studied and because patients took variable doses of Cerezyme. Combination therapy with Cerezyme (imiglucerase) and Zavesca is not indicated (see CLINICAL PHARMACOLOGY, Drug Interactions).
Animal Toxicology
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 52-week oral gavage toxicity study using doses of 750 and 2000 mg/kg/d.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
Two year carcinogenicity studies have been conducted with miglustat in CD-1 mice at oral doses up to 500 mg/kg/day and in Sprague Dawley rats at oral doses up to 180 mg/kg/day. Oral administration of miglustat for 104 weeks produced mucinous adenocarcinomas of the large intestine at 210, 420 and 500 mg/kg/day (about 3, 6 and 7 times the recommended human dose, respectively, based on the body surface area) in male mice and at 420 and 500 mg/kg/day (about 6 and 7 times the recommended human dose, respectively, based on the body surface area) in female mice. The adenocarcinomas were considered rare in CD-1 mice and occurred in the presence of inflammatory and hyperplastic lesions in the large intestine of both males and females. In rats, oral administration of miglustat for 100 weeks produced increased incidences of interstitial cell adenomas of the testis at 30, 60 and 180 mg/kg/day (about 1, 2 and 5 times the recommended human dose, respectively, based on the body surface area).
Miglustat was not mutagenic or clastogenic in a battery of in vitro and in vivo assays including the bacterial reverse mutation (Ames), chromosomal aberration (in human lymphocytes), gene mutation in mammalian cells (Chinese hamster ovary), and mouse micronucleus assays.
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