Mitoxantrone (Page 2 of 11)

Drug Interactions

In vitro drug interaction studies have demonstrated that mitoxantrone did not inhibit CYP450, 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4 across a broad concentration range. The results of in vitro induction studies are inconclusive, but suggest that mitoxantrone may be a weak inducer of CYP450 2E1 activity.

Pharmacokinetic studies of the interaction of mitoxantrone with concomitantly administered medications in humans have not been performed. The pathways leading to the metabolism of mitoxantrone have not been elucidated. To date, post-marketing experience has not revealed any significant drug interactions in patients who have received mitoxantrone for treatment of cancer. Information on drug interactions in patients with multiple sclerosis is limited.

CLINICAL TRIALS

Multiple Sclerosis

The safety and efficacy of mitoxantrone in multiple sclerosis were assessed in two randomized, multicenter clinical studies.

One randomized, controlled study (Study 1) was conducted in patients with secondary progressive or progressive relapsing multiple sclerosis. Patients in this study demonstrated significant neurological disability based on the Kurtzke Expanded Disability Status Scale (EDSS). The EDSS is an ordinal scale with 0.5 point increments ranging from 0.0 to 10.0 (increasing score indicates worsening) and based largely on ambulatory impairment in its middle range (EDSS 4.5 to 7.5 points). Patients in this study had experienced a mean deterioration in EDSS of about 1.6 points over the 18 months prior to enrollment.

Patients were randomized to receive placebo, 5 mg/m2 mitoxantrone, or 12 mg/m2 mitoxantrone administered IV every 3 months for 2 years. High dose methylprednisolone was administered to treat relapses. The intent-to-treat analysis cohort consisted of 188 patients; 149 completed the 2-year study. Patients were evaluated every 3 months, and clinical outcome was determined after 24 months. In addition, a subset of patients was assessed with magnetic resonance imaging (MRI) at baseline, Month 12, and Month 24. Neurologic assessments and MRI reviews were performed by evaluators blinded to study drug and clinical outcome, although the diagnosis of relapse and the decision to treat relapses with steroids were made by unblinded treating physicians. A multivariate analysis of five clinical variables (EDSS, Ambulation Index [AI], number of relapses requiring treatment with steroids, months to first relapse needing treatment with steroids, and Standard Neurological Status [SNS]) was used to determine primary efficacy. The AI is an ordinal scale ranging from 0 to 9 in one point increments to define progressive ambulatory impairment. The SNS provides an overall measure of neurologic impairment and disability, with scores ranging from 0 (normal neurologic examination) to 99 (worst possible score).

Results of Study 1 are summarized in Table 1.

Table 1: Efficacy Results at Month 24. Study 1
Treatment Groups p-value
Primary Endpoints Placebo (n=64) Mitoxantrone 5 mg/m2 (N=64)

Mitoxantrone

12 mg/m2 (N=60)

Placebo vs.

12 mg/m2 Mitoxantrone

Primary efficacy multivariate analysis* Primary clinical variables analyzed: < 0.0001
EDSS change** (mean) 0.23 – 0.23 – 0.13 0.0194
Ambulation Index change** (mean) 0.77 0.41 0.30 0.0306
Mean number of relapses per patient

requiring corticosteroid treatment

(adjusted for discontinuation)

1.20 0.73 0.40 0.0002
Months to first relapse requiring corticosteroid treatment (median [1st quartile]) 14.2 [6.7] NR [6.9] NR [20.4] 0.0004
Standard Neurological Status change** (mean) 0.77 – 0.38 – 1.07 0.0269
MRI‡
No. of patients with new Gd-enhancing lesions 5/32 (16%) 4/37 (11%) 0/31 0.022
Change in number of T2-weighted lesions, mean (n)** 1.94 (32) 0.68 (34) 0.29 (28) 0.027

NR = not reached within 24 months; MRI = magnetic resonance imaging.

* Wei-Lachin test.

** Month 24 value minus baseline.

‡ A subset of 110 patients was selected for MRI analysis. MRI results were not available for all patients at all time points.

A second randomized, controlled study (Study 2) evaluated mitoxantrone in combination with methylprednisolone (MP) and was conducted in patients with secondary progressive or worsening relapsing-remitting multiple sclerosis who had residual neurological deficit between relapses. All patients had experienced at least two relapses with sequelae or neurological deterioration within the previous 12 months. The average deterioration in EDSS was 2.2 points during the previous 12 months. During the screening period, patients were treated with two monthly doses of 1 g of IV MP and underwent monthly MRI scans. Only patients who developed at least one new Gd-enhancing MRI lesion during the 2-month screening period were eligible for randomization. A total of 42 evaluable patients received monthly treatments of 1 g of IV MP alone (n = 21) or ~12 mg/m2 of IV mitoxantrone plus 1 g of IV MP (n = 21) (MITO + MP) for 6 months. Patients were evaluated monthly, and study outcome was determined after 6 months. The primary measure of effectiveness in this study was a comparison of the proportion of patients in each treatment group who developed no new Gd-enhancing MRI lesions at 6 months; these MRIs were assessed by a blinded panel. Additional outcomes were measured, including EDSS and number of relapses, but all clinical measures in this trial were assessed by an unblinded treating physician. Five patients, all in the MP alone arm, failed to complete the study due to lack of efficacy.

The results of this trial are displayed in Table 2.

Table 2: Efficacy Results. Study 2
Primary Endpoint MP alone (N = 21) MITO + MP (N = 21) p-value
Patients (%) without new Gd-enhancing lesions on MRIs (primary endpoint)* 5 (31%) 19 (90%) 0.001

EDSS change (Month 6 minus baseline)* (mean)

-0.1 -1.1 0.013
Annualized relapse rate (mean per patient) 3.0 0.7 0.003
Patients (%) without relapses 7 (33%) 14 (67%) 0.031

MP = methylprednisolone; MITO + MP = mitoxantrone plus methylprednisolone.

* Results at Month 6, not including data for 5 withdrawals in the MP alone group.

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