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Pomalyst

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Pomalyst

CLINICAL PHARMACOLOGY

Mechanism of action

Pomalidomide, an analogue of thalidomide, is an immunomodulatory agent with antineoplastic activity. In in vitro cellular assays, pomalidomide inhibited proliferation and induced apoptosis of hematopoietic tumor cells. Additionally, pomalidomide inhibited the proliferation of lenalidomide-resistant multiple myeloma cell lines and synergized with dexamethasone in both lenalidomide-sensitive and lenalidomide-resistant cell lines to induce tumor cell apoptosis. Pomalidomide enhanced T cell- and natural killer (NK) cell-mediated immunity and inhibited production of pro-inflammatory cytokines (e.g., TNF-α and IL-6) by monocytes. Pomalidomide demonstrated anti-angiogenic activity in a mouse tumor model and in the in vitro umbilical cord model.

Pharmacokinetics

Absorption

Following administration of single oral doses of POMALYST, the Cmax for pomalidomide occurs at 2 and 3 hours post dose. The systemic exposure (AUC) of pomalidomide increases in an approximately dose proportional manner.

In patients with multiple myeloma who received POMALYST 4 mg daily alone or in combination with dexamethasone, pomalidomide steady-state drug exposure was characterized by AUC(T) of 400 ng.hr/ mL and maximum plasma concentration (Cmax) of 75 ng/mL. Following multiple doses, pomalidomide has an accumulation ratio of 27 to 31 %.

Distribution

Pomalidomide has a mean apparent volume of distribution (Vd/F) between 62 and 138 L at steady state. Pomalidomide is distributed in semen of healthy subjects at a concentration of approximately 67% of plasma level at 4 hours post-dose (~Tmax) after 4 days of once daily dosing at 2 mg. Human plasma protein binding ranges from 12% to 44% and is not concentration dependent.

Metabolism

Pomalidomide is primarily metabolized in the liver by CYP1A2 and CYP3A4. In vitro, CYP1A2 and CYP3A4 were identified as the primary enzymes involved in the CYP-mediated hydroxylation of pomalidomide, with additional minor contributions from CYP2C19 and CYP2D6.

Elimination

Pomalidomide is eliminated with a median plasma half-life of approximately 9.5 hours in healthy subjects and approximately 7.5 hours in patients with multiple myeloma. Pomalidomide has a mean total body clearance (CL/ F) of 7-10 L/ hr.

Following a single oral administration of [14C]-pomalidomide (2 mg) to healthy subjects, approximately 73% and 15% of the radioactive dose was eliminated in urine and feces, respectively, with approximately 2% and 8% of the radiolabeled dose eliminated unchanged as pomalidomide in urine and feces.

Drug-Drug Interactions

Pomalidomide does not inhibit or induce CYP450 enzymes or any of the transporters in vitro.

Clinical Studies

Multiple Myeloma

Trial 1 was a Phase 2, multicenter, randomized open label study in patients with relapsed multiple myeloma who were refractory to their last myeloma therapy and had received lenalidomide and bortezomib. Patients were considered relapsed if they had achieved at least stable disease for at least one cycle of treatment to at least one prior regimen and then developed progressive disease. Patients were considered refractory if they experienced disease progression on or within 60 days of their last therapy. A total of 221 patients were randomized to receive POMALYST alone or POMALYST with Low dose Dex. In Trial 1, the safety and efficacy of POMALYST 4 mg, once daily for 21 of 28 days, until disease progression, were evaluated alone and in combination with Low dose Dex (40 mg per day given only on Days 1, 8, 15 and 22 of each 28-day cycle for patients 75 years or younger, or 20mg per day given only on Days 1, 8, 15 and 22 of each 28-day cycle for patients greater than 75 years of age). Patients in the POMALYST alone arm were allowed to add Low dose Dex upon disease progression.

Table 5 summarizes the baseline patient and disease characteristics in study Trial 1. The baseline demographics and disease characteristics were balanced and comparable between the study arms.

Table 5: Baseline Demographic and Disease-Related Characteristics – Trial 1

  POMALYST
(N=108)
POMALYST/Low dose Dex
(N=113)
Patient Characteristics
Median Age, years (range) 61 (37, 88) 64 (34, 88)
Age Distribution n (%)
   < 65 years 65 (60.2) 60 (53.1)
  greater than or equal to 65 years 43 (39.8) 53 (46.9)
Sex n (%)
  Male 57 (52.8) 62 (54.9)
  Female 51 (47.2) 51 (45.1)
Race/Ethnicity n (%)
  White 86 (79.6) 92 (81.4)
  Black or African American 16 (14.8) 17 (15)
  All Other Race 6 (5.6) 4 (3.6)
ECOG Performance n (%) Status 0-1 95 (87.9) 100 (88.5)
Disease Characteristics
Number of Prior Therapies Median, (Min, Max) 5 (2, 12) 5 (2,13)
Prior transplant n (%) 82 (75.9) 84 (74.3)
Refractory to bortezomib and lenalidomide n (%) 64 (59.3) 69 (61.1)

Table 6 summarizes the analysis results of overall response rate (ORR) and duration of response (DOR), based on assessments by the Independent Review Adjudication Committee for the treatment arms in Study 1. Overall response rate did not differ based on type of prior anti-myeloma therapy.

Table 6: Trial 1 Results

  POMALYST2
(N=108)
POMALYST/ Low dose Dex
(N = 113)
Response
Overall Response Rate (ORR)1 , n (%) 8 (7.4) 33 (29.2)
95% CI for ORR (%) (3.3, 14.1) (21.0, 38.5)
Complete Response (CR), n (%) 0 (0.0) 1 (0.9)
Partial Response (PR), n (%) 8 (7.4) 32 (28 .3)
Duration of Response (DOR)
Median (months) NE 7.4
95% CI for DOR (months) NE (5.1, 9.2)
1ORR =PR+CR per EBMT criteria,
2Results are prior to the addition of dexamethasone
NE = not established (the median has not yet been reached), CI: confidence interval

REFERENCES

1. OSHA Hazardous Drugs. OSHA. [Accessed on 29 January 2013, from http://www.osha.gov/SLTC/hazardousdrugs/index.html]

Last reviewed on RxList: 2/21/2013
This monograph has been modified to include the generic and brand name in many instances.

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