"Sabahaddin Akman, owner of the Istanbul, Turkey, firm Ozay Pharmaceuticals, has pleaded guilty to charges of smuggling misbranded and adulterated cancer treatment drugs into the United States.
Akman pleaded guilty in the U.S. District Court"...
Mechanism Of Action
Romidepsin is a histone deacetylase (HDAC) inhibitor. HDACs catalyze the removal of acetyl groups from acetylated lysine residues in histones, resulting in the modulation of gene expression. HDACs also deacetylate non-histone proteins, such as transcription factors. In vitro, romidepsin causes the accumulation of acetylated histones, and induces cell cycle arrest and apoptosis of some cancer cell lines with IC50 values in the nanomolar range. The mechanism of the antineoplastic effect of romidepsin observed in nonclinical and clinical studies has not been fully characterized.
The effect of romidepsin on the heart-rate corrected QTc/QTcF was evaluated in 26 subjects with advanced malignancies given romidepsin at doses of 14 mg/m² as a 4-hour intravenous infusion, and at doses of 8, 10 or 12 mg/m² as a 1–hour infusion. Patients received premedications with antiemetics. No large changes in the mean QTc interval ( > 20 milliseconds) from baseline based on Fridericia correction method were detected in the trial. Small increase in mean QT interval ( < 10 milliseconds) and mean QT interval increase between 10 to 20 milliseconds cannot be excluded because of the limitations in the trial design.
Romidepsin was associated with a delayed concentration-dependent increase in heart rate in patients with advanced cancer with a maximum mean increase in heart rate of 20 beats per minute occurring at the 6 hour time point after start of romidepsin infusion for patients receiving 14 mg/m² as a 4-hour infusion.
Romidepsin exhibited linear pharmacokinetics across doses ranging from 1.0 to 24.9 mg/m² when administered intravenously over 4 hours in patients with advanced cancers.
In patients with T-cell lymphomas who received 14 mg/m² of romidepsin intravenously over a 4-hour period on days 1, 8, and 15 of a 28-day cycle, geometric mean values of the maximum plasma concentration (Cmax) and the area under the plasma concentration versus time curve (AUC0-inf) were 377 ng/mL and 1549 ng*hr/mL, respectively.
Romidepsin is highly protein bound in plasma (92% to 94%) over the concentration range of 50 ng/mL to 1000 ng/mL with α1-acid-glycoprotein (AAG) being the principal binding protein. Romidepsin is a substrate of the efflux transporter P-glycoprotein (P-gp, ABCB1).
In vitro, romidepsin accumulates into human hepatocytes via an unknown active uptake process. Romidepsin is not a substrate of the following uptake transporters: BCRP, BSEP, MRP2, OAT1, OAT3, OATP1B1, OATP1B3, or OCT2. In addition, romidepsin is not an inhibitor of BCRP, MRP2, MDR1 or OAT3. Although romidepsin did not inhibit OAT1, OCT2, and OATP1B3 at concentrations seen clinically (1 μmol/L), modest inhibition was observed at 10 μmol/L. Romidepsin was found to be an inhibitor of BSEP and OATP1B1.
Romidepsin undergoes extensive metabolism in vitro primarily by CYP3A4 with minor contribution from CYP3A5, CYP1A1, CYP2B6, and CYP2C19. At therapeutic concentrations, romidepsin did not competitively inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4 in vitro.
At therapeutic concentrations, romidepsin did not cause notable induction of CYP1A2, CYP2B6 and CYP3A4 in vitro. Therefore, pharmacokinetic drug-drug interactions are unlikely to occur due to CYP450 induction or inhibition by romidepsin when co-administered with CYP450 substrates.
Following 4-hour intravenous administration of romidepsin at 14 mg/m² on days 1, 8, and 15 of a 28-day cycle in patients with T-cell lymphomas, the terminal half-life (t½) was approximately 3 hours. No accumulation of plasma concentration of romidepsin was observed after repeated dosing.
Ketoconazole: A drug interaction clinical trial with the strong CYP3A4 inhibitor, ketoconazole, was conducted in patients with advanced cancer. Following coadministration of 8 mg/m² ISTODAX (4-hour infusion) with ketoconazole, the overall romidepsin exposure was increased by approximately 25% and 10% for AUC0-∞ and Cmax, respectively, compared to romidepsin alone, and the difference in AUC0-∞ between the 2 treatments was statistically significant. Co-administration of ketoconazole slightly decreased the romidepsin clearance and volume of distribution, but did not have a statistically significant effect on peak exposure (Cmax) [see DRUG INTERACTIONS].
Rifampin: A drug interaction clinical trial with the strong CYP3A4 inducer, rifampin, was conducted in patients with advanced cancer. Following co-administration of 14 mg/m² ISTODAX (4-hour infusion) with rifampin, the overall romidepsin exposure was unexpectedly increased by approximately 80% and 60% for AUC0-∞ and Cmax, respectively, compared to romidepsin alone, and the difference between the 2 treatments was statistically significant. Co-administration of rifampin decreased the romidepsin clearance and volume of distribution by 44% and 52%, respectively. The increase in exposure seen after co-administration with rifampin is likely due to rifampin's inhibition of an undetermined hepatic uptake process that is predominant for the disposition of ISTODAX [see DRUG INTERACTIONS].
Use in Specific Populations
Effect of Age, Gender or Race
The population pharmacokinetic analysis of romidepsin showed that age, gender, or race (white vs. black) did not appear to influence the pharmacokinetics of romidepsin.
Effect of Hepatic Impairment
No dedicated hepatic impairment study ha s been conducted for ISTODAX. The population pharmacokinetic analysis indicates that mild hepatic impairment [total bilirubin (TB) ≤ upper limit of normal (ULN) and aspartate aminotransferase (AST) > ULN; or TB > 1.0x -1.5x ULN and any AST] had no significant influence on romidepsin pharmacokinetics. As the effect of moderate (TB > 1.5x -3x ULN and any AST) and severe (TB > 3x ULN and any AST) hepatic impairment on the pharmacokinetics of romidepsin is unknown, patients with moderate and severe hepatic impairment should be treated with caution [see Use in Specific Populations].
Effect of Renal Impairment
No dedicated renal impairment study has been conducted for ISTODAX. The population pharmacokinetic analysis showed that romidepsin pharmacokinetics were not affected by mild (estimated creatinine clearance 50 -80 mL/min), moderate (estimated creatinine clearance 30 -50 mL/min), or severe (estimated creatinine clearance < 30 mL/min) renal impairment. Nonetheless, the effect of end-stage renal disease on romidepsin pharmacokinetics has not been studied. Thus, patients with end-stage renal disease should be treated with caution [see Use in Specific Populations].
Cutaneous T-Cell Lymphoma
ISTODAX was evaluated in 2 multicenter, single-arm clinical studies in patients with CTCL. Overall, 167 patients with CTCL were treated in the US, Europe, and Au stralia. Study 1 included 96 patients with confirmed CTCL after failure of at least 1 prior systemic therapy. Study 2 included 71 patients with a primary diagnosis of CTCL who received at least 2 prior skin directed therapies or one or more systemic therapies. Patients were treated with ISTODAX at a starting dose of 14 mg/m² infused over 4 hours on days 1, 8, and 15 every 28 days.
In both studies, patients could be treated until disease progression at the discretion of the investigator and local regulators. Objective disease response was evaluated according to a composite endpoint that included assessments of skin involvement, lymph node and visceral involvement, and abnormal circulating T-cells (“Sézary cells”).
The primary efficacy endpoint for both studies was overall objective disease response rate (ORR) based on the investigator assessments, and defined as the proportion of patients with confirmed complete response (CR) or partial response (PR). CR was defined as no evidence of disease and PR as ≥ 50% improvement in disease. Secondary endpoints in both studies included duration of response and time to response.
Baseline Patient Characteristics
Demographic and disease characteristics of the patients in Study 1 and Study 2 are provided in Table 3.
Table 3: Baseline Patient Characteristics (CTCL
|Characteristic||Study 1 (N=96)||Study 2 (N=71)|
|Mean (SD)||57 (12)||56 (13)|
|Median (Range)||57 (21, 89)||57 (28, 84)|
|Sex, n (%)|
|Men||59 (61)||48 (68)|
|Women||37 (39)||23 (32)|
|Race, n (%)|
|White||90 (94)||55 (77)|
|Black||5 ( 5)||15 (21)|
|Other/Not Reported||1 ( 1)||1 ( 1)|
|Stage of Disease at Study Entry, n (%)|
|IA||0 ( 0)||1 ( 1)|
|IB||15 (16)||6 ( 9)|
|IIA||13 (14)||2 ( 3)|
|IIB||21 (22)||14 (20)|
|III||23 (24)||9 (13)|
|IVA||24 (25)||27 (38)|
|IVB||0 ( 0)||12 (17)|
|Number of Prior Skin-Directed Therapies|
|Median (Range)||2 (0,6)||1 (0,3)|
|Number of Prior Systemic Therapies|
|Median (Range)||2 (1, 8)||2 (0, 7)|
Efficacy outcomes for CTCL patients are provided in Table 4. Median time to first response was 2 months (range 1 to 6) in both studies. Median time to CR was 4 months in Study 1 and 6 months in Study 2 (range 2 to 9).
Table 4: Clinical Results
for CTCL Patients
|Response Rate||Study 1
|ORR (CR + PR), n (%)||33 (34)||25 (35)|
|[95% Confidence Interval]||[25, 45]||[25, 49]|
|CR, n (%)||6 (6)||4 (6)|
|[95% Confidence Interval]||[2, 13]||[2, 14]|
|PR, n (%)||27 (28)||21 (30)|
|[95% Confidence Interval]||[19, 38]||[20, 43]|
|Duration of Response (months)|
|Median (range)||15 (1, 20*)||11 (1, 66*)|
|*denotes censored value|
Peripheral T-Cell Lymphoma
ISTODAX was evaluated in a multicenter, single-arm, international clinical study in patients with PTCL who had failed at least 1 prior systemic therapy (Study 3). Patients in US, Europe, and Australia were treated with ISTODAX at a dose of 14 mg/m² infused over 4 hours on days 1, 8, and 15 every 28 days. Of the 131 patients treated, 130 patients had histological confirmation by independent central review and were evaluable for efficacy (HC Population). Six cycles of treatment were planned; patients who developed progressive disease (PD), significant toxicity, or who met another criterion for study termination were to discontinue treatment. Responding patients had the option of continuing treatment beyond 6 cycles at the discretion of the patient and Investigator until study withdrawal criteria were met.
Primary assessment of efficacy was based on rate of complete response (CR + CRu) as determined by an Independent Review Committee (IRC) using the International Workshop Response Criteria (IWC). Secondary measures of efficacy included IRC assessment of duration of response and objective disease response (ORR, CR + CRu + PR).
Baseline Patient Characteristics
Demographic and disease characteristics of the PTCL patients are provided in Table 5.
Table 5: Baseline Patient
Characteristics (PTCL Population)
|Age (years), n||130||47|
|Mean (SD)||59 (13)||59 (13)|
|Sex, n (%)|
|Male||88 (68)||25 (53)|
|Female||42 (32)||22 (47)|
|Race, n (%)|
|White||116 (89)||40 (85)|
|Black||7 (5)||4 (9)|
|Asian||3 (2)||3 (6)|
|PTCL Subtype Based on Central Diagnosis, n (%)|
|PTCL Unspecified (NOS)||69 (53)||28 (60)|
|Angioimmunoblastic T-cell lymphoma (AITL)||27 (21)||7 (15)|
|ALK-1 negative anaplastic large cell lymphoma (ALCL)||21 (16)||5 (11)|
|Other||13 (10)||7 (16)|
|Stage of Disease, n (%)*|
|I/II||39 (30)||2 (4)|
|III/IV||91 (70)||45 (96)|
|ECOG Performance Status, n (%)|
|0||46 (35)||20 (43)|
|1||67 (51)||22 (47)|
|2||17 (13)||4 (9)|
|Number of Prior Systemic Therapies|
|Median (Range)||2 (1, 8)||3 (1, 6)|
|*Stage of disease was reported at time of diagnosis for Study 3 and at time of study entry for Study 4.|
All patients in both studies had received prior systemic therapy for PTCL. In Study 4, a greater percentage of patients had extensive prior radiation and chemotherapy. Twenty-one patients (16%) in Study 3 and 18 patients (38%) in Study 4 had received prior autologous stem cell transplant and 31 (24%) and 19 (40%) patients, respectively, had received prior radiation therapy.
Efficacy outcomes for PTCL patients as determined by the IRC are provided in Table 6 for Study 3. The complete response rate was 15% and overall response rate was 26%. Similar complete response rates were observed by the IRC across the 3 major PTCL subtypes (NOS, AITL, and ALK-1 negative ALCL). Median time to objective response was 1.8 months (~2 cycles) for the 34 patients who achieved CR, CRu, or PR and median time to CR was 3.5 months (~4 cycles) for the 20 patients with complete response. The responses in 12 of the 20 patients achieving CR and CRu were known to exceed 11.6 months; the follow-up on the remaining 8 patients was discontinued prior to 8.5 months.
Table 6: Clinical Results
for PTCL Patients
|Response Rate||Study 3 (N=130)|
|CR+CRu, n (%)1||20 (15.4) [9.7, 22.8]3|
|PR, n (%)2||14 (10.8) [6.0, 17.4]3|
|ORR (CR+CRu+PR), n (%)2||34 (26.2) [18.8, 34.6]3|
3Two-sided 95% Confidence Interval.
In a second single-arm clinical study in patients with PTCL who had failed prior therapy (Study 4), patients were treated with ISTODAX at a starting dose of 14 mg/m² infused over 4 hours on days 1, 8, and 15 every 28 days. Patients could be treated until disease progression at the discretion of the patient and the Investigator. The percentage of patients achieving CR + CRu in Study 4 was similar to that in Study 3.
Last reviewed on RxList: 11/3/2014
This monograph has been modified to include the generic and brand name in many instances.
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