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Simon Zhou - One of the best experts on this subject based on the ideXlab platform.

  • Recurrent or progressive pediatric brain tumors: population pharmacokinetics and exposure–response analysis of Pomalidomide
    Pediatric Research, 2021
    Co-Authors: Ken Ogasawara, Xiaomin Wang, Simon Zhou, Nastya Kassir, Bouchra Benettaib, Maria Palmisano
    Abstract:

    Background Pomalidomide, an immunomodulatory drug, was investigated for pediatric brain tumors. The objectives of this analysis were to characterize the PK of Pomalidomide and to examine exposure–response relationship in pediatric patients with recurrent or progressive primary brain tumors. Methods Nonlinear mixed effects modeling was employed in developing a population PK model of Pomalidomide using a total of 343 concentrations from 70 patients. Logistic regression models were used for exposure–response analyses. Results The PK of Pomalidomide was adequately described with a one compartment model with first-order absorption and elimination. Body surface area (BSA) was identified as a statistically significant covariate of apparent clearance and volume of distribution; however, the impact of BSA on exposure parameters was not deemed clinically relevant. Pomalidomide exposure was not associated with higher probabilities of treatment-emergent adverse events or Pomalidomide dose interruptions during Cycle 1. Covariates such as BSA, weight, sex, age, and race had no significant effect on safety endpoints. The PK of Pomalidomide in pediatric patients with brain tumors was generally consistent with that in adult patients with multiple myeloma after adjustment for BSA. Conclusions This is the first study to characterize PK of Pomalidomide in pediatric patients, which supports BSA-based dosing for pediatric patients. Impact This is the first study to characterize PK of Pomalidomide in pediatric patients, which supports BSA-based dosing for pediatric patients. There is no significant Pomalidomide PK difference between adults and pediatrics. Pomalidomide exposure was not associated with higher probabilities of treatment-emergent adverse event or Pomalidomide dose interruptions during Cycle 1.

  • Recurrent or progressive pediatric brain tumors: population pharmacokinetics and exposure-response analysis of Pomalidomide.
    Pediatric research, 2021
    Co-Authors: Ken Ogasawara, Xiaomin Wang, Simon Zhou, Nastya Kassir, Bouchra Benettaib, Maria Palmisano
    Abstract:

    Pomalidomide, an immunomodulatory drug, was investigated for pediatric brain tumors. The objectives of this analysis were to characterize the PK of Pomalidomide and to examine exposure-response relationship in pediatric patients with recurrent or progressive primary brain tumors. Nonlinear mixed effects modeling was employed in developing a population PK model of Pomalidomide using a total of 343 concentrations from 70 patients. Logistic regression models were used for exposure-response analyses. The PK of Pomalidomide was adequately described with a one compartment model with first-order absorption and elimination. Body surface area (BSA) was identified as a statistically significant covariate of apparent clearance and volume of distribution; however, the impact of BSA on exposure parameters was not deemed clinically relevant. Pomalidomide exposure was not associated with higher probabilities of treatment-emergent adverse events or Pomalidomide dose interruptions during Cycle 1. Covariates such as BSA, weight, sex, age, and race had no significant effect on safety endpoints. The PK of Pomalidomide in pediatric patients with brain tumors was generally consistent with that in adult patients with multiple myeloma after adjustment for BSA. This is the first study to characterize PK of Pomalidomide in pediatric patients, which supports BSA-based dosing for pediatric patients. This is the first study to characterize PK of Pomalidomide in pediatric patients, which supports BSA-based dosing for pediatric patients. There is no significant Pomalidomide PK difference between adults and pediatrics. Pomalidomide exposure was not associated with higher probabilities of treatment-emergent adverse event or Pomalidomide dose interruptions during Cycle 1.

  • Population Pharmacokinetics and Exposure Response Analysis of Pomalidomide in Subjects With Relapsed or Refractory Multiple Myeloma From the Novel Combination Treatment of Pomalidomide, Bortezomib, and Low-Dose Dexamethasone.
    Journal of clinical pharmacology, 2020
    Co-Authors: Nastya Kassir, Xiaomin Wang, Maria Palmisano, Simon Zhou
    Abstract:

    Multiple myeloma is an incurable progressive neoplastic disease that accounts for 10% of all hematologic malignancies. Even though significant progress has been made in the treatment of newly diagnosed multiple myeloma, the disease follows a relapsing course in the majority of patients, and there is a need for more effective therapeutic options for the treatment of relapsed or refractory multiple myeloma. CC-4047-MM-005 and CC-4047-MM-007 were phase 1 and 3 studies to evaluate the novel combination of Pomalidomide, bortezomib, and low-dose dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma who have already received lenalidomide-based treatments early. This analysis was performed to characterize the population pharmacokinetics (PK) of Pomalidomide from the combination treatment and to examine exposure-response relationships. Our analysis showed that Pomalidomide concentration-time profiles from the combination treatment were adequately described with a 1-compartment PK model, with first-order absorption and elimination and Pomalidomide exhibiting linear and time-invariant PK with moderate variability from the combination treatment. Except for the body surface area, none of the tested covariates had an effect on Pomalidomide PK. Although body surface area was identified as a statistically significant covariate of Pomalidomide PK, the impact was not deemed clinically relevant. A flat exposure-response curve was observed, consistent with a near-saturated drug effect at the tested exposure range suggesting an appropriately recommended clinical dose of 4 mg of Pomalidomide for the combination treatment. Finally, Pomalidomide exposure was not associated with higher probabilities of dose interruption during cycle 1 or dose reduction during the treatment period.

  • In Vivo Assessment of the Effect of CYP1A2 Inhibition and Induction on Pomalidomide Pharmacokinetics in Healthy Subjects
    Journal of clinical pharmacology, 2018
    Co-Authors: Liangang Liu, Xiaomin Wang, Chengyue Zhang, Josephine Reyes, Maria Palmisano, Matthew Hoffmann, Simon Zhou
    Abstract:

    Pomalidomide is an immunomodulatory drug, and the dosage of 4 mg per day taken orally on days 1-21 of repeated 28-day cycles has been approved in the European Union and the United States to treat patients with relapsed/refractory multiple myeloma. In vitro data showed that Pomalidomide is a substrate of multiple cytochrome P450 (CYP) isozymes and that its oxidative metabolism is mediated primarily by CYP1A2 and CYP3A4, with minor contributions from CYP2C19 and CYP2D6. The effect of CYP1A2 inhibition by fluvoxamine (a strong CYP1A2 inhibitor) and CYP1A2 induction by smoking on Pomalidomide pharmacokinetics in healthy subjects has been assessed in 2 separate phase 1 open-label, single-dose studies. Following administration of a single oral dose of 4 mg Pomalidomide, the plasma exposure when coadministered with fluvoxamine was 225.1% and 123.7% of that when administered alone for the total plasma exposure (AUC0-inf ) and the plasma peak exposure (Cmax ), respectively. In smokers with elevated CYP1A2 activity demonstrated by high caffeine clearance (a marker of CYP1A2 induction), the AUC0-inf was 32.3% lower, whereas the Cmax was 14.4% higher than that in nonsmokers. In addition, Pomalidomide was safe and well tolerated as a single oral dose of 4 mg in healthy male smokers and nonsmokers ≥ 40 to ≤ 80 years old, and a single oral dose of 4 mg Pomalidomide coadministered with multiple oral 50-mg doses of the CYP1A2 inhibitor fluvoxamine compared with Pomalidomide alone was safe and well tolerated by the healthy male subjects.

  • An Open-Label, Phase 1 Study to Assess the Effects of Hepatic Impairment on Pomalidomide Pharmacokinetics.
    Clinical Pharmacology in Drug Development, 2018
    Co-Authors: Xiaomin Wang, Liangang Liu, Chengyue Zhang, Diana Gomez, Josephine Reyes, Maria Palmisano, Simon Zhou
    Abstract:

    Pomalidomide is an immunomodulatory drug and the dosage of 4 mg per day taken orally on days 1-21 of repeated 28-day cycles has been approved in the European Union and United States to treat patients with relapsed/refractory multiple myeloma. Because Pomalidomide is extensively metabolized prior to excretion, a total of 32 subjects (8 healthy subjects in group 1; 8 subjects with severe hepatic impairment in group 2; 8 subjects with moderate hepatic impairment in group 3; and 8 subjects with mild hepatic impairment in group 4) were enrolled in a multicenter, open-label, single-dose study to assess the impact of hepatic impairment on Pomalidomide exposure. Following administration of a single oral dose of 4-mg Pomalidomide, the geometric mean ratios of Pomalidomide total plasma exposures (AUC) were 171.5%, 157.5%, and 151.2% and the geometric mean ratios of Pomalidomide plasma peak exposures (Cmax ) were 75.8%, 94.8%, and 94.2% for subjects with severe, moderate, or mild hepatic impairment, respectively, versus healthy subjects. Pomalidomide administered as a single oral 4-mg dose was safe and well tolerated by healthy subjects and subjects with severe, moderate, or mild hepatic impairment. Based on the pharmacokinetic results from this study, the Pomalidomide prescribing information approved by the US Food and Drug Administration recommends for patients with mild or moderate hepatic impairment (Child-Pugh classes A or B), a 3-mg starting daily dose (25% dose reduction) and for patients with severe hepatic impairment (Child-Pugh class C), a 2-mg starting daily dose (50% dose reduction).

Maria Palmisano - One of the best experts on this subject based on the ideXlab platform.

  • Recurrent or progressive pediatric brain tumors: population pharmacokinetics and exposure–response analysis of Pomalidomide
    Pediatric Research, 2021
    Co-Authors: Ken Ogasawara, Xiaomin Wang, Simon Zhou, Nastya Kassir, Bouchra Benettaib, Maria Palmisano
    Abstract:

    Background Pomalidomide, an immunomodulatory drug, was investigated for pediatric brain tumors. The objectives of this analysis were to characterize the PK of Pomalidomide and to examine exposure–response relationship in pediatric patients with recurrent or progressive primary brain tumors. Methods Nonlinear mixed effects modeling was employed in developing a population PK model of Pomalidomide using a total of 343 concentrations from 70 patients. Logistic regression models were used for exposure–response analyses. Results The PK of Pomalidomide was adequately described with a one compartment model with first-order absorption and elimination. Body surface area (BSA) was identified as a statistically significant covariate of apparent clearance and volume of distribution; however, the impact of BSA on exposure parameters was not deemed clinically relevant. Pomalidomide exposure was not associated with higher probabilities of treatment-emergent adverse events or Pomalidomide dose interruptions during Cycle 1. Covariates such as BSA, weight, sex, age, and race had no significant effect on safety endpoints. The PK of Pomalidomide in pediatric patients with brain tumors was generally consistent with that in adult patients with multiple myeloma after adjustment for BSA. Conclusions This is the first study to characterize PK of Pomalidomide in pediatric patients, which supports BSA-based dosing for pediatric patients. Impact This is the first study to characterize PK of Pomalidomide in pediatric patients, which supports BSA-based dosing for pediatric patients. There is no significant Pomalidomide PK difference between adults and pediatrics. Pomalidomide exposure was not associated with higher probabilities of treatment-emergent adverse event or Pomalidomide dose interruptions during Cycle 1.

  • Recurrent or progressive pediatric brain tumors: population pharmacokinetics and exposure-response analysis of Pomalidomide.
    Pediatric research, 2021
    Co-Authors: Ken Ogasawara, Xiaomin Wang, Simon Zhou, Nastya Kassir, Bouchra Benettaib, Maria Palmisano
    Abstract:

    Pomalidomide, an immunomodulatory drug, was investigated for pediatric brain tumors. The objectives of this analysis were to characterize the PK of Pomalidomide and to examine exposure-response relationship in pediatric patients with recurrent or progressive primary brain tumors. Nonlinear mixed effects modeling was employed in developing a population PK model of Pomalidomide using a total of 343 concentrations from 70 patients. Logistic regression models were used for exposure-response analyses. The PK of Pomalidomide was adequately described with a one compartment model with first-order absorption and elimination. Body surface area (BSA) was identified as a statistically significant covariate of apparent clearance and volume of distribution; however, the impact of BSA on exposure parameters was not deemed clinically relevant. Pomalidomide exposure was not associated with higher probabilities of treatment-emergent adverse events or Pomalidomide dose interruptions during Cycle 1. Covariates such as BSA, weight, sex, age, and race had no significant effect on safety endpoints. The PK of Pomalidomide in pediatric patients with brain tumors was generally consistent with that in adult patients with multiple myeloma after adjustment for BSA. This is the first study to characterize PK of Pomalidomide in pediatric patients, which supports BSA-based dosing for pediatric patients. This is the first study to characterize PK of Pomalidomide in pediatric patients, which supports BSA-based dosing for pediatric patients. There is no significant Pomalidomide PK difference between adults and pediatrics. Pomalidomide exposure was not associated with higher probabilities of treatment-emergent adverse event or Pomalidomide dose interruptions during Cycle 1.

  • Population Pharmacokinetics and Exposure Response Analysis of Pomalidomide in Subjects With Relapsed or Refractory Multiple Myeloma From the Novel Combination Treatment of Pomalidomide, Bortezomib, and Low-Dose Dexamethasone.
    Journal of clinical pharmacology, 2020
    Co-Authors: Nastya Kassir, Xiaomin Wang, Maria Palmisano, Simon Zhou
    Abstract:

    Multiple myeloma is an incurable progressive neoplastic disease that accounts for 10% of all hematologic malignancies. Even though significant progress has been made in the treatment of newly diagnosed multiple myeloma, the disease follows a relapsing course in the majority of patients, and there is a need for more effective therapeutic options for the treatment of relapsed or refractory multiple myeloma. CC-4047-MM-005 and CC-4047-MM-007 were phase 1 and 3 studies to evaluate the novel combination of Pomalidomide, bortezomib, and low-dose dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma who have already received lenalidomide-based treatments early. This analysis was performed to characterize the population pharmacokinetics (PK) of Pomalidomide from the combination treatment and to examine exposure-response relationships. Our analysis showed that Pomalidomide concentration-time profiles from the combination treatment were adequately described with a 1-compartment PK model, with first-order absorption and elimination and Pomalidomide exhibiting linear and time-invariant PK with moderate variability from the combination treatment. Except for the body surface area, none of the tested covariates had an effect on Pomalidomide PK. Although body surface area was identified as a statistically significant covariate of Pomalidomide PK, the impact was not deemed clinically relevant. A flat exposure-response curve was observed, consistent with a near-saturated drug effect at the tested exposure range suggesting an appropriately recommended clinical dose of 4 mg of Pomalidomide for the combination treatment. Finally, Pomalidomide exposure was not associated with higher probabilities of dose interruption during cycle 1 or dose reduction during the treatment period.

  • In Vivo Assessment of the Effect of CYP1A2 Inhibition and Induction on Pomalidomide Pharmacokinetics in Healthy Subjects
    Journal of clinical pharmacology, 2018
    Co-Authors: Liangang Liu, Xiaomin Wang, Chengyue Zhang, Josephine Reyes, Maria Palmisano, Matthew Hoffmann, Simon Zhou
    Abstract:

    Pomalidomide is an immunomodulatory drug, and the dosage of 4 mg per day taken orally on days 1-21 of repeated 28-day cycles has been approved in the European Union and the United States to treat patients with relapsed/refractory multiple myeloma. In vitro data showed that Pomalidomide is a substrate of multiple cytochrome P450 (CYP) isozymes and that its oxidative metabolism is mediated primarily by CYP1A2 and CYP3A4, with minor contributions from CYP2C19 and CYP2D6. The effect of CYP1A2 inhibition by fluvoxamine (a strong CYP1A2 inhibitor) and CYP1A2 induction by smoking on Pomalidomide pharmacokinetics in healthy subjects has been assessed in 2 separate phase 1 open-label, single-dose studies. Following administration of a single oral dose of 4 mg Pomalidomide, the plasma exposure when coadministered with fluvoxamine was 225.1% and 123.7% of that when administered alone for the total plasma exposure (AUC0-inf ) and the plasma peak exposure (Cmax ), respectively. In smokers with elevated CYP1A2 activity demonstrated by high caffeine clearance (a marker of CYP1A2 induction), the AUC0-inf was 32.3% lower, whereas the Cmax was 14.4% higher than that in nonsmokers. In addition, Pomalidomide was safe and well tolerated as a single oral dose of 4 mg in healthy male smokers and nonsmokers ≥ 40 to ≤ 80 years old, and a single oral dose of 4 mg Pomalidomide coadministered with multiple oral 50-mg doses of the CYP1A2 inhibitor fluvoxamine compared with Pomalidomide alone was safe and well tolerated by the healthy male subjects.

  • An Open-Label, Phase 1 Study to Assess the Effects of Hepatic Impairment on Pomalidomide Pharmacokinetics.
    Clinical Pharmacology in Drug Development, 2018
    Co-Authors: Xiaomin Wang, Liangang Liu, Chengyue Zhang, Diana Gomez, Josephine Reyes, Maria Palmisano, Simon Zhou
    Abstract:

    Pomalidomide is an immunomodulatory drug and the dosage of 4 mg per day taken orally on days 1-21 of repeated 28-day cycles has been approved in the European Union and United States to treat patients with relapsed/refractory multiple myeloma. Because Pomalidomide is extensively metabolized prior to excretion, a total of 32 subjects (8 healthy subjects in group 1; 8 subjects with severe hepatic impairment in group 2; 8 subjects with moderate hepatic impairment in group 3; and 8 subjects with mild hepatic impairment in group 4) were enrolled in a multicenter, open-label, single-dose study to assess the impact of hepatic impairment on Pomalidomide exposure. Following administration of a single oral dose of 4-mg Pomalidomide, the geometric mean ratios of Pomalidomide total plasma exposures (AUC) were 171.5%, 157.5%, and 151.2% and the geometric mean ratios of Pomalidomide plasma peak exposures (Cmax ) were 75.8%, 94.8%, and 94.2% for subjects with severe, moderate, or mild hepatic impairment, respectively, versus healthy subjects. Pomalidomide administered as a single oral 4-mg dose was safe and well tolerated by healthy subjects and subjects with severe, moderate, or mild hepatic impairment. Based on the pharmacokinetic results from this study, the Pomalidomide prescribing information approved by the US Food and Drug Administration recommends for patients with mild or moderate hepatic impairment (Child-Pugh classes A or B), a 3-mg starting daily dose (25% dose reduction) and for patients with severe hepatic impairment (Child-Pugh class C), a 2-mg starting daily dose (50% dose reduction).

Xiaomin Wang - One of the best experts on this subject based on the ideXlab platform.

  • Recurrent or progressive pediatric brain tumors: population pharmacokinetics and exposure–response analysis of Pomalidomide
    Pediatric Research, 2021
    Co-Authors: Ken Ogasawara, Xiaomin Wang, Simon Zhou, Nastya Kassir, Bouchra Benettaib, Maria Palmisano
    Abstract:

    Background Pomalidomide, an immunomodulatory drug, was investigated for pediatric brain tumors. The objectives of this analysis were to characterize the PK of Pomalidomide and to examine exposure–response relationship in pediatric patients with recurrent or progressive primary brain tumors. Methods Nonlinear mixed effects modeling was employed in developing a population PK model of Pomalidomide using a total of 343 concentrations from 70 patients. Logistic regression models were used for exposure–response analyses. Results The PK of Pomalidomide was adequately described with a one compartment model with first-order absorption and elimination. Body surface area (BSA) was identified as a statistically significant covariate of apparent clearance and volume of distribution; however, the impact of BSA on exposure parameters was not deemed clinically relevant. Pomalidomide exposure was not associated with higher probabilities of treatment-emergent adverse events or Pomalidomide dose interruptions during Cycle 1. Covariates such as BSA, weight, sex, age, and race had no significant effect on safety endpoints. The PK of Pomalidomide in pediatric patients with brain tumors was generally consistent with that in adult patients with multiple myeloma after adjustment for BSA. Conclusions This is the first study to characterize PK of Pomalidomide in pediatric patients, which supports BSA-based dosing for pediatric patients. Impact This is the first study to characterize PK of Pomalidomide in pediatric patients, which supports BSA-based dosing for pediatric patients. There is no significant Pomalidomide PK difference between adults and pediatrics. Pomalidomide exposure was not associated with higher probabilities of treatment-emergent adverse event or Pomalidomide dose interruptions during Cycle 1.

  • Recurrent or progressive pediatric brain tumors: population pharmacokinetics and exposure-response analysis of Pomalidomide.
    Pediatric research, 2021
    Co-Authors: Ken Ogasawara, Xiaomin Wang, Simon Zhou, Nastya Kassir, Bouchra Benettaib, Maria Palmisano
    Abstract:

    Pomalidomide, an immunomodulatory drug, was investigated for pediatric brain tumors. The objectives of this analysis were to characterize the PK of Pomalidomide and to examine exposure-response relationship in pediatric patients with recurrent or progressive primary brain tumors. Nonlinear mixed effects modeling was employed in developing a population PK model of Pomalidomide using a total of 343 concentrations from 70 patients. Logistic regression models were used for exposure-response analyses. The PK of Pomalidomide was adequately described with a one compartment model with first-order absorption and elimination. Body surface area (BSA) was identified as a statistically significant covariate of apparent clearance and volume of distribution; however, the impact of BSA on exposure parameters was not deemed clinically relevant. Pomalidomide exposure was not associated with higher probabilities of treatment-emergent adverse events or Pomalidomide dose interruptions during Cycle 1. Covariates such as BSA, weight, sex, age, and race had no significant effect on safety endpoints. The PK of Pomalidomide in pediatric patients with brain tumors was generally consistent with that in adult patients with multiple myeloma after adjustment for BSA. This is the first study to characterize PK of Pomalidomide in pediatric patients, which supports BSA-based dosing for pediatric patients. This is the first study to characterize PK of Pomalidomide in pediatric patients, which supports BSA-based dosing for pediatric patients. There is no significant Pomalidomide PK difference between adults and pediatrics. Pomalidomide exposure was not associated with higher probabilities of treatment-emergent adverse event or Pomalidomide dose interruptions during Cycle 1.

  • Population Pharmacokinetics and Exposure Response Analysis of Pomalidomide in Subjects With Relapsed or Refractory Multiple Myeloma From the Novel Combination Treatment of Pomalidomide, Bortezomib, and Low-Dose Dexamethasone.
    Journal of clinical pharmacology, 2020
    Co-Authors: Nastya Kassir, Xiaomin Wang, Maria Palmisano, Simon Zhou
    Abstract:

    Multiple myeloma is an incurable progressive neoplastic disease that accounts for 10% of all hematologic malignancies. Even though significant progress has been made in the treatment of newly diagnosed multiple myeloma, the disease follows a relapsing course in the majority of patients, and there is a need for more effective therapeutic options for the treatment of relapsed or refractory multiple myeloma. CC-4047-MM-005 and CC-4047-MM-007 were phase 1 and 3 studies to evaluate the novel combination of Pomalidomide, bortezomib, and low-dose dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma who have already received lenalidomide-based treatments early. This analysis was performed to characterize the population pharmacokinetics (PK) of Pomalidomide from the combination treatment and to examine exposure-response relationships. Our analysis showed that Pomalidomide concentration-time profiles from the combination treatment were adequately described with a 1-compartment PK model, with first-order absorption and elimination and Pomalidomide exhibiting linear and time-invariant PK with moderate variability from the combination treatment. Except for the body surface area, none of the tested covariates had an effect on Pomalidomide PK. Although body surface area was identified as a statistically significant covariate of Pomalidomide PK, the impact was not deemed clinically relevant. A flat exposure-response curve was observed, consistent with a near-saturated drug effect at the tested exposure range suggesting an appropriately recommended clinical dose of 4 mg of Pomalidomide for the combination treatment. Finally, Pomalidomide exposure was not associated with higher probabilities of dose interruption during cycle 1 or dose reduction during the treatment period.

  • In Vivo Assessment of the Effect of CYP1A2 Inhibition and Induction on Pomalidomide Pharmacokinetics in Healthy Subjects
    Journal of clinical pharmacology, 2018
    Co-Authors: Liangang Liu, Xiaomin Wang, Chengyue Zhang, Josephine Reyes, Maria Palmisano, Matthew Hoffmann, Simon Zhou
    Abstract:

    Pomalidomide is an immunomodulatory drug, and the dosage of 4 mg per day taken orally on days 1-21 of repeated 28-day cycles has been approved in the European Union and the United States to treat patients with relapsed/refractory multiple myeloma. In vitro data showed that Pomalidomide is a substrate of multiple cytochrome P450 (CYP) isozymes and that its oxidative metabolism is mediated primarily by CYP1A2 and CYP3A4, with minor contributions from CYP2C19 and CYP2D6. The effect of CYP1A2 inhibition by fluvoxamine (a strong CYP1A2 inhibitor) and CYP1A2 induction by smoking on Pomalidomide pharmacokinetics in healthy subjects has been assessed in 2 separate phase 1 open-label, single-dose studies. Following administration of a single oral dose of 4 mg Pomalidomide, the plasma exposure when coadministered with fluvoxamine was 225.1% and 123.7% of that when administered alone for the total plasma exposure (AUC0-inf ) and the plasma peak exposure (Cmax ), respectively. In smokers with elevated CYP1A2 activity demonstrated by high caffeine clearance (a marker of CYP1A2 induction), the AUC0-inf was 32.3% lower, whereas the Cmax was 14.4% higher than that in nonsmokers. In addition, Pomalidomide was safe and well tolerated as a single oral dose of 4 mg in healthy male smokers and nonsmokers ≥ 40 to ≤ 80 years old, and a single oral dose of 4 mg Pomalidomide coadministered with multiple oral 50-mg doses of the CYP1A2 inhibitor fluvoxamine compared with Pomalidomide alone was safe and well tolerated by the healthy male subjects.

  • An Open-Label, Phase 1 Study to Assess the Effects of Hepatic Impairment on Pomalidomide Pharmacokinetics.
    Clinical Pharmacology in Drug Development, 2018
    Co-Authors: Xiaomin Wang, Liangang Liu, Chengyue Zhang, Diana Gomez, Josephine Reyes, Maria Palmisano, Simon Zhou
    Abstract:

    Pomalidomide is an immunomodulatory drug and the dosage of 4 mg per day taken orally on days 1-21 of repeated 28-day cycles has been approved in the European Union and United States to treat patients with relapsed/refractory multiple myeloma. Because Pomalidomide is extensively metabolized prior to excretion, a total of 32 subjects (8 healthy subjects in group 1; 8 subjects with severe hepatic impairment in group 2; 8 subjects with moderate hepatic impairment in group 3; and 8 subjects with mild hepatic impairment in group 4) were enrolled in a multicenter, open-label, single-dose study to assess the impact of hepatic impairment on Pomalidomide exposure. Following administration of a single oral dose of 4-mg Pomalidomide, the geometric mean ratios of Pomalidomide total plasma exposures (AUC) were 171.5%, 157.5%, and 151.2% and the geometric mean ratios of Pomalidomide plasma peak exposures (Cmax ) were 75.8%, 94.8%, and 94.2% for subjects with severe, moderate, or mild hepatic impairment, respectively, versus healthy subjects. Pomalidomide administered as a single oral 4-mg dose was safe and well tolerated by healthy subjects and subjects with severe, moderate, or mild hepatic impairment. Based on the pharmacokinetic results from this study, the Pomalidomide prescribing information approved by the US Food and Drug Administration recommends for patients with mild or moderate hepatic impairment (Child-Pugh classes A or B), a 3-mg starting daily dose (25% dose reduction) and for patients with severe hepatic impairment (Child-Pugh class C), a 2-mg starting daily dose (50% dose reduction).

Meletios A. Dimopoulos - One of the best experts on this subject based on the ideXlab platform.

  • Isatuximab plus Pomalidomide and low-dose dexamethasone versus Pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): a randomised, multicentre, open-label, phase 3 study
    Lancet (London England), 2019
    Co-Authors: Michel Attal, Paul G. Richardson, S. Vincent Rajkumar, Jesús F. San-miguel, Meral Beksac, Ivan Spicka, Xavier Leleu, Fredrik Schjesvold, Philippe Moreau, Meletios A. Dimopoulos
    Abstract:

    Summary Background Isatuximab is a monoclonal antibody that binds a specific epitope on the human CD38 receptor and has antitumour activity via multiple mechanisms of action. In a previous phase 1b study, around 65% of patients with relapsed and refractory multiple myeloma achieved an overall response with a combination of isatuximab with Pomalidomide and low-dose dexamethasone. The aim of this study was to determine the progression-free survival benefit of isatuximab plus Pomalidomide and dexamethasone compared with Pomalidomide and dexamethasone in patients with relapsed and refractory multiple myeloma. Methods We did a randomised, multicentre, open-label, phase 3 study at 102 hospitals in 24 countries in Europe, North America, and the Asia-Pacific regions. Eligible participants were adult patients with relapsed and refractory multiple myeloma who had received at least two previous lines of treatment, including lenalidomide and a proteasome inhibitor. Patients were excluded if they were refractory to previous treatment with an anti-CD38 monoclonal antibody. We randomly assigned patients (1:1) to either isatuximab 10 mg/kg plus Pomalidomide 4 mg plus dexamethasone 40 mg (20 mg for patients aged ≥75 years), or Pomalidomide 4 mg plus dexamethasone 40 mg. Randomisation was done using interactive response technology and stratified according to the number of previous lines of treatment (2–3 vs >3) and age ( ClinicalTrials.gov , number NCT02990338 . Findings Between Jan 10, 2017, and Feb 2, 2018, we randomly assigned 307 patients to treatment: 154 to isatuximab–Pomalidomide–dexamethasone, and 153 to Pomalidomide–dexamethasone. At a median follow-up of 11·6 months (IQR 10·1–13·9), median progression-free survival was 11·5 months (95% CI 8·9–13·9) in the isatuximab–Pomalidomide–dexamethasone group versus 6·5 months (4·5–8·3) in the Pomalidomide–dexamethasone group; hazard ratio 0·596, 95% CI 0·44–0·81; p=0·001 by stratified log-rank test. The most frequent treatment-emergent adverse events (any grade; isatuximab–Pomalidomide–dexamethasone vs Pomalidomide–dexamethasone) were infusion reactions (56 [38%] vs 0), upper respiratory tract infections (43 [28%] vs 26 [17%]), and diarrhoea (39 [26%] vs 29 [20%]). Adverse events with a fatal outcome were reported in 12 patients (8%) in the isatuximab–Pomalidomide–dexamethasone group and 14 (9%) in the Pomalidomide–dexamethasone group. Deaths due to treatment-related adverse events were reported for one patient ( Interpretation The addition of isatuximab to Pomalidomide–dexamethasone significantly improves progression-free survival in patients with relapsed and refractory multiple myeloma. Isatuximab is an important new treatment option for the management of relapsed and refractory myeloma, particularly for patients who become refractory to lenalidomide and a proteasome inhibitor. Funding Sanofi. Video Abstract Download : Download video (69MB) Paul Richardson introduces the paper on isatuximab plus Pomalidomide and low-dose dexamethasone versus Pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma as part of the ICARIA-MM study. Watch this abstract on YouTube

  • Elotuzumab in combination with Pomalidomide and dexamethasone for the treatment of multiple myeloma.
    Expert review of anticancer therapy, 2019
    Co-Authors: Evangelos Eleutherakis-papaiakovou, Maria Gavriatopoulou, Ioannis Ntanasis-stathopoulos, Efstathios Kastritis, Evangelos Terpos, Meletios A. Dimopoulos
    Abstract:

    Introduction: Despite major advances in the therapeutic management of multiple myeloma (MM), it remains an incurable disease. Several combinations of monoclonal antibodies with novel agents are being investigated with promising results in order to prolong progression-free and overall survival.Areas covered: This paper aims to critically present available data from clinical trials investigating the combination of elotuzumab with Pomalidomide and dexamethasone in refractory/relapsed MM patients and determine its current role in clinical practice.Expert opinion: Pomalidomide-based combinations with monoclonal antibodies have been shown to be effective in patients with MM who are refractory to or have relapsed following treatment with lenalidomide and/or a proteasome inhibitor (PI). These regimens seem to be more effective than the standard combination of Pomalidomide with dexamethasone alone. Taking into consideration that the vast majority of MM patients will receive upfront treatment including a PI and lenalidomide in the near future, Pomalidomide-based triplets, such as elotuzumab-Pomalidomide-dexamethasone, will become the standard of care in the second line of therapy.

  • Population pharmacokinetics of Pomalidomide in patients with relapsed or refractory multiple myeloma with various degrees of impaired renal function.
    Clinical pharmacology : advances and applications, 2017
    Co-Authors: Xiaomin Wang, David S Siegel, Edward O'mara, Meletios A. Dimopoulos, Pieter Sonneveld, Katja Weisel, Jeffrey Matous, Jatin J. Shah, Elisabeth Kueenburg
    Abstract:

    Pomalidomide is an immunomodulatory drug for treatment of relapsed or refractory multiple myeloma (rrMM) in patients who often have comorbid renal conditions. To assess the impact of renal impairment on Pomalidomide exposure, a population pharmacokinetics (PPK) model of Pomalidomide in rrMM patients with various degrees of impaired renal function was developed. Intensive and sparse Pomalidomide concentration data collected from two clinical studies in rrMM patients with normal renal function, moderately impaired renal function, severely impaired renal function not requiring dialysis, and with severely impaired renal function requiring dialysis were pooled over the dose range of 2 to 4 mg, to assess specifically the influence of the impaired renal function as a categorical variable and a continuous variable on Pomalidomide clearance and plasma exposure. In addition, Pomalidomide concentration data collected on dialysis days from both the withdrawal (arterial) side and from the returning (venous) side of the dialyzer, from rrMM patients with severely impaired renal function requiring dialysis, were used to assess the extent to which dialysis contributes to the removal of Pomalidomide from blood circulation. PPK analyses demonstrated that moderate to severe renal impairment not requiring dialysis has no influence on Pomalidomide clearance or plasma exposure, as compared to those patients with normal renal function, while Pomalidomide exposure increased approximately 35% in patients with severe renal impairment requiring dialysis on nondialysis days. In addition, dialysis increased total body Pomalidomide clearance from 5 L/h to 12 L/h, indicating that dialysis will significantly remove Pomalidomide from the blood circulation. Thus, Pomalidomide should be administered post-dialysis on the days of dialysis.

  • cytogenetics and long term survival of patients with refractory or relapsed and refractory multiple myeloma treated with Pomalidomide and low dose dexamethasone
    Haematologica, 2015
    Co-Authors: Meletios A. Dimopoulos, Katja Weisel, Lionel Karlin, Philippe Moreau, Albert Oriol, Kevin W Song, Michel Delforge, Hartmut Goldschmidt, Anne Banos, Laurent Garderet
    Abstract:

    Patients with refractory or relapsed and refractory multiple myeloma who no longer receive benefit from novel agents have limited treatment options and short expected survival. del(17p) and t(4;14) are correlated with shortened survival. The phase 3 MM-003 trial demonstrated significant progression-free and overall survival benefits from treatment with Pomalidomide plus low-dose dexamethasone compared to high-dose dexamethasone among patients in whom bortezomib and lenalidomide treatment had failed. At an updated median follow-up of 15.4 months, the progression-free survival was 4.0 versus 1.9 months (HR, 0.50; P<0.001), and median overall survival was 13.1 versus 8.1 months (HR, 0.72; P=0.009). Pomalidomide plus low-dose dexamethasone, compared with high-dose dexamethasone, improved progression-free survival in patients with del(17p) (4.6 versus 1.1 months; HR, 0.34; P <0.001), t(4;14) (2.8 versus 1.9 months; HR, 0.49; P=0.028), and in standard-risk patients (4.2 versus 2.3 months; HR, 0.55; P<0.001). Although the majority of patients treated with high-dose dexamethasone took Pomalidomide after discontinuation, the overall survival of patients treated with Pomalidomide plus low-dose dexamethasone or high-dose dexamethasone was 12.6 versus 7.7 months (HR, 0.45; P=0.008) in patients with del(17p), 7.5 versus 4.9 months (HR, 1.12; P=0.761) in those with t(4;14), and 14.0 versus 9.0 months (HR, 0.85; P=0.380) in standard-risk subjects. The overall response rate was higher in patients treated with Pomalidomide plus low-dose dexamethasone than in those treated with high-dose dexamethasone both among standard-risk patients (35.2% versus 9.7%) and those with del(17p) (31.8% versus 4.3%), whereas it was similar in patients with t(4;14) (15.9% versus 13.3%). The safety of Pomalidomide plus low-dose dexamethasone was consistent with initial reports. In conclusion, Pomalidomide plus low-dose dexamethasone is efficacious in patients with relapsed/refractory multiple myeloma and del(17p) and/or t(4;14). This study is registered at ClinicalTrials.gov as NCT01311687 and with EudraCT as 2010-019820-30.

  • Pomalidomide - An appraisal of its clinical development and role in the treatment of relapsed/refractory multiple myeloma
    European Oncology & Haematology, 2015
    Co-Authors: Paul G. Richardson, Meletios A. Dimopoulos, Katja Weisel, Xavier Leleu, Antonio Palumbo, Martha Q. Lacy, Stephen Schey, Thierry Facon, Peter O'gorman, Matthew Streetly
    Abstract:

    Pomalidomide is a distinct immunomodulatory agent with significant activity in relapsed/refractory multiple myeloma (RRMM). The optimal treatment schedule in patients with RRMM who have received multiple lines of treatment, including bortezomib and lenalidomide, is 4 mg/day on days 1–21 of a 28-day cycle in combination with weekly low-dose dexamethasone. Improved responses and outcomes relative to traditional therapies continue to be confirmed in recently completed and ongoing trials. Pomalidomide exhibits direct tumoricidal, immunomodulatory, anti-angiogenic and anti-inflammatory activities, which facilitate combination therapy with agents with complementary mechanisms of action, resulting in greater anti-myeloma effects than single-agent therapy or previous combination therapies. For example, in combination with proteasome inhibitors and traditional chemotherapeutic agents in doublet or triplet regimens, Pomalidomide provides high rates of durable response, and represents an important new treatment option for patients with RRMM requiring effective new therapies. Additionally, Pomalidomide maintains its efficacy and tolerability profile in difficult-to-treat patients, including the elderly, patients with poor cytogenetics and those with renal impairment. This review summarises the clinical development of Pomalidomide and discusses this effective agent for the treatment of patients with RRMM in the context of current myeloma treatment options, as well as potential future directions to further improve patient outcomes.

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  • In Vivo Assessment of the Effect of CYP1A2 Inhibition and Induction on Pomalidomide Pharmacokinetics in Healthy Subjects
    Journal of clinical pharmacology, 2018
    Co-Authors: Liangang Liu, Xiaomin Wang, Chengyue Zhang, Josephine Reyes, Maria Palmisano, Matthew Hoffmann, Simon Zhou
    Abstract:

    Pomalidomide is an immunomodulatory drug, and the dosage of 4 mg per day taken orally on days 1-21 of repeated 28-day cycles has been approved in the European Union and the United States to treat patients with relapsed/refractory multiple myeloma. In vitro data showed that Pomalidomide is a substrate of multiple cytochrome P450 (CYP) isozymes and that its oxidative metabolism is mediated primarily by CYP1A2 and CYP3A4, with minor contributions from CYP2C19 and CYP2D6. The effect of CYP1A2 inhibition by fluvoxamine (a strong CYP1A2 inhibitor) and CYP1A2 induction by smoking on Pomalidomide pharmacokinetics in healthy subjects has been assessed in 2 separate phase 1 open-label, single-dose studies. Following administration of a single oral dose of 4 mg Pomalidomide, the plasma exposure when coadministered with fluvoxamine was 225.1% and 123.7% of that when administered alone for the total plasma exposure (AUC0-inf ) and the plasma peak exposure (Cmax ), respectively. In smokers with elevated CYP1A2 activity demonstrated by high caffeine clearance (a marker of CYP1A2 induction), the AUC0-inf was 32.3% lower, whereas the Cmax was 14.4% higher than that in nonsmokers. In addition, Pomalidomide was safe and well tolerated as a single oral dose of 4 mg in healthy male smokers and nonsmokers ≥ 40 to ≤ 80 years old, and a single oral dose of 4 mg Pomalidomide coadministered with multiple oral 50-mg doses of the CYP1A2 inhibitor fluvoxamine compared with Pomalidomide alone was safe and well tolerated by the healthy male subjects.

  • An Open-Label, Phase 1 Study to Assess the Effects of Hepatic Impairment on Pomalidomide Pharmacokinetics.
    Clinical Pharmacology in Drug Development, 2018
    Co-Authors: Xiaomin Wang, Liangang Liu, Chengyue Zhang, Diana Gomez, Josephine Reyes, Maria Palmisano, Simon Zhou
    Abstract:

    Pomalidomide is an immunomodulatory drug and the dosage of 4 mg per day taken orally on days 1-21 of repeated 28-day cycles has been approved in the European Union and United States to treat patients with relapsed/refractory multiple myeloma. Because Pomalidomide is extensively metabolized prior to excretion, a total of 32 subjects (8 healthy subjects in group 1; 8 subjects with severe hepatic impairment in group 2; 8 subjects with moderate hepatic impairment in group 3; and 8 subjects with mild hepatic impairment in group 4) were enrolled in a multicenter, open-label, single-dose study to assess the impact of hepatic impairment on Pomalidomide exposure. Following administration of a single oral dose of 4-mg Pomalidomide, the geometric mean ratios of Pomalidomide total plasma exposures (AUC) were 171.5%, 157.5%, and 151.2% and the geometric mean ratios of Pomalidomide plasma peak exposures (Cmax ) were 75.8%, 94.8%, and 94.2% for subjects with severe, moderate, or mild hepatic impairment, respectively, versus healthy subjects. Pomalidomide administered as a single oral 4-mg dose was safe and well tolerated by healthy subjects and subjects with severe, moderate, or mild hepatic impairment. Based on the pharmacokinetic results from this study, the Pomalidomide prescribing information approved by the US Food and Drug Administration recommends for patients with mild or moderate hepatic impairment (Child-Pugh classes A or B), a 3-mg starting daily dose (25% dose reduction) and for patients with severe hepatic impairment (Child-Pugh class C), a 2-mg starting daily dose (50% dose reduction).

  • Distribution of Pomalidomide into semen of healthy male subjects after multiple doses.
    Clinical pharmacology : advances and applications, 2018
    Co-Authors: Xiaomin Wang, Liangang Liu, Josephine Reyes, Maria Palmisano, Simon Zhou
    Abstract:

    Objective To assess whether Pomalidomide can distribute into human semen and its duration in human semen. Method A phase 1, randomized, double-blind, placebo-controlled study (CC-4047-CP-006) was conducted to evaluate the safety, tolerability, and pharmacokinetics of Pomalidomide (CC-4047) following multiple daily doses in healthy male subjects. Semen samples were collected on Day -1 and 4 hours after dosing on Day 4 to quantify the Pomalidomide concentrations in ejaculate after multiple oral doses of Pomalidomide. Result Our study showed that Pomalidomide was present in male subjects' semen samples, and the average amount of Pomalidomide in a single ejaculate 4 hours after dosing was less than 0.0022% of the daily 2 mg dose. There was a good correlation between the semen concentrations and the plasma concentrations, suggesting that the plasma concentration may be the main driving force for the distribution of Pomalidomide into the seminal reservoirs. Simulation results suggest that Pomalidomide was undetectable in semen 48 hours after stopping dosing. Conclusion Based on the results from this study, the Pomalidomide prescribing information approved by the US Food and Drug Administration includes a statement that "Pomalidomide is present in the semen of patients receiving the drug. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 4 weeks after discontinuing POMALYST, even if they have undergone a successful vasectomy. Male patients taking POMALYST must not donate sperm.

  • Population pharmacokinetics of Pomalidomide.
    Journal of clinical pharmacology, 2015
    Co-Authors: Liangang Liu, Xiaomin Wang, Maria Palmisano, Simon Zhou
    Abstract:

    A population pharmacokinetic (PPK) model of Pomalidomide was developed and the influence of demographic and disease-related covariates on PPK parameters was assessed based on data from 6 clinical trials of Pomalidomide (dose range, 0.5–10 mg) in healthy participants (n = 96) and patients with multiple myeloma (MM; n = 144). PPK data described herein suggest that systemic clearance of Pomalidomide is comparable between healthy study participants and patients with MM. However, apparent peripheral volume of distribution and apparent intercompartmental clearance between central and peripheral compartments were 8- and 3.7-fold higher in patients with MM vs. healthy subjects, suggesting drug exposure is higher in peripheral compartments of patients with MM vs. healthy subjects. Covariate analysis suggested Pomalidomide clearance is not affected by demographic factors except for gender, and it is unlikely this factor is clinically relevant. In addition, renal function as measured by creatinine clearance or renal impairment (RI) does not significantly affect clearance of Pomalidomide. In conclusion, Pomalidomide has robust pharmacokinetic exposure, not affected by demographic factors or renal impairment. Pomalidomide is preferentially taken up by tumors over healthy tissues in patients with MM.

  • Pomalidomide: evaluation of cytochrome P450 and transporter-mediated drug-drug interaction potential in vitro and in healthy subjects.
    Journal of clinical pharmacology, 2014
    Co-Authors: Claudia Kasserra, Xiaomin Wang, Liangang Liu, Mahmoud Assaf, Matthew Hoffmann, Gondi Kumar, Maria Palmisano
    Abstract:

    Abstract Pomalidomide offers an alternative for patients with relapsed/refractory multiple myeloma who have exhausted treatment options with lenalidomide and bortezomib. Little is known about Pomalidomide's potential for drug-drug interactions (DDIs); as Pomalidomide clearance includes hydrolysis and cytochrome P450 (CYP450)-mediated hydroxylation, possible DDIs via CYP450 and drug-transporter proteins were investigated in vitro and in a clinical study. In vitro Pomalidomide was neither an inducer nor inhibitor of CYP450, nor an inhibitor of transporter proteins P glycoprotein (P-gp), BCRP, OAT1, OAT3, OCT2, OATP1B1, and OATP1B3. Oxidative metabolism of Pomalidomide was predominately mediated by CYP1A2 and CYP3A4, and Pomalidomide was shown to be a P-gp substrate. In healthy males, co-administration of oral (4 mg) Pomalidomide with ketoconazole (CYP3A/P-gp inhibitor) or carbamazepine (CYP3A/P-gp inducer) did not result in clinically relevant changes in Pomalidomide exposure. Co-administration of Pomalidomide with fluvoxamine (CYP1A2 inhibitor) in the presence of ketoconazole approximately doubled Pomalidomide exposure. Pomalidomide appears to have low potential for clinically relevant DDI and is unlikely to affect the clinical exposure of other drugs. Avoid co-administration of strong CYP1A2 inhibitors unless medically necessary. Pomalidomide dose should be reduced by 50% if co-administered with strong CYP1A2 inhibitors and strong CYP3A/P-gp inhibitors.