Tag Archives: Pharmacokinetics

U.S. Food & Drug Administration (FDA) Clinical Pharmacology Corner Update: FDA Approves PORTRAZZA (necitumumab)

U.S. Food & Drug Administration (FDA) Clinical Pharmacology Corner Update: FDA Approves PORTRAZZA (necitumumab)

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*FDA Approves PORTRAZZA (necitumumab) in Combination with Gemcitabine and Cisplatin, for First-Line Treatment of Patients with Metastatic Squamous Non-Small Cell Lung Cancer*

On November 24, 2015, the United States Food and Drug Administration (FDA) approved PORTRAZZA (necitumumab) in combination with gemcitabine and cisplatin, for first-line treatment of patients with metastatic squamous non-small cell lung cancer (NSCLC). PORTRAZZA is not indicated for treatment of non squamous NSCLC. The approved recommended dosage of PORTRAZZA is 800 mg as an intravenous infusion over 60 minutes on Days 1 and 8 of each 3-week cycle (Q3W) prior to gemcitabine and cisplatin infusion. Patients receiving PORTRAZZA should be pre-medicated as follows:

* For patients who have experienced a previous Grade 1 or 2 infusion-related reaction (IRR), pre-medicate with diphenhydramine hydrochloride (or equivalent) prior to all subsequent PORTRAZZA infusions.
* For patients who have experienced a second Grade 1 or 2 occurrence of IRR, pre-medicate for all subsequent infusions, with
diphenhydramine hydrochloride (or equivalent), acetaminophen (or equivalent), and dexamethasone (or equivalent) prior to each PORTRAZZA infusion.

_Mechanism of Action (MOA), General Pharmacokinetics (PK) and Pharmacodynamics (PD) of Necitumumab_

* /MOA:/ Necitumumab is a recombinant human IgG1 monoclonal antibody that binds to the human epidermal growth factor receptor (EGFR) and blocks the binding of EGFR to its ligands.
* /Dose proportionality:/ Necitumumab PK is characterized by a target-mediated drug disposition, exhibiting dose-dependent kinetics on total clearance and steady state volume of distribution. * /Accumulation:/ Steady state exposure is achieved after 3 cycles of treatment.
* /Terminal half-life (mean):/ Approximately 14 days.
* /Exposure-safety:/ No apparent relationship between average serum necitumumab concentrations (C_ss,ave ) and all grades
hypomagnesemia, rash, arterial (ATE) or venous (VTE) thromboembolic events.

_Drug Interaction Potential_

* Coadministration of necitumumab (800 mg) with gemcitabine (1250 mg/m^2 ) and cisplatin increased the geometric mean dose-normalized gemcitabine AUC by 22% and C_max by 63% compared to administration of gemcitabine and cisplatin alone. This increased exposure to gemcitabine may have contributed to the higher toxicity observed with the necitumumab containing arm. The coadministration of necitumumab did not have an effect on the exposure to cisplatin (as measured by dose-normalized AUC_0-5h and dose-normalized Cmax for total platinum) in the presence of gemcitabine.
* Gemcitabine and cisplatin have no effect on the exposure to necitumumab.

_Use in Specific Populations_

The following population characteristics were not associated with a clinically significant effect on the PK of necitumumab: age (range: 19-84 years), sex (75% male), race (85% Whites), renal function [as measured by Cockcroft-Gault creatinine clearance (CL_cr ), range:11-250 mL/min] or hepatic function [as measured by alanine aminotransferase (range: 2-615 U/L), aspartate aminotransferase (range:1.2-619 U/L) and total bilirubin (range: 0.1-106 μmol/L). Body weight is identified as a covariate in the population PK analysis; however, weight-based dosing is not expected to significantly decrease the variability in exposure. No dose adjustment based on body weight is recommended.

_Efficacy and Safety_

The efficacy and safety of necitumumab at the recommended dose were demonstrated in an open-label, global, multi-center, 2-arm, randomized trial in 1093 patients with squamous NSCLC (Trial JFCC [SQUIRE]). A 1.6-month improvement in median overall survival (OS) among patients in the gemcitabine/ cisplatin + necitumumab Arm compared with those in the gemcitabine/cisplatin Arm (HR = 0.842 [0.736, 0.962]; p=0.012) was demonstrated. The most common adverse reactions (all grades) observed in PORTRAZZA-treated patients at a rate of greater than or equal to 30% and greater than or equal to 2% higher than gemcitabine and cisplatin alone arm were rash and hypomagnesemia. Cardiopulmonary arrest and/or sudden death occurred in 3% of patients treated with PORTRAZZA in combination with gemcitabine and cisplatin. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, with aggressive replacement when warranted during and after PORTRAZZA administration.

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U.S. Food & Drug Administration (FDA) Clinical Pharmacology Corner Update: FDA Approves YONDELIS (trabectedin)

U.S. Food & Drug Administration (FDA) Clinical Pharmacology Corner Update: FDA Approves YONDELIS (trabectedin)

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*FDA Approves YONDELIS^® (trabectedin) for Advanced Soft Tissue Sarcoma Subtypes, Liposarcoma, and Leiomyosarcoma, With Prior Chemotherapy*

On October 23, 2015, the United States Food and Drug Administration (FDA) approved YONDELIS (trabectedin) for the treatment of patients with advanced soft tissue sarcoma (STS), liposarcoma, and leiomyosarcoma subtypes (L-type sarcoma), who have received prior chemotherapy, including an anthracycline regimen. The approved recommended dosage of YONDELIS lyophilized powder for injection is 1.5 mg/m2 administered as a 24-hour intravenous (IV) infusion once every three weeks (Q3W). Patients receiving YONDELIS will be premedicated with dexamethasone 20 mg IV or an equivalent dose of an IV corticosteroid on day 1 of each treatment cycle, 30 minutes before the infusion.

_Mechanism of Action (MOA), General Pharmacokinetics (PK) and Pharmacodynamics (PD) of Trabectedin_

* /MOA:/ Trabectedin disrupts the cell cycle and inhibits cell proliferation.
* /Dose proportionality:/ Exhibited dose-proportional increases in systemic exposure over the dose range of 0.024 mg/m2 to 1.8 mg/m2 (i.e., 0.016 times to 1.2 times the approved recommended dosage). * /Accumulation:/ No accumulation was observed at the approved recommended dosage.
* /Plasma protein binding:/ Approximately 97%.
* /Terminal half-life (mean):/ Approximately 175 hours in patients. * /Metabolism:/ Extensive. Primarily metabolized by CYP3A.
* /Excretion:/ Approximately 58% of the total recovered radio-labeled trabectedin dose was eliminated in the feces and 6% was eliminated in the urine. Unchanged trabectedin recovery was negligible. * /Exposure-safety:/ Adverse reactions (ARs), mainly neutropenia and elevation in transaminases, led to dose reductions in 35% of patients receiving trabectedin in the registration trial. The proposed dose adjustment from 1.5 mg/m2 to 1.2 mg/m2 and then to 1 mg/m2 due to toxicity was used in the registration trial. Exposure-response (E-R) relationships were identified for the common ARs in the registration trial, including neutropenia, elevation in transaminases, and hyperbilirubinemia, using data from Phase 1 and 2 studies. The proposed dose adjustments are likely to decrease toxicity based on the exposure-toxicity relationships.

_Drug Interaction Potential_

* Avoid strong CYP3A inhibitors (e.g., oral ketoconazole,
itraconazole, posaconazole, voriconazole, clarithromycin, telithromycin, indinavir, lopinavir, ritonavir, boceprevir, nelfinavir, saquinavir, telaprevir, nefazodone, conivaptan) in patients taking YONDELIS. Avoid taking grapefruit or grapefruit juice during YONDELIS treatment. Administer the strong CYP3A inhibitor 1 week after the YONDELIS infusion, and discontinue it the day prior to the next YONDELIS infusion if short term strong CYP3A inhibitor use (i.e., less than 14 days) must be used.
Coadministration of a strong CYP3A4 inhibitor (i.e., ketoconazole) increased the trabectedin dose normalized AUC by 66% and Cmax by 22%. * Avoid strong CYP3A inducers. Coadministration of a strong CYP3A4 inducer (i.e.., rifampicin) decreased trabectedin dose normalized AUC by 31% and Cmax by 21%.

_Use in Specific Populations_

The following population characteristics were not associated with a clinically significant effect on the pharmacokinetics of trabectedin: sex, age (19 to 83 years), body weight (36 to 148 kg), BSA (0.9 to 2.8 m2), mild to moderate (creatinine clearance (CLcr) 30 to 89 mL/min) renal impairment. The effect of any degree of hepatic impairment, severe renal impairment (CLcr 15 to 29 mL/min), or end stage renal disease (CLcr less than 15 mL/min) with or without hemodialysis on trabectedin exposure is unknown.

_Safety and Efficacy_

Clinical effectiveness and safety of trabectedin were demonstrated at the recommended dose in a multicenter, randomized, open-label, active-controlled trial that enrolled 518 patients with L-type sarcoma who received prior chemotherapy, including an anthracycline regimen. The median progression-free survival was 4.2 months in trabectedin-treated patients compared to 1.5 months in those receiving dacarbazine [hazard ratio: 0.55 (0.4, 0.7, p < 0.0001)]. The most common ARs were nausea, fatigue, vomiting, diarrhea, constipation, decreased appetite, dyspnea, headache, fever, cough, increases in AST or ALT, neutropenia, and anemia.

Source: FDA.GOV

Clinical Pharmacology Corner Update: FDA Approves REXULTI (Brexpiprazole)

FDA Approves REXULTI® (Brexpiprazole) for the Treatment of Schizophrenia and Adjunctive Treatment of Major Depressive Disorder  

On July 10, 2015, the FDA approved REXULTI (brexpiprazole) immediate-release tablets for the treatment of schizophrenia and the adjunctive treatment of major depressive disorder (MDD).

Dosage and Administration

  • Treatment of Schizophrenia: The recommended starting dose for REXULTI in the treatment of patients with schizophrenia is 1 mg once daily (QD). The dose should be increased to 2 mg after Day 4 and may subsequently be increased to 4 mg after Day 7 based on the patient’s clinical response and tolerability. The maximum recommended dose is 4 mg QD.
  • Adjunctive Treatment of MDD: The recommended starting dose for REXULTI as adjunctive treatment for MDD is 0.5 mg/day or 1 mg QD. Dose titration to 1 mg/day and up to the target dose of 2 mg/day should occur at intervals of up to 1 week based on the patient’s clinical response and tolerability. The maximum recommended dose is 3 mg QD.
  • REXULTI can be administered with or without food.

General Pharmacokinetics and Pharmacodynamics of Brexpiprazole

The mechanism of action of brexpiprazole is unknown.  However, the efficacy of brexpiprazole may be mediated through a combination of partial agonist activity at serotonin 5-HT1A and dopamine D2 receptors, and antagonist activity at serotonin 5-HT2A receptors.

  • Dose Proportionality: Brexpiprazole Cmax and AUC are approximately dose proportional after oral administration in the therapeutic dosage range.
  • Accumulation: About 4-fold at steady state (time to steady state 10 to 12 days)
  • Absolute bioavailability (tablets): 95% (Tmax within 4 hours).
  • Plasma protein binding: Greater than 99%.
  • Terminal half-life (mean): 91 hours at steady state.
  • Metabolism: Extensive. Predominately by CYP3A and CYP2D6.
  • Excretion: About 14% and less than 1% of the dose is excreted as unchanged parent drug in the feces and urine, respectively.
  • Exposure-safety: At a dose 3 times the maximum recommended dose, REXULTI does not prolong the QT interval to any clinically relevant extent.

Drug Interaction Potential

  • An approximately 2-fold increase in brexpiprazole exposure (AUC) was observed following coadministration of a strong CYP3A4 inhibitor (e.g., ketoconazole, itraconazole) with REXULTI. Decrease the REXULTI dosage by half if coadministration is required.
  • An approximately 2-fold increase in brexpiprazole exposure was observed following coadministration of a strong CYP2D6 inhibitor (e.g., quinidine, fluoxetine, paroxetine) with REXULTI. Decrease the REXULTI dosage by half if coadministration is required for the treatment of schizophrenia. A REXULTI dosage reduction is not required with coadministration in patients with MDD because this effect was factored into the general dosing recommendations (i.e., coadministration was permitted without dosage adjustment in the clinical trials supporting this indication).
  • An approximately 5.1-fold increase in steady-state brexpiprazole exposure is expected when extensive CYP2D6 metabolizers are coadministered REXULTI with both strong CYP2D6 and CYP3A4 inhibitors. Similarly, an approximately 4.8-fold increase in steady-state brexpiprazole exposure is expected when poor CYP2D6 metabolizers are coadministered REXULTI with strong CYP3A4 inhibitors. Decrease the REXULTI dosage by 75% if coadministration is required in patients with these polymorphisms.
  • An approximately 73% decrease in brexpiprazole exposure was observed following coadministration with a strong CYP3A4 inducer (e.g., rifampin, carbamazepine, phenytoin) with REXULTI. Double the REXULTI dosage one to two weeks following strong CYP3A4 inducer coadministration.

Use in Specific Populations

  • A 26%, 73%, and 4% increase in brexpiprazole exposure was observed in subjects with mild, moderate, and severe hepatic impairment compared to subjects with normal hepatic function, respectively. The maximum recommended REXULTI dosage for patients with moderate to severe hepatic impairment (Child-Pugh score ≥ 7) is 2 mg QD for patients with MDD and 3 mg QD for patients with schizophrenia.
  • A 7%, 71%, and 72% increase in brexpiprazole exposure was observed or predicted in subjects or patients with mild, moderate, and severe renal impairment compared to subjects with normal renal function. The maximum recommended REXULTI dosage for patients with moderate or severe renal impairment (i.e., creatinine clearance less than 60 mL /minute) is 2 mg QD for patients with MDD and 3 mg QD for patients with schizophrenia.
  • Half of the usual dosage is recommended for patients with known CYP2D6 poor metabolizer status.

Safety and Efficacy

The efficacy and safety of REXULTI in schizophrenia was demonstrated in two 6-week controlled studies in adult patients at doses of 2 to 4 mg administered orally once daily. The primary efficacy endpoint in schizophrenia trials is change in PANSS Total Score from baseline to week 6. The efficacy and safety of REXULTI as an adjunctive therapy for MDD was evaluated in two 6-week controlled studies in adult patients at doses of 1 to 3 mg administered once daily, with one trial showing statistical superiority of REXULTI over placebo. The primary efficacy endpoint in MDD trials is the mean change in MADRS Total Score from baseline to week 6. Safety profiles were similar in MDD and schizophrenia patients. The most common treatment emergent adverse events were increased weight, headache, akathisia, somnolence, fatigue, anxiety, and increased appetite.

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