Tag Archives: Clinical Pharmacology

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 COTELLIC (Cobimetinib)

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

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*FDA Approves COTELLIC^® (Cobimetinib) for the Treatment of Patients with Unresectable or Metastatic Melanoma with a BRAF V600E or V600K Mutation, in Combination with Vemurafenib *

On November 10, 2015, the United States Food and Drug Administration (FDA) approved COTELLIC (Cobimetinib) in combination with vemurafenib for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K Mutation. The approved recommended dosage of COTELLIC tablets is 60 mg orally once daily with or without food for the first 21 days of each 28 day cycle until disease progression or unacceptable toxicity. The dosage of COTELLIC may be reduced to 40 mg or 20 mg once daily for adverse reactions. Clinically relevant QT prolongation has been reported with vemurafenib, further QTc prolongation was not observed when cobimetinib 60 mg daily was co-administered with vemurafenib. Monitor ECG and electrolytes before initiating treatment and routinely during treatment with cobimetinib, when administered with vemurafenib.

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

* /MOA:/ Cobimetinib reversibly inhibits mitogen-activated protein kinase (MAPK)/extracellular signal regulated kinase 1 (MEK1) and MEK2. * /Dose proportionality:/ Exhibited dose-proportional increases in systemic exposure over the dose range of 3.5 to 100 mg (i.e., 0.06 to 1.7 times the approved recommended dosage).
* /Accumulation:/ Mean of 2.4-fold at the approved recommended dosage. * /Absorption:/ The absolute bioavailability of COTELLIC was 46% in healthy subjects. The Tmax was 2.4 hours (range:1 to 24 hours) in cancer patients.
* /Plasma protein binding:/ Approximately 95%.
* /Terminal half-life (mean):/ Approximately 44 hours (range: 23 to 70 hours) in cancer patients.
* /Metabolism:/ Primarily metabolized by CYP3A and glucuronidated by UGT2B7.
* /Excretion:/ Approximately 76% of the total recovered radio-labeled cobimetinib dose was eliminated in the feces (with 6.6% as unchanged drug) and 17.8% was eliminated in the urine (with 1.6% as unchanged drug).

_Drug Interaction Potential_

* Avoid strong or moderate CYP3A inhibitors. If concurrent short term (14 days or less) use of moderate CYP3A inhibitors including certain antibiotics (e.g., erythromycin, ciprofloxacin) is unavoidable for patients who are taking COTELLIC 60 mg, reduce COTELLIC dose to 20 mg. After discontinuation of a moderate CYP3A inhibitor, resume COTELLIC at the previous dose. Use an alternative to a strong or moderate CYP3A inhibitor in patients who are taking a reduced dose of COTELLIC (40 or 20 mg daily). Coadministration of the strong CYP3A inhibitor itraconazole increased cobimetinib AUC by 6.7-fold and Cmax by 3.2-fold.
* Avoid strong or moderate CYP3A inducers. Cobimetinib exposures are estimated to decrease by 83% when coadministered with a strong CYP3A inducer and by 73% when coadministered with a moderate CYP3A inducer. * Cobimetinib is a substrate of efflux transporter P-glycoprotein (P-gp) in vitro. Drugs that inhibit P-gp may increase cobimetinib concentrations; however, the clinical relevance of this finding is unknown.
* Clinically relevant pharmacokinetic interactions were not observed following coadministration of COTELLIC with the following medications: vemurafenib, midazolam (sensitive CYP3A substrate), dextromethorphan (sensitive CYP2D6 substrate), or rabeprazole (proton pump inhibitor).

_Use in Specific Populations_

The following population characteristics were not associated with a clinically significant effect on the pharmacokinetics of cobimetinib: sex, age (19 to 88 years), race/ethnicity, mild to moderate renal impairment (creatinine clearance [CLcr] 30 to 89 mL/min), and mild hepatic impairment (total bilirubin ≤ upper limit of normal [ULN] and AST > ULN or total bilirubin > ULN but ≤ 1.5 × ULN and any AST). The effect of moderate to severe hepatic impairment (total bilirubin > 1.5 to 3 × ULN and any AST), severe renal impairment or end-stage renal disease with or without hemodialysis (CLcr less than 29 mL/min) on cobimetinib exposure (i.e., AUC and Cmax) is unknown.

_Safety and Efficacy_

Clinical effectiveness and safety of cobimetinib were demonstrated at the approved recommended dosage in a multicenter, randomized (1:1), double-blinded, placebo-controlled trial in patients with previously untreated, BRAF V600 mutation-positive, unresectable or metastatic, melanoma. The median progression-free survival (PFS) was 12.3 months in patients treated with cobimetinib and vemurafenib compared with 7.2 months in those receiving vemurafenib as a single agent [hazard ratio: 0.56 (0.45, 0.70, p < 0.001)].

The most common adverse reactions were diarrhea, photosensitivity reaction, nausea, and vomiting. Advise patients to avoid sun exposure. Monitor for severe skin rashes and interrupt, reduce, or discontinue COTELLIC if required.

U.S. Food & Drug Administration (FDA) Clinical Pharmacology Corner Update:FDA Approves LONSURF (trifluridine and tipiracil)

U.S. Food & Drug Administration (FDA) Clinical Pharmacology Corner Update:FDA Approves LONSURF (trifluridine and tipiracil)

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FDA Approves LONSURF^® (trifluridine and tipiracil) for the Treatment of Advanced Metastatic Colorectal Cancer

On September 22, 2015, the United States Food and Drug Administration (FDA) approved LONSURF (trifluridine and tipiracil) tablets for the treatment of patients with metastatic colorectal cancer who have been previously treated with fluoropyrimidine-, oxaliplatin- and
irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type, an anti-EGFR therapy. The approved recommended dosage is 35 mg/m^2 (based on the trifluridine component and rounded to the nearest 5 mg increment) orally twice daily within one hour of completion of morning and evening meals on Days 1 through 5 and Days 8 through 12 of each 28-day cycle until disease progression or unacceptable toxicity. Do not exceed 80 mg/dose.

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

* /MOA:/ Trifluridine is a thymidine-based nucleoside analogue and tipiracil is a thymidine phosphorylase inhibitor.
* /Dose proportionality:/ The AUC of trifluridine increased more than dose-proportionally over the dose range of 15 (0.43 times the recommended approved dosage) to 35 mg/m^2 . Tipiracil appeared to be dose proportional.
* /Accumulation:/ 3-fold for AUC_0-last and 2-fold for C_max at steady-state for trifluridine. No accumulation was observed for tipiracil.
* /Absorption (tablets):/ The mean relative bioavailability of LONSURF is 100% for trifluridine (T_max [mean]: 2 hours) and 96% for tipiracil (T_max [mean]: 3.5 hours) compared to oral solution. * /Food effect:/ An approximately 40% decrease in trifluridine C_max and tipiracil C_max and AUC was observed following the
administration of LONSURF with a high-fat meal to patients. * /Plasma protein binding:/ Greater than 96% for trifluridine and less than 8% for tipiracil.
* /Terminal half-life (mean):/ 2.1 hours for trifluridine and 2.4 hours for tipiracil at steady state.
* /Metabolism:/ Trifluridine and tipiracil are not metabolized by cytochrome P450 (CYP) enzymes. Trifluridine is mainly eliminated by metabolism via thymidine phosphorylase to form an inactive metabolite 5-(trifluoromethyl) uracil (FTY).
* /Excretion:/ The mean 48-hour cumulative urinary excretion of unchanged trifluridine and tipiracil was 1.5% and 29.3%, respectively. * /Exposure-safety:/ LONSURF did not have a large effect (i.e. > 20 ms) on the mean QTc interval compared to placebo when administered to cancer patients at the approved recommended dosage.

_Drug Interaction Potential_

* The mean trifluridine AUC_0-last and C_max increased by 37-fold and C_max by 22-fold, respectively, following coadministration of tipiracil and trifluridine as LONSURF compared to trifluridine administered alone.
* Trifluridine, tipiracil, and FTY did not inhibit the CYP enzymes and had no inductive effect on CYP1A2, CYP2B6 or CYP3A4/5 in vitro. * Trifluridine was not an inhibitor of or substrate for human uptake and efflux transporter systems in vitro.

_Use in Specific Populations_

* No dose adjustment to the starting dose of LONSURF is recommended in patients with mild or moderate renal impairment (creatinine clearance (CLcr): 30 to 89 mL/min); however patients with moderate renal impairment may require dose modification for increased toxicity. The estimated mean AUC of trifluridine and tipiracil at steady state was 31% and 34% higher in patients with mild renal impairment (CLcr = 60-89 mL/min) and 43% and 65% higher in patients with moderate renal impairment (CLcr: 30 to 59 mL/min) based upon a pop-PK analysis of a Phase 3 trial. In addition, patients with moderate renal impairment had a higher incidence of Grade 3 or higher adverse events, serious adverse events, and dose delays and reductions compared to patients with normal renal function (CLcr greater than or equal to 90 mL/min) or patients with mild renal impairment (CLcr: 60 to 89 mL/min) in this trial. The effect of severe renal impairment or end-stage renal disease (CLcr less than 30 mL/min) on trifluridine and tipiracil exposure is unknown. * The following population characteristics were not associated with a clinically significant effect on the pharmacokinetics of
trifluridine or tipiracil: age, sex, race (White or Asian), or mild hepatic impairment. The effect of moderate to severe hepatic impairment on trifluridine and tipiracil exposure is unknown.

_Safety and Efficacy_

The clinical efficacy and safety of LONSURF were evaluated in an international, randomized, double-blind, placebo-controlled study conducted in patients with previously treated metastatic colorectal cancer. The major efficacy outcome measure was overall survival (OS). A statistically significant median 1.8 month improvement in overall survival (Hazard ratio [95% CI]: 0.68 (0.58, 0.81) p <0.001) was demonstrated in patients in the LONSURF plus best supportive care (BSC) arm compared to those who received placebo plus BSC. The most common adverse reactions reported in this trial were anemia, neutropenia, asthenia/fatigue, nausea, thrombocytopenia, decreased appetite, diarrhea, vomiting, abdominal pain, and pyrexia.

Full prescribing information is available at http://go.usa.gov

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm
by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

The Office of Clinical Pharmacology (OCP) regulatory reviews for new drugs or biologics are often available for viewing shortly following approval at the Agency’s Drugs@FDA website http://go.usa.gov

We always welcome your thoughts regarding the format, content, and utility of information you receive via this Burst email initiative. Comments may be sent via email to ocp@fda.hhs.gov .

/This burst was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA./

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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