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Active
Ingredient: CRIZOTINIB
Proprietary Name: XALKORI
Dosage Form; Route of Administration: CAPSULE; ORAL
Strength: 200 MG and 250 MG
Reference Listed Drug: 200 MG and 250 MG
Reference Standard: 250 MG
TE Code: None
Application Number: N202570
Approval Date: Aug 26, 2011
Applicant Holder Full Name: PF PRISM CV
Marketing Status: Prescription
· Approval in different country:
US FDA: Aug 26, 2011
EMA: 23 October 2012
Health Canada: May 10, 2012
Australia: 13 December 2017
Note:
XALKORI has received approval for patients with ALK-positive NSCLC in more than 90 countries including Australia, Canada, China, Japan, South Korea and the European Union. XALKORI is also approved for ROS1-positive NSCLC in more than 60 countries.
· Exclusivity Data
Exclusivity Code (Expiration): ODE-111 (03/11/2023)
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Patent No |
Patent Expiration |
Drug Substance |
Drug Product |
Submission Date |
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08/26/2025 |
DS |
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05/12/2027 |
09/14/2011 |
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Claim 1: A method of reversing or inhibiting the progress of abnormal cell growth in a mammal comprising, administering to said mammal a therapeutically effective amount of (R)-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine or a pharmaceutically acceptable salt thereof, wherein the abnormal cell growth is a cancer mediated by an anaplastic lymphoma kinase. |
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10/08/2029 |
DS |
DP |
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Claim 1: Compound as per figure mentioned in API information Claim 2: A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier. |
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11/06/2029 |
DS |
DP |
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Claim 1:A crystalline form of free base of (R)-3-[1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine having a powder X-ray diffraction pattern substantially. Claim 5. The crystalline form of claim 1, wherein the powder X-ray diffraction pattern has peaks at diffraction angles (2θ) of 15.7±0.1, 17.3±0.1, 19.7±0.1, and 26.8±0.1. Claim 10. The capsule of claim 7 comprising from 50 to 100 mg of the crystalline form of (R)-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine. |
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03/01/2025 |
DS |
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Structure: Click here for structure
Chemical Name: (R)-3-[1-(2,6-Dichloro-3-fluorophenyl)ethoxy]-5-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]pyridin-2-amine
Molecular Formula: C21H22Cl2FN5O
Molecular Weight: 450.34 daltons
Appearance: White to pale-yellow powder
Hygroscopic: non-hygroscopic
Solubility: The solubility of crizotinib in aqueous media decreases over the range pH 1.6 to pH 8.2 from greater than 10 mg/mL to less than 0.1 mg/mL. Crizotinib solubility in aqueous media decreases with increasing pH.
BCS Class:IV
Polymorphism: Only one crystalline form has been found, this is the thermodynamically stable form A, no other crystalline form has been found.
pKa: 9.4 (piperidinium cation) and 5.6 (pyridinium cation)
pKa (Strongest Basic): (Predicted) -0.25
Log P: The log of the distribution coefficient (octanol/water) at pH 7.4 is 1.65.
CAS No: 877399-52-5
Chiral center: The crizotinib structure contains one chiral center
Degradation and Stability: Stability results have been provided for up to 12 months at 25°C/60%RH and 6 months at 40°C/75%RH. They show a good stability for the active substance. The parameters tested were the same as those included in the release specification. Stress studies were performed at high temperatures and no significant degradation was observed after 14 days stored at 100°C. Minor degradation was observed when crizotinib was exposed to strongly acidic, strongly basic, intense light and oxidative conditions.
· API MSDS:
Click here for Download MSDS of API
· API DMF and supplier Information
Updated soon...
· Composition
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200 mg |
Capsule Fill: colloidal silicon dioxide (2mg), microcrystalline cellulose (83mg), anhydrous dibasic calcium phosphate (83mg), sodium starch glycolate (20mg), magnesium stearate (12mg) Capsule shells: The pink opaque hard
gelatin capsule shell components contain gelatin, titanium dioxide, and red
iron oxide. The white opaque hard gelatin capsule shell components contain
gelatin and titanium dioxide. |
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250 mg |
Capsule Fill: colloidal silicon dioxide (2.5mg), microcrystalline cellulose (103.75mg), anhydrous dibasic calcium phosphate (103.75mg), sodium starch glycolate (25mg), magnesium stearate (15mg) Capsule shells: The
pink opaque hard gelatin capsule shell components contain gelatin, titanium
dioxide, and red iron oxide. The white opaque hard gelatin capsule shell
components contain gelatin and titanium dioxide. |
· Manufacturing process details:
Development Background:
The aim of the development was to obtain an immediate release hard gelatin capsule to deliver 200 mg and 250 mg crizotinib as a single unit dose. The initial dosage form used during early Phase 1 clinical studies was a powder in capsule (PIC), consisting of crizotinib in a hard gelatin capsule shell. Then a tablet dosage form was developed containing 50 mg and 100 mg crizotinib (drug substance loading of 12.5%), to meet increased clinical demand for Phase 3 clinical studies. In vitro dissolution profiles for both the clinical tablet and PIC dosage forms demonstrated rapid release within 30 minutes in 0.1N HCl. In vivo performance was subsequently shown to be bioequivalent between the clinical tablet and PIC. However for manufacturability reasons, the crizotinib capsule form was developed and it was designed to be qualitatively similar to the clinical tablet formulation. The pharmaceutical development was based on the Quality by Design concept. No design space has been claimed by the applicant in the manufacturing process of the finished product.
Manufacturing Process:
The
manufacturing process is considered as standard, and adequate information has
been provided.
The main critical steps have been studied in detail and the critical process
parameters (CPPs) have been described adequately. The target normal operating
ranges and proven for these CPPs are considered acceptable. A satisfactory
validation protocol was filed.
· Capsule Details
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Parameters |
200 mg |
250 mg |
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Description |
Hard gelatin capsule, size 1, white opaque body and pink opaque cap, printed with black ink “Pfizer” on the cap and “CRZ 200” on the body |
hard gelatin capsule, size 0, pink opaque cap and body, printed with black ink “Pfizer” on the cap and “CRZ 250” on the body |
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Capsule Image |
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Capsule Dimension |
Size 1 |
Size 0 |
Apparatus: I (Basket)
Speed: 60 RPM
Volume: 900 mL
Medium: 0.1N HCl (degassed)
Time point (min): 5, 10, 15, 30 and 45
Updated date: 04/14/2016
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Market |
200 mg |
250 mg |
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US |
Bottles of 60 capsules: NDC 0069-8140-20 |
Bottles of 60 capsules: NDC 0069-8141-20 |
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EU |
HDPE bottles with a polypropylene closure containing 60 hard capsules. PVC-foil blisters containing 10 hard capsules. Each carton contains 60 hard capsules. |
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Australia |
Blister pack (ARTG: 190964 ) Bottle (ARTG: 190966) |
Blister pack (ARTG: 190965) Bottle (ARTG: 190963) |
For Blister Pack (EU)
· Results are provided for up to 12 months at 25°C/60%RH and 30°C/75%RH and 6 months at 40°C/75%RH in both packaging systems.
· Samples stored in PVC/aluminium foil blisters showed some caking of the capsule contents at the 6 month time point at 30°C/75%RH and from the 2 month time point onwards at 40°C/75%RH.
· Brittleness of the capsule shells was also seen at the 6 month time point at 40°C/75%RH.
· These observations were not associated with changes in degradation product levels, assay or dissolution results.
· Also, they were not been observed through 9 months at the 25°C/60%RH or 30°C/75%RH storage conditions. For samples stored in PVC/aluminium foil blisters, the water content increased by about 0.5% at 25°C/60%RH and by about 1.5% at 30°C/75%RH and 40°C/75%RH through 6 months.
· The water content did not increase at the 9 month time point. This increased water content has not led to any changes in degradation product levels, assay or dissolution results
· The capsules are also stable to light. Also in use stability of capsules packed in the HDPE bottle has been demonstrated.
For US (Bottle)
· Based on the stability data provided, the Agency grants a fifteen (15) month expiry for the drug product, as packaged in the commercial configuration and when stored at USP controlled room temperature.
Shelf life:
· EU: 4 years
· US: 15 Months
Mechanism of Action:
Crizotinib is an inhibitor of receptor tyrosine kinases including ALK, Hepatocyte Growth Factor Receptor (HGFR, c-Met), ROS1 (c-ros), and Recepteur d’Origine Nantais (RON). Translocations can affect the ALK gene resulting in the expression of oncogenic fusion proteins. The formation of ALK fusion proteins results in activation and dysregulation of the gene’s expression and signaling which can contribute to increased cell proliferation and survival in tumors expressing these proteins. Crizotinib demonstrated concentration-dependent inhibition of ALK, ROS1, and c-Met phosphorylation in cell-based assays using tumor cell lines and demonstrated antitumor activity in mice bearing tumor xenografts that expressed echinoderm microtubule-associated protein-like 4 (EML4)- or nucleophosmin (NPM)-ALK fusion proteins or c-Met
Absorption
Following a single oral dose, crizotinib was absorbed with median time to achieve peak concentration of 4 to 6 hours. Following crizotinib 250 mg twice daily, steady state was reached within 15 days and remained stable, with a median accumulation ratio of 4.8. Steady-state systemic exposure [observed minimum concentration (Cmin) and AUC] appeared to increase in a greater than dose-proportional manner over the dose range of 200-300 mg twice daily. The mean absolute bioavailability of crizotinib was 43% (range: 32% to 66%) following a single 250 mg oral dose. A high-fat meal reduced crizotinib AUC from time zero to infinity (AUCinf) and maximum observed plasma concentration (Cmax) by approximately 14%. XALKORI can be administered with or without
Food effect in patients:
In the food effect sub-study of Trial 1001 using the CIC dosage form, 12 patients with solid tumors received a 250-mg dose of crizotinib under either the “fed” or “fasted” conditions on Day -7 and Cycle 1 Day 1. The evening dose of Cycle 1 Day 1 was cancelled for these patients. The fed/fasted ratios of the geometric means for crizotinib exposure were 84.64% (90% CI: 65.11%- 110.05%) for AUC24hrs and 87.65% (90% CI: 69.23%-110.98%) for Cmax.
Food effect in healthy subjects:
The effect of a standard high-fat meal on the single dose PK of crizotinib was evaluated in Trial 1011 using the CIC dosage form in 35 healthy subjects. Based on the ratios of the adjusted geometric means (fed/fasted), the coadministration of a high fat meal decreased both AUCinf and Cmax of approximately 14%. The ratios (fed/fasted) of geometric mean for AUCinf and Cmax were 85.76% with 90% CI [78.88%, 93.25%] and 86.22 with 90% CI [77.89%, 95.43%], respectively
Distribution
The geometric mean volume of distribution (Vss) of crizotinib was 1772 L following intravenous administration of a 50 mg dose, indicating extensive distribution into tissues from the plasma. Binding of crizotinib to human plasma proteins in vitro is 91% and is independent of drug concentration. In vitro studies suggested that crizotinib is a substrate for P-glycoprotein (P-gp). The blood-to-plasma concentration ratio is approximately 1.
Elimination
Following single doses of crizotinib, the mean apparent plasma terminal half-life of crizotinib was 42 hours in patients. Following the administration of a single 250 mg radiolabeled crizotinib dose to healthy subjects, 63% and 22% of the administered dose was recovered in feces and urine, respectively. Unchanged crizotinib represented approximately 53% and 2.3% of the administered dose in feces and urine, respectively. The mean apparent clearance (CL/F) of crizotinib was lower at steady state (60 L/h) after 250 mg twice daily than after a single 250 mg oral dose (100 L/h), which was likely due to auto-inhibition of CYP3A by crizotinib after multiple dosing.
Metabolism
Crizotinib is predominantly metabolized by CYP3A4/5. The primary metabolic pathways in humans were oxidation of the piperidine ring to crizotinib lactam and O-dealkylation, with subsequent Phase 2 conjugation of O-dealkylated metabolites.
Inter- and intra-subject variability
Moderate variability in crizotinib PK parameters has been observed in both healthy subjects and patients with advanced solid tumors.
Following multiple oral crizotinib dosing of 250 mg BID, the coefficient of variation (%CV) is 36-38% and 38-44% for AUCτ and Cmax, respectively. CV% values in AUCinf and Cmax range from 28% to 34% for oral administration compared to 18% to 19% following intravenous infusion (Trial 1010). The variability may be attributable to the variation in extrinsic factors (concomitant medications, live styles, measurement errors in PK concentration) and intrinsic factors (e.g., bodyweight, race, gastro-intestinal pH variation, genetics, etc) in patients with cancers.
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FDA Label |
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Dailymed |
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Summary of product characteristic |
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Patient leaflet |
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FDA chemistry review |
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FDA Pharmacology Review(s) |
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FDA Clinical Pharmacology Biopharmaceutics Review(s) |
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FDA BE Recommendation |
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European Public Assessment Report |
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Australia Public Assessment Report |
- Sales
for Xalkori (crizotinib)
in the Global NSCLC Market Global drug sales for Xalkori
are forecast to increase from $123.35m in 2012 to $272.11m in 2022 at a
Compound Annual Growth Rate (CAGR) of 8.23%.
- The major drivers of Xalkori sales growth in the NSCLC therapeutics market
will include:
- Sales will be driven by
increased testing for ALK translocations in all the major markets
- China approval in
Q2’2013 will boost the sales significantly in forecasted period
- A growing aging
population and increasing NSCLC incident cases in the majority of the
markets covered, especially in Japan and the emerging markets of China and
India The major barriers responsible for the decline in Xalkori sales of NSCLC therapeutics will
include:
- Xalkori will
initially face competition from Novartis’ LDK378 in the second line and
subsequently in the first line after LDK378’s label extension into that
patient segment in 2019.
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Xalkori (Crizotinib): Key
Metrics in NSCLC Markets |
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Xalkori Sales |
2012 |
2022 |
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US |
$80.72 m |
$66.48 m |
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5EU |
$6.62 m |
$20.72 m |
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Japan |
$35.34 m |
$17.70 m |
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China |
NA |
$165.49 m |
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India |
$0.67 m |
$1.72 m |
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Total |
$123.35 |
$272.11 m |
·
Not
yet recruiting: The study has not started recruiting participants.
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Recruiting: The
study is currently recruiting participants.
·
Completed: The
study has ended normally, and participants are no longer being examined or
treated (that is, the last participant's last visit has occurred).
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