DRUG MASTER FILE: [18F]FDG



DRUG MASTER FILE: [11C]MP

1. Name of Radiopharmaceutical (active ingredient)

d-threo-methyl-2-phenyl-2-(2-piperidyl) acetate ([11C]methylphenidate), ([11C]MP)

2. Indicate the chemical structure for low molecular weight drug molecules

(not required for antibodies, proteins, or polymeric agents)

3. Has an Investigational New Drug (IND) application been filed for this radiopharmaceutical?

NO:

YES:

If Yes:

IND #      

Institution:      

4. State specific details of techniques to analyze and quantify the compound

(ex: spectrophotometer – make, settings, sample dilutions, etc.)

This radiotracer will be analyzed by high performance liquid chromatography (HPLC). This is done using a Spectra-Physics HPLC pump equipped with a UV detector and a custom built NaI flow radioactivity detector. The HPLC column to be used is a C8 reverse phase column (Keystone BetaBasic C8 column 4.6 mm x 150mm), with a mobile phase of acetonitrile:0.17 M ammonium formate (2:3) at a flow rate of 1 ml/min. Data are recorded and integrated using a recording integrator, providing a printed copy of retention times and purities.

4a. Active Ingredient and Quantity (milligrams) to be administered.

Methylphenidate is the active ingredient and less 25 micrograms will be administered.

4b. Indicate the minimum detectable mass of the drug by HPLC analysis.

0.4 μg/ml

5. Radioisotopes

Carbon-11

5b. Total activity of each isotope per administration (injection, IV, oral, etc.)

6. Method of assaying radioisotope activity prior to administration

(ex: Capintec ion chamber, gamma counter, or liquid scintillation counter; include details of make, setting, type of standard, etc.)

Calibrated dose calibrators; Capintec CRC-12. Cross standardization to [137Cs] is performed daily; assay of each unit-dose container (syringe) prior to administration.

7. Radionuclidic Purity

(in %)

>99%

8. Significant radionuclidic impurities and means of assay

Carbon-11 is obtained without any radionuclidic impurities, as determined by observing the decay rate of a batch of product.

9. Radiochemical Purity

(in %)

>90%

10. Significant radiochemical impurities and means of assay

(ex: Chromatographic techniques and procedure for analyzing radiochromatogram).

The radiochemical impurity will be routinely confirmed by co-injection of the radiolabeled product with authentic methylphenidate on HPLC.

11. Provide evidence that the tracer will be stable over period of storage prior to administration.

(Give details of storage conditions and on-going quality assurance procedures for sterility, apyrogenicity, and radiochemical purity.)

The 20-min half-life of carbon-11 requires that [11C]MP be administered to the patient within 40 min (maximum) of synthesis. Repeated injections of the drug product onto the analytical HPLC have demonstrated that the product is stable at room temperature for this period of time. [11C]MP will be stored at room temperature prior to patient administration.

12. What, if any, toxic or pharmacological effects may occur?

(Attach pharmacological dose calculations based on data available from published literature or from other valid human studies).

(NOTE: If study is being performed under 9C, evidence must be presented that there will be no pharmacological effect in human subjects. In addition, references for pharmacological dose data must be listed below)

The procedure we are using for the synthesis of [11C]methylphenidate is a duplication of that which is currently in use at the Brookhaven National Laboratory PET center. No untoward pharmacological effects have been reported in any of these prior studies. Examples of scientific publications which utilize the procedure stated in the attached MFC card to be used for the proposed clinical studies are provided in the appendices.

Methylphenidate (Ritalin) is used widely in the treatment of disorders of arousal and attention in both children and adults. The most widespread usage is in the treatment of attention deficit hyperactivity disorder (ADHD) in children. In adults, methlyphenidate is used in the treatment of excessive sleepiness, particularly as it may occur in patients with narcolepsy. The usual adult dosage of methylphenidate for these purposes is in the range of 20 to 60 mg daily in 2 or 3 divided doses. A minimum of 5 mg is used per dose during introduction of the medication. This may or may not have detectable effects on the target symptoms, and is usually escalated until effects are observed. Our maximal dosage of 25 micrograms is over 20-fold below the dosage producing human pharmacological effects, and has been used by other investigators in similar PET imaging studies without reported physiological/pharmacological effects (Ref Volkow, Fowler, etc….).

12b. Attach pharmacological dose calculations based on data available from published literature or from other valid human studies.

You may add supporting documentation for this question in the Supporting Documents section of question 21-3.2.1.

13. Route(s) of Administration

Intravenous injection

14. Provide detailed information on how the pharmaceutical quality of the radioactive drug will be assured at the time of administration.

Include the following:

• pH

• Sterility

• Apyrogenicity

• Identify (chemical and radiochemical purity)

• Concentration

a. pH

A small amount of each batch of the final drug products will be spotted on Merck pH paper. The pH will be in the physiological range (4.0-8.5) and will be consistent from batch to batch.

b. Sterility/Apyrogenicity

During preclinical studies, the final drug product was produced utilizing established synthesis procedures [See appended Master Formula Card]. When tested as described below, the prepared batches were sterile and pyrogen-free. During clinical trials, the radioactive drug product will be produced utilizing these established procedures and a synthesis apparatus which will be appropriately maintained to assure that each batch of the drug product will be sterile and pyrogen-free. Sterility and bacterial endotoxin tests will be routinely performed on batches of the drug product in an ex post facto manner utilizing residual samples.

An aliquot of the final drug products will be inoculated into each of the appropriate sterility test media and incubated according to USP recommendations:

i. Fluid Thioglycollate Media (BBL, Division of Becton-Dickinson Co., Cockeysville, MD): 14 days at 30-35° C.

ii. Soybean Casein Broth (BBL, Division of Becton-Dickinson Co., Cockeysville, MD): 14 days at 20-25° C.

Positive growth is indicated by cloudiness in the culture media. Results will be compared to positive and negative controls. The efficacy of utilizing a 0.22 µm membrane filter for terminal sterilization [See appended Master Formula Card] warrants release of the drug products for patient administration prior to results of sterility testing as stipulated by current USP.

An aliquot of the final drug product will be tested for the presence of bacterial endotoxin utilizing the Limulus Amebocyte Lysate (LAL) Test with positive sample, positive, and negative controls. The currently used LAL test reagents are manufactured by Endosafe Inc., Charleston, SC under U.S. License No. 1073. Positive results are indicated by the presence of a firm gel that adheres to the bottom of the test tube when placed in the inverted position. Negative results are indicated if the contents slide down the side of the test tube when placed in the inverted position. Qualitative and quantitative test procedures will be utilized as appropriate to assure that the established USP endotoxin limit (175 EU per dose) for radiopharmaceuticals is not exceeded.

c. Identify (chemical and radiochemical purity)

The radiochemical impurity will be routinely confirmed by co-injection of the radiolabeled product with authentic methylphenidate on HPLC. MP will be analyzed by high performance liquid chromatography (HPLC). This is done using a Spectra-Physics HPLC pump equipped with a UV detector and a custom built NaI flow radioactivity detector. The HPLC column to be used is a C8 reverse phase column (Keystone BetaBasic C8 column 4.6 mm x 150mm), with a mobile phase of acetonitrile:0.17M ammonium formate (2:3) at a flow rate of 1 ml/min. Data are recorded and integrated using a recording integrator, providing a printed copy of retention times and purities.

d. Concentration

i. Mass Concentration (mass/volume)

Range: 1.0 – 8.0 μg/ml

Mass concentration will be determined using HPLC, by comparison of UV absorbance intensity with a standard of known concentration.

ii. Activity Concentration (activity/volume)

Range: 5 – 50 mCi/ml

iii. Specific Activity (activity per mass of drug)

The specific activity of each batch of drug product will be determined following synthesis utilizing HPLC and a radiation detector. The specific activity will be calculated from the concentration determined as described above, the volume of the formulated drug (usually 10 ml) and the total radioactivity determined by a Capintec dose calibrator. The product will have specific activity >800 Ci/mmol.

For questions or concerns, contact:

Scott E. Snyder, Ph.D.

Assistant Research Scientist

Division of Nuclear Medicine

(734) 763-0902

Fax: (734) 764-0288

Email: snyderse@umich.edu

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