Gleolan

Chemical Properties

Gleolan (aminolevulinic acid hydrochloride) is an optical imaging agent for oral solution. The 50-mL, clear vial contains 1,500 mg of lyophilized ALA HCl powder (equivalent to 1,170 mg ALA). After reconstitution, the product has a concentration of 30 mg ALA HCl per mL (equivalent to 23.4 mg ALA per mL). The chemical name is 5-amino-4-oxo-pentanoic acid hydrochloride. The chemical formula for ALA HCl is C5H10ClNO3. Its molecular weight is 167.59 g/mol with the following structural formula:

Dosage Forms And Strengths

For oral solution: 1,500 mg ALA HCl lyophilized powder, equivalent to 1,170 mg ALA, in a 50 mL single-dose clear, colorless, glass vial with rubber stopper. After reconstitution with 50 mL drinking water, the solution contains 30 mg per mL of ALA HCl (equivalent to 23.4 mg per mL of ALA) and is clear and colorless to slightly yellowish in color.

Storage And Handling

Gleolan is supplied as 1,500 mg of lyophilized ALA HCl powder (equivalent to 1,170 mg ALA), for oral solution in a 50-mL clear, colorless, glass vial with a rubber stopper and an aluminum crimp seal.

Store at 25 °C (77 °F); excursions permitted to 15-30 °C (59-86 °F).

Manufactured by: IDT Biologika GmbH Am Pharmapark Dessau-Rosslau, 06861, Germany (DEU). Revised: June 2017

Mechanism Of Action

ALA occurs endogenously as a metabolite that is formed in the mitochondria from succinyl-CoA and glycine. Exogenous administration of ALA leads to accumulation of the ALA metabolite PpIX in tumor cells. The reason for the accumulation of PpIX in neoplastic brain tissue is not known.

During glioma surgery, Gleolan is used with an operating microscope adapted with a blue emitting light source (power density 40-80 mW/cm2) and filters for excitation light of wavelength 375 to 440 nm, and observation at wavelengths of 620 to 710 nm. This allows tumor tissue to be visualized as red fluorescence. Tissue lacking sufficient PpIX concentrations appears blue.

Pharmacodynamics

The effect of the timing of the Gleolan dosing on fluorescence intensity in brain tissue is unknown. The relationship between systemic ALA plasma concentrations at the time of visualization and fluorescence intensity in brain is also unknown. The dose of 20 mg / kg provided stronger ALA-induced fluorescence in glioma tissue by both visual and spectrophotometric assessment compared to lower doses tested.

Administration of the approved recommended dose of Gleolan did not prolong the QT interval to any clinically relevant extent.

Pharmacokinetics

In 12 healthy subjects, the mean half-life of ALA following the recommended dose of Gleolan solution was 0.9 ± 1.2 hours (mean ± std dev) with a range of 0.8 to 1.3 hours. Maximum concentrations of the PpIX metabolite (Tmax for PpIX) occurred with a median of 4 hours and a range of 1.2 to 7.8 hours. The elimination half-life of PpIX was 3.6 ± 1.8 hours (mean ± std dev) with a range of 1.2 to 7.8 hours.

In 12 healthy subjects, the absolute bioavailability of ALA following the recommended dose of Gleolan solution was 100.0% ± 1.1 with a range of 78.5% to 131.2%. Maximum ALA plasma concentrations were reached with a median of 0.8 hour (range 0.5 – 1.0 hour). Distribution In in vitro experiments using ALA concentrations up to approximately 25% of the maximal concentration that occurs in plasma following the recommended dose of Gleolan solution, the mean protein binding of ALA was 12%.

Metabolism

Exogenous ALA is metabolized to PpIX, but the fraction of administered ALA that is metabolized to PpIX is unknown. The average plasma AUC of PpIX is less than 6% of that of ALA.

Excretion

In 12 healthy subjects, excretion of parent ALA in urine in the 12 hours following administration of the recommended dose of Gleolan solution was 34 ± 8% (mean ± std dev) with a range of 27% to 57%.

Specific Populations

The effect of renal or hepatic impairment on the pharmacokinetics of ALA following Gleolan administration is unknown.

Drug Interaction Studies

In vitro studies suggest that phenytoin and other anti-convulsants may decrease cellular PpIX accumulation following Gleolan dosing.

ALA is not an inhibitor of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A.

Clinical Studies

The efficacy of 20 mg / kg ALA HCl was evaluated in 3 clinical studies (Study 1-3) involving patients, ages 18 to 75 years old, who had a preoperative MRI compatible with high-grade glioma (WHO Grade III or IV) and were undergoing surgical resection.

Study 1 was an open-label study of 33 patients with newly diagnosed high-grade glioma and Study 2 was an open-label study of 36 patients with recurrent high-grade glioma. In Studies 1 and 2, after initial debulking was carried out under white light, biopsies were obtained under fluorescent light from fluorescent and nonfluorescent sites. Presence of fluorescence (positive/negative) was compared to tumor status (true/false) using histopathology as the reference standard. True positives and false positives among fluorescent biopsies and true negatives and false negatives among nonfluorescent biopsies are provided in Table 1.

Study 3 was a randomized, multicenter study in 415 patients with a preoperative diagnosis of high-grade glioma by MRI. Patients were randomized in 1:1 ratio to ALA fluorescence arm or to white light control arm. Biopsies were obtained from tumor-core, tumor-margin and regions just distant to the tumor margins. In 349 patients high grade glioma was confirmed by a blinded central read and histopathology. The remaining patients were diagnosed with metastatic disease, abscess, low-grade glioma or other conditions.

In patients with confirmed high-grade glioma randomized to the ALA fluorescence arm, presence of fluorescence at a biopsy level was compared to tumor status using histopathology as the reference standard (Table 1). In 4 patients with low-grade glioma (WHO Grade I or II) who received ALA, 9 out of 10 biopsies were false negative.

The extent of resection among patients with confirmed high-grade glioma in the ALA fluorescence arm was compared to that among patient in the control arm, with the “completeness” of resection being determined by a central blinded read of early post-surgical MRI. Percentage of patients who had “completeness” of resection was 64% in the ALA arm and 38% in the control arm, with the difference of 26% [95% CI: (16%, 36%)].

Table 1. Presence of Fluorescence Compared to Histopathology (biopsy level)

In the U.S.

• Gleolan

Available Dosage Forms:

• Powder for Solution

Therapeutic Class: Photosensitizing Agent

Aminolevulinic acid is used to help your doctor see an image of a malignant (cancer) tissue during surgery in patients with glioma (tumor in the brain or spine). It is an optical imaging agent.

This medicine is to be given only by or under the supervision of a doctor.

It is very important that your doctor check your progress closely while you are receiving this medicine. This will allow your doctor to see if the medicine is working properly and to decide if you should continue to receive it.

Avoid exposure to sunlight or room lights for 24 hours after surgery.

This medicine may cause serious allergic reactions, including anaphylaxis. This can be life-threatening and requires immediate medical attention. Tell your doctor right away if you have a rash, itching, hoarseness, trouble breathing, trouble swallowing, or any swelling of your hands, face, or mouth after you receive this medicine.

Make sure any doctor or dentist who treats you knows that you are using this medicine. This medicine may affect the results of certain medical tests.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.