Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties
Pharmacotherapeutic group: Antineoplastic agents, sensitisers used in photodynamic therapy, ATC code: L01XD04

Mechanism of action
5-ALA is a natural biochemical precursor of heme that is metabolised in a series of enzymatic reactions to fluorescent porphyrins, particularly PPIX. 5-ALA synthesis is regulated by an intracellular pool of free heme via a negative feedback mechanism. Administration of excess exogenous 5-ALA avoids the negative feedback control, and accumulation of PPIX occurs in target tissue. In the presence of visible light, fluorescence of PPIX (photodynamic effect) in certain target tissues can be used for photodynamic diagnosis.

Pharmacodynamic effects
Systemic administration of 5-ALA results in an overload of the cellular porphyrin metabolism and accumulation of PPIX in various epithelia and cancer tissues. Malignant glioma tissue (WHO-grade III and IV, e.g., glioblastoma, gliosarcoma or anaplastic astrocytoma) has also been demonstrated to synthesise and accumulate porphyrins in response to 5-ALA administration. The concentration of PPIX is significantly lower in white matter than in cortex and tumour. Tissue surrounding the tumour and normal brain may also be affected. However, 5-ALA induced PPIX formation is significantly higher in malignant tissue than in normal brain.

In contrast, in low-grade tumours (WHO-grade I and II, e.g., oligodendroglioma) no fluorescence could be observed after application of the active substance. Medulloblastomas or brain metastases revealed inconsistent results or no fluorescence.

The phenomenon of PPIX accumulation in WHO-grade III and IV malignant gliomas may be explained by higher 5-ALA uptake into the tumour tissue or an altered pattern of expression or activity of enzymes (e.g. ferrochelatase) involved in haemoglobin biosynthesis in tumour cells. Explanations for higher 5-ALA uptake include a disrupted blood-brain barrier, increased neo-vascularisation, and the overexpression of membrane transporters in glioma tissue.

After excitation with blue light (λ=400-410 nm), PPIX is strongly fluorescent (peak at λ=635 nm) and can be visualised after appropriate modifications to a standard neurosurgical microscope.

Fluorescence emission can be classified as intense (solid) red fluorescence (corresponds to vital, solid tumour tissue) and vague pink fluorescence (corresponds to infiltrating tumour cells), whereas normal brain tissue lacking enhanced PPIX levels reflects the violet-blue light and appears blue.
Clinical efficacy and safety
In a phase I/II trial including 21 patients, a dose-efficacy relationship between the dose levels and the extent and quality of fluorescence in the tumour core was detected: higher doses of 5-ALA enhanced the fluorescence quality and the fluorescence extent of the tumour core compared to demarcation of the tumour core under standard white illumination in a monotone, non-falling fashion. The highest dose (20 mg/kg body weight) was determined to be the most efficient.

A positive predictive value of tissue fluorescence of 84.8 % (90 % CI: 70.7 %-93.8 %) was found.
This value was defined as the percentage of patients with positive tumour cell identification in all biopsies taken from areas of weak and strong fluorescence. The positive predictive value of strong fluorescence was higher (100.0 %; 90 % CI: 91.1 %-100.0 %) than of weak fluorescence (83.3 %; 90 % CI: 68.1 %-93.2 %). Results were based on a phase II trial including 33 patients receiving 5-ALA HCl in a dose of 20 mg/kg body weight.

The resulting fluorescence was used as an intraoperative marker for malignant glioma tissue with the aim of improving the surgical resection of these tumours.

In a phase III trial with 349 patients with suspected malignant glioma amenable to complete resection of contrast-enhancing tumour were randomised to fluorescence-guided resection after administration of 20 mg/kg body weight 5-ALA HCl or conventional resection under white light. Contrast-enhancing tumour was resected in 64 % of patients in the experimental group compared to 38 % in the control- group (p<0.0001).
At the visit six months after tumour resection, 20.5 % of 5-ALA-treated-patients and 11 % of patients who underwent standard surgery were alive at the six-month visit without progression. The difference was statistically significant using the chi-square test (p=0.015).
No significant increase in overall survival has been observed in this trial; however, it was not powered to detect such a difference.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

General characteristics
This medicinal product shows good solubility in aqueous solutions. After ingestion, 5-ALA itself is not fluorescent but is taken up by tumour tissue (see section 5.1) and is intracellularly metabolised to fluorescent porphyrins, predominantly PPIX.

Absorption
5-ALA as drinking solution is rapidly and completely absorbed and peak plasma levels of 5-ALA are reached 0.5–2 hours after oral administration of 20 mg/kg body weight. Plasma levels return to baseline values 24 hours after administration of an oral dose of 20 mg/kg body weight. The influence of food has not been investigated because this medicinal product is generally given on empty stomach prior to induction of anaesthesia.

Distribution and biotransformation
5-ALA is preferentially taken up by the liver, kidney, endothelials and skin as well as by malignant gliomas (WHO grade III and IV) and metabolised to fluorescent PPIX. Four hours after oral administration of 20 mg/kg body weight 5-ALA HCl, the maximum PPIX plasma level is reached.
PPIX plasma levels rapidly decline during the subsequent 20 hours and are not detectable anymore 48 hours after administration. At the recommended oral dose of 20 mg/kg body weight, tumour to normal brain fluorescence ratios are usually high and offer lucid contrast for visual perception of tumour tissue under violet-blue light for at least 9 hours.

Besides tumour tissue, faint fluorescence of the choroid plexus was reported. 5-ALA is also taken up and metabolised to PPIX by other tissues, e.g., liver, kidneys or skin (see section 4.4). Plasma protein binding of 5-ALA is unknown.


Elimination
5-ALA is eliminated quickly with a terminal half-life of 1-3 hours. Approximately 30 % of an orally administered dose of 20 mg/kg body weight is excreted unchanged in urine within 12 hours.

Linearity/non-linearity
There is dose proportionality between AUC0-inf. of 5-ALA values and different oral doses of this medicinal product.

Renal or hepatic impairment
Pharmacokinetics of 5-ALA in patients with renal or liver impairment has not been investigated.