Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2011 Publisher: Medac Gesellschaft für klinische Spezialpräparate mbH Fehlandtstraße 3 D-20354 Hamburg, Germany Tel. + 49 4103 8006 0 Fax: +49 4103 8006 100
Pharmacotherapeutic group: sensitisers used in photodynamic therapy
ATC code: L01XD04
5-aminolevulinic acid (5-ALA), the active substance of Gliolan, is a natural biochemical precursor of heme that is metabolised in a series of enzymatic reactions to fluorescent porphyrins, particularly protoporphyrin IX (PPIX). 5-ALA synthesis is regulated by an intracellular pool of free heme via a negative feedback mechanism.
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 multiforme, 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. medulloblastoma, oligodendroglioma) no fluorescence could be observed after application of the active substance. Brain metastases revealed inconsistent 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.
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 HCl 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<0.001).
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 study, however, the trial was not powered to detect such a difference.
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 intracellularily metabolised to fluorescent porphyrins, predominantly protoporphyrin IX (PPIX).
5-ALA HCl 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.
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.
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 are excreted unchanged in urine within 12 hours.
There is dose proportionality between AUC0-inf. of 5-ALA values and different oral doses of this medicinal product.
Pharmacokinetics of 5-ALA in patients with renal or liver impairment has not been investigated.
Standard safety pharmacology experiments were performed under light protection in the mouse, rat and dog. 5-ALA HCl administration does not influence the function of the gastro-intestinal and central nervous systems. A slight increase in saluresis cannot be excluded.
Single administration of high doses of 5-ALA HCl to mice or rats leads to unspecific findings of intolerance without macroscopic abnormalities or signs of delayed toxicity. Repeat-dose toxicity studies performed in rats and dogs demonstrate dose-dependent adverse reactions affecting changes in bile duct histology (non-reversible within a 14 day recovery period), transient increase in transaminases, LDH, total bilirubin, total cholesterin, creatinine, urea and vomiting (only in dogs). Signs of systemic toxicity (cardiovascular and respiratory parameters) occurred at higher doses in the anaesthetised dog: at 45 mg/kg body weight intravenously a slight decrease in peripheral arterial blood pressure and systolic left ventricular pressure was recorded. Five minutes after administration, the baseline values had been reached again. The cardiovascular effects seen are considered to be related to the intravenous route of administration.
Phototoxicity observed after 5-ALA HCl treatment in vitro and in vivo is obviously closely related to dose- and time- dependent induction of PPIX synthesis in the irradiated cells or tissues. Destruction of sebaceous cells, focal epidermal necrosis with a transient acute inflammation and diffuse reactive changes in the keratinocytes as well as transient secondary oedema and inflammation of dermis are observed. Light exposed skin recovered completely except for a persistent reduction in the number of hair follicles. Accordingly, general light protective measures of eyes and skin are recommended for at least 24 hours after administration of this medicinal product.
Although pivotal studies on the reproductive and developmental behaviour of 5-ALA have not been performed, it can be concluded that 5-ALA induced porphyrin synthesis may lead to embryotoxic activity in mouse, rat and chick embryos only under the condition of direct concomitant light exposure. This medicinal product should, therefore, not be administered to pregnant women. Excessive single dose treatment of rats with 5-ALA reversibly impaired male fertility for two weeks after dosing.
The majority of genotoxicity studies performed in the dark do not reveal a genotoxic potential of 5-ALA. The compound potentially induces photogenotoxicity after subsequent irradiation or light exposure which is obviously related to the induction of porphyrin synthesis.
Long-term in vivo carcinogenicity studies have not been conducted. However, considering the therapeutic indication, a single oral treatment with 5-ALA HCl might not be related to any serious potential carcinogenic risk.
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