Porfimer

Porfimer sodium is a mixture of porphyrin units, which are linked together in chains of two to eight units The cytotoxic actions of porfimer sodium are light and oxygen-dependent. Photodynamic therapy with porfimer sodium is a 2-stage process. The first stage is the intravenous injection of porfimer sodium. Clearance from a variety of tissues occurs over 40-72 hours, but tumours, skin, and organs of the reticuloendothelial system (including liver and spleen) retain porfimer sodium for a longer period. Illumination of the target area with 630 nm wavelength laser light constitutes the second stage of therapy.

Tumour and dysplastic tissue selectivity in treatment may occur partly through selective retention of porfimer sodium but mainly through a selective delivery of light. Cellular damage caused by porfimer sodium PDT is a consequence of the propagation of free radical reactions. Radical initiation may occur after porfimer sodium absorbs light to form a porphyrin excited state. Spin transfer from porfimer sodium to molecular oxygen may then generate singlet oxygen. Subsequent free radical reactions can form superoxide and hydroxyl radicals. Tumour cell death also occurs through ischaemic necrosis secondary to vascular occlusion that appears to be partly mediated by thromboxane A2 release. The laser treatment induces a photochemical, not a thermal, effect. The necrotic reaction and associated inflammatory response evolve over several days.

The pharmacokinetics of porfimer sodium have been studied in 12 patients with endobronchial cancer and 23 healthy subjects (11 men and 12 women), given 2 mg/kg porfimer sodium through slow intravenous injection. Plasma samples were obtained out to 56 days (patients) or 36 days (volunteers) post-injection.

In patients, the mean peak plasma concentration (C_max) was 79.6 μg/ml (CV 61%, range 39-222), whereas in volunteers C_max was 40 μg/ml and AUC_inf was 2400 μg/h/ml.

Distribution

In vitro binding of porfimer sodium to human serum protein is around 90% and independent of concentration between 20 and 100 μg/ml.

Elimination

Porfimer sodium is cleared slowly from the body, with a mean CL_T of 0.859 ml/h/kg (CV 53%) in patients. The serum decay was bi-exponential, with a slow distribution phase and a very long elimination phase that started approximately 24 hours after injection. The mean elimination half-life (t_1/2) was 21.5 days (CV 26%, range 264-672) in patients and 17 days in volunteers.

Special populations

The influence of renal and hepatic impairment on exposure to porfimer sodium has not been evaluated.

Gender had no effect on pharmacokinetic parameters except for t_max, which was approximately 1.5 hours in women and 0.17 hours in men. At the time of intended photoactivation 40-50 hours after injection, the pharmacokinetic profiles of porfimer sodium in men and women were very similar.

Porfimer sodium was not mutagenic in standard genotoxicity tests in the absence of light. With light activation, porfimer sodium was mutagenic in some in-vitro tests.

Reproductive toxicology studies were insufficient to support the safety of porfimer sodium during pregnancy, as no light activation had been used. In these studies foetotoxicity, but not teratogenicity, occurred in rats and rabbits only at evaluated intravenous doses (greater than of equal to 4 mg/kg) and at greater frequency (daily) compared in the clinical use.

Preclinical studies indicate that the excretion of porfimer sodium components occurs primarily via the faecal route.