Source: European Medicines Agency (EU) Revision Year: 2012 Publisher: Pinnacle Biologics B.V., p/a Trust Company Amsterdam B.V., Crystal Tower 21st Floor, Orlyplein 10, 1043 DP Amsterdam, The Netherlands
Pharmacotherapeutic group: Sensitizers used in photodynamic/radiation therapy
ATC code: L01XD01
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 PhotoBarr is a 2-stage process. The first stage is the intravenous injection of PhotoBarr. 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.
In a controlled clinical trial, a PhotoBarr PDT + OM (omeprazole) patient group (n=183)was compared to a group of patients receiving OM only (n=70). Eligible patients for this study were to have biopsy-proven HGD in Barrett’s oesophagus (BO). Patients were excluded from the study if there was a presence of invasive oesophageal cancer, if they had a history of cancer other than nonmelanoma skin cancer or if they had received prior PDT to the oesophagus. Other exclusion criteria were patients in whom omeprazole therapy was contraindicated.
Patients randomised to treatment with PDT received PhotoBarr at a dose of 2 mg/kg body weight through slow intravenous injection over 3 to 5 minutes. One or 2 laser light treatments were administered following PhotoBarr injection. The first laser light session occurred 40-50 hours after injection and a second session, if indicated, occurred 96-120 hours after injection. Co-administration of omeprazole (20 mg BID) began at least 2 days before PhotoBarr injection. Patients randomised to the OM only group received orally omeprazole 20 mg BID for the duration of the study.
Patients were followed every 3 months until 4 consecutive, quarterly follow-up endoscopic biopsy results were negative for HGD, and then biannually until the last enrolled patient had completed a minimum of 24 months of follow-up evaluations after randomisation.
PhotoBarr PDT + OM was effective in eliminating HGD in patients with BO. At final analysis, performed at a minimum of 24 months follow-up, a statistically significant percentage of patients (77%) in the PhotoBarr PDT + OM group demonstrated complete HGD ablation compared to 39% of patients in the OM alone group (p<0.0001). Fifty-two percent of patients in the PDT + OM group showed normal squamous cell epithelium while 59% had absence of dysplasia compared to 7% and 14% in the OM alone group, respectively (p<0.0001). These results confirm those observed after a minimum of 6 months follow-up which showed HGD ablation in 72% of patients in the PhotoBarr PDT + OM group compared to 31% in the OM only group. Forty-one percent of patients showed normal squamous cell epithelium and 49% had absence of dysplasia.
By the end of the minimum follow-up of two years, 13% in the PhotoBarr PDT + OM group had progressed to cancer compared to 28% in the OM only group in the intent-to-treat (ITT) population. The proportion of patients who progressed to cancer in the PhotoBarr PDT + OM group was statistically lower than in the OM only group (p=0.0060). The survival curves indicated that, by the end of the entire follow-up period, patients in the PhotoBarr PDT + OM group had a 83% chance of being cancer-free as compared to a 53% chance for patients in the OM only group. Comparison between the survival curves of the two treatment arms using the log rank test showed a statistically significant difference between the curves of the two groups in the ITT population (p=0.0014), indicating a significant delay in the progression to cancer.
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 (Cmax) was 79.6 μg/ml (CV 61%, range 39-222), whereas in volunteers Cmax was 40 μg/ml and AUCinf was 2400 μg/h/ml.
In vitro binding of porfimer sodium to human serum protein is around 90% and independent of concentration between 20 and 100 μg/ml.
Porfimer sodium is cleared slowly from the body, with a mean CLT 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 (t1/2) was 21.5 days (CV 26%, range 264-672) in patients and 17 days in volunteers.
The influence of renal and hepatic impairment on exposure to porfimer sodium has not been evaluated (see sections 4.2, 4.3 and 4.4).
Gender had no effect on pharmacokinetic parameters except for tmax, 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.
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