Photosensitizer Radachlorin®: Skin cancer PDT phase II clinical trials

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Summary

“Radachlorin”®, also known in the EU as Bremachlorin, a composition of 3 chlorophyll a derivatives in an aqueous solution, was introduced into the Russian Pharmacopoeia. Its GMP (Good Manufacturing Practice) facility based manufacturing method was patented. Laboratory experiments and clinical phase I were performed.

Protocols were designed for PDT of basal cell carcinoma of the skin to result in GCP (Good Clinical Practice)-conformed randomized phase II clinical studies. “Radachlorin”® solution for intravenous infusions 0.35% 10 mL in the doses of 0.5–0.6 and 1.0–1.2 mg/kg and a gel for topical application 0.1% 25 g in the dose of 0.1 g/cm2 were photoactivated by 2.5W 662 nm semiconductor laser “LAKHTA-MILON®” (St. Petersburg, Russia) in light doses of 200, 300 (solution), 400, 600, 800 (gel) J/cm2.

Safety study showed no side effects and a good tolerability of “Radachlorin”® by patients. There was no normal skin/subdermal tissue damage after both laser and sun light exposure. The main part (98%) of the drug was excreted or metabolized in the first 48 h. Drug administration at a dose of 1.0–1.2 mg/kg and irradiation at 3 h with 662 ± 3 nm light at a dose of 300 J/cm2 (solution) and 4 PDT sessions at an interval of 1 week with 3 h gel exposure, followed by 400 J/cm2 light exposure (gel) were found to be the optimal treatment regimes.

Having successfully passed clinical trials, “Radachlorin”® achieved marketing authorization in Russia in 2009 and a conditional approval in South Korea in 2008. It is a candidate for phase III clinical trials in the EC and may be commercialized as a prospective second-generation photosensitizer.

Introduction

This paper represents the full report of a phase IIb clinical trials for the photosensitizer Radachlorin [1] in Russia (August 2003–August 2005), previously published partly [2], [3], [4], [5], set forth in 2 different clinical trial Protocols (3 hospitals for “Radachlorin”®, i.v. administration (RCS); 2 hospitals for “Radachlorin”®, topical administration, RCG), aimed at obtaining confirmation of previous data [6], [7], [8] on applicability, safety and tolerability of Radachlorin-LAKHTA-MILON photodynamic therapy, as well as optimizing PDT regimes for improving photodynamic tumor destruction examining various drug doses, and light exposures. This followed laboratory studies (1999–2001) and clinical phase 0 and I trials (conducted in Russia in 3 hospitals in July 2001–March 2003, involving 67 patients with i.v. and 35 patients with topical administration of photosensitizer), for cutaneous basal cell carcinoma (BCC) treatment protocols.

Section snippets

Photosensitizer

“Radachlorin”® active pharmaceutical ingredient (API) as well as its finished formulation “Radachlorin”® gel for topical application 0.1% 25 g (RCG) were produced in a GMP-certified facility of RADA-PHARMA Co. Ltd. (Moscow, Russia).

“Radachlorin”® active pharmaceutical ingredient (API) is represented by the total sodium salts of chlorins (6.50/7.50 g), and purified water (up to 100.00 mL).

RCG is “Radachlorin”® (1.43 g) (total sodium salts of chlorins—0.10 g), purified water (up to 100.00 mL), and

Results

Safety study showed no side effects and a good tolerability of RCS by patients, save for moderate pain, depending on individual sensitivity, tumor localization and irradiation field. There was no normal skin/subdermal tissue damage after both laser and sunlight exposure. The main part (98%) of the drug was excreted or metabolized in the first 48 h.

A low dark toxicity, 48 h clearance of RCS from the human's body and a low affinity to the skin helped to avoid the skin photosensitivity to daylight

Discussion

“Radachlorin”® active substance is chemically stable in solutions for 1.5 years at 0 + 8 °C in the dark. When introduced to embryocarcinoma T36 bearing mice, it had maximal tumor uptake within 0.5–5 h post-injection with tumour-to-skin ratio around 14 by 3 h post-injection and clearance period about 24 h. In the animal PDT experiments “Radachlorin”®, active substance showed an expressed specific PDT activity, causing an intensive but bearable by animals necrotic action to the tumors [10], [11], [12],

Acknowledgments

The authors are highly grateful to the supervisors of the clinical trials V.A. Privalov (Prof., M.D., D.Med.Sc.), V.V. Sokolov (Prof., M.D., D.Med.Sc.), A.V. Geinits (Prof., M.D., D.Med.Sc.), as well as to physicists making fluorescent diagnosis possible: A.V.Lappa (Prof., D.Med.Sc.), M.V.Evnevich (Ph.D.), N.N.Boulgakova (Ph.D.).

This work would certainly have been impossible without I.D. Zalevskiy (Ph.D.) and S.E.Goncharov, who provided the lasers.

We would also like to thank the staff member of

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This paper was supported by the Natural Health Foundation (Noordwijkerhout, The Netherlands, www.naturalhealthfoundation.com).

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