Case Studies

Case 1: Fluoroquinolone antibiotic and monochromator testing

Background Information

• The drug absorbs in UVB and UVA spectrum
• In vitro study, (3T3) neutral red uptake phototoxic assay showed positive results
• Phototoxicity study on healthy volunteers was conducted not using a Spectratox study method but elsewhere using a solar simulator alone and the results were reported as negative
• This study, which also included ciprofloxacin as an intended positive control, showed negative results, probably due to suboptimal light source choice and dosimetry. This (negative results with a positive control) should probably have cast uncertainty on whether the negative results with the test drug were “true negative”.
• During launch in spring: 300 severe phototoxicity events were reported over 4 months and 20 subjects required hospitalisation

Conclusion

• Clinically serious phototoxicity could have been detected using a Spectratox study method using monochromator testing, so avoiding patient injury

Case 2: Drug and phototoxicity during phase 2 in clinical trial

Background information

• The investigated drug absorbs in UVB and UVA range
• In vitro study, (3T3) neutral red uptake phototoxic assay showed positive results
• No animal phototoxicity study was conducted
• In the Phase 2 clinical trial phase 2, 6/200 subjects developed skin photosensitivity during the summer months

First study proposed

• Single dose phototoxic ‘look-see’ type study gave negative results

Full regulatory study (requested after the photostudy)

• Phototoxicity study in which placebo vs ciprofloxacin (positive control known to cause delayed phototoxicity) vs higher dose of drug were compared

Results

• Placebo and ciprofloxacin were negative for immediate erythema
• Ciprofloxacin was positive for delayed erythema (so confirming the ability of the study design to detect drug phototoxicity)
• Drug in question is negative

Conclusion

• No reproducible phototoxicity (as opposed to a rare idiosyncratic phenomenon, whereby accounting for the clinical phase 2 study finding) with the test drug.

Case 3: Anti-diabetic agent showing a clinically relevant photosensitisation issue

Background information

• The drug absorbs in UVA
• In vitro study, (3T3) neutral red uptake phototoxic assay showed positive results

Full regulatory study proposed

• In vivo human volunteer regulatory type study was conducted

Results

• The clinical trial was abandoned after 3 subjects show a Phototoxic Index (PI) >10 within the UVA region

Conclusion

• The drug caused clinically relevant severe phototoxicity and knowing this informed further decisions about this drug.