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Case Studies


Case 1


The Problem
  • Molecule absorbed in UVB and UVA range
  • 3T3 phototoxic fibroblast model positive PIF 30
  • Animal phototoxicity study (not conducted)
  • Phase 2 development - 6/200 cases of photosensitivity during the summer months
The Solution
  • Single dose phototoxic 'look-see' type study - negative
  • Full regulatory study with placebo vs Ciproflaxacin vs higher dose of drug
  • Placebo and Ciprofloxacin negative for immediate erythema
  • Ciprofloxacin positive for delayed erythema
  • Drug in question - negative: placebo - negative i.e. N.A.D.

Case 2


The Problem
  • Drug for chronic use - Phase 1
  • UVB/A/visible absorber - skin distributed
  • 3T3 positive
  • Rat phototoxicity study positive
Full regulatory study
  • Ciprofloxacin positive. Placebo negative - as expected
  • High dose drug positive 10/12, immediate phototoxicity UVA wavelengths (urticaria)
  • Low dose drug positive 4/12, immediate phototoxicity UVA wavelengths (urticaria)
Full regulatory study
  • positive high dose
  • negative low dose
Question

What is the significance of the urticarial responses which were occurring at only high doses and which were not present at baseline testing?

Answer

Further study with physiological irradiances at 335 and 365 revealed that drug induced phototoxicity was confined to non physiological irradiances.

Conclusion

Drug has an immediate phototoxic potential (not of clinical relevance). Phase 3 clinical surveillance.


Case 3

ANTIBIOTIC (potentially for chronic use)


The Problem
  • Absorbs in the UVB/A and visible spectrum
  • 3T3 assay positive
  • Animal model work not conducted
The Solution
  • In vivo human volunteer regulatory type study conducted
  • Evidence of dose related phototoxicity but
  • Phototoxic index similar to that seen with Ciprofloxacin but waveband extended to 430 ± 30nm
Regulatory request: is this visible light sensitivity, i.e. is there a potential for retinal phototoxicity?
  • Further study in individuals taking the drug using long and short pass filters demonstrated the phototoxicity to be in the UVA region i.e. was blocked by the adult lens, therefore retinal phototoxicity unlikely

Case 4

ANTI-DIABETIC AGENT


The Problem
  • Absorbs in UVA with 3T3 positive: PIF 90
The Solution
  • Full clinical regulatory type study
  • Abandoned after 3 x PI >10 within the UVA region
  • Drug has a clinically relevant photosensitisation issue

Case 5

FLUOROQUINOLONE ANTIBIOTIC


The Problem
  • Absorbs in UVB/A with 3T3 positve
  • Phototoxicity study (volunteers) conducted elsewhere was negative
  • During launch in spring: 300 severe phototoxicity events over 4/12: ~20 required hospitalisation
The Solution
  • Clinically serious phototoxicity could have been detected using the Spectratox study
  • Would have avoided patient injury

Case 6

FLUOROQUINOLONE ANTIBIOTIC


The Problem
  • Absorbs in UVB/A with 3T3 positive
  • Phototoxicity regulatory type study (volunteers) conducted elsewhere (was negative including Ciprofloxacin control!). Probably due to suboptimal light source choice and dosimetry.
The Solution
  • What would have been the outcome of the Spectratox study?
 

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18th April 2008