Beruflich Dokumente
Kultur Dokumente
Dr.R.Jayashree
First Human dose
• Toxicological data
LD 50
Dose by factor approach
• Based on normalization of
body surface area
• NOAEL or MTD scales well
between species when doses
are normalized to BSA.
• ACCEPTED BY REGULATORY
BODIES
Determine NOAEL (mg/kg)using toxicity
studies
Convert it into Human Equivalent dose (HED)
• STARTING POINT
NOAEL
The highest dose level that does not
produce a significant increase in adverse
effects (statistically significant and
clinically significant)
• Based on BSA
• WIDE SPREAD PRACTICE
• Increase clinical trial safety
• Apply BSA-CF
A.Table 1: Conversion of Animal Doses to Human Equivalent Doses (HED) Based on Body Surface Area
A.Species To convert animal dose in mg/kg to dose in mg/m2, multiply by km below: To convert animal dose in mg/kg to HEDa in mg/kg, either:
A.Primates:
• Sensitive species
Appropriate species
selection
• ICH-GCP GUIDANCE S6
• FACTORS-
• ADME
• MODEL
• LIMITED CROSS SPECIES
PHARMACOLOGICAL ACTIVITY
SAFETY FACTOR
• Assurance and margin of safety
• Cushion for
Therapeutic activity
Certain toxicities
Unexpected toxicities
Receptor densities and affinity
Inter species difference(ADME)
Increase safety factor
• Steep dose response curve
• Severe toxicities
• Non-monitorable toxicity
• Variable bioavailability
• Unexplained mortality
• Novel therapeutic targets
• Animal models with limited utility
Decrease safety factor
• Members of well characterized
class
• Toxicities can be easily
monitored
• NOAEL determined on long
duration toxicity studies
Dose by factor approach
• Pros
– Simple easy to implement and easy to
review
– Ensures consistency
• Cons
– Uses doses not systemic exposure
– Based on old and limited observations
– No retrospective validation
Similar drug approach