FIRST HUMAN DOSE

Dr.R.Jayashree
 First Human dose

“One of the most controversial

areas in clinical pharmacology
is the choice of the initial human
dose.”
FIRST HUMAN DOSE
• REGULATORY BODIES-SAFETY

• SCIENTIFIC BODIES- EFFICACY

FIRST HUMAN DOSE
DOSE
- LESS ADVERSE DRUG
REACTIONS
-PHASE 1 OBJECTIVES
TO BE ATTAINED
OUTLINE

• Starting Dose (SD)

– Different approaches to calculate
• Dose-Escalation Scheme (DES)
• Entry in to man (EIM)
– Safety Comes First
STARTING DOSE
• Four different approaches
– Dose by factor approach
– Similar drug approach
– Pharmacokinetically guided
approach
– Comparative approach
DATA AVAILABLE
• Animal pharmacology data
– Pharmocokinetics
– Pharmacodynamics
– Effective 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)

Pick HED from most appropriate species

Choose safety factor and divide HED (generally 10)

Maximum Recommended starting dose

Consider Lowering Starting Dose

NOAEL
• BENCH MARK

• STARTING POINT
NOAEL
 The highest dose level that does not
produce a significant increase in adverse
effects (statistically significant and
clinically significant)

 Review and evaluate the available

animal toxicolgical data for
• Overt toxicity
• Surrogate markers of toxicity
• Exaggerated pharmacodynamic effects
HUMAN EQUIVALENT DOSE

• 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:

Divide animal dose by: Multiply Animal dose by:

A.Human 37 --- ---

• Child (20 kg)b 25 --- ---

A.Mouse 3 12.3 0.08

A.Hamster 5 7.4 0.13

A.Rat 6 6.2 0.16

A.Ferret 7 5.3 0.19

A.Guinea pig 8 4.6 0.22

A.Rabbit 12 3.1 0.32

A.Dog 20 1.8 0.54

A.Primates:

• Monkeysc 12 3.1 0.32

A. Marmoset 6 6.2 0.16

A. Squirrel 7 5.3 0.19

monkey

A. Baboon 20 1.8 0.54

A.Micro-pig 27 1.4 0.73

A.Mini-pig 35 1.1 0.95

HED
• EXCEPTIONS-
• mg/kg
Appropriate species
• Appropriate species

• 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

• When human data are available

for similar drug(s).
PK Guided approach
• Uses concentration instead of
dose foe extrapolation
• A target systemic exposure is
defined(AUC)
• Clearance in man predicted
Comparative approach
• Estimate safe dose using all
approaches
• Compare results
• Interpret differences
Dose escalation
schemes
• ARITHMETIC
• GEOMETRIC
• MODIFIED FIBONACCI
• X2X3.3X5X7X9X12