FIRST HUMAN DOSEFIRST HUMAN DOSE

Dr.R.JayashreeDr.R.Jayashree

First Human doseFirst Human dose

““One of the most controversial areas One of the most controversial areas in clinical pharmacology is the in clinical pharmacology is the choice of the initial human dose.”choice of the initial human dose.”

FIRST HUMAN DOSEFIRST HUMAN DOSE

• REGULATORY BODIES-SAFETYREGULATORY BODIES-SAFETY

• SCIENTIFIC BODIES- EFFICACYSCIENTIFIC BODIES- EFFICACY

FIRST HUMAN DOSEFIRST HUMAN DOSE

DOSE DOSE

- LESS ADVERSE DRUG - LESS ADVERSE DRUG REACTIONSREACTIONS

-PHASE 1 OBJECTIVES TO -PHASE 1 OBJECTIVES TO BE ATTAINEDBE ATTAINED

OUTLINEOUTLINE

• Starting Dose (SD)Starting Dose (SD)– Different approaches to calculateDifferent approaches to calculate

• Dose-Escalation Scheme (DES)Dose-Escalation Scheme (DES)• Entry in to man (EIM)Entry in to man (EIM)

– Safety Comes FirstSafety Comes First

STARTING DOSESTARTING DOSE

• Four different approachesFour different approaches– Dose by factor approachDose by factor approach– Similar drug approachSimilar drug approach– Pharmacokinetically guided approachPharmacokinetically guided approach– Comparative approachComparative approach

DATA AVAILABLEDATA AVAILABLE

• Animal pharmacology dataAnimal pharmacology data– PharmocokineticsPharmocokinetics– PharmacodynamicsPharmacodynamics– Effective dose Effective dose

• Toxicological dataToxicological dataLD 50 LD 50

Dose by factor approachDose by factor approach

• Based on normalization of Based on normalization of body surface areabody surface area

• NOAEL or MTD scales well NOAEL or MTD scales well between species when doses are between species when doses are normalized to BSA.normalized to BSA.

• ACCEPTED BY REGULATORY ACCEPTED BY REGULATORY BODIESBODIES

DetermineDetermine NOAEL (mg/kg)using toxicity NOAEL (mg/kg)using toxicity studiesstudies

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

NOAELNOAEL

• BENCH MARKBENCH MARK

• STARTING POINTSTARTING POINT

NOAELNOAEL

The highest dose level that does not produce The highest dose level that does not produce a significant increase in adverse effects a significant increase in adverse effects (statistically significant and clinically (statistically significant and clinically significant)significant)

Review and evaluate the available animal Review and evaluate the available animal toxicolgical data fortoxicolgical data for• Overt toxicityOvert toxicity• Surrogate markers of toxicity Surrogate markers of toxicity • Exaggerated pharmacodynamic effectsExaggerated pharmacodynamic effects

HUMAN EQUIVALENT DOSEHUMAN EQUIVALENT DOSE

• Based on BSABased on BSA• WIDE SPREAD PRACTICEWIDE SPREAD PRACTICE• Increase clinical trial safetyIncrease clinical trial safety• Apply BSA-CFApply 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 --- ---

A.  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:

A.    Monkeysc 12 3.1 0.32

A.    Marmoset 6 6.2 0.16

A.    Squirrel monkey

7 5.3 0.19

A.    Baboon 20 1.8 0.54

A.Micro-pig 27 1.4 0.73

A.Mini-pig 35 1.1 0.95

HEDHED

• EXCEPTIONS-EXCEPTIONS-• mg/kgmg/kg

Appropriate speciesAppropriate species

• Appropriate speciesAppropriate species

• Sensitive speciesSensitive species

Appropriate species Appropriate species selection selection

• ICH-GCP GUIDANCE S6ICH-GCP GUIDANCE S6• FACTORS-FACTORS-

• ADMEADME• MODEL MODEL • LIMITED CROSS SPECIES LIMITED CROSS SPECIES

PHARMACOLOGICAL ACTIVITYPHARMACOLOGICAL ACTIVITY

SAFETY FACTORSAFETY FACTOR

• Assurance and margin of safetyAssurance and margin of safety• Cushion for Cushion for

Therapeutic activityTherapeutic activity

Certain toxicitiesCertain toxicities

Unexpected toxicitiesUnexpected toxicities

Receptor densities and affinityReceptor densities and affinity

Inter species difference(ADME)Inter species difference(ADME)

Increase safety factorIncrease safety factor

• Steep dose response curveSteep dose response curve• Severe toxicitiesSevere toxicities• Non-monitorable toxicityNon-monitorable toxicity• Variable bioavailabilityVariable bioavailability• Unexplained mortalityUnexplained mortality• Novel therapeutic targetsNovel therapeutic targets• Animal models with limited utilityAnimal models with limited utility

Decrease safety factorDecrease safety factor

• Members of well characterized Members of well characterized classclass

• Toxicities can be easily monitoredToxicities can be easily monitored• NOAEL determined on long NOAEL determined on long

duration toxicity studiesduration toxicity studies

Dose by factor approachDose by factor approach

• ProsPros– Simple easy to implement and easy to Simple easy to implement and easy to

review review – Ensures consistencyEnsures consistency

• ConsCons– Uses doses not systemic exposureUses doses not systemic exposure– Based on old and limited observationsBased on old and limited observations– No retrospective validationNo retrospective validation

Similar drug approachSimilar drug approach

• When human data are available for When human data are available for similar drug(s).similar drug(s).

PK Guided approachPK Guided approach

• Uses concentration instead of dose Uses concentration instead of dose foe extrapolationfoe extrapolation

• A target systemic exposure is A target systemic exposure is defined(AUC)defined(AUC)

• Clearance in man predictedClearance in man predicted

Comparative approachComparative approach

• Estimate safe dose using all Estimate safe dose using all approachesapproaches

• Compare resultsCompare results• Interpret differencesInterpret differences

Dose escalation schemesDose escalation schemes

• ARITHMETICARITHMETIC• GEOMETRICGEOMETRIC• MODIFIED FIBONACCIMODIFIED FIBONACCI• X2X3.3X5X7X9X12X2X3.3X5X7X9X12