Estimation of First Human Dose For Phase I Studies
Ganesh Mugundu, MS University of Cincinnati
Overview Introduction Selecting an appropriate dose for First-in-Human Trials 9Determining the No Observed Adverse Effect Level (NOAEL) 9Calculating the Human Equivalent Dose (HED) 9Selecting the most appropriate species 9Applying the Safety Factor 9Considering the Pharmacologically Active Dose (PAD) Other Considerations Summary
Phases of Clinical Trial
http://www.fda.gov/cder/handbook/develop.htm
Phase I • Healthy Volunteers (20-80) • Safety & Tolerability • Pharmacokinetics after single & multiple doses • Also evaluate drug metabolism, structureactivity relationships, and the mechanism of action in humans.
Information Required Pre-Phase 1 Efficacy Preclinical animal model of disease In vitro cell-based assays In vivo biomarker validation Safety Preclinical animal model of toxicity Dose-exposure-response for toxicity In vitro metabolism data metabolic stability in microsomes, hepatocytes or S9 fractions Enzyme identification Drug interaction potential: induction/inhibition
Drugability Physicochemical properties: pKa, LogD, lipophilicity, solubility, protein binding, tissue partitioning, Caco2 permeability and Pgp transport In vivo bioavailability studies
Safety in Preliminary Clinical Trials Assessing variability: Species-species and species-human differences Drug absorption, distribution, metabolism, excretion (ADME) Physiology/ adverse effect profiles e.g. Thalidomide Teratogenic in humans and not in rats e.g. TGN412 (monoclonal antibody) March 2006- severe toxicity in six healthy male volunteers in a first-in-human clinical trial
Importance of selecting an appropriate and safe starting dose
FDA Guidance Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers July 2005 http://www.fda.gov/cder/guidance/5541fnl.pdf
Objectives To determine: The maximum recommended starting dose (MRSD) for adult healthy subjects when beginning a clinical investigation of any new drug or biological therapeutic that has been studied in animals
Not applicable to: Endogenous hormones and proteins (i.e. recombinant clotting factors) used at physiological concentrations or prophylactic vaccines
Limitations: Applies to drug products for which systemic exposure is intended Does not address dose escalation or maximum allowable doses in clinical trials
Estimating the MRSD Calculations based on: 1. Administered doses 2. Observed toxicities 3. Algorithmic calculation Alternatively: Animal pharmacokinetic and modeling may be used. Often insufficient data to construct a scientifically valid PKmodel.
MRSD Avoid toxicity at initial dose
Dose needs to be high enough to allow reasonably
rapid attainment of phase I trial objectives (therapeutic tolerability, pharmacodynamic (PD) and pharmacokinetic (PK) profile)
All relevant pre-clinical data
Pharmacologically active doses Full toxicological profile PK (absorption, distribution, metabolism and excretion[ADME])
Step 1: NOAEL No observed adverse effect level (NOAEL) = the highest dose level that does not produce a
significant increase in adverse effects in comparison to the control group; where AE are effects that are biological Significant
NOAEL does not equal NOEL (refers to any effect) Values identified for each species tested (at least three species, one of which in non-rodent)
NOAEL Three types of findings in non-clinical toxicology Overt Toxicity (e.g. clinical signs, macro-and microscopic lesions) Surrogate markers of toxicity (hepatotoxicity, nephrotoxicity) Exaggerated pharmacodynamic effects
Step 2: Human Equivalent Dose (HED) HED is calculated by a conversion based on body surface area (BSA) Convert all NOAEL to HED Based on mg/m2 and assumption that there is a 1:1 relation between species when body surface area is normalized
HED
Step 3: Most Appropriate Species Selection • Selection of the most appropriate HED to use in calculation of MRSD • If most appropriate species cannot be determined, then most sensitive species should be selected (i.e. with the lowest HED) • Most appropriate species based on ADME • Class experience that indicates a species is more predictiveof human toxicology
Step 4: Application of Safety Factor Once HED from NOAEL of the most appropriate (sensitive) species is determined a safety factor should be applied Safety factor applied because – Variability in extrapolating – Uncertainty about enhanced sensitivity in humans – Difficulties in detecting toxicity (e.g. headaches, mental disturbances) – Difference in receptor densities or affinities – Unexpected toxicities – Interspecies differences in ADME Default safety factor is 10X Increased/decreased under certain circumstances
Step 4: Application of Safety Factor Increasing the Safety Factor (> 10) Steep dose response curve Severe toxicities Nonmonitorable toxicity Toxicities without premonitory signs Variable bioavailability Irreversible toxicity Unexplained mortality Large variability in doses of plasma drug levels eliciting effects Nonlinear pharmacokinetics Inadequate dose-response data Novel therapeutic targets Animal models with limited utility
Step 4: Application of Safety Factor Decreasing the Safety Factor (< 10) 9 Usually for therapeutics of a well characterized class 9 Administered by same route, schedule and duration 9 Similar metabolic profile and bioavailability 9 Similar toxicity profiles across all the species tested including humans 9 Toxicity is easily monitored, reversible, predictable and exhibits a moderate-to-shallow dose-response relationship with toxicities consistent across tested species 9 NOAEL determined based on toxicity studies of a longer duration compared to the proposed clinical schedule in healthy volunteers 9 Assumes that toxicities are cumulative, are not associated with acute peaks in therapeutic concentrations and did not occur early in the repeated dose study
STEP 5: CONSIDERATION OF THE PHARMACOLOGICALLY ACTIVE DOSE (PAD) • Once the MRSD has been determined, it can be compare to the PAD derived from appropriate pharmacodynamic models. • If this pharmacologic HED is lower than the MRSD, it may be appropriate to decrease the clinical starting dose.
Examples
PK Guided Approach • Systemic exposure instead of dose is used for extrapolation from animal to man. • A desired systemic exposure (e.g.,AUC) for humans is defined as the systemic exposure corresponding to the NOAEL. • If a NOAEL and its corresponding AUC are available from more than one animal species, the animal species with the lowest AUC is used. • The clearance of the drug in humans (CLh) is predicted using allometric scaling. SD = Starting Dose Reigner BG, Blesch KS. Eur J Clin Pharmacol. 2002 Feb;57(12):835-45
PK Guided Approach- Example • AUC of mofarotene in dogs was 17.3 μg h/ml at the NOAEL. • Using allometric scaling, in vivo PK and intrinsic clearance data from three animal species (mouse, rat, and dog), the predicted CLh was 16.0 l/h. • SD = 17.3 μg h/ml X 16.0 l/h = 277mg • Applying a safety factor of 1/3, SD = 92 mg. Reigner BG, Blesch KS. Eur J Clin Pharmacol. 2002 Feb;57(12):835-45
PK Guided Approach-Issues • Uncertainity in prediction of CL(h) using allometry scaling. • EC50 (human)/EC50 (animal) = 0.1, drug is ten times more potent in humans. In such a case, a safety factor of 1/10 has to be used. • Plasma concentrations of unbound drug (Cu) need to be used for AUC or Cmax calculations. • Non liner pharmacokinetics & active metabolites . • Use of different formulation in animals and humans.
Unified Theory of Allometry LnY = Lna + b * TBW
Principle of allometry: Treat species as one large animal ¾ one common slope and one common intercept ¾ Slope is dictated by biological processes thus has an exponent with median a value of 0.75 or 0.67. ¾ Intercept is a function of drug properties, thus ~ intrinsic clearance
If true can scale from one species CLhuman
⎛ Weight human = CLanimal × ⎜⎜ ⎝ Weightanimal
⎞ ⎟⎟ ⎠
b
Prediction of Clearance 1 2 MLP= Max Lifespan Potential Human MLP = 8.18 x 105 hr
BW= Brain Weight
3 Iftekhar Mahmood et al J. Clin. Pharmacol. 2003; 43; 692
Example of Inter-species scaling
Approach I
Clearances of the species (used in the
prediction of clearance for humans) are plotted on linear scale against the dose given to the species. Resultant equation used to recommend the starting dose in humans as follows: Dose = a + b(x) where a is the intercept, b is the slope, and x is the predicted clearance in humans
Approach 2 and 3 • Dose multiplied by the HED and then plotted against clearance in each species on a linear scale.
• Slightly modified approach than the previously seen PK guided approach (No safety factor)
Approach 4 • Species whose clearance (per kg body weight) is nearest to the predicted human clearance is selected (based on kg body weight). • A correction factor is then obtained by dividing the clearance of the chosen species by the predicted human clearance
• For felbamate, the observed clearance in rat, rabbit, and dog was 2.54, 0.98, and 1.55 mL/min/kg, respectively • Predicted clearance in man was 0.3 mL/min/kg (close to rabbit). Correction factor = 3.27 (0.98/0.3) • Dose (mg) = (474 μg•h/mL × 1.26 L/h)/3.27.
Observed Vs Predicted CL
Estimated First Dose
Assignment • Han Junghee et.al., Biol. Pharm. Bull. 26:832-839 2003 • Determine first in human dose using the NOAEL provided in the paper.
References
FDA Guidance Document (http://www.fda.gov/cder/guidance/5541fnl.pdf) Reigner BG, Blesch KS. Estimating the startting dose for entry into humans principles and practice. Eur J Clin Pharmacol. 2002 Feb;57(12):835-45 Iftekhar Mahmood, Martin David Green and J. Edward Fisher. Selection of the First-Time Dose in Humans: Comparison of Different Approaches Based on Interspecies Scaling of Clearance. J. Clin. Pharmacol. 2003; 43; 692
