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FIRST IN HUMAN DOSE

INTRODUCTION • Estimating the first in human (FIH) dose is one of the initial steps in the

clinical development of any molecule that has successfully gone through all of the hurdles in preclinical evaluations.

• It is an important parameter in the FIH clinical trials, since a high starting dose may cause serious toxicity in volunteers, while a low starting dose could prolong the dose escalation/optimisation, leading to unnecessary delay in the clinical programs.

• In 2005, the US Food and Drug Administration (FDA) issued guidance on estimating the maximum safe starting dose in initial clinical trials for therapeutics in adult healthy volunteers, which provided a framework to carry out the estimation.

• The process of calculating the MRSD should begin after the toxicity data have been analyzed.

DEFINITIONS1) MRSD: MAXIMUM RECOMMENDED STARTING DOSE2) LEVEL: Refers to the dose or dosage, generally expressed as mg/kg or

mg/kg/day. 3) NOAEL: NO OBSERVED ADVERSE EFFECT LEVEL (NOAEL) : The highest dose

level that does not produce a significant increase in adverse effects.4) NOEL: NO OBSERVED EFFECT LEVEL: Refers to any effect, not just adverse

ones, although in some cases the two might be identical. 5) LOWEST OBSERVED ADVERSE EFFECT LEVEL (LOAEL): The lowest dose that

produces adverse effects. 6) HED: HUMAN EQUIVALENT DOSE: The quantity of a chemical that, when

administered to humans, produces an effect equal to that produced in test animals by a smaller dose.

7) MABEL: MINIMAL ANTICIPATED BIOLOGICAL EFFECT LEVELS : The lowest dose that is associated with any biological effect, whether it be toxicity or a desired pharmacological effect

MAXIMUM RECOMMENDED STARTING DOSE (MRSD)

Aim of MSRD:• Avoid toxicity at initial dose• Dose needs to be high enough to allow reasonably rapid attainment of

phase I trial objectives.Not applicable to:• Endogenous hormones and proteins (i.e. recombinant clotting factors) used

at physiological concentrations• VaccinesLimitations:• Does not address dose escalation or maximum allowable doses in clinical

trials

ESTIMATING THE MRSD-METHODS1) NOAEL Method2) MABEL Method3) Similar Drug Comparison Method4) Pharmacokinetic Guided Approach5) PK/PD Modelling Guided Approach

Calculations based on:6) Animal pharmacokinetic data7) Administered doses8) Observed toxicities9) Algorithmic calculation

NOAEL METHOD• The NOAEL method is based on selecting a dose with minimal risk of toxicity,

rather than selecting one with minimal pharmacologic activity in humans. • This approach works well with new molecules that act on established targets

and/or have the pharmacology that is more or less understood.

• 5 Steps using animal toxicology data:1) Determine No Observed Adverse Effect Level (NOAEL) �2) Convert NOAEL to Human Equivalent Dose (HED) �3) Select most appropriate species �4) Apply Safety Factor �5) Consider Pharmacologically Active Dose

STEP 1: NO OBSERVED ADVERSE EFFECT LEVEL DETERMINATION

The NOAEL is a generally accepted benchmark for safety when derived from appropriate animal studies.

The available animal toxicology data is reviewed and evaluated so that a NOAEL can be determined for each study.

While reviewing the animal toxicology data, the adverse effects that are statistically significant and adverse effects that may be clinically significant (even if they are not statistically significant) should be considered in the determination of the NOAEL.

TYPES OF FINDINGS IN NONCLINICAL TOXICOLOGY STUDIES THAT CAN BE USED TO DETERMINE THE NOAEL

Overt toxicity (e.g., clinical signs, macro- and microscopic lesions) Surrogate markers of toxicity (e.g., serum liver enzyme levels) and Exaggerated pharmacodynamic effects.

As a general rule, an adverse effect observed in nonclinical toxicology studies used to define a NOAEL for the purpose of dose-setting should be based on an effect that would be unacceptable if produced by the initial dose of a therapeutic in a phase 1 clinical trial conducted in adult healthy volunteers.

PK INFLUENCE ON NOAEL: Bioavailability, metabolite profile, and plasma drug levels associated with

toxicity may influence the choice of the NOAEL. Ex: Saturation of drug absorption at a dose that produces no toxicity. In

this case, the lowest saturating dose, not the highest (non-toxic) dose, should be used for calculating the HED.

STEP 2: HUMAN EQUIVALENT DOSE CALCULATION

Conversion Based on Body Surface Area

• After the NOAELs in the relevant animal studies have been determined, they are converted to human equivalent doses (HEDs) using appropriate scaling factors.

• The most appropriate method for extrapolating the animal dose to the equivalent human dose should be decided.

• Toxic endpoints for therapeutics administered systemically to animals, such as the MTD or NOAEL, are usually assumed to scale well (doses scaled 1:1) between species when doses are normalized to body surface area (mg/m2).

• The basis for this assumption: Doses lethal to 10% of rodents (LD10) and MTDs in non-rodents both correlated with the human MTD when the doses were normalized to the same administration schedule and expressed as mg/m2.

STEP 2: HUMAN EQUIVALENT DOSE CALCULATION

• Correcting for body surface area increases clinical trial safety by resulting in a more conservative starting dose estimate.

• Hence, it was concluded that the approach of converting NOAEL doses to an HED based on body surface area correction factors (i.e., W0.67) should be maintained for selecting starting doses for initial studies in adult healthy volunteers.

CONVERSION FACTORS: • These are recommended as the standard values to be used for interspecies

dose conversions for NOAELs. • Since surface area varies with W0.67, the conversion factors are therefore

dependent on the weight of the animals in the studies.• These factors may also be applied when comparing safety margins for other

toxicity endpoints (e.g., reproductive toxicity and carcinogenicity) when data for comparison, (i.e., AUCs) are unavailable or are otherwise inappropriate for comparison.

STEP 2: HUMAN EQUIVALENT DOSE CALCULATION

HED = Animal NOAEL x (W animal/W human)(1-b)

Conversion factors = (W animal/W human)(1-b)

Conventionally, for a mg/m2 normalization b would be 0.67, but studies have shown that MTDs scale best across species when b=0.75.

Conversion factors are calculated over a range of animal and human weights using (Wanimal/Whuman)0.33 or (Wanimal/Whuman)0.25 to assess the effect on starting dose selection of using b = 0.75 instead of b = 0.67.

However, converting doses based on an exponent of 0.75 would lead to higher, more aggressive and potentially more dangerous starting doses.

• Nonetheless, use of a different dose normalization approach, such as directly equating the human dose to the NOAEL in mg/kg, may be appropriate in some circumstances.

STEP 2: HUMAN EQUIVALENT DOSE CALCULATION

BASIS FOR USING Mg/Kg CONVERSIONS The “mg/kg” scaling will give a 12-,6- & 2- fold higher HED than the default

mg/m2 approach for mice, rats, and dogs, respectively. Circumstances for using mg/kg for calculating HED1. NOAELs occur at a similar mg/kg dose across test species (for the studies

with a given dosing regimen relevant to the proposed initial clinical trial). 2. When toxicity in humans (for a particular class) is dependent on an

exposure parameter that is highly correlated across species with dose on a mg/kg basis. Ex: Complement activation by systemically administered antisense oligonucleotides in humans is believed to be dependent upon Cmax. For some antisense drugs, the Cmax correlates across nonclinical species with mg/kg dose and in such instances mg/kg scaling would be justified. Also there is a robust correlation between plasma drug levels (Cmax and AUC) and dose in mg/kg.

3. Other pharmacologic and toxicologic endpoints also scale between species by mg/kg for the therapeutic. Examples of such endpoints include the MTD, lowest lethal dose, and the pharmacologically active dose.

BASIS FOR USING MG/KG CONVERSIONS

4. Therapeutics administered by alternative routes (e.g., topical, intranasal, subcutaneous, intramuscular) for which the dose is limited by local toxicities. Such therapeutics should be normalized to concentration (e.g., mg/area of application) or amount of drug (mg) at the application site.

5. Therapeutics administered into anatomical compartments that have little subsequent distribution outside of the compartment.

Ex: Intrathecal, Intravesical, Intraocular, or Intrapleural administration. Such therapeutics should be normalized between species according to the

compartmental volumes and concentrations of the therapeutic. 6. Biological products administered intravascularly with MW > 100,000

daltons. Such therapeutics should be normalized to mg/kg.

mg/m2 = km × mg/kg where km = 100/K × W0.33 where K is a value unique to each species (Freireich

et al. 1966)

CONVERSION OF ANIMAL DOSES TO HUMAN EQUIVALENT DOSES BASED ON BODY SURFACE AREA

STEP 3: MOST APPROPRIATE SPECIES SELECTION HED should be chosen from the most appropriate species. Most sensitive species (i.e., the species in which the lowest HED can be

identified). Factors that could influence the choice of the most appropriate species: (1) Differences in the absorption, distribution, metabolism, and excretion

(ADME) of the therapeutic between the species. When determining the MRSD for the first dose of a new therapeutic in

humans, the ADME parameters will not be known. Comparative metabolism data, however, might be available based on in vitro studies. These data are particularly relevant when there are marked differences in both the in vivo metabolite profiles and HEDs in animals.

MOST APPROPRIATE SPECIES SELECTION

(2) Class experience that may indicate a particular animal model is more predictive of human toxicity.

Class experience implies that previous studies have demonstrated that a particular animal model is more appropriate for the assessment of safety for a particular class of therapeutics.Selection of the most appropriate species for certain biological products involves consideration of various factors unique to these products.

(a) Factors such as whether an animal species expresses relevant receptors or epitopes may affect species selection.

Ex: In the nonclinical safety assessment of the phosphorothioate antisense drugs, the monkey is considered the most appropriate species because monkeys experience the same dose limiting toxicity as humans (e.g., complement activation) whereas rodents do not.

MOST APPROPRIATE SPECIES SELECTION

For this class of therapeutics, the MRSD would be based on the HED for the NOAEL in monkeys regardless of whether it was lower than that in rodents, unless unique dose limiting toxicities were observed with the new antisense compound in the rodent species.

(b) Similarities of biochemistry and physiology between the species and humans that are relevant to the limiting toxicities of the therapeutic should also be considered under class experience.

If a species is the most sensitive but has differences in physiology compared to humans, it may not be the most appropriate species for selecting the MRSD.

(3) Limited biological cross-species pharmacologic reactivity of the therapeutic. This is especially important for biological therapeutics as many are human proteins that bind to human or non-human primate targets.

STEP 4: APPLICATION OF SAFETY FACTOR A safety factor is applied in order to provide a margin of safety for

protection of human subjects receiving the initial clinical dose. This safety factor allows for variability in extrapolating from animal toxicity

studies to studies in humans resulting from: (1) Uncertainties due to enhanced sensitivity to pharmacologic activity in

humans versus animals (2) Difficulties in detecting certain toxicities in animals (e.g., headache,

myalgias, mental disturbances) (3) Differences in receptor densities or affinities(4) Unexpected toxicities and (5) Interspecies differences in ADME of the therapeutic. These differences can be accommodated by lowering the human starting

dose from the HED of the selected species NOAEL.

APPLYING SAFETY FACTOR In practice, the MRSD for the clinical trial is determined by dividing the

HED derived from the animal NOAEL by the default safety factor of “10”. While a safety factor of 10 can generally be considered adequate for

protection of human subjects participating in initial clinical trials, this safety factor may not be appropriate for all cases.

The safety factor should be raised when there is reason for increased concern, and lowered when concern is reduced because of available data that provide added assurance of safety.

INCREASING THE SAFETY FACTOR

Steep dose response curve. Severe toxicities. Nonmonitorable toxicity Toxicities without premonitory signs. Variable bioavailability. Irreversible toxicity Unexplained mortality

Large variability in doses or AUC levels eliciting effect. Nonlinear pharmacokinetics. Questionable study design or conductInadequate dose-response data. Novel therapeutic targets. Animal models with limited utility.

DECREASING THE SAFETY FACTOR

When the toxicologic testing in these cases is of the highest caliber in both conduct and design.

When the candidate therapeutics are members of a well-characterized class.

When within the class, the therapeutics are administered by the same route, schedule, and duration of administration; have a similar metabolic profile and bioavailability; and have similar toxicity profiles across all the species tested including humans.

When toxicities produced by the therapeutic are easily monitored, reversible, predictable, and exhibit a moderate-to-shallow dose-response relationship with toxicities that are consistent across the tested species (both qualitatively and with respect to appropriately scaled dose and exposure).

When the NOAEL was determined based on toxicity studies of longer duration compared to the proposed clinical schedule in healthy volunteers.

STEP 5: CONSIDERATION OF THE PHARMACOLOGICALLY ACTIVE DOSE(PAD) Selection of a PAD depends upon many factors and differs markedly

among pharmacological drug classes and clinical indications. Once the MRSD has been determined, it may be of value to compare it to

the PAD derived from appropriate pharmacodynamic models. If the PAD is from an in vivo study, an HED can be derived from a PAD

estimate by using a body surface area conversion factor (BSA-CF). This HED value should be compared directly to the MRSD.

If this pharmacologic HED is lower than the MRSD, it may be appropriate to decrease the clinical starting dose for scientific reasons.

Additionally, for certain classes of drugs or biologics, toxicity may arise from exaggerated pharmacologic effects. The PAD in these cases may be a more sensitive indicator of potential toxicity than the NOAEL and might therefore warrant lowering the MRSD.

STARTING DOSE CALCULATION

IT IS ALWAYS ACCEPTABLE (FROM A SAFETY PERSPECTIVE) TO USE A CLINICAL START DOSE LOWER THAN THE MRSD.

IS NOAEL APPROACH THE FOOLPROOF METHOD FOR CALCULATING FIH DOSE?

• NOAEL approach= safety window based on toxicological threshold

• TRAGIC TRIAL OF TGN1412• TGN1412 : A novel CD28 super-agonist antibody immunomodulator• Developed by TeGenero Immuno Therapeutics,London, tested by

Parexel and manufactured by Boehringer-Ingelheim.• Intended for the treatment of B cell chronic lymphocytic leukemia (B-CLL)

and rheumatoid arthritis.• Caused cytokine storm.• Dose in humans was 1/160 of the NOAEL in monkeys, so it was well within

accepted safety margins.

COULD THIS TOXICITY HAVE BEENPREDICTED?

• No evidence of contamination of the product.• Conduct of the trial appeared to have followed the protocol, e.g., no

dosing errors.• Nothing in the preclinical data that predicted the overwhelming systemic

reaction to the antibody.

Initial dose 0.1 mg/kg would achieve plasma level of ~16nM compared with binding affinity of 2nM. 8X the binding affinity of “super agonist” might result in 90% CD28 receptor binding on first dose.

This occupancy is considered sufficient for an antagonist but too high for FIH with agonist. If starting dose was established using pharmacological principles, the dose might have been started 100X lower.

DUFF REPORT RECOMMENDATIONS SELECTION OF THE FIH DOSE FOR CLINICAL TRIAL

The EMEA proposed for micro dosing a safety factor of 1/100th of the dose calculated to yield a pharmacologic effect, on a mg/m2 basis, and suggested that such a dose should be 1/1000th of the minimal toxic effect dose (MTED) from a single-dose toxicology study.

Special consideration should be given to new agents for which the primary pharmacological action, for the proposed therapeutic effect, cannot be demonstrated in an animal model.

A broader approach to dose calculation, beyond reliance on NOEL or NOAEL in animal studies, should be taken.

DUFF REPORT FOR FIH DOSE SELECTION

The calculation of starting dose should utilize all relevant information. Factors to be taken into account include

The novelty of the agent Biological potency and its mechanism of action Degree of species-specificity of the agent Dose-response curves of biological effects in human and animal cells Dose-response data from in vivo animal studies Pharmacokinetic and pharmacodynamic modeling Calculation of target occupancy versus concentration Calculated exposure of targets or target cells in humans in vivo.

If different methods give different estimates of a safe dose in humans, the lowest value should be taken as the starting point in first-in-man trials and a margin of safety introduced in calculation of the actual starting doses in man.

THE MABEL APPROACH FOR DOSE SELECTION

• This is an improved approach to dose selection through the combined analysis of all of the pharmacology, safety and efficacy preclinical data.

• The main objective of the new process is to define a starting dose that is expected to result in a minimum anticipated biological effect level (MABEL), particularly for investigational medicinal products where risk factors were identified in (1) Mode of action(2) Nature of the target and (3) Relevance of animal species and models.

THE MABEL APPROACH FOR DOSE SELECTION

(1) The mode of action : • This refers to the knowledge on the nature and intensity of the effect of the

medicinal product on the specific target and non-targets and subsequent mechanisms.

• Certain modes of action have been identified to require special attention: Targets that have pleiotropic effects or are ubiquitously expressed (e.g., as

often occur in the immune system) Targets that have a biological cascade or cytokine release, including those

leading to an amplification of an effect that might not be sufficiently controlled by a physiological feedback mechanisms (e.g., Monoclonal antibodies against the T cell targets).

(2) The nature of the target • This may include information on the structure, tissue distribution, cell

specificity, disease specificity, regulation, polymorphisms, level of expression, and biological function of the human target, including downstream effects, and how it might vary between individuals in different populations of healthy subjects and patients.

(3) The relevance of animal models. • The available animal species should be compared to humans taking into

account the target, its structural homology, distribution, signal transduction pathways and the nature of pharmacological effects.

• Where the available animal species/models or surrogates are perceived to be of questionable relevance for thorough investigation of the pharmacological and toxicological effects of the medicinal product, this should be considered as adding to the risk.

• The risk assessment should be performed on a ‘‘case-by-case’’ basis and that a ‘‘weight-of-evidence’’ approach should be used.

• The calculation of MABEL should use all in vitro and in vivo information available from PK/PD, which may include the following:

(1) Target binding and receptor occupancy studies in vitro in target cells from human and the relevant animal species

(2) Concentration-response curves in vitro in target cells from human and the relevant animal species and dose/exposure-response in vivo in the relevant animal species

(3) Exposures at pharmacological doses in the relevant animal species• To further limit the potential for adverse reactions in humans, a safety

factor may be applied in the calculation of the first dose in humans from MABEL.

• In cases where the methods of calculation (e.g. NOAEL, MABEL) give different estimations of the first dose in man, the lowest value should be used.

SIMILAR DRUG COMPARISON APPROACH

• This may be used when human PK/PD data are available for a drug similar to the one under investigation.

• The dose of the investigated drug can be calculated from the dose of the reference drug:

Dosei = Doser NOAELi / NOAELr

• The dose obtained is usually corrected by an arbitrary safety factor to accommodate uncertainty.

PHARMACOKINETIC-GUIDED APPROACH

• In this approach, the NOAEL and corresponding AUC in several animal species are determined.

• The species that results the lowest NOAEL is used as the index species for scaling.

• The starting oral dose can be calculated as follows: Dose = CL AUC / F

Dose = Clhuman Css Dosing Interval /F

Dose = {AUCanimal CLhuman} / Correction factor

A Correction factor is obtained by dividing the clearance of the chosen species by the predicted human clearance.

• A few assumptions are made with pharmacokinetic-guided approaches: (1) Only the parent compound is active, and (2) The drug shows equal pharmacological activity or toxicity in human and

nonhuman animal species at equal plasma concentrations. • This results in the inability to account for interspecies differences in

pharmacodynamics, which are extremely important to identify prior to phase I trials.

PK/PD MODEL-GUIDED APPROACH

• To avoid inaccuracy caused by interspecies differences in exposure–response relationships, PK/PD modeling has been utilized to estimate the FIH dose.

• The human PK/PD profile could be projected using animal data from a single species.

Estimation of human doses using a four-step approach (Lowe et al): 1) First step: Set up the concentration–effect relationships to identify

biomarkers, determined PD parameters such as EC50, and develop the PD models.

2) Second step: Identify the interspecies differences in the concentration–response profiles, for both desired and adverse effects. This includes differences in tissue distribution, tissue and plasma protein binding, blood cell binding, and target receptor occupancy.

3) Third step: Human PK parameters, such as CL, bioavailability, and plasma concentration–time profiles are predicted.

4) Fourth step: Integrate human PK and PD models to predict human dose–response relationships, which involves further two approaches. A) Threshold model: A dosing regimen is designed to keep drug

concentrations above the threshold of efficacy (e.g.,EC50) but below the threshold of adverse effects.

B) PK/PD model: To simulate the dose–exposure–response–time profiles, which could incorporate the complex PD models.

The PK/PD model- based approach is successful for monoclonal antibodies, whose PK properties are usually uniform based on their isotype.

• The receptor occupancy (RO), which can be measured by in vitro experiments, may be used as the biomarker for the human PK/PD model.

• When estimating the starting dose the RO value is recommended to be low for an agonist and high for an antagonist.

METHOD APPLICABILITY ADVANTAGES DISADVANTAGES

NOAEL To drugs administered orally, intranasally, SC, or IM and the dose is limited by local toxicities. Proteins administered intravascularly with MW >100 kDa

Good safety record forsmall molecule drugs;easy to use

Arbitrary safety factor makes the approach very conservative. Neglect the interspecies differences in pharmacology, such as binding affinity and potency

MABEL To both biotherapeutics and small molecule chemical entities

Based on pharmacologicknowledge rather thanan empirical factor

Requires extensivemechanistic data

SIMILAR DRUG COMPARISON

Human PK data are available for a drug similar to the one under investigation

Easy to use; very limiteddata are required

Only applicable to very limited drug candidates

METHOD APPLICABILITY ADVANTAGES DISADVANTAGES

PK-GUIDEDAPPROACH

Human PK parameters predicted frompreclinical data with a reasonable accuracy.

Based on pharmacokineticproperties rather thanan empirical factor

Neglect interspeciesdifferences inpharmacodynamics;depends on the predictionaccuracy of human PKparameters

PK/PD MODELING-GUIDED APPROACH

Human dose–exposure– response relationships are simulated by a mathematic model

Interspecies differences inboth PK and PD areconsidered; reduce thereliance on empiricalsafety factors

A lot of efforts are requiredto establish and validatePK/PD models

Adequate preclinical in vivo toxicological testing may not be possible due to lack of cross-reactivity in commonly accepted toxicological test species such as rats and dogs.

Even for cross-reactive MABs, due to differences in the pharmacology between test species and humans, the NOAEL obtained in test species may not be relevant to human testing in some cases.

Furthermore, toxicity for many biologics is typically due to exaggerated pharmacology

Predicting human pharmacological response from preclinical data also presents unique challenges in the case of biologics compared with small molecules.

Therefore, characterizing the preclinical pharmacological response is critical to understanding potential clinical safety implications for these compounds.

POINTS TO CONSIDER IN THE SELECTIONOF FIH DOSES FOR BIOLOGICS

INTERACTION OF MABs WITH THEIR TARGET IS, DIFFERS FROM THAT OF SMALL MOLECULES:

Because of their high affinity, MABs are typically dosed at equal molar ratios to their targets.

The on- and off-rates of MABs at their receptors are, slower than those of small molecules.

Binding of target by MAB may change the natural kinetics of the receptor, e.g. trigger internalization or stabilization of the receptor.

Due to the relatively slow distribution to the site of action and target mediated elimination of MABs, unbound MAB concentrations at the biophase after single doses and at steady state may be one to three orders of magnitude below unbound MAB concentrations in plasma.

Because of these characteristics, simple equilibrium calculations of in vivo RO based on affinity that are applied for many small molecules may not be applicable for MAB therapeutics.

Toxic effects in humans are likely to be sustained for long durations due to the long half-lives

Selection of too low a starting dose could substantially increase the duration of clinical studies, increasing the cost and duration of development with limited additional safety benefit.

Rational selection of starting doses is of added importance for MAB programmes

PROPOSED APPROACH BY REGULATORS

(a) Obtain the predicted human dose–response for all measured biological effects. in vivo biomarker studies, receptor binding affinity and occupancy experiments, antibody-dependant cell cytotoxicity (ADCC) assay, PK–PD experiments

(b) Select the dose that would result in minimal biological activity – MABEL dose.b-agonists produce maximal bronchodilation at <5% RO, and ERAs produce maximum effect at 20–30% RO, antagonists require generally higher RO to exert their effect: anti-IgE and anti-CCR5 therapeutics are clinically effective at >90% and >99% RO, respectively. Therefore, based on target-mediated effects, a starting dose targeting 50% RO could be considered a MABEL dose for a CCR5 antagonist, whereas <3% RO is more appropriate for an ERA.Hence, the choice of starting dose should take into consideration all available information on the relationship between RO and biological effect for the relevant class of compounds.(c) Obtain the NOAEL from toxicological testing