Pharmacology & Therapeutics 178 (2017) 141–147

Contents lists available at ScienceDirect

Pharmacology & Therapeutics

journal homepage: www.elsevier.com/locate/pharmthera

Inhaled efficacious dose translation from rodent to human: A

retrospective analysis of clinical standards for respiratory diseases
J.E. Phillips ⁎
Amgen, Thousand Oaks, CA, USA

a r t i c l e i n f o a b s t r a c t

Available online 23 April 2017 Clinical pharmacologists and toxicologists are often faced with predicting equivalent dosages for humans from
biological observations in laboratory animals. Allometric scaling has been used extensively as the basis for extrap-
Keywords: olation of drug dosage that might be expected to produce the equivalent biological effects. Allometry is the study
Interspecies scaling of size and its consequences and it is based on the anatomical, physiological, and biochemical similarities be-
Allometric tween animals. In this review, retrospective analyses have been performed based on data reported in the litera-
Aerosol
ture in an attempt to determine the utility of allometric scaling for human dose projections from pre-clinical data
Inhalation toxicology
Human dose projections
for compounds that are delivered by inhalation. The limited pre-clinical efficacy data available on inhaled drugs
Deposited dose that are also used clinically supports the current method of scaling using a fixed allometric exponent of 0.67. An
Delivered dose example of the utility of the human inhaled dose projections for planning inhaled toxicology studies is also
Intranasal presented.
Intratracheal © 2017 The Author. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license
Oropharyngeal aspiration (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Nose-only inhalation
Deposition fraction

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
2. Aerosol dose definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
3. Pre-clinical studies for inhaled drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
4. Allometric scaling of drug dose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
5. Inhaled pulmonary deposited dose translation: Retrospective analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144
6. Inhaled delivered dose: toxicology study design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144
7. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144
Conflict of interest. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146
Appendix A. Derivation of the allometric interspecies scaling equation as a function of total drug dose . . . . . . . . . . . . . . . . . . . . . . . 146
Appendix B. Derivation of the allometric interspecies scaling equation as a function of body mass normalized drug dose . . . . . . . . . . . . . . . 146
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146

1. Introduction is an important advantage that can greatly increase the therapeutic

There are many advantages to inhaled administration of drugs for
the treatment of respiratory diseases. Inhaled delivery applies the ther-
apeutic agent directly to the site of action; the lungs. A high local con-
centration of the drug in the lungs offers a significant advantage that
minimizes dose and systemic exposure, and maximizes efficacy. This
Abbreviations: TI, therapeutic index; LABA, long acting beta agonist; LAMA, long acting
muscarinic antagonist.
⁎ Amgen, One Amgen Center Drive, Thousand Oaks, CA, USA, 91320.
E-mail address: jonathan.phillips@amgen.com.
index (TI). The TI is the ratio of dose of drug that causes a side-effect
over the dose of drug that provides efficacy.
As new drugs delivered by the inhaled route are developed, it is es-
sential to appropriately translate the efficacious drug dose from pre-
clinical efficacy studies to predict an efficacious human dose for clinical
trials. An estimate of the effective human inhaled dose deposited in the
lungs also helps to plan the delivered doses used in inhalation toxicolo-
gy studies required for clinical trials (Degeorge et al., 1997). It is com-
mon to use an allometric approach to predict human drug doses from
pre-clinical efficacy studies (Boxenbaum & DiLea, 1995). Allometry is
the study of size and its consequences (Gould, 1966), and it is based

http://dx.doi.org/10.1016/j.pharmthera.2017.04.003
0163-7258/© 2017 The Author. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
142 J.E. Phillips / Pharmacology & Therapeutics 178 (2017) 141–147
on the assumption that there are anatomical, physiological, and bio-
chemical similarities between animals (Mahmood, 1999). Fig. 1 demon-
strates how the allometric scaling concept applies to interspecies
scaling for a few physiological parameters, and that these parameters
scale with different allometric exponents. Herein an allometric scaling
exponent is retrospectively calculated from experimental rodent effica-
cy data and the known inhaled clinical dose that needs to be deposited
in the human lung. This is done for four inhaled compounds currently
used clinically; the inhaled corticosteroids mometasone and
budesonide, the β-agonist bronchodilator salbutamol, and the anticho-
linergic bronchodilator ipratropium.
This review attempts to determine the utility of an allometric scaling
approach to allow interspecies correlation of inhaled drug dose, a phar-
macologic parameter. The limited pre-clinical efficacy data available on
inhaled drugs that are also used clinically supports the current method
of scaling using a fixed allometric exponent of 0.67 (FDA, 2015). It must
be remembered that any allometric approach is empirical and is but a
Fig. 1. Allometric plots for the physiological parameters body surface area, lung mass, and
lung surface area scale log-linearly with body mass. Power function curve fits for each
parameter in lower right hand corner of each graph. Data from (Chappell & Mordenti,
1991), (Snipes, 1989), and (Gehr et al., 1981).
simple and useful correlation (Boxenbaum & DiLea, 1995). One must
also keep in mind that the dose predicted by these scaling methods can-
not be used in clinical trials without supporting pre-clinical toxicology
studies with appropriate safety margins above the predicted efficacious
dose (Degeorge et al., 1997; Forbes et al., 2011). Therefore, an example
of the process of how the human dose projections are used to plan the
pre-clinical inhaled toxicology studies is presented.
2. Aerosol dose definitions
There are many ways in which the dose can be expressed for drugs
delivered by inhalation. This can lead to confusion when comparing re-
sults from studies performed in different laboratories. Recently, it was
recommended that delivered dose and deposited dose be adopted as
the standard terminology (Alexander et al., 2008; Forbes et al., 2011).
The delivered dose is the amount of drug inhaled by the animal and
the deposited dose is the amount of drug deposited in the lungs. In gen-
eral, an “inhaled dose” to a toxicologist is a delivered dose and an “in-
haled dose” to a pharmacologist is a deposited dose. It is therefore
important to clarify if the “inhaled dose” is a delivered or deposited
dose. The delivered dose differs from the dose generated by the inhala-
tion device (or metered dose) by an amount that is retained by the inha-
lation device (some of the drug aerosol particles stick to the walls of the
device). The delivered dose differs from the deposited dose (or dose de-
posited in the lungs) by the pulmonary deposition fraction or the
amount of aerosol that can make it into the lungs (i.e. does not get
stuck in the back of the mouth, or in the nose if delivered by nose-
only inhalation). To convert the delivered dose to the deposited dose,
one must know the pulmonary deposition fraction (Alexander et al.,
2008; Forbes et al., 2011). Airway geometry makes the pulmonary de-
position fraction not only species dependent, but also highly dependent
on the particle size distribution of the aerosol (Scheuch & Siekmeier,
2007). Throughout this manuscript we will assume for simplicity in all
rodent, canine, nonhuman primate, and human dose calculations, the
pulmonary deposition fractions are 10%, 25%, 30%, and 40% (Snipes,
McClellan, Mauderly, & Wolff, 1989), respectively. These pulmonary de-
position fraction values do not necessarily reflect the actual pulmonary
deposition fraction of pharmaceutical aerosols. The inherent limitations
associated with using these pulmonary deposition fraction values has
been reviewed at length (Forbes et al., 2011). These pulmonary deposi-
tion fraction values should be replaced with more accurate values based
on the animal species and the experimentally measured aerosol particle
size distribution for the drug, if available (Olsson, Borgstrom, Lundback,
& Svensson, 2013).
3. Pre-clinical studies for inhaled drugs
Pre-clinically, inhaled compounds are optimized to increase the TI
which requires in vivo efficacy and side effect measurements. Initially,
these measurements can be made in separate assays. Usually the drug
is delivered topically to the lungs for the efficacy measurement and sys-
temically for the side-effect measurement. Final determination of a TI
for an inhaled drug, where efficacy and side effect are measured in the
same animals after inhaled administration, requires dose/response
studies that achieve exposure at least 10 times greater than the effica-
cious dose deposited in the lungs. At these supramaximal efficacious
levels, either a measureable side effect is induced or the targeted safety
margin (TI N 10) is confirmed.
Conformation of an appropriate safety margin enables inhaled toxi-
cology studies. The outcome of the toxicology studies will be used to set
the maximum dose allowed in clinical trials. The inhaled human depos-
ited efficacious dose projected from the pre-clinical efficacy studies re-
assures that the maximum dose allowed in the clinical trials by the
toxicology studies is not a sub-efficacious dose. A TI calculated from an-
imals dosed by inhalation derisks the toxicology studies, but it is not
 J.E. Phillips / Pharmacology & Therapeutics 178 (2017) 141–147
required in order to proceed with toxicology studies. Safety margins are
often estimated in separate assays as discussed earlier.
It is often asked, why perform the relatively complicated pre-clinical
aerosol inhalation efficacy studies when it is easier to deliver the drug
by direct instillation into the lung? The short answer is; drugs can be
much more potent when delivered by aerosol inhalation than direct in-
stillation due to the non-uniform distribution in the lung using direct in-
stillation (Cooper, Ferguson, & Grime, 2012). The only current way to
uniformly deliver large doses of drug to the lungs of animals is by aero-
sol inhalation.
3.1. Aerosol delivery vs direct instillation into the lung
The nose-only aerosol inhalation technique for rodents currently re-
quires hundreds of milligrams of micronized drug to create a high qual-
ity aerosol with a large inhalable fraction to achieve a uniform
pulmonary distribution. Nose-only inhalation is the only inhaled drug
delivery technique that provides a uniform drug distribution through-
out the lungs (Brain, Knudson, Sorokin, & Davis, 1976; Cooper et al.,
2012; Leong, Coombs, Sabaitis, Rop, & Aaron, 1998; Liu, Li, Pauluhn,
Trubel, & Wang, 2013; Zecchi et al., 2013). Uniform drug distribution
in the lung is possible with nose-only inhalation as a high quality respi-
rable aerosol is generated and maintained for a period long enough to
allow the animals to inhale an efficacious deposited dose (Alexander
et al., 2008). The deposited dose can be utilized as the denominator to
calculate a TI (Biju et al., 2011), ensuring that the drug has an appropri-
ate exposure multiple (usually N10 for rodents (Degeorge et al., 1997))
present to mitigate the potential risk of manifestation of any systemic
side effects. It is also useful when planning inhaled toxicology studies
and clinical trials. When combined with animal disease models and
pharmacodynamic measurements, nose-only inhalation dosing not
only provides information on the efficacious deposited dose, but also
the duration of action required to maintain the targeted efficacy; both
helpful for dose translation to humans.
Direct instillation delivery methods are an option when the amount
of drug is limited, usually due to cost associated with chemical synthe-
sis. All direct instillation delivery methods will suffer from non-homo-
geneous pulmonary deposition, with more drug concentrated along
the central airways and less well represented in the parenchymal/alve-
olar regions (Cooper et al., 2012; Leong et al., 1998; Zecchi et al., 2013).
Therefore, caution should be used when scaling doses from data gener-
ated by direct instillation methods, as drugs tend to be more potent
when delivered by aerosol inhalation compared to direct instillation
methods (Cooper et al., 2012). Direct instillation methods including:
intranasal (Siddiqui et al., 2008) or intratracheal liquid (Brain et al.,
1976; Liu et al., 2013) and spray instillation (Bivas-Benita, Zwier,
Junginger, & Borchard, 2005) or dry-powder insufflation (Guillon et
al., 2012; Morello et al., 2009); can be used as a screening tool to de-
termine the approximate dose range for later inhalation studies, or
to determine the ranking of efficacy/toxicity for a series of structur-
ally similar drugs (Pauluhn & Mohr, 2000). Efficacy data generated
by direct instillation methods complements inhaled aerosol ap-
proaches as it provides an opportunity to demonstrate efficacy
with a few milligrams of compound and without specialized aerosol
generation equipment.
The fundamental requirement in a pharmacodynamic study is that
the dose delivered be known. In inhalation pharmacology, due to diffi-
culties in measuring the actual inhaled dose that deposited in the
lungs, deposited doses must be estimated using mathematical relation-
ships in order to interpret experimental results. During a typical pre-
clinical inhalation drug efficacy experiment, the aerosol particle size
and concentration are measured (Oldham, Phalen, & Budiman, 2009)
and these values are used to calculate the delivered dose, pulmonary de-
position fraction, and deposited dose (Alexander et al., 2008; Forbes et
al., 2011).
143
4. Allometric scaling of drug dose
4.1. Introduction to allometric scaling
The infamous death of Tusko the elephant (West, Pierce, & Thomas,
1962) is commonly cited in the literature to remind us that drug doses
should not be extrapolated on the basis of a simple comparison of
body masses. One reason for this is that larger animals have slower me-
tabolism of drugs which likely lead to the overdosage of Tusko
(Harwood, 1963). Extrapolating animal data to humans by allometric
scaling is based on the observation that many diverse anatomical, bio-
chemical, pharmacokinetic, and physiological parameters correlate as
a power-law function of body mass (Adolph, 1949). The power-law
equation (Eq. (1)) yields
Y ¼ aMb ð1Þ
linear plots as the body mass (M) from multiple species is plotted
against a parameter of interest (Y) on a log-log scale (Fig. 1). The allome-
tric coefficient (a) represents the value of the parameter of interest for a
1 kg animal and the allometric exponent (b) is an interspecies scaling
factor which relates the body mass to the parameter of interest. When
a parameter scales log-linearly with body mass for multiple species,
the allometric approach may be useful to extrapolate non-human ani-
mal data to predict the value of the parameter of interest (in our case
drug dose) in humans. The power-law function turns into a linear func-
tion after logarithmic transformation (Eq. (2)), so that estimates of the
intercept (log(a)) and slope (b) can be computed by linear regression.
logðY Þ ¼ logðaÞ þ b logðMÞ ð2Þ
4.2. Dose scaling for systemically delivered drugs
The idea of using allometric scaling to estimate a human dose from
pre-clinical pharmacology data for drugs delivered by inhalation
comes from the common use of allometric dose scaling for systemically
administered drugs. Human dose estimation from pre-clinical pharma-
cology data for systemically administered drugs is based on the normal-
ization of doses to body surface area (FDA, 2015). Fixed exponent body
surface area allometric scaling (b = 0.67, Fig. 1) is the standard way to
approximate equivalent interspecies doses unless extrapolating doses
based on other parameters is known to be more appropriate.
Why would dose scale with the same allometric coefficient as body
surface area? A possible explanation is that human doses are dependent
on many factors (physicochemical properties, pharmacokinetics, active
metabolites, etc.) however dose can sometimes be correlated with only
one variable. Commonly that variable is the removal of drug from a
fixed volume of blood per unit time (Davidson, Parker, & Beliles,
1986). Clearance (a pharmacokinetic parameter) for some drugs is de-
pendent on metabolic rate. Metabolic rate and body surface area scale
with the same allometric exponent (Davidson et al., 1986; Mahmood
& Balian, 1999). Subsequently, large animals have a lower metabolic
rate due to their minimal requirement compared to small animals to
generate heat by metabolism to maintain their body temperature. This
is due to their smaller body surface area to mass ratio (Chappell &
Mordenti, 1991; Kleiber, 1947).
Pharmacokinetic parameters like clearance can control the concen-
tration of drug in the body and therefore the dose required. This line
of reasoning suggests that the link between drug dose and body surface
area relies on drug clearance and metabolic rate; and all of these param-
eters could scale with the same allometric exponent. Therefore, it is pos-
sible to consider scaling drug dose for systemically delivered drugs
across species based on an allometric equation with b = 0.67. The fact
that some drug doses can scale proportional to body surface area or me-
tabolism (Boxenbaum & DiLea, 1995; Chappell & Mordenti, 1991;
144 J.E. Phillips / Pharmacology & Therapeutics 178 (2017) 141–147
Davidson et al., 1986) does not imply that body surface area or metabol-
ic rate are determinants of the required efficacious drug dose; it simply
correlates.
Assuming that drug dose per unit body mass (i.e. μg/kg) scales log-
linearly with body mass according to a power-law function enables
the allometric approach to extrapolate non-human animal data to pre-
dict the human dose using Eq. (10) (derived in the Appendix). In Eq.
(10): Xh is the human drug dose normalized to body mass (μg/kg), Mh
is the human body mass (kg), Xa is the animal drug dose per unit body
mass (μg/kg), Ma is the animal body mass (kg), and b is the allometric
exponent.
 ð1bÞ
Ma
Xh ¼ Xa
Mh
4.3. Dose scaling for inhaled drugs
Unlike the data for systemically delivered drugs described above,
scientific literature to support the assumption that allometric scaling
is useful to predict the dose of a drug delivered by inhalation is lacking.
Nonetheless, Eq. (10) can be used to calculate a predicted human effec-
tive dose using a known effective dose and body mass of a non-human
animal, human body mass, and the appropriate allometric exponent.
The exponent used ideally should be empirically determined individual-
ly for each drug using data from multiple animal species. Unfortunately,
to my knowledge, this has never been done for any inhaled drug. This is
due to the difficulty of developing a similar animal disease model in
multiple species and the different methods required to deliver aerosols
to different species. Using a single species is pragmatic and may lead to
incorrect estimation of the drug dose due to body mass independent dif-
ferences between the species used and humans. An example of a body
mass independent source of interspecies variability is differences in cy-
tochrome P450 isoenzymes which affect drug metabolism (Riviere,
Martin-Jimenez, Sundlof, & Craigmill, 1997). Single species retrospec-
tive human effective dose allometric analysis is performed in the next
section. This is due to the lack of pre-clinical deposited inhaled effica-
cious dose data in multiples species for a drug that also has complimen-
tary human inhaled effective dose data.
5. Inhaled pulmonary deposited dose translation: Retrospective
analysis
The motivation behind this retrospective analysis is to determine the
validity of using allometry with a fixed exponent of 0.67, as is currently
done with systemically delivered drugs, to scale doses of inhaled drugs.
The line of reasoning describe above that links drug clearance/metabo-
lism, to metabolic rate, to body surface area (b = 0.67), could apply to
inhaled drug dose. An equally valid line of reasoning might correlate in-
haled drug dose scaling to lung mass or lung surface area, which have
the allometric exponents shown in Fig. 1 of 1.1 and 0.9, respectively.
To retrospectively determine applicable allometric exponents for in-
haled dose scaling, inhaled rodent efficacy data from inhaled com-
pounds that are currently used clinically were used as input to Eq.
(10). The allometric exponent required to predict the known clinically
effective deposited dose was backcalculated. The rodent effective
Table 1
Retrospective comparison of pre-clinical rodent efficacy data with clinical dose.
Drug Species Pre-clinical ED80 Deposited Clinical Dose Deposited
dose (μg/kg) dose (μg/kg)
Salbutamol mouse 48 0.7
Budesonide mouse 103 4.8
Ipratropium mouse 0.3 0.2
Mometasone rat 9 2.7
deposited doses and clinically effective deposited doses for salbutamol,
budesonide, ipratropium, and mometasone, are summarized in Table 1.
Utilizing Eq. (10) with a mouse body mass of 0.03 kg, a rat body mass of
0.25 kg, and a human body mass of 60 kg; the allometric exponents that
would allow the clinical inhaled deposited dose to be calculated from
the rodent efficacy data are 0.44, 0.60, 0.95, and 0.78; respectively. Albe-
it inappropriate to draw firm conclusions from such a small dataset (n
= 4), the average of these allometric exponents is 0.69, which supports
the current method of scaling using a fixed allometric exponent of 0.67.
The observation that all the exponents are less than one supports the
fact that equivalent efficacious doses should be smaller (on a body
mass (μg/kg) basis) in larger animals. This reinforces the utility of
fixed exponent allometric scaling with an exponent less than one for in-
ð10Þ
terspecies inhaled dose scaling.
6. Inhaled delivered dose: toxicology study design
The most obvious need for human dose projections is for planning
clinical trials to include what should be an efficacious dose. As men-
tioned above, the doses in clinical trials are capped by supporting toxi-
cology studies. The question of how to plan the toxicology studies to
ensure the predicted human effective dose can be tested in the clinical
trial is not simple to answer and should be planned by an inhalation tox-
icologist. To partially outline the process, one potential scenario to cal-
culate targeted toxicology study delivered doses is outlined in Fig. 2. It
uses allometric scaling (b = 0.67) of the efficacious pre-clinical depos-
ited dose and recommended literature safety margins (Degeorge et al.,
1997) and pulmonary deposition fractions (Snipes et al., 1989) for the
species tested in the inhaled toxicology studies to calculate targeted de-
livered doses for toxicology studies. The graphs in Fig. 3 use the scenario
outlined in Fig. 2 and standard values for body masses (Snipes et al.,
1989) to enable quick estimates of the projected efficacious human de-
livered dose from the experimentally determined efficacious deposited
dose (top graph) and the target toxicology delivered dose from the
projected efficacious human delivered dose (bottom graph) for multiple
species. These graphs are helpful for rough compound requirement pro-
jections needed for the toxicology studies.
7. Conclusions
The potential utility of allometric scaling to provide an initial esti-
mate for a human deposited efficacious dose of a novel inhaled drug
has been demonstrated. It illustrates the relevance of pharmacodynamic
studies conducted in animals where the drug is delivered by inhalation.
The complexity of the pharmacokinetic and pharmacodynamic re-
sponses to inhaled drugs decreases the probability that there is one
common extrapolation base (M0.67). Therefore, the exponent for in-
haled dose allometric scaling should be empirically determined for
each compound, preferably in multiple species. This is rarely done due
to the difficulty of developing a similar animal disease model in multiple
species and the different methods required to deliver aerosols to differ-
ent species. Further complicating matters, we have also recently shown
that the allometric exponent can depend on the biologic function (effi-
cacy endpoint) measured. In pre-clinical respiratory disease models,
improvements in lung function may require higher doses than to de-
crease pulmonary inflammation (Phillips et al., 2016). This suggests
Allometric exponent required to Reference for pre-clinical data
match rodent ED80 to clinical dose
0.44 Phillips et al. (2016)
0.60 Phillips et al. (2016)
0.95 Phillips, Zhang, & Johnston (2017)
0.78 Anthes et al. (2009)
 J.E. Phillips / Pharmacology & Therapeutics 178 (2017) 141–147 145

Efficacious animal
deposited dose
Allometricscaling
(b=0.67)
Projected effective human
deposited dose
Multiply by 2.5
(40% deposition)
Projected effective human
delivered dose
Multiply by 10 Multiply by 6
for rat toxicology for canine toxicology
safety margin safety margin
Deposited human Deposited human
equivalent dose needed equivalent dose needed
in rat toxicology study in canine toxicology study
Allometric scaling
(b=0.67)
Target deposited dose Target deposited dose in
in rat toxicology study canine toxicology study

Multiply by 10 Multiply by 4
(10% deposition) (25% deposition)
Target delivered dose Target delivered dose in
in rat toxicology study canine toxicology study

Fig. 2. Flow chart for estimating the human delivered dose and rat/canine target delivered doses for toxicology studies using an experimentally determined efficacious deposited dose from
a pre-clinical animal efficacy study. The delivered dose is the amount of drug inhaled by the subject and the deposited dose is the amount of drug calculated to be deposited in the lungs.

the pharmacodynamic endpoint to identify clinical drug candidates
should be chosen carefully (Stevenson, Sridhar, & Phillips, 2013).
The utility of allometic scaling for interspecies inhaled dose extrapo-
lations mainly comes from the requirement for only 4 input values (an
efficacious deposited dose for the pre-clinical species, body masses for
both species, and the allometric scaling coefficient) to calculate an esti-
mated effective deposited dose for humans. This utility is somewhat off-
set by the significant intrinsic limitations of allometric dose scaling
(Boxenbaum & DiLea, 1995). Also the experiments used to obtain the ef-
ficacious deposited dose for the pre-clinical species often contain many
assumptions that could be improved (i.e. minute ventilation rate during
aerosol inhalation is calculated and not measured, deposition fraction is
calculated assuming the aerosol is monodisperse). Despite these limita-
tions, allometric scaling does have a place in the drug development de-
cision making process. A better understanding of the mechanisms and
assumptions which are used to calculate the estimate of the effective
dose delivered to the lung that is used as input to the allometric scaling
equation may improve the predictive nature of allometry, but does not
make the allometric scaling method “mechanistic”. Allometric scaling of
lung deposited dose is empirical and the exponent used has no physio-
logical meaning. Therefore, addition of mechanistic “correction factors”,
like a factor to account for the difference in the nose-only aerosol deliv-
ery used pre-clinically versus oral inhalation with an inhaler that is used
in the clinic, are unnecessary as they are already part of the assumptions
that went into the calculation of the pre-clinical and clinical efficacious
deposited doses.
The utility of allometric scaling to extrapolate duration of action (a
pharmacokinetic endpoint) of inhaled drugs should also be explored
as biological time measured in heartbeats scales with the allometric ex-
ponent 0.25 (Mordenti, 1986) and may suggest that a duration of action
in chronological time of 3.6 h in mice (calculated using Appendix Eq.
(6)) would represent 24 h of efficacy (or q.d. dosing) in humans. This
hypothesis could be tested with the recently approved long acting
beta agonist (LABA) or long acting muscarinic antagonist (LAMA)
drugs (Spina, 2014) and would provide pre-clinical drug development
a duration of action goal when optimizing the properties of novel in-
haled drugs.
The limited pre-clinical efficacy data available in the literature on in-
haled drugs that are also used clinically supports the current method of
scaling using a fixed allometric exponent of 0.67 (FDA, 2015). The utility
of fixed exponent (b = 0.67) allometric scaling from a single species to
project an inhaled efficacious human dose is pragmatic but should be
146 J.E. Phillips / Pharmacology & Therapeutics 178 (2017) 141–147
Fig. 3. Diagrams to allow a graphical approximation of projected efficacious human
delivered dose from a pre-clinical experimentally determined efficacious deposited dose
(upper panel) and an approximation of target delivered doses for rat and canine
toxicology studies from the projected efficacious human delivered dose (lower panel).
These diagrams can be used in conjunction with experimentally determined pre-clinical
efficacious deposited doses from mouse, rat, nonhuman primate or canine studies.
Assumptions: mouse body mass 0.03 kg, rat body mass, 0.25 kg, nonhuman primate
body mass 2.4 kg, canine body mass 10 kg, human body mass 60 kg, allometric scaling
coefficient b = 0.67, 10% deposition rat, 25% deposition canine, 40% deposition human,
6× safety margin canine, 10× safety margin rat.
used cautiously. The limited number of marketed inhaled drugs, com-
bined with the limited number of pre-clinical datasets with pharmaco-
dynamic endpoints for drugs delivered by inhalation precludes a more
detailed assessment of the utility for fixed exponent allometric scaling
for inhaled dose extrapolation.
Conflict of interest
Dr. Jonathan Phillips is employed by Amgen.
Appendix A. Derivation of the allometric interspecies scaling equa-
tion as a function of total drug dose
A power-law equation can be written for a human (Eq. (3)) and an
animal (Eq. (4)).
Y h ¼ aMbh ð3Þ
Y a ¼ aMba ð4Þ
where Yh is the human drug dose (μg), Mh is the human body mass (kg),
Ya is the animal drug dose (μg), Ma is the animal body mass (kg), and a
and b are the allometric coefficient and exponent, respectively. Since a is
the same value in Eqs. (3) & (4) if the drug dose follows an allometric
relationship, Eqs. (3) & (4) can be solved for a and set equal to each
other yielding Eq. (5).
Yh Ya
¼ ð5Þ
Mbh M ba
Solving Eq. (5) for Yh and simplifying using the properties of expo-
nents yields Eq. (6).
 −b
Ma
Yh ¼ Ya ð6Þ
Mh
Appendix B. Derivation of the allometric interspecies scaling equa-
tion as a function of body mass normalized drug dose
A power-law equation can be written for a human (Eq. (7)) and an
animal (Eq. (8))
X h Mh ¼ aMbh ð7Þ
X a Ma ¼ aMba ð8Þ
Where Xh is the human drug dose normalized to body mass (μg/kg), Mh
is the human body mass (kg), Xa is the animal drug dose per unit body
mass (μg/kg), Ma is the animal body mass (kg), and a and b are the allo-
metric coefficient and exponent, respectively. Since a is the same value
in Eqs. (7) & (8) if the drug dose follows an allometric relationship, Eqs.
(7) & (8) can be solved for a and set equal to each other yielding Eq. (9).
X h Mh X a Ma
¼ ð9Þ
Mbh M ba
Solving Eq. (9) for Xh and simplifying using the properties of expo-
nents yields Eq. (10).
 ð1bÞ
Ma
Xh ¼ Xa ð10Þ
Mh
Eqs. (6) and (10) will give the same answer for the body mass nor-
malized (μg/kg) or non-body mass normalized (μg) drug dose. The
form used is a matter of convenience.
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