The FASEB Journal Life Sciences Forum
`Dose translation from animal to human studies
`revisited
`Shannon Reagan-Shaw,* Minakshi Nihal,* ,† and Nihal Ahmad* ,†,‡,1
`*Department of Dermatology, †Paul P. Carbone Comprehensive Cancer Center; ‡Molecular and
`Environmental Toxicology Center, University of Wisconsin, Madison, Wisconsin, USA
`ABSTRACT As new drugs are developed, it is essen-
`tial to appropriately translate the drug dosage from one
`animal species to another. A misunderstanding appears
`to exist regarding the appropriate method for allomet-
`ric dose translations, especially when starting new ani-
`mal or clinical studies. The need for education regard-
`ing appropriate translation is evident from the media
`response regarding some recent studies where authors
`have shown that resveratrol, a compound found in
`grapes and red wine, improves the health and life span
`of mice. Immediately after the online publication of
`these papers, the scientific community and popular
`press voiced concerns regarding the relevance of the
`dose of resveratrol used by the authors. The animal
`dose should not be extrapolated to a human equivalent
`dose (HED) by a simple conversion based on body
`weight, as was reported. For the more appropriate
`conversion of drug doses from animal studies to human
`studies, we suggest using the body surface area (BSA)
`normalization method. BSA correlates well across sev-
`eral mammalian species with several parameters of
`biology, including oxygen utilization, caloric expendi-
`ture, basal metabolism, blood volume, circulating
`plasma proteins, and renal function. We advocate the
`use of BSA as a factor when converting a dose for
`translation from animals to humans, especially for
`phase I and phase II clinical trials.—Reagan-Shaw, S.,
`Nihal, M., Ahmad, N. Dose translation from animal to
`human studies revisited. FASEB J.22, 659–661 (2007)
`Key Words: drug dose conversion/H18528body surface area
`In the development of new drugsto manage dis-
`eases, the scientific community relies heavily on animal
`studies that provide a framework for human clinical
`trials. Often, a drug that works well in animals is
`ostensibly not effective in humans. Several explanations
`exist for the lack of effectiveness.
`One often-ignored explanation for drug ineffective-
`ness is the inappropriate translation of a drug dose
`from one animal species to another. The scientific as
`well as nonscientific communities seem to misunder-
`stand the need for an appropriate method of allometric
`dose translation, especially when starting new animal or
`clinical studies. The calculations for determining start-
`ing dose in humans as extrapolated from animals
`should use the more appropriate normalization of body
`surface area (BSA). This method was first introduced
`into medical oncology in order to derive a safe starting
`dose for phase I studies of anticancer drugs from
`preclinical animal toxicology data. Unfortunately, for a
`translational study, many convert the safe starting dose
`based on body weight alone, which can result in
`inappropriate comparisons between studies.
`Two excellent examples of dissemination of misinfor-
`mation are based on recent studies by Lagougeet al.(1)
`and Baur et al. (2), who suggest that the antioxidant
`resveratrol found in red wine can improve energy
`balance and protect against the diseases of aging. These
`studies gained popularity in the news media and sub-
`sequently were highlighted and critiqued by scientists
`around the world. Many media sources stressed that the
`doses used in mice could be interpreted to mean
`several hundred or even thousands of liters of wine per
`day in human equivalent doses (HEDs) (3–5). This
`serious misinterpretation resulted in skepticism of the
`scientific research. Unfortunately, the invalid calcula-
`tions used to provide this interpretation demonstrate
`the ignorance of the scientific community and general
`public regarding appropriate methods of dose transla-
`tion between species.
`In this article, we provide pertinent information
`regarding appropriate methods for the translation of
`drug doses from animal studies to human studies for
`use in interpreting research results.
`CORRECT DOSE CALCULATION: AN EXAMPLE
`As described above, confusion and concerns emanated
`from a recent study by Baur et al. (2), where a dose of
`22.4 mg/kg (body weight) of resveratrol was used in a
`mouse study on aging and obesity-related disorders.
`The media reported that a 60 kg human would have to
`consume 1344 mg of resveratrol per day in order to
`receive a like benefit, a serious misinterpretation of the
`research. Using an average of 2 mg resveratrol per
`bottle of wine (6), this calculation implies that a person
`1 Correspondence: Department of Dermatology, University
`of Wisconsin, B-25 Medical Science Center, 1300 University
`Ave., Madison, WI 53706, USA. E-mail: nahmad@wisc.edu
`doi: 10.1096/fj.07-9574LSF
`6590892-6638/07/0022-0659 © FASEB
`BONERGE Ex. 1005, p. 1
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`would have to drink 672 bottles of red wine to approx-
`imate the resveratrol equivalent.
`However, the Food and Drug Administration (7) has
`suggested that the extrapolation of animal dose to
`human dose is correctly performed only through nor-
`malization to BSA, which often is represented in mg/
`m
`2. The human dose equivalent can be more appropri-
`ately calculated by using the formula shown in Fig. 1.
`To convert the dose used in a mouse to a dose based on
`surface area for humans, multiply 22.4 mg/kg (Baur’s
`mouse dose) by the K
`m factor (3) for a mouse and then
`divide by the Km factor (37) for a human ( Table 1).
`This calculation results in a human equivalent dose for
`resveratrol of 1.82 mg/kg, which equates to a 109 mg
`dose of resveratrol for a 60 kg person. While not
`reasonably achievable through consumption of wine,
`this concentration may be provided through a daily oral
`supplement. We would like to emphasize that an ap-
`propriately calculated dose based on research in mice is
`achievable in humans. However, while supplements at
`this dose (109 mg) and higher are readily available in
`pill or capsule form for general public consumption, we
`do not advocate their usage.
`THE USE OF BSA FOR DOSE TRANSLATION
`Research has used BSA for conversion of drug doses
`between species for many years. The origin for under-
`standing the relationship between the BSA of different
`species began in 1883 when observations that oxygen
`utilization and caloric expenditure were similar for
`various mammalian species and differently sized mem-
`bers of the same species when computed on the basis of
`body surface (8). These observations were then con-
`firmed and applied to humans, which gave rise to
`expressing human basal metabolism in terms of BSA
`rather than body weight (9). Correlations between
`blood volume, circulating plasma proteins, and renal
`function with BSA in several species also have been
`illustrated (10). Thus, BSA correlates well with param-
`eters of mammalian biology, which makes BSA normal-
`ization logical for allometric scaling of drug doses
`between species, given that the activity of most drugs
`corresponds to the relationship between the drug and
`some physiological process or function. Further, work
`by Freireich et al. (11) and Schein et al. (12) showed
`that for antineoplastic drugs, lethal doses to 10%
`(LD
`10) of rodents and maximum tolerated doses
`(MTD) in nonrodents correlated with the human MTD
`when the doses were normalized to the same adminis-
`tration schedule and expressed in terms of BSA in
`mg/m
`2. The authors of these studies pointed out that
`the evaluation of animal toxicity screening systems can
`be used as a tool to enable safe introduction of new
`drugs into humans, although the authors did not
`attempt to relate therapeutic doses in various species
`(11, 12).
`When testing new drugs, the most appropriate spe-
`cies for assessing human risk is determined and then
`followed by toxicology studies. The K
`m factor, body
`weight (kg) divided by BSA (m2), is used to convert the
`mg/kg dose used in a study to an mg/m2 dose. The Km
`values based on average BSA calculations for human,
`baboon, dog, monkey, rabbit, guinea pig, rat, hamster,
`and mouse are shown in Table 1 For the purpose of
`initial clinical trials in healthy adult volunteers, the
`HED is calculated (Fig. 1) using BSA normalization of
`the animal dose where no observed adverse effects were
`observed (7). In phase I studies, data derived from
`animal models where the drug doses are tested until
`the LD
`10 is reached are used to derive the safe starting
`dose for human studies. The first human dose em-
`ployed is the allometric conversion, based on BSA, of
`1/10 of the LD
`10 for the relevant animal species (7).
`BSA normalization of doses must be used to determine
`safe starting doses of new drugs because initial studies
`conducted in humans, by definition, lack formal allo-
`metric comparison of the pharmacokinetics of absorp-
`tion, distribution, and elimination parameters (13).
`EXPANDED USE OF BSA IN CLINICAL
`MEDICINE
`Some drugs are administered to patients based on
`estimations for desired plasma concentrations using
`available pharmacokinetics and pharmacodynamics
`data. Studies have suggested that the role of BSA could
`be expanded for drug dose calculation in an attempt to
`more accurately administer cytotoxic drugs to children.
`The major problem with using BSA as a factor for dose
`individualization is that BSA can only be estimated with
`a formula generally incorporating measures of body
`Figure 1. Formula for dose translation based on BSA.
`TABLE 1. Conversion of animal doses to HED based on BSA
`Species Weight (kg) BSA (m 2) Km factor
`Human
`Adult 60 1.6 37
`Child 20 0.8 25
`Baboon 12 0.6 20
`Dog 10 0.5 20
`Monkey 3 0.24 12
`Rabbit 1.8 0.15 12
`Guinea pig 0.4 0.05 8
`Rat 0.15 0.025 6
`Hamster 0.08 0.02 5
`Mouse 0.02 0.007 3
`Values based on data from FDA Draft Guidelines (7). To convert
`dose in mg/kg to dose in mg/m 2, multiply by Km value.
`660 Vol. 22 March 2007 REAGAN-SHAW ET AL.The FASEB Journal
` 15306860, 2008, 3, Downloaded from https://faseb.onlinelibrary.wiley.com/doi/10.1096/fj.07-9574LSF by Cornell University E-Resources & Serials Department, Wiley Online Library on [04/04/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
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`weight and height. The customary approach for calcu-
`lation of BSA uses the Du Bois height-weight formula:
`BSA (m
`2) equals body weight (kg) 0.425 multiplied by
`height (cm)0.725 multiplied by 0.007184, for which the
`constants were derived from only 9 patients (14;15).
`Subsequently, this formula has been challenged and
`re-evaluated in similar forms with updated constants.
`Alternative body-size measurements have been pro-
`posed, including lean body mass, ideal body weight,
`adjusted ideal body weight, and body mass index.
`However, scientific evidence does not favor one alter-
`native formula over another (16–18). While the reli-
`ability of the Du Bois formula has been contested, the
`resultant approximation should be accepted not as a
`method of precise measurement but as a means of
`achieving more correct comparisons among species.
`The question then becomes, what is the appropriate
`method for conducting human studies? Based on the
`allometric conversion of drug doses from animals that
`have undergone toxicology testing, the current practice
`in phase I trials involves calculating starting drug doses
`on the basis of the BSA of individual patients. The
`unfortunate side effect of this strategy is that unpredict-
`able variations in effect are observed because BSA
`dosing does not take into account the complex process
`of drug elimination (19). Thus, overdosing can occur
`and is easily recognized, but underdosing can be just as
`frequent and leads to a reduced therapeutic result (19).
`Many researchers advocate abandoning this approach
`in favor of the administration of fixed drug doses that
`are calculated on the basis of an average 1.86 m
`2 BSA,
`as calculated by one study (20). Dose refinement then
`would reflect the desired therapeutic outcome for
`individual patients with the added benefit of reducing
`errors in calculations and possibly reducing costs as
`well.
`CONCLUSION
`Unfortunately, the debate surrounding the use of BSA
`to adjust an individual patient’s drug dose clouds the
`use of BSA for allometric conversion of doses and
`creates confusion in the scientific community as well as
`in the media. When animal studies such as those
`involving resveratrol are completed and media reports
`distort the dose translation between the study mice and
`the HED, misinformation regarding the effectiveness of
`resveratrol against a disease or condition hampers the
`significance of preclinical data. Understanding the
`more appropriate method based on BSA conversion for
`dose translation across species is an important issue for
`both the scientific community as well as the general
`public. Currently, BSA-based dose calculation is the
`most appropriate method and is far superior to the
`simple conversion based on body weight. However, a
`concerted effort toward designing more appropriate
`conversions that eliminate the problems associated with
`the BSA method is needed in order to improve thera-
`peutic outcomes in trials.
`We thank Dr. N. L. Karls, Associate Faculty Associate and
`Science Writing Specialist at the Writing Center of the
`University of Wisconsin-Madison, and C. Valentine, Instruc-
`tional Resource Teacher, for a critical reading and careful
`editing of this manuscript.
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`661DOSE TRANSLATION FROM ANIMAL TO HUMAN
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