Review Article
How to Choose Drug Dosage for Human
Experiments Based on Drug Dose Used on Animal
Experiments: A Review
UB Rajasekaran1, US Krishna Nayak2
1
Research Scholar, Department of Orthodontics, AB Shetty Memorial Institute of Dental Sciences, Nitte University, Mangalore, Karnataka, India, 2Head
and Dean, Department of Orthodontics, AB Shetty Memorial Institute of Dental Sciences, Nitte University, Mangalore, Karnataka, India
The orthodontic tooth movement is a biological response to orthodontic force. The biological response is very strongly-related to local bone
metabolism. There is a strong evidence in the literature that bone metabolism can be altered by drugs. There are various studies published in
dental journals on administration of drugs for the purpose of affecting orthodontic tooth movement both for augmentation of anchorage and
to increase the rate of tooth movement. Most of these studies are animal studies. The aim of this article is to give insight to how to convert
drug dose from animal studies to human trails. Dose per kilogram of body weight for one species is not the same for another species, it has
to be converted first based on body surface area (BSA)normalization method. BSA correlates well across several mammalian species with
several parameters of biology, including oxygen utilization, caloric expenditure, basal metabolism, blood volume, circulating plasma proteins,
and renal function.
Keywords: Body surface area, Normalization method drug dose conversion, Km factor
INTRODUCTION
The orthodontic tooth movement is a biological response to
orthodontic force.1 The biological response is very stronglyrelated to local bone metabolism.2,3 There is a strong evidence
in the literature that bone metabolism can be altered by drugs.4-6
There are various studies published in dental journals on
administration of drugs for the purpose of affecting orthodontic
tooth movement as well as for augmentation of anchorage
and retention. Most of these studies are animal studies.7-9
The problem in the application of these drugs for therapeutic
purpose in human subjects or at least for the purpose of
clinical trial is hesitated by many researchers mainly because of
determining the effective dosage for humans. If drug influenced
orthodontics incorporated into mainstream orthodontics, it will
be a great addition to orthodontic biomechanics. The aim of
this article is to give insight to how to convert drug dose from
animal studies to human trails.
METHODOLOGY USED IN LITERATURE SEARCH
The database Medline-PubMed, was searched using the key
terms “animal studies in orthodontics using drugs,” and
“conversion of animal drug dosage for human studies in
dentistry.” All articles published before December 2013 were
included in the study. For the first search term, there were a
total of 21 hits for the search. The second search term had 66
hits. This was further reduced 40 articles by setting a limit in
PubMed search by limiting them to articles published in last
3 years. All the 61 articles including their bibliography section
was studied and reviewed.
HOW TO CHOOSE DRUG DOSAGE FOR INITIAL
ANIMAL STUDIES
1. Selection of appropriate animal species that best
represents humans are selected10
2. Based on toxicological studies, the lethal dose (LD)
(dose per kilogram body weight that kills 50% of the test
animals) is determined for that species11
3. Then LD10 is determined, that is when dose per kilogram
body weight given to a group of the same species animals
only 10% of the animals will die12
4. The LD10 dose is administered to the animals for the
experimental purpose
5. When we observe the desired effects in the animals, the
next step is to conduct human trails.
CAN WE USE LD10 DOSAGE FROM ANIMAL
EXPERIMENTS TO CLINICAL TRIALS DIRECTLY?
1. Dose per kilogram of body weight for one species is not
the same for another species, it has to be converted first
based on body surface area (BSA)12,13
Corresponding Author:
Dr. UB Rajasekaran, Department of Orthodontics, AB Shetty Memorial Institute of Dental Sciences, Nitte University, Mangalore, Karnataka, India.
Phone: +91-8012537202/9845242020. E-mail: [email protected]
IJSS Case Reports & Reviews | August 2014 | Vol 1 | Issue 3
31
Rajasekaran and Nayak: Drug dose for human experiments
Table 1: BSA and Km factor values based on FDA
guidelines
Species
Human
Adult
Child
Baboon
Dog
Monkey
Rabbit
Guinea pig
Rat
Hamster
Mouse
Weight (kg)
BSA (m2)
Km factor
60
20
12
10
3
1.8
0.4
0.15
0.08
0.02
1.6
0.8
0.6
0.5
0.24
0.15
0.05
0.025
0.02
0.007
37
25
20
20
12
12
8
6
5
3
BAS: Body surface area
2. The formula used in human dosage calculation based on dose
used in animal experiments is (animal Km factor divided by
human Km factor) multiplied by animal dose (mg/kg); the Km
factor, body weight (kg) divided by BSA (m2). The Km values
based on average BSA calculations for human, baboon, dog,
monkey, rabbit, guinea pig, rat, hamster, and mouse.14-20
Values based on data from Food and Drug Administration
(FDA) Draft Guidelines10 (Table 1)
3. The reason why we cannot convert the drug dosage
directly from animal experiments to humans is that
pharmacodynamics and pharmacokinetics of the given
drug depends on the body metabolism. Different species
have different rates and different mechanisms as related
to their body metabolism.12-15
CONCLUSION
LD values for humans are best estimated by extrapolating
results from human cell cultures. The degree of error from
animal-extrapolated LD values is very large.21 The biology of
test animals differs in important aspects to that of humans.
Researchers are now shifting away from animal-based LD
measurements. The US FDA has begun to approve more
reliable non-animal methods in response to research cruelty
concerns and the lack of validity/sensitivity of animal tests
as they relate to humans.21 Currently, BSA-based dose
calculation is the most appropriate method and is far superior
to a simple conversion based on body weight.11 Efforts toward
designing more appropriate means of selecting drug dosages
for human trials will be very advantageous in the near future.
REFERENCES
1. Krishnan V, Davidovitch Z. On a path to unfolding the biological
mechanisms of orthodontic tooth movement. J Dent Res 2009;88:597-608.
2. Kohno T, Matsumoto Y, Kanno Z, Warita H, Soma K. Experimental
tooth movement under light orthodontic forces: Rates of tooth
32
movement and changes of the periodontium. J Orthod 2002;29:129-35.
3. Verna C, Dalstra M, Melsen B. The rate and the type of orthodontic
tooth movement is influenced by bone turnover in a rat model. Eur
J Orthod 2000;22:343-52.
4. Alberto C, Vanessa BM, Milton SJ, Maria FC. Sources of
controversies over analgesics prescribed after activation of
orthodontic appliances: Acetylsalicylic acid or acetaminophen?
Dent Press J Orthod 2010;15:16-24.
5. Lapatki BG, Bartholomeyczik J, Ruther P, Jonas IE, Paul O. Smart
bracket for multi-dimensional force and moment measurement.
J Dent Res 2007;86:73-8.
6. Howard PS, Kucich U, Taliwal R, Korostoff JM. Mechanical forces
alter extracellular matrix synthesis by human periodontal ligament
fibroblasts. J Periodontal Res 1998;33:500-8.
7. Richard SM, Ping-Lin C. Thinking beyond the wire: Emerging
biologic relationships in orthodontics and periodontology. Semin
Orthod 2008;14:290-304.
8. Yamasaki K, Shibata Y, Imai S, Tani Y, Shibasaki Y, Fukuhara T.
Clinical application of prostaglandin E1 (PGE1) upon orthodontic
tooth movement. Am J Orthod 1984;85:508-18.
9. Bartzela T, Türp JC, Motschall E, Maltha JC. Medication effects on
the rate of orthodontic tooth movement: A systematic literature
review. Am J Orthod Dentofacial Orthop 2009;135:16-26.
10. Center for Drug Evaluation and Research, Center for Biologics
Evaluation and Research. Estimating the safe starting dose in
clinical trials for therapeutics in adult healthy volunteers. Rockville,
Maryland, USA: U.S. Food and Drug Administration; 2002.
11. Reagan-Shaw S, Nihal M, Ahmad N. Dose translation from animal
to human studies revisited. FASEB J 2008;22:659-61.
12. Pinkel D. The use of body surface area as a criterion of drug dosage
in cancer chemotherapy. Cancer Res 1958;18:853-6.
13. Freireich EJ, Gehan EA, Rall DP, Schmidt LH, Skipper HE. Quantitative
comparison of toxicity of anticancer agents in mouse, rat, hamster,
dog, monkey, and man. Cancer Chemother Rep 1966;50:219-44.
14. Schein PS, Davis RD, Carter S, Newman J, Schein DR,
Rall DP. The evaluation of anticancer drugs in dogs and
monkeys for the prediction of qualitative toxicities in man.
Clin Pharmacol Ther 1970;11:3-40.
15. Kaestner SA, Sewell GJ. Chemotherapy dosing part I: Scientific
basis for current practice and use of body surface area. Clin Oncol
(R Coll Radiol)2007;19:23-37.
16. Du Bois D, Du Bois EF. The measurement of the surface area of
man. Arch Intern Med 1915;15:868-81.
17. Du Bois D, Du Bois EF. A formula to estimate the approximate surface
area if height and weight be known. Arch Intern Med 1916;17:863-71.
18. Wang J, Hihara E. A unified formula for calculating body surface
area of humans and animals. Eur J Appl Physiol 2004;92:13-7.
19. Sawyer M, Ratain MJ. Body surface area as a determinant of
pharmacokinetics and drug dosing. Invest New Drugs 2001;19:171-7.
20. B a k e r S D , Ve r we i j J , R o w i n s k y E K , D o n e h o we r R C ,
Schellens JH, Grochow LB, et al. Role of body surface area in
dosing of investigational anticancer agents in adults, 1991-2001.
J Natl Cancer Inst 2002;94:1883-8.
21. Available from: http://www.en.wikipedia.org/wiki/Lethal_dose.
[Last accessed on 2014 Aug 02]
How to cite this article: Rajasekaran UB, Nayak US. How to choose
drug dosage for human experiments based on drug dose used on animal
experiments: A review. IJSS Case Reports & Reviews 2014;1(3):31-32.
Source of Support: Nil, Conflict of Interest: None declared.
IJSS Case Reports & Reviews| August 2014 | Vol 1 | Issue 3