A simple practice guide for dose conversion between animals and human
Address for correspondence: Dr. Anroop B. Nair, Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, P.O. Box 400, Al-Ahsa 31982, Kingdom of Saudi Arabia. E-mail: as.ude.ufk@riana
Copyright : © 2016 Journal of Basic and Clinical Pharmacy
This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.
Abstract
Understanding the concept of extrapolation of dose between species is important for pharmaceutical researchers when initiating new animal or human experiments. Interspecies allometric scaling for dose conversion from animal to human studies is one of the most controversial areas in clinical pharmacology. Allometric approach considers the differences in body surface area, which is associated with animal weight while extrapolating the doses of therapeutic agents among the species. This review provides basic information about translation of doses between species and estimation of starting dose for clinical trials using allometric scaling. The method of calculation of injection volume for parenteral formulation based on human equivalent dose is also briefed.
Keywords: Calculation, clinical trials, experiment, extrapolation, parenteral, species, starting dose, translation
Introduction
Safe and effective drug dosing is necessary, regardless of its purpose of administration. There are several instances, wherein the initial dose of a particular drug is unavailable in a specific species. Therefore, choosing starting dose of such drugs for research, experiments, or clinical trials in animals and humans is a concern. It should be emphasized that the common perception of scaling of dose based on the body weight (mg/kg) alone is not the right approach. This is primarily because the biochemical, functional systems in species vary which in turn alter pharmacokinetics. Therefore, extrapolation of dose from animals to humans needs consideration of body surface area, pharmacokinetics, and physiological time to increase clinical trial safety. There are four different methods namely dose by factor, similar drug, pharmacokinetically guided, and comparative approaches are described in literature to assess the initial dose.[1] The dose by factor method is an empirical approach and use the no observed adverse effect levels (NOAEL) of drug from preclinical toxicological studies to estimate human equivalent dose (HED).[2] Here, the dose selection is based on minimum risk of toxicity, instead of choosing one with minimum pharmacologic activity in humans. In similar drug approach, the existing pharmacokinetics data for another drug of the same pharmacological category may be used.[3] On the other hand, pharmacokinetically guided approach utilizes the drug activity instead of scaling of dose among species.[4] In case of comparative approach, different methods are utilized to determine initial dose, and the data are compared and optimize to get an initial dose.
Allometric scaling is an empirical approach where the exchange of drug dose is based on normalization of dose to body surface area. This approach assumes that there are some unique characteristics on anatomical, physiological, and biochemical process among species, and the possible difference in pharmacokinetics/physiological time is accounted by allometric scaling.[5,6] This method is frequently used in research for experimental purpose to predict an approximate dose on the basis of data existing in other species. Drugs with lesser hepatic metabolism, low volume of distribution, and excreted by renal route are ideal candidates for scaling of dose by this approach. The US Food and Drug Administration’s current guidance is based on dose by factor approach where the NOAEL of drug is scaled by making use of allometry to derive the maximum recommended starting dose (MRSD) for clinical studies.[7] This simple empirical approach considers the sizes of individual species based on body surface area which is related to metabolic rate of an animal that is established through evolutionary adaptation of animals to their size.[8,9] Moreover, the MRSD is usually scaled well across animal species when normalized to body surface area (mg/m 2 ). Typically, MRSD is calculated from preclinical toxicology studies and applying a factor.[10] Figure 1 depicts the five steps to calculate MRSD in entry into human studies. Briefly, determine NOAEL’s in animal species, then convert NOAEL to HED, select appropriate animal species, apply safety factor, and finally, convert to pharmacologically active dose. NOAEL, the highest dose level that does not cause significant adverse effects, is a typical index for safety obtained from proper animal experiments to determine a safe starting dose.[7] In step 2, the NOAELs value is converted to HED on the basis of the body surface area correction factor (i.e., W 0.67 , which depends on the animal weight), using appropriate scaling factors from animal species.[11] Table 1 summarizes the factors for converting doses. The next step is selection of most appropriate species to use in calculation of MRSD. In general, animal species with the lowest HED is considered most sensitive species for determining human risk and is usually selected.[12] However, one can be more accurate by considering the change in pharmacokinetic parameters of drug between species. On the other hand, a specific animal that is more sensitive toward adverse effect can also be a suitable species. In step 4, the HED is divided by a factor value of 10, to increase safety of first human dose. This safety factor is accountable for differences in physiological and biological processes between human and animal species. In the final step, the value obtained is converted to pharmacologically active dose in humans.
Schematic representation of five steps to estimate starting dose in human studies
Uncomplicated animal illustrations with a step-by-step approach
Simple step-by-step lessons for drawing 60 animals + video tutorials via QR codes!
Drawing Class: Animals is a collection of 60 fun, beginner-level lessons for drawing whimsical animals in pencil and colored pencil .
Written and illustrated by artist and author Heegyum Kim, the fun, easy lessons—one for every animal—present step-by-step illustrations and instructions demonstrating how each one is drawn in pencil, with each step showing how and where to add simple shapes to create a wide variety of comical creatures , including:
- Home and Farm: Cat, Dog, Horse, Pig
- Woodlands, Plains, and Grasslands: Brown Bear, Moose, Elephant, Wolf
- Crawlers and Fliers: Cricket, Dragonfly, Hummingbird, Quail
- Rainforest: Iguana, Jaguar, Sloth, Orangutan
- Sea, Shore, and Wetlands: Alligator, Walrus, Frog, Shark
- Legendary Creatures: Dinosaur, Dodo, Unicorn
For extra inspiration, several colored pencil versions of each animal are shown, along with a special feature— QR codes that give you access to a bonus video tutorial for every animal !
Sharpen your pencils—it’s time for Drawing Class: Animals !
About the Author
Heegyum Kim is a graphic designer and illustrator. She holds a Master of Science in Communication Design from Pratt Institute and is the author of two illustrated books featuring Mr. Fox, the charming and humorous character whose activities and musings drive her popular Instagram account and make her followers giggle, as do a menagerie of other delightful animal friends. She is also the author and illustrator behind several titles published by Quarry Books: Drawing Class: Animals , which presents step-by-step illustrated instruction for 60 whimsical animals along with video tutorials accessible via QR codes; and the Draw 62…and Make Them Cute series, which provides step-by-step illustrations for drawing different types of cute characters. Heegyum also received honors recognition at the Society of Children’s Book Writers and Illustrators (SCBWI) 2022 Winter Conference Portfolio Showcase. She lives in Elmsford, New York. See more of Heegyum’s work on her website (mrfox.nyc) and follow her drawing adventures on Instagram (@hee_cookingdiary).
“Artists and doodlers will love this step-by-step method of drawing 60 different animals using simple shapes, such as rectangles, triangles and semicircles. Fun and easy-to-follow, this book of techniques can be enjoyed by children, teens, and adults.”—Library Journal STARRED Review
- Art / Techniques / Drawing
- Art / Techniques / Pencil Drawing
- Art / Subjects & Themes / Plants & Animals
