Can You Compound W On An Animal

• Journal Listing
• J Basic Clin Pharm
• v.7(two); March 2016-May 2016
• PMC4804402

J Basic Clin Pharm. March 2016-May 2016; 7(2): 27–31.

A simple practice guide for dose conversion between animals and human being

Anroop B. Nair

Section of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa, Kingdom of Saudi arabia

Shery Jacob

¹ Department of Pharmaceutics, College of Chemist's shop, Gulf Medical University, Ajman, UAE

Abstruse

Understanding the concept of extrapolation of dose betwixt species is important for pharmaceutical researchers when initiating new animal or human experiments. Interspecies allometric scaling for dose conversion from fauna to human studies is ane of the virtually controversial areas in clinical pharmacology. Allometric approach considers the differences in body surface area, which is associated with animate being weight while extrapolating the doses of therapeutic agents amongst the species. This review provides basic data most translation of doses betwixt species and estimation of starting dose for clinical trials using allometric scaling. The method of calculation of injection volume for parenteral formulation based on man equivalent dose is also briefed.

Keywords: Calculation, clinical trials, experiment, extrapolation, parenteral, species, starting dose, translation

Introduction

Safety and effective drug dosing is necessary, regardless of its purpose of assistants. 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. Information technology should be emphasized that the common perception of scaling of dose based on the torso weight (mg/kg) alone is not the right approach. This is primarily because the biochemical, functional systems in species vary which in plow alter pharmacokinetics. Therefore, extrapolation of dose from animals to humans needs consideration of body surface surface area, pharmacokinetics, and physiological time to increment clinical trial condom. There are four unlike methods namely dose by factor, like drug, pharmacokinetically guided, and comparative approaches are described in literature to assess the initial dose.[one] The dose by factor method is an empirical arroyo and use the no observed adverse effect levels (NOAEL) of drug from preclinical toxicological studies to estimate homo equivalent dose (HED).[ii] Here, the dose selection is based on minimum take a chance of toxicity, instead of choosing i with minimum pharmacologic activity in humans. In similar drug approach, the existing pharmacokinetics information for some other drug of the same pharmacological category may be used.[iii] On the other mitt, pharmacokinetically guided approach utilizes the drug activity instead of scaling of dose among species.[four] In example of comparative arroyo, 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 torso surface expanse. This arroyo assumes that in that location are some unique characteristics on anatomical, physiological, and biochemical process amid species, and the possible difference in pharmacokinetics/physiological time is accounted by allometric scaling.[5,half dozen] 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 platonic candidates for scaling of dose by this arroyo. The U.s.a. 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 expanse which is related to metabolic rate of an animal that is established through evolutionary adaptation of animals to their size.[8,nine] Moreover, the MRSD is usually scaled well beyond animate being species when normalized to body surface area (mg/m²). Typically, MRSD is calculated from preclinical toxicology studies and applying a factor.[10] Effigy 1 depicts the five steps to calculate MRSD in entry into human studies. Briefly, determine NOAEL's in fauna species, then catechumen NOAEL to HED, select advisable creature species, use safety cistron, and finally, convert to pharmacologically active dose. NOAEL, the highest dose level that does not cause significant adverse effects, is a typical index for prophylactic obtained from proper animal experiments to determine a condom 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 fauna weight), using appropriate scaling factors from animal species.[11] Table ane summarizes the factors for converting doses. The next step is option of most appropriate species to use in calculation of MRSD. In general, animal species with the everyman HED is considered most sensitive species for determining human take a chance and is usually selected.[12] However, ane can be more accurate by considering the modify in pharmacokinetic parameters of drug betwixt species. On the other hand, a specific animal that is more than sensitive toward adverse outcome can likewise be a suitable species. In step 4, the HED is divided by a gene value of ten, to increase safety of outset human being dose. This safe 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 agile dose in humans.

Schematic representation of v steps to approximate starting dose in human being studies

Tabular array 1

Homo equivalent dose calculation based on body surface expanse*

Key Points in Scaling of Dose

• Larger animals have lower metabolic rates

• Physiological process of larger animals is slower

• Larger animals required smaller drug dose on weight basis

• Allometry accounts the departure in physiological time amongst species

• Do non apply allometric scaling to convert developed doses to kids.

Dose Calculations and Examples

The dose by factor method applies an exponent for trunk expanse (0.67), which account for deviation in metabolic rate, to convert doses between animals and humans. Thus, HED is determined by the equation:

HED (mg / kg = Animate being NOAEL mg/kg) × (Weight_creature [kg]/Weight_human [kg])^(1–0.67) Eq. (one)

For example, for a newly developed drug molecule, the NOAEL value in rat weighing approximately 150 grand is eighteen mg/kg. To calculate the starting dose for human studies, use Equation 1.

HED (mg / kg = xviii × (0.15 / 60)^(0.33) = 2.5 mg / kg

Thus, for a 60 kg human, the dose is 150 mg. This HED value is further divided past a gene value of 10; thus, the initial dose in entry into human being studies is fifteen mg.

Dose is equally related to torso weight although it is not the lone factor which influences the scaling for dose calculation. The correction factor (K_m) is estimated by dividing the average body weight (kg) of species to its torso surface area (m²). For example, the average homo body weight is sixty kg, and the body surface surface area is 1.62 m². Therefore, the K_m factor for human is calculated past dividing 60 past ane.62, which is 37 [Table one]. The K_m factor values of various animal species [Table 1] is used to gauge the HED every bit:

HED (mg / kg) = Fauna does (mg / kg) × (Animal Thousand_m / Human K_m)      Eq. (2)

As the Chiliad_m factor for each species is constant, the K₁₀₀₀ ratio is used to simplify calculations. Hence, Equation 2 is modified as:

HED (mg / kg) = Brute does (mg / kg) × M_thousand ratio      Eq. (three)

The Grand_m ratio values provided in Tabular array 1 is easily obtained past dividing human Chiliad_thou factor by fauna K_m factor or vice versa. For instance, the Chiliad_grand ratio values for rat is 6.2 and 0.162, obtained by dividing 37 (human Yard_m factor) by 6 (animal K_thou cistron) and vice versa, respectively. Thus, normally to obtain the HED values (mg/kg), one tin can either divide or multiply the animal dose (mg/kg) past the Yard_m ratio provided in Table 1. For example, for a particular drug, the NOAEL in rats is 50 mg/kg. Using Equation iii, HED is calculated either by multiplying or dividing the animal dose with the K_thou ratio values given in Table one. Accordingly, separate the rat dose (fifty mg/kg) by 6.2 or multiply by 0.162, the HED is –8.1 mg/kg.

However, information technology must be borne in listen that the one thousand_{one thousand} factor varies beyond beast species and increases proportional to W^2/iii inside a species equally body weight increases. For example, the 1000_m value in rats varies from 5.2 (100 yard rat), 6 (150 yard rat), and 7 (250 g rat). Therefore, adding of HED for a drug of NOAEL in rats is 50 mg/kg with an average weight of 250 m is equally below:

HED(mg/kg)=l(mg/kg)×=9.5 mg/kg in humans

Using the standard k_m factor value of 6 for rats with average weight of 150 g [Table 1], the dose varies appropriately every bit seen below:

HED(mg/kg)=50(mg/kg)×=viii.ane mg/kg in humans

Interchange of unit of measurement (mg/kg to mg/m²) of dose of animals or human is carried out using the Grand₁₀₀₀ gene [Table 1] as:

mg / m^two = K_k × mg / kg      Eq. (four)

However, conversion between species based on mg/mⁱⁱ is non supported for drugs administered by topical, nasal, subcutaneous, or intramuscular routes as well equally proteins administered parenterally with molecular weight >100,000 Daltons.

Similar to the HED estimation, the fauna equivalent dose (AED) can also be calculated on the basis of body surface surface area by either dividing or multiplying the human dose (mg/kg) by the K_m ratio provided in Table 2. AED is calculated past minor modification of Equation 3 equally:

Table 2

Animate being equivalent dose adding based on body surface surface area*

AED (mg / kg) = Human does (mg / kg) × K_thousand ratio      Eq. (5)

For example, if the maximum dose of a detail drug in human is 10 mg/kg, the AED is calculated by multiplying the HED by 6.ii or dividing past 0.162; AED is 62 mg/kg.

For parenteral administration, HED conversion (mg/kg) is also based on body surface area normalization. The conversion tin be made by dividing the NOAEL in appropriate species by the conversion cistron. Guidelines for maximum injection volumes, by species, site location, and gauge size are summarized in Table three. Injection book of parenteral formulation is calculated past post-obit equation.

Table 3

Guidelines for maximum injection volume, by species, site location, and gauge size*

Suppose the concentration of the formulation (say nanoparticles) is 10 mg/mL, its AED is 62 mg/kg, the rat weight is 250 yard and is administered through intraperitoneal road, and then the injection volume is calculated every bit

The injection book observed hither (ane.55 mL) is well beneath the maximum injection volume (v–x mL) for rat through intraperitoneal road and the injection site is lower left quadrant [Table three].

Conclusion

Dose estimation always requires conscientious consideration about the divergence in pharmacokinetics and pharmacodynamics amid species. Allometric scaling assists scientists to substitution doses between species during research, experiments, and clinical trials. Different equations described in this review could be used for dose extrapolation among species. Allometric scaling is generally used to convert doses amidst the species and is not preferred within species.

Fiscal support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Acquittance

Authors are grateful to Dr. Mohamed 1000. Morsy, College of Clinical Chemist's, Rex Faisal University for his perceptive discussions and expert advice during the training of manuscript.

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Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4804402/

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