Interspecies Scaling

Interspecies scaling in pharmacokinetics allow the prediction of in vivo drug disposition behavior in human from the experimental observations made in one or more species. Interspecies scaling of the pharmacokinetic processes of absorption, distribution, and clearance of drugs can be performed by allometry. The allometric approach involves estimation of the pharmacokinetic parameters – clearance (CL), half-life, volume of distribution (Vd) etc. – in humans based on their relationship to body mass in several test animal species. PKMP interspecies scaling module includes the following methods for prediction of human pharmacokinetics and estimating a maximum safe starting dose (MSSD) in initial clinical trials for drugs in human subjects as per the FDA guidance.

Method 1 – NCA

In this method pharmacokinetic data after intravenous administration of a drug in three or more animal species is needed. Intravenous data is preferred for the complete bioavailability of a drug, although extravascular route PK data can be used with consideration to differences in bioavailability across the species. In this method pharmacokinetic parameters, CL and Vd, among animal species are correlated as exponential functions of body weight or body surface area using the simple allometric equation

Y=aW^b

or its logarithmic transformation.

log Y = log a + b log W

Where Y is a pharmacokinetic parameter, W is body weight, a is the allometric coefficient, and b is the allometric exponent. A plot of log CL vs log W is shown below.

Human predicted PK parameters based on allometric scale up are shown below.

Dose	Kel	Body Weight	Body Surface Area	T1/2	AUC 0-inf	Cl/F	Vd/F	Cmax	tau	Cavg
mg/kg	1/hr	kg	m^2	hr	mg/L*hr	L/hr	L	mg/L	hr	mg/L
1.0	0.156	60.0	1.62	4.4	4.931	12.2	78.1	0.769	24	0.205

Method 2 – PK Param

In this method PK parameters from animal species are converted to human parameters or animal parameters using the BSA ratio extrapolation. Prediction of human parameter from each species as well as average from all species is calculated as shown below.

Species	Human Body Surface Area	Human Body Weight	Human Dose	Body Surface Area Ratio	Dosing frequency (tau)	AUC(0-inf)	Cavg	CL	Vd	Cmax
Units	m2	kg	mg/kg		hr	mcg*hr/ml	mcg/ml	mL/hr	L	mcg/ml
Mouse	1.6	60.0	1.0	231.4	24	2.6	0.1	23143	23.1	2.6
Rat	1.6	60.0	1.0	64.8	24	18.5	0.8	3240	32.4	1.9
Dog	1.6	60.0	1.0	3.2	24	740.7	30.9	81.0	94.3	0.6
Mean						254.0	10.6	8821	49.9	1.7
SD						421.6	17.6	12503	38.7	1.0
Using Average Value		60.0	1.0			6.8	0.3			1.2

Method 3 – HED

Human equivalent dose (HED) from animal no observed adverse effect level (NOAEL) is calculated as per the FDA guidance using:

HED = animal NOAEL/HED factor

or

HED = animal NOAEL x (Wanimal/Whuman)^(1-b)

Where,

W=body weight

b=allometric exponent

HED data is presented in table below.

Species	HED	+20%	-20%	Human Body Weight	Dose
Units	mg/kg	mg/kg	mg/kg	kg	mg
Rat	8.1	9.7	6.5	60.0	483.9
Mouse	8.1	9.8	6.5	60.0	487.8
Dog	5.6	6.7	4.4	60.0	333.3

Dose Escalation

This module computes dose escalation schemes for the Phase 1 clinical studies based on starting dose from animal NOAEL.

Empiric			Fibonacci			Log
Dose No.	Factor	Dose Value	Dose No.	Factor	Dose Value	Dose No.	Factor	Dose Value
1	1	10	1	1	10	1	0	10
2	2	20	2	0.65	17	2	0.5	16
3	1.5	30	3	0.52	25	3	1	27
4	1.3	39	4	0.4	35	4	1.5	45
5	1.3	51	5	0.29	45	5	2	74
6	1.3	66	6	0.33	60	6	2.5	122
7	1.2	79	7	0.33	80	7	3	201
8	1.1	87	8	0.33	107	8	3.5	331