NON COMPARTMENTAL ANALYSIS

SOBHA DEEPTHI KOMPELLA Y10MPPC140015 M.PHARMACY(CEUTICS) KVSRSCOPS

PHARMACOKINETIC MODELS
Drug movement within the body is a complex process.

The major objective is therefore to develop a generalized and simple approach to describe ,analyze and interpret the data obtained during in vivo drug disposition studies. The 2 major approaches are Model approach Model independent approach ( non compartmental analysis)

METHODS FOR ANALYSIS OF PHARMACOKINETIC DATA

MODEL APPROACH

MODEL INDEPENDENT APPROACH

NON COMPARTMENTAL ANALYSIS

COMPARTMENTAL MODEL MAMMILLARY MODEL

PHYSIOLOGICAL MODEL

DISTRIBUTED PARAMETER MODEL

PERFUSION LIMITED MODEL

DIFFUSION LIMITED MODEL CATENARY MODEL

Deficiencies of compartmental analysis:

1. Lack of meaningful physiological basis for derived parameters. 2. Lack of rigorous criteria to determine # of compartments necessary to describe disposition. 3. Lack of ability to elucidate organ specific elimination. 4. Inability to relate derived parameters to quantifiable physiological parameters. 5. Inability to predict impact of pathophysiology. 6. Inability to provide insight into mechanism of drug-drug and drug-nutrient interactions. 7. Highly sensitive to sampling frequency.

NON COMPARTMENTAL ANALYSIS

Also called as model independent method Doesn't require the assumption of specific compartment model to calculate the pharmacokinetic parameters. Based on assumption that drugs/metabolites follow linear kinetics. Thus it can be applied to any compartmental model

ADVANTAGES: DISADVANTAGES: It provides limited information Ease of derivation of pharmacokinetic parameters regarding the plasma drug concentration time profile. by simple algebraic More often it deals with equations. averages. The same mathematical The method doesn't adequately treatment can be applied to treat non-linear cases. almost any drug/metabolite provided they follow 1st order kinetics. A detailed description of drug disposition characteristics is not required.

APPLICATIONS:
Non compartmental analysis is used to estimate MRT,MTT,MAT Bioavailability Clearance Apparent volume of distribution Half-life Fraction of drug eliminated from body

Key terms:
MEAN RESIDENCE TIME: The average total time molecules of a given dose spend in the body before being eliminated out. MEAN TRANSIT TIME: The average time molecules of a given dose spend in the kinetic system. MEAN ABSORPTION TIME: The time taken for the drug to appear in systemic circulation. When determined after non-instantaneous administration, the MTT =MRT + MAT After I.V.bolus dose, MRT=MTT

MEAN RESIDENCE TIME:

STATISTICAL MOMENT:: :A mathematical description of a discrete distribution of data. Statistical moments calculated from a set of conc.-time data represent an estimate of true moment.

MRT
Mean residence time =

AUMC AUC

0 g

tC

( t ) dt

C ( t ) dt

MRT= first moment/zero moment

AUMC

AUC

AREA DETERMINATION
A. Integration of Specific Function B. Numerical Integration 1. Linear trapezoidal 2. Log trapezoidal 3. Extrapolation to infinity A. Integration of Specific Function Must elucidate the specific function Influenced by the quality of the fit

AUC
AUMC

Ci P i
Ci P2 i

example : AUC
example : AUMC

C1 C2  P1 P2
C1 C2  2 2 P1 P2

B. Numerical Integration
1.LINEAR TRAPEZOIDAL:

Area t

t2
1

1 2

(t 2  t1 )(C1  C2 )

Area

tn 0

1 2

(C1  C 2 )( t 2  t1 )  1 (C 2  C 3 )( t 3  t 2 )  ... 2

 1 (C n 1  C n )( t n  t n 1 ) 2

1.Linear trapezoidal
Advantages: Simple (can calculate by hand) Disadvantages: Assumes straight line btwn data points If curve is steep, error may be large Under or over estimate depends on whether curve is ascending of descending

2.Log trapezoidal

Area

t2 t1

( C 1  C 2 )( t 2  t 1 ) ! ln C 1  ln C 2

Advantages: Disadvantages: Hand calculator Limited application Very accurate for mono May produce large errors exponential on an ascending curve, near the peak, or steeply Very accurate in late time declining points where interval btwn polyexponential curve points is substantially increased

IN GENERAL:

AUC 0
AUMC 0
g

Cn AUC 0  Pz
tn

Cn Cn AUMC 0  2  t n v Pz Pz
tn

Where

Pz

= 2.303 x Ke

AUMC Determination AUC Determination Time (hr) C (mg/L) 0 2.55 1 2.00 3 1.13 5 0.70 7 0.43 10 0.20 18 0.025 Area (mg-hr/L) 2.275 3.13 1.83 1.13 0.945 0.900 Total 10.21
t18

Cxt Area (mg/L)(hr) (mg-hr2/L) 0 2.00 1.00 3.39 5.39 6.89 3.50 6.51 3.01 7.52 2.00 9.80 0.45 37.11

AUC 0 ! 10.21 mg hr / L AUMC 0 ! 37.11 mg hr / L

16

t18

AUC 0 ! AUC 0 AUC 0

g g

t18

C18 Pz

0.025 mg / L ! 10.21 mg hr / L 0.26 hr 1

AUC 0 ! 10.31 mg hr / L

AUMC 0 ! AUMC 0
g

t18

t18C18 C18   2 Pz Pz
2

0.45 mg hr / L 0.025 mg / L AUMC 0 ! 37.11 mg hr / L   1 1 2 0.26 hr 0.26 hr

AUMC 0 ! 39.21 g hr 2 / L
17

Systemic availability:
The fraction of administered drug that reaches the systemic circulation. Commonly used to measure the extent to which drug is available in the body after nonintravenous administration.

AUCoral v Div F! AUCiv v Doral

CLEARANCE
Total (systemic) Clearance:
dX CLT ! Elimination rate dt ! C concentration in blood

Integrating from 0 p g,
g

CLT !

dX dt dt 0
g

Cdt
0

, where
0

dX dt ! total amt eliminated (Div) dt

and Cdt ! AUC

0

Therefore CLT !

Div AUC 0
g

Additivity of clearance:
Rate of elimination = Rate of Renal Excretion + Rate of Hepatic Metabolism Dividing removal rate by incoming concentration:
ate o liminatio n ! Ca ate o enal Ca xcretion


ate o

epatic Ca

etabolism

Total Clearance = Renal Clearance + Hepatic Clearance CLT = CLR + CLH

X fR ! , Div

g u

CLR ! CLT v f R

100 mg drug administered to a volunteer resulted in 10 mg excreted in urine unchanged:

X 10 mg fR ! ! ! 0.1 Div 100 mg Div CLR ! CLT v f R ! v fR AUC

g u

APPARENT VOLUME OF DISTRUBUTION:

Calculation via moment analysis Vss = CL*MRT

VSS !

iv

AUMC 2 AUC
2

If administration via a short term infusion:

K 0T ( AUMC ) K 0T VSS !  2 AUC 2 AUC

K0 = infusion rate T = infusion duration

HALF LIFE

MRT

V ss ! CL

If drug declines via monoexponential decline MRT=AUMC = C0 /K2 = 1 AUC C0 /K K MRT I.V = 1/K t1/2 = 0.693* 1 k t1/2= o.693 * MRT I.V

Extraction Ratio:
Ratio of the rate of xenobiotic elimination and the rate at which xenobiotic enters the organ.

Rate of Elimination E! Rate of Entry Q (Ca  Cv ) Ca  Cv E! ! QCa Ca

CONCLUSION:
This overview of noncompartmental methods based on statistical moment theory permits a wide range of analysis, that in most instances, will be adequate to characterize the pharmacokinetics of a drug. There are ofcourse,certain limitations like Nonlinear events are not adequately treated by SMT. Also SMT provides only limited information regarding time course of drug concentration ( averages are considered).