Dec 2, 2009 - Pharmacokinetics (PK) involves the kinetics of drug absorption ... L. Shargel and A. Yu Applied Biopharmaceutics and Pharmacokinetics. 2.
D fi iti Definitions y Pharmacokinetics (PK) involves the kinetics of drug absorption distribution
and elimination (description of drug kinetics is often termed drug disposition) y Pharmacodynamics (PD) refers to the relationship between the drug concentration at the site of action (receptor) and pharmacological response, including biochemical and physiological effects that influence the interaction of drug with the receptor y Toxicokinetics (TK) is the application of pharmacokinetic principles to the design, conduct and interpretation of drug safety evaluation studies and used in validating dose related exposure in animals. in validating dose related exposure in animals y Human Equivalent Dose (HED) is a dose in humans anticipated to provide the same degree of effect as that observed in animals at a given dose.
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L. Shargel and A L A. Yu - Applied Biopharmaceutics and Pharmacokinetics FDA guidance for Industry - Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers July - 2005
December 2009
Editor: Stefano Porzio
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P li i l PK ( Preclinical PK (namely PK/PD) l PK/PD) (Common interfaces with other departments in drug development*)
* From P.L. Bonate and D.R. Howard Ed. – Pharmacokinetics in Drug Development – AAPS Press (2004) December 2009 Editor: Stefano Porzio
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PK – The Concepts y Drug Disposition (or Drug Kinetics) y Introduction into the body I d i i h b d y Distribution into the body y Elimination from the body l f h b d
y Exposure as final Result of Disposition
December 2009
Editor: Stefano Porzio
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PK – The starting point (Concentration vs. time profiles) (Concentration vs. time profiles)
December 2009
Editor: Stefano Porzio
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PK –t1/2 and AUC (Exposure) Rsq=1.0 Rsq_adjusted=1.0 HL_Lambda_z=6.9201 (hr) (9 points used in calculation) Uniform Weighting
Terminal phase (z phase) of concentration vs. time profile is always log-linear.
1.000
1.0 0.9
Slope of terminal phase is λz and terminal half life is
08 0.8 0.7
t1/2=ln(2)/ λz
0.100
0.6
Exposure p expressed p as
Observed
0.5
Predicted Observed Predicted
0.4
AUC
0.010
0.3 0.2 0.1 0.0 0 8 1624324048 Time (hr)
December 2009
0 001 0.001 0
8
16
24
32
40
48
Time (hr)
Editor: Stefano Porzio
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PK ‐ Distribution
December 2009
Editor: Stefano Porzio
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PK Distribution Example PK ‐ Di ib i E l (5 mg iv – BW = 70 kg) Rsq=1.0 Rsq_adjusted=1.0 HL_Lambda_z=6.9201 (hr) (9 points used in calculation) Uniform Weighting
1.000 Rsq_adjusted=1.0 R dj t d 1 0 HL HL_Lambda_z=6.9 L bd 69 (9 points used in calculation) Uniform Weighting
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Co is the concentration at the administration time. Dose, at this time point, is distributed apparently in the Dose/Co volume (Vc) Vc is the volume of central compartment (plasma, i.e. Vc = Vp)
Elimination: 1.10 L including 10 units in 1 min. 2.10 L including 9 units in 1 min 3.Etc. Elimination process includes a constant component (V) and could be expressed as [constant volume]/[time unit] (= 10 L/min)
N=9
70
41
40
36 31 27 24 21 18 16 14 12 11 98 76 65 4
30
20
Elimination constant = Volume x K
10
10/80 [L]/[min]/[L] = 0.125 min-1 0 0
Elimination half-life = ln(2)/K = 5.5 min
December 2009
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10
15
20
V = 80 L N = 61
25
Minutes
Editor: Stefano Porzio
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PK Clearance PK ‐ Cl The body is a space that contains a a definite volume of body fluid (i.e. Vss) in which drug is dissolved. CL is defined as the fixed volume of fluid (containing the drug) cleared of drug per unit of time. CL= Vss k Clearance has dimensions of a flux: Volume/time (L/h or ml/min) Drug elimination may be divided in two major components excretion and biotransformation: total body CL is considered as the sum of single g organs metabolic and/or excretory clearances: CL = CLR + CLH + CLL +……..CLn
December 2009
Editor: Stefano Porzio
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PK (Dose‐Exposure relationship) It’s usual preclinical practice to check exposure (AUC) after a particular Dose. The q question, in terms of p prediction, can be reversed: we could be interested to know amount of dose required to obtain a particular level of exposure. Direct relationship is expected between Dose and AUC with linear PK: i.e. it’s required dose doubling for AUC doubling. doubling Dose = Slope x AUC 12
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Slope = Clerarance = CL
Dose e (mg)
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This relationship is known as model independent definition of clearance:
y = 1.1095x R2 = 0.9972
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2
0 0
1
2
3
4
5 AUC0-inf (mg/L x h)
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9
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CL = Dose/AUC D /AUC or Dose = CL AUC
CL = December 2009
Editor: Stefano Porzio
Dose [mg ] ⋅ [ L] [ L] = = AUC [mg ] ⋅ [h] [h] 11
PK – Plasma profiles (Profiles) (Profiles)
December 2009
Editor: Stefano Porzio
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PK – PO
Cmax
December 2009
tEditor: max
Stefano Porzio
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PK – Bioavailabilityy Exposure after IV is 100% (by definition) p after PO can be
