1 One compartment Single bolus

1.1 Drug that undergoes elimination exclusively by Renal Excretion

K is the proportion constant between the rate of change of the total drug in
body and the current amount of drug in body.

D = G + A + U + MU = U∞ + M∞ (1)

 
dA dG dU dM
= − + (2)
dt dt dt dt

D = A0 = A + U = U∞ = Ae∞ (3)

dA dU
− =K ·A= = CL · C (4)
dt dt

1.2 Plasma data

D D A
C0 = ⇒V = = (5)
V C0 C

 
 − dA = K · A  − dC =K ·C
 dt  dt

 

A = A0 · e−K·t = D · e−K·t C= A
V = C0 · e−K·t = D
V · e−K·t

 


 ln A = lnA − K · t 
0
 ln C = lnC0 − K · t
(6)

t
n= (7)
t 12

1
  n
1
C = C0 · 2−n = C0 · (8)
2

ln 2 0.693
t 12 = = (9)
K K

1.3 Urine Data

dU
= ke · A = ke · De−K·t = CLr · C0 e−K·t (10)
dt

A = U∞ − U = D − U (11)

dU
dt = ke · D − K · t
(12)
= ke · V · C0 − K · t

U = U∞ 1 − e−K·t = U∞ 1 − 2−n



(13)

U∞ − U = U∞ e−K·t = U∞ · 2−n (14)

ln (U∞ − U ) = ln U∞ − K · t (15)

1.4 Combinations of Urine and Plasma data

dA dU
= = ke · A = CLr · C (16)
dt dt

D
CL = K · V = (17)
AU C

2
 Analytical calculation

D C0
AU C = = (18)
CL K

Numerical Calculation:

∗ C∗
AU Ct→∞ = (19)
K

(C0 + C1 )(t1 − t0 ) C∗
AU C = + ··· + (20)
2 K

1.5 Elimination in several pathways

D = A0 = A + U + M + E = U∞ + M∞ + E∞ (21)

K = k e + km + k 0 (22)

CL = CLf = CLm + CLother (23)

1.6 Elimination Pathways

D
CL = K · V = (24)
AU C
The urine pathway

dU
= ke A = ke · D · e−k·t = ke · V · C = CLr · C (25)
dt

dU
ln = ln(ke · D) − K · t (26)
dt

3
 Instead of U∞ ke CLr
Substiture M∞ km CLm
Substiture E∞ k0 CLe

U∞ U0→t
CLr = ke · V = = (27)
AU C AU C0→t

U = U∞ 1 − e−K·t = U∞ 1 − 2−n



(28)

ln (U∞ − U ) = ln U∞ − K · t (29)

U∞ ke CLr ke
fe = = = ⇒ U∞ = fe · D = ·D (30)
D K CL K
For other pathways substitute

1.7 Renal Clearance

dU
dt
CLr = = (GF R + T SR − T RA) · fu (31)
C
Rate of filtration = GF R · CU = GF R · fU · C

Secretion Rate - Reabsorption Rate

CLr = GF R · fU + (32)
Plasma Drug Concentration

Urine Flow · Urine Concentration

CLr = (33)
Plasma Concentration

4
1.8 Hepatic Clearance
Rate of Extraction Q (CA − Cv ) CA − Cv
E= = = (34)
Rate of Presentation Q · CA CA

Q (CA − CV )
CLf = Q · E = (35)
CA

dM Vmax · C
= (36)
dt Km + C

dM
dt Vmax
CLin = = (37)
C Km + C
E+F = 1 Under certain assumptions.

1.9 Renal Clearance

dU
= CLf · C (38)
dt

U∞ CLr ke
fe = = = (39)
D CL K

M∞ CLm
fm = = (40)
D CL

0 E∞ CL0
f = = (41)
D CL

ml
0.5−0.8 min
z }| {
bile flow ·Concenrtation in bile
Bilary clearance = (42)
C

5
1.10 Elimination by metabolism
rate of extraction Q (CA − Cv ) CA − Cv
E= = = (43)
rate of presentation Q · CA CA

CLm = Q · E (44)

Q · fu · CLint
CLm = (45)
Q + fu · CLint
E + Fh = 1

1.11 Metabolism in the micro level: Enzymes

dM
dt Vmax
CLm,int = = CLm,u = (46)
Cu Km + Cu

dM Vmax [D]
=V = (47)
dt [D] + Km
Competitive Inhibition

V [D]
V =  max  (48)
[I]
D+ 1+ K I
Km
Noncompetitve Inhibition

Vmax [D]
V =   (49)
[I]
(D + Km ) 1 + KI

6
2 Extravascular Administration (single dose)

2.1 First Order Absorption & First order Elimination

ka  K The drug in the formulation

dG
− = ka · G (50)
dt

G = G0 e−ka·t = F · D · e−ka·t (51)

ln G = ln G0 − ka · t (52)

ln 2
t 1 absorption = (53)
2 ka

2.2 Plasma data

dA
= input − output = ka · G − K · A = ka · F · D · e−ka·t − K · A (54)
dt
Kit Kat Equation:

F · D · ka
e−K·t − e−ka·t


C= (55)
V (ka − K)
| {z }
A00

ln ka


K
tmax = (56)
ka − K

F · D −K·tmax
Cmax = e (57)
V

7
2.3 Pharmacokinetics parameters
F ·D
CL = K · V = (58)
AU C

Z t
AU C = C · dt (59)
0

U∞
CLr = (60)
AU C

2.4 General Case, ka  K

C 0 = A00 · e−K·t (61)

ln C = ln A00 − K · t (62)

C 0 − C = A00 · e−ka·t (63)

ln (C 0 − C) = ln A00 − ka · t (64)

2.5 ka ≈ K

Dost Equation
K · F · D · t −K·t
C= e (65)
V

1
K = ka = (66)
tmax

8
 1
tmax = (67)
K

F ·D
Cmax = (68)
V ·e

AU C
Cmax · tmax = (69)
e

2.6 With Lag time t0

F · D · ka h −K(t−t0 ) −ka(t−t0 )
i
C= e −e (70)
V (ka − K)

ln ka


K
tmax = t0 + (71)
ka − K

2.7 Urine Data

dU
= ke · A = ke · V · C = CLr · C (72)
dt

dU F · D · ka h −K(t) −ka(t)
i
= ke e −e (73)
dt (ka − K)

F · D · ka
A0 = k e (74)
(ka − K)

dU
= A0 e−K·t − e−ka·t


(75)
dt

U∞
fe = (76)
F ·D

9
3 Zero Order Input and First Order Output

3.1 Drug in formulation

dG
− = k0 (77)
dt

G = G 0 − k0 · t = D − k0 · t (78)

F ·D
t 1 Absorption = (79)
2 2k0

3.2 Plasma data

dA
= input − output = k0 − K · A (80)
dt

dA
= k0 − K · V · C = k0 − CL · C (81)
dt

ln(CSS − C) = ln(CSS ) − K · t (82)

3.3 In Steady state

k0
Ass = (83)
K

Ass k0 k0
Css = = = (84)
V K ·V CL

10
3.4 Before Steady state
F · k0
1 − e−K·t = Ass 1 − e−K·t = Ass 1 − 2−n




A= (85)
K

F · k0
1 − e−K·t = Css 1 − e−K·t = Css 1 − 2−n




C= (86)
CL

t K ·t
n= = (87)
t 12 ln 2

3.5 Loading Dose DL

F · k0
DL −K·t
C= 1 − e−K·t + e (88)
CL V

 
DL F · k 0
C = Css + − e−K·t (89)
V CL

F · k0 F · k0
D∗ = Css · V = V = (90)
CL K

3.6 After Infusion stop

k0
1 − e−K·tmax


Cmax = (91)
CL

0
t = T + t0 ⇒ C = Cmax eK·t = Cmax e−K(t−T ) (92)

←−
G0 D (93)
T = k0 = k0 G = 0 G = G0 − k0 · t

11
3.7 Urine Data

During infusion

dU k0
1 − e−K·t = ke · Ass 1 − e−K·t



= ke (94)
dt K

ke
fe = (95)
K

dU
= fe · k0 1 − e−K·t


(96)
dt

3.8 IV Bolus + IV infusion

D −K·t K0
1 − e−K·t = C0 e−K·t + Css 1 − e−K·t



C= e + (97)
|V {z } |K · V {z }
IV Bolus IV Infusion
 n
CSS − C −K·t 1
=e = (98)
CSS − C0 2

4 Bioavailability

4.1 Plasma Data

Absolute Bioavailability

AU CP O
DP O if Div =DP O AU CP O
F = AU CIV
−→ F = (99)
DIV
AU CIV
Relative Bioavailability
AU CT est
DT est if DRef =DT est AU CT est
F = AU CRef
−→ F = (100)
AU CRef
DRef

12
4.2 Urine Data
U∞P O
DP O if DRef =DT est U∞P O
F = U∞IV
−→ F = (101)
U∞IV
DIV

4.3 Pre-systemic metabolism

CLM
F =1−E =1− (102)
Q
Under certain assumptions.

5 Single Compartment - Multiple dose regimen

5.1 Multiple dose regimen - IV bolus

D
C0 = Cmax(1) = (103)
V

D
C̄ss = (104)
CL · τ

D D 1 − e−n·k·τ 1 − e−n·k·τ
Cmax(n) = S= · = Cmax(1) = Cmax(1) S (105)
V V 1 − e−k·τ 1 − e−k·τ

D 1 − e−n·k·τ −k·τ −k·τ D

Cmin(n) = · −k·τ
· e = Cmax(n) · e = · S · e−k·τ (106)
V 1−e V

D
Cmax(n) − Cmin(n) = · S · (1 − e−k·τ ) (107)
V

D 1 − en·k·τ −kt
C(n)t (0≤t≤τ ) = −k·τ
· e = Cmax(n) e−k·t (108)
V 1−e
13
 
D D
 C = =
 SSmax V (1−e−kτ ) V (1−2−n )


D·e−kτ
CSSmin = V (1−e−kτ )
= CSSmax · e−k·τ


= CSSmax · e−k·t

C
SS,t
 (109)


 ASS,max = (1−eD−kτ ) = (1−2
D
−n )

D·e−kτ
ASS,min = (1−e −kτ )



A −A
SS,max =F ·D
SS,min

5.2 Concentration in steady state

F ·D F ·D AU Csingle dose
C̄ss = = = (110)
V ·K ·τ CL · τ τ

F ·D F ·D 1.44 · D · t 12 F
Āss = = ln 2 = (111)
·K · τ t1 · τ
τ
2

5.3 Accumulation Ration

1 AU CSS,0→τ
RAC = = (112)
1 − e−kτ AU Csingle dose,0 → τ

5.4 Loading Dose

DM DM
DL = V · CSS,max = = n (113)
1 − e−kτ 1 − 12

AU C0→∞ = AU CSS0→τ (114)

5.5 Planning the administration route

C
ln Cupper
lower
τmax = (115)
K

14
 Cupper − Clower
C̄SS,av = Cupper
(116)
ln Clower

6 Multiple regimen of extravascular administration

F · D · ka 1 − e−nKτ −K·t 1 − e−nkaτ −ka·t
 
Cn(t) = ·e − ·e (117)
V (ka − K) 1 − e−Kτ 1 − e−kaτ

Cmax(1) (1 − e−nKτ ) F · D(1 − e−nKτ )

Cmax(n) = = (118)
1 − e−Kτ V (1 − e−Kτ )

F · D(1 − e−nKτ ) −Kτ

Cmin(n) = Cmax(n) · e−Kτ = ·e (119)
V (1 − e−Kτ )

F ·D Cmax(1)
 C = =
 SS,max V (1−e−Kτ ) 1−e−Kτ


F ·D·eKτ Cmin(1)
ka  K CSS,min = V (1−e−Kτ ) = 1−e−Kτ
(120)


1

R
AC = 1−e−Kτ

F ·D F ·D
ASS,max = CSS,max · V = = (121)
(1 − e−Kτ ) (1 − 2−m )

F · D · e−kτ F · D · 2−m
ASS,min = CSS,min · V = = (122)
(1 − e−Kτ ) (1 − 2−m )
τ
m= t1
2

F ·D t 12
ĀSS = = 1.44 · · F · D (123)
K ·τ τ

AU Csingle dose F ·D F ·D CSS,max − CSS,min

C̄SS,av = = = = C
τ K ·V ·τ CL · τ ln CSS,max
SS,min
(124)

15
 D
= Dosing Rate (125)
τ

6.1 Loading Dose DL

Dm kaK;ka>K Dm
DL = −→ DL = (126)
(1 − e−Kτ ) (1 − e−kaτ ) (1 − e−Kτ )

CSS,max
= eKτmax (127)
CSS,min

1 CSS,max
τmax = ln (When ka  K) (128)
K CSS,min

V ASS,max ASS,min
Dm = (CSS,max − CSS,min ) = − (129)
F F F

V
Dm F (CSS,max − CSS,min )
= C
(130)
τmax 1
ln CSS,max
K SS,max

6.2 Fluctuations

CSS,max −CSS,min


 Fluctuation Ratio = 100 · CSS,min

CSS,max −CSS,min
IV Bolus Fluctuation Index = 100 · (131)
 C̄SS


 AUC Fluctuation = 100 · AU Cabove −AU Cbelow
AU CSS

ASS,max
F luctuation = = ek·τ (132)
ASS,min

16
7 Protein Binding

Cb Cu (133)
fb = C fu = C fu + fb = 1

1 [DP ]
ka = = (134)
kd [D][P ]

moles of bound drug [DP ] [DP ] ka[D]

r= = = = (135)
total moles of protein [P ]t [DP ] + [P ] 1 + ka[D]

n · ka[D]
r= (136)
1 + ka[D]
where n is the number of binding sites.

n · ka1 [D] n · ka2 [D]

r= + + ... (137)
1 + ka1 [D] 1 + ka2 [D]
with different kai for each binding site.

1 1 + ka[D] 1 1
= = + (138)
r n · ka[D] n · ka[D] n

r
= n · ka − ka · r (139)
[D]

Cbound
= n · [P ]t · ka − ka · Cb (140)
Cunbound

A A
V = ; Vu = (141)
C Cu

17
 [P ] 1
fu p = ; fu = (142)
[P ]t 1 + ka[P ]

VT W · fu VT W · fu
V = Vp + ≈ (143)
fuT fuT

A · fuT
Cu = (144)
VT
T BW 42
% of unbound drug in the body = Vu · 100 = Vu · 100

8 Two compartment Model - i.v. Bolus

k10 = ke + km + k 0 (145)

C = A · e−α·t + B · e−β·t
αβ;After some time
−→ (146)

C = B · e−β·t

α · β = k21 · k10 (147)

α + β = k21 + k10 + k12 (148)

A B
AU C = + (149)
α β

A = A0 e−αt + B 0 e−βt (150)

18
8.1 Pharmacokinetical parameters

ln 2 ln 2 (151)
t 12 α = α t 12 β = β

D
CL = = k10 · V1 (152)
AU C

CL D
Vβ = = (153)
β AU C · β
 
A B

k12
 D α2 + β2
VSS = V1 + VT = V1 1 + =  2 (154)
k21 A B
α + β

8.2 Urine data

du
= ke · Ac = ke · V1 · C = CLr · C (155)
dt
Ac - amount in centeral compartment.

8.3 Extravascular

C = A · e−α·t + B · e−β·t + D · e−ka·t (156)

8.4 Three compartment model

C = A · e−α·t + B · e−β·t + P · e−π·t (157)

A B P
AU C = + + (158)
α β π
where α > β > π .

19
8.5 Renal Clearance
du
= CLr · C (159)
dt

U∞ CLr ke
fe = = = (160)
D CL K

M∞ CLm
fm = = (161)
D CL

0 E∞ CL0
f = = (162)
D CL

9 Elimination by Metabolism

Rate of extraction = rate of entry - rate of leaving = Q(CA − CV ) (163)

Rate of extraction Q(CA − CV ) CA − CV

E= = = (164)
rate of presentation A · CA CA

Q · fu · CLint
CLm = Q · E = (165)
Q + fu · CLint

10 Clinical Pharmacokinetics

10.1 Dose response curve

E−b
E = m · ln C + b ⇒ ln C = (166)
m
Since ln C = ln C0 − K · t

20
 E = E0 − K · m · t (167)

10.2 Hill Equation

Emax · C γ
E= γ (168)
EC50 + Cγ

10.3 Minimum dose for effect

Cmin = C0 · e−K·td (169)

1 1
td = (ln C0 · V − ln Cmin · V ) = (ln D − ln Amin ) (170)
K K

t 12
 
1 D D
td = ln = ln (171)
K Amin ln 2 Amin

11 Metabolite Kinetics
kf k(m)
A −→ M −→ U (172)

dM i.v.bolus
= kf · A − k(m) · M −→ kf · De−Kt − k(m) · M (173)
dt

kf DF
e−Kt − e−k(m) t


M= (174)
k(m) − K

kf CLf M∞
fm = = = (175)
K CL D

21
11.1 Metabolite that appears in plasma only and not in urine
(AU Cm )D CLf fm · CL
= = (176)
AU C CL(m) CL(m)

(AU Cm )D
D
M.W
fm = AU Cm
(177)
M
M.W

fm · F · D
CL(m) =
(178)
AU C(m) D

dM
= kf · A − k(m) M = CLf · C − CL(m) Cm (179)
dt

kf · ASS kf k0 fm · k0
MSS = = · = (180)
k(m) K k(m) k(m)

CLf · CSS CLf k0 fm · k0

Cm,SS = = · = (181)
CL(m) CL CL(m) CL(m)

(AU Cm )D After single dose

C̄m,SS = (182)
τ

Cm,ss CLf
= (183)
CSS CL(m)

fm · k0
MSS = (184)
k(m)

11.2 Multiple dose regimen

F ·D Dosing Rate
Css,av = C¯SS = = (185)
CL · τ CL

22
 ¯ = fm · F · D Formation rate of metabolism
Cm,ss,av = CmSS = (186)
CL(m) · τ CL(m)

¯ = AU Csingle
CSS,av (187)
τ

¯ AU C(m),single
Cm,SS,av = (188)
τ


AU C(m) D Fm · CL CLf
= = (189)
AU C CL(m) CL(m)
Low E
F ·D F ·D
C̄SS = = (190)
CL · τ fU · CLint · τ

fU · F · D F ·D
C̄USS = fU · C¯SS = = (191)
fU · Clint · τ CLint · τ

12 Non compartmental analysis

R∞
0 t · dn
M RT = (192)
N

n · MW
Ael(mg) = (193)
NA
R∞
0 t · dAel
M RT = (194)
Ael
| {z∞}
Dose
Where Ael∞ = M∞ + U∞ + E∞ = Dose

23
 RN
0 (Dose − Ael)dt
M RT = (195)
Dose

AU M C 1 1
M RTP.O = = + (196)
AU C ka K
c∗t∗ c∗
AU M C extrapolated = k + k2

T 1
M RTinf usion = + (197)
2 K

T
M RTi.v = M RTinf usion − (198)
2

D · AU M C
VSS = CL · M RTi.v bolus = (199)
AU C 2

k0 · T · AU M C k0 · T 2
VSS = − (200)
AU C 2 2AU C

M RTP.O − M RTI.V = M AT (201)

For first order absorption kinetics

1
M RTP.O − M RTI.V = (202)
ka
For zero order input
T
= M RTInf usion − M RTI.V (203)
2

M RTT ablet − M RToral solution = Mean dissolution time (in vivo) (204)

24
 M RTT ablet − M RTpowder = Mean disintegration time (in vivo) (205)

12.1 Two compartment MRT

A B
AU M C α2 + β2
M RTP.O = = A B
(206)
AU C α + β

A B
D · AU M C α2 + β 2
VSS = = 2 (207)
AU C 2 A B
α + β

1 1 1
M RT = + − (208)
α β k21

25