1. Pharmacokinetics and
Pharmacodynamics
Dr. Bhaswat S Chakraborty
Senior VP, Research and Development
Cadila Pharmaceuticals Ltd.
2. Contents
• Definitions
• Basic concepts
– Pharmacokinetics (PK)
– Pharmacodynamics (PD)
• PK-PD relationship and modeling
• Contexts of modeling
• PK-PD in new drug development
• Predictive usefulness
• Population PK-PD
• Case studies
• Conclusions
4. Plasma Conc. at
Conc. Site of
action
Dose Effect
5.
6. What is the objective of any
pharmacotherapy?
To deliver effective (preferably optimal) therapeutic benefit
~75% Efficacy
Efficacy
Toxicity
~5%
With no or very low toxicity
Concentration
7.
8. PK-PD: conceptual understanding
through interactions
• Fluoxetine increases plasma
concentrations of amitriptyline. This is a
pharmacokinetic drug interaction.
• Fluoxetine inhibits the metabolism of
amitriptyline and increases the plasma
concentration of amitriptytline.
9. PK-PD: conceptual understanding
through interactions
• If fluoxetine is given with tramadol serotonin
syndrom can result. This is a pharmacodynamic
drug interaction.
• Fluoxetine and tramadol both increase
availability of serotonin leading to the possibility
of “serotonin overload” This happens without a
change in the concentration of either drug.
10. Pharmacokinetics
• Helps understand
– Safe and tolerable levels of exposure
– Dose
– Dosing regimen
– Optimization od dosage form
– Fate (LADME)
11. Inter-subject variation in pharmacokinetics
• Patients may have very different absorption, distribution, or
elimination characteristics
• Thus, attained plasma concentration profiles may differ
considerably among patients following the same dosing
regimen
• Identify patient characteristics such as sex, age, weight, renal
function that have a systematic effect on PK behavior, and
adjust dosing accordingly
• If there is substantial inter-subject variability in kinetic
behavior that cannot be controlled, and if the therapeutic
window is narrow, some monitoring of attained
concentrations, with subsequent individualization of dosing,
may be needed
Source: David Giltinan
12. Pharmacodynamics
• Drug-response or concentration-response
relationships
– Effect on body
– Effect on microorganisms or tumors in the body
• Mechanism of action
– Drug-receptor interactions
– Ligand- receptor dynamics
– Signal transduction
• Therapeutic window
13. Summary of important PK principles
• Initial drug concentration = loading dose x F / Vd
• Steady-state concentration =
– Fraction absorbed x maintenance dose / dosing
interval x clearance
– Or; F x D / dose interval x CL
• t1/2 = 0.7 x Vd / CL
• Vd is important for determining loading dose
• CL is important for determining maintenance dose
• t1/2 is important for determining time to steady state
Source: internet
14. Calculating doses – loading dose
• Sometimes we want to promptly raises plasma
concentration of a drug
– mostly true with drugs that have long half-lives
• This can be done with a loading dose
• Loading dose = amount in body immediately
following the dose
• Loading dose = Vd x TC
Source: internet
15. Calculating doses – maintenance dose
• Usually we want to maintain a steady-state level of drug
in the body
• Rate in must equal rate out
– dosing rate = rate of elimination
– dosing rate = CL x TC (target concentration)
• If bioavailability is < 1.0 dosing rate needs to be modified
– dosing rate (oral) = dosing rate / F(oral)
• If dosing is intermittent (e.g., oral tablets)
– maintenance dose = dosing rate x dosing interval
16. IV Loading Dose & Maintenance Dose
Loading Dose
Conc.
Maintenance Dose
Time
17. A Note on Initial Target Concentration
• Target concentraion has been taken very low because of reported EM
mean concentration of ~0.15 ng/mL at steady state (how do you
reconcile 28 ng/mL from one paper and trough conc. of 0.40 ng/mL
from another?)
• Oral Cpss has built up from repeat doses: if you directly put an IV which
would give you a C0 concentration of 28 ng/mL, it may result in
hypotension.
• If you take an initial value of IV dose of 1 mg/day, then
Ctarget = Cpss/Doral * Foral
= 28/5000 * 0.12
= 0.047 ng/mL
22. What have we learnt so far from calculations and
simulations?
• If the model is reasonably correct,
– C0 is ~0.16 ng/mL from an IV bolus dose of 0.5 mg/day
– This coincides with the trough conc. of one isomer following oral
dosing of 5 mg/day
– Kel is 0.04, i.e., T1/2 is ~17 hr
• The 0.5 mg dose accumulates upon repetition
– This will give a true steady state
– Accumulation factor of 1.6 when dosed every 24 hr
– Accumulation factor of 2.6 when dosed every 12 hr
• Assuming an initial Cmax of 1.0 ng/mL
23. Effect of sitagliptine on blood pressure in
non-diabetic hypertensive patients
Mistry et al., J Clin Pharmacol 2008;48:592-598
24. Effect of sitagliptine on systoloic &diastolic blood
pressures in non-diabetic hypertensive patients
Mistry et al., J Clin Pharmacol 2008;48:592-598
25. Effect of sitagliptine on systoloic &diastolic blood
pressures in non-diabetic hypertensive patients
• Many patients with type 2 diabetes have hypertension and may receive
concomitant therapy with one or more antihypertensive agents and
antihyperglycemic therapies that may impact BP control.
• Thus, the effects of sitagliptin on BP (positive or negative) was assessed in
a highly controlled setting in patients with mild to moderate hypertension
who take one or more antihypertensive agents.
• Sitagliptin produced small and mostly significant reductions in ambulatory
• SBP and DBP on the order of 2 to 3 mm Hg in the acute state (day 1) and
at steady state (day 5).
• These reductions are not considered to represent a potential safety issue
and may even be a potential therapeutic benefit in diabetic patients with
elevated BP.
• Diabetic patients with hypertension may receive additional
vascular benefits with their antihypertensive drugs combined
with an antihyperglycemic agent that improves glycemic
control and also lowers BP.
Mistry et al., J Clin Pharmacol 2008;48:592-598
26.
27. Population PK-PD of Warfarin
Yuen et al., J Pharmacokinet Pharmacodyn (2010) 37:3–24
28. Population PK-PD of Warfarin
PCA= Prothrombin complex activity, the PD parameter, PCA0 is PCA in the absence of
warfarin, kd is the degradation rate constant of PCA, Cgamma,s is the S-warfarin conc.,
Cgamma,50,s is the conc. of S-warfarin which reduces the synthesis rate by 50% and gamma
is a shape parameter . Yuen et al., J Pharmacokinet Pharmacodyn (2010) 37:3–24
29. Population PK-PD of Warfarin
Yuen et al., J Pharmacokinet Pharmacodyn (2010) 37:3–24
30. Population PK-PD of Warfarin
Yuen et al., J Pharmacokinet Pharmacodyn (2010) 37:3–24
31. Simulated steady state S-warfarin plasma concentrations following a 5 mg racemic
warfarin dose with 90% prediction intervals in CYP2C9 wt/wt or *2/wt and *3/wt subjects
(medians shown in bold).
Yuen et al., J Pharmacokinet Pharmacodyn (2010) 37:3–24
32. Population PK-PD of Warfarin
• Ethnic differences in warfarin maintenance doses have been
documented amongst the three major Asian ethnic groups
(Chinese, Malay and Indian) in Singapore.
• Oberved steady state concentrations and simulations showed
that whilst CYP2C9 polymorphisms affect the PK of warfarin,
VKORC1 haplotypes may be better predictors of warfarin
response.
• 90% of Chinese subjects had the VKORC1 H1 haplotype and
100% of Indian subjects the H7 haplotype in this study.
• Ethnic differences in warfarin response in this study appear to
be linked to differences in VKORC1 haplotypes (rather than
CYP2C9 genotypes).
Yuen et al., J Pharmacokinet Pharmacodyn (2010) 37:3–24
The effect of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on ambulatory blood pressure was assessed in nondiabetic patients with mild to moderate hypertension in a randomized, double-blind, placebo-controlled, 3-period crossover study.
The effect of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on ambulatory blood pressure was assessed in nondiabetic patients with mild to moderate hypertension in a randomized, double-blind, placebo-controlled, 3-period crossover study.
The effect of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on ambulatory blood pressure was assessed in nondiabetic patients with mild to moderate hypertension in a randomized, double-blind, placebo-controlled, 3-period crossover study.
