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Pharmacokinetics and Pharmacodynamics
Dr. Bhaswat S ChakrabortySenior VP, Research and Development
Cadila Pharmaceuticals Ltd.
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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
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Pharmacokinetics and Pharmacodynamics
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Dose
Plasma Conc.
Conc. atSite of action
Effect
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What is the objective of any pharmacotherapy?
To deliver effective (preferably optimal) therapeutic benefit
With no or very low toxicity
Effica
cy
Concentration
~75%
~5%
Efficacy
Toxicity
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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.
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• 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.
PK-PD: conceptual understanding through interactions
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Pharmacokinetics
• Helps understand– Safe and tolerable levels of exposure – Dose– Dosing regimen– Optimization od dosage form– Fate (LADME)
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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
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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
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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
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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
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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
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IV Loading Dose & Maintenance Dose
Con
c.
Time
Loading Dose
Maintenance Dose
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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
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Loading Dose
Loading Dose = Ctarget * Vd / F
= 0.05 μg/L* 786 L / 0.12
= 0.327 mg/day
Therefore, Loading dose ~ 0.350 mg/day
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Maintenance Dose
Maintenance Dose = Ctarget * Clearance * Tau / F
= 0.05 μg/L * 61.6 L/h * 24 h / 0.12= 0.616 mg
Therefore, Maintenance dose = 0.6 mg/day
Note: T1/2 (~15 h) < Tau (24 h)
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Simulation with a single dose of 0.5 mg/day
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Simulation with loading and maintenance doses of 0.5 mg/day
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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
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Effect of sitagliptine on blood pressure in non-diabetic hypertensive patients
Mistry et al., J Clin Pharmacol 2008;48:592-598
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Effect of sitagliptine on systoloic &diastolic blood pressures in non-diabetic hypertensive patients
Mistry et al., J Clin Pharmacol 2008;48:592-598
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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
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Population PK-PD of Warfarin
Yuen et al., J Pharmacokinet Pharmacodyn (2010) 37:3–24
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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
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Population PK-PD of Warfarin
Yuen et al., J Pharmacokinet Pharmacodyn (2010) 37:3–24
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Population PK-PD of Warfarin
Yuen et al., J Pharmacokinet Pharmacodyn (2010) 37:3–24
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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
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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
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