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Pharmacokinetics and Pharmacodynamics Dr. Bhaswat S Chakraborty Senior VP, Research and Development Cadila Pharmaceuticals Ltd.

Pharmacokinetics and Pharmacodynamics

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Page 1: Pharmacokinetics and Pharmacodynamics

Pharmacokinetics and Pharmacodynamics

Dr. Bhaswat S ChakrabortySenior VP, Research and Development

Cadila Pharmaceuticals Ltd.

Page 2: Pharmacokinetics and Pharmacodynamics

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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Thank You for Your Attention