pharmacokinetics and pharmacodynamics

Pharmacokinetics and Pharmacodynamics

Dr. Bhaswat S ChakrabortySenior VP, Research and Development

Cadila Pharmaceuticals Ltd.

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

Pharmacokinetics and Pharmacodynamics

Dose

Plasma Conc.

Conc. atSite of action

Effect

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

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.

• 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

Pharmacokinetics

• Helps understand– Safe and tolerable levels of exposure – Dose– Dosing regimen– Optimization od dosage form– Fate (LADME)

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

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

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

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

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

IV Loading Dose & Maintenance Dose

Con

c.

Time

Loading Dose

Maintenance Dose

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

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

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)

Simulation with a single dose of 0.5 mg/day

Simulation with loading and maintenance doses of 0.5 mg/day

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

Effect of sitagliptine on blood pressure in non-diabetic hypertensive patients

Mistry et al., J Clin Pharmacol 2008;48:592-598

Effect of sitagliptine on systoloic &diastolic blood pressures in non-diabetic hypertensive patients

Mistry et al., J Clin Pharmacol 2008;48:592-598

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

Population PK-PD of Warfarin

Yuen et al., J Pharmacokinet Pharmacodyn (2010) 37:3–24

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

Population PK-PD of Warfarin

Yuen et al., J Pharmacokinet Pharmacodyn (2010) 37:3–24

Population PK-PD of Warfarin

Yuen et al., J Pharmacokinet Pharmacodyn (2010) 37:3–24

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

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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