Pharmacokinetics and Pharmacodynamics

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  • 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.

Transcript

  • 1. Pharmacokinetics and Pharmacodynamics Dr. Bhaswat S ChakrabortySenior 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
  • 3. Pharmacokinetics and Pharmacodynamics
  • 4. Plasma Conc. at Conc. Site of actionDose Effect
  • 5. What is the objective of any pharmacotherapy? To deliver effective (preferably optimal) therapeutic benefit ~75% EfficacyEfficacy Toxicity ~5% With no or very low toxicity Concentration
  • 6. 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.
  • 7. 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.
  • 8. Pharmacokinetics• Helps understand – Safe and tolerable levels of exposure – Dose – Dosing regimen – Optimization od dosage form – Fate (LADME)
  • 9. 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
  • 10. 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
  • 11. 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
  • 12. 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
  • 13. 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
  • 14. IV Loading Dose & Maintenance Dose Loading Dose Conc. Maintenance Dose Time
  • 15. 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
  • 16. Loading DoseLoading Dose = Ctarget * Vd / F = 0.05 μg/L* 786 L / 0.12 = 0.327 mg/day Therefore, Loading dose ~ 0.350 mg/day
  • 17. Maintenance DoseMaintenance 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)
  • 18. Simulation with a single dose of 0.5 mg/day
  • 19. Simulation with loading and maintenance doses of 0.5 mg/day
  • 20. 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
  • 21. Effect of sitagliptine on blood pressure in non-diabetic hypertensive patients Mistry et al., J Clin Pharmacol 2008;48:592-598
  • 22. Effect of sitagliptine on systoloic &diastolic blood pressures in non-diabetic hypertensive patients Mistry et al., J Clin Pharmacol 2008;48:592-598
  • 23. 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
  • 24. Population PK-PD of Warfarin Yuen et al., J Pharmacokinet Pharmacodyn (2010) 37:3–24
  • 25. Population PK-PD of WarfarinPCA= Prothrombin complex activity, the PD parameter, PCA0 is PCA in the absence ofwarfarin, 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 gammais a shape parameter . Yuen et al., J Pharmacokinet Pharmacodyn (2010) 37:3–24
  • 26. Population PK-PD of Warfarin Yuen et al., J Pharmacokinet Pharmacodyn (2010) 37:3–24
  • 27. Population PK-PD of Warfarin Yuen et al., J Pharmacokinet Pharmacodyn (2010) 37:3–24
  • 28. Simulated steady state S-warfarin plasma concentrations following a 5 mg racemicwarfarin 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
  • 29. 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
  • 30. Thank You for Your Attention