Pharmacokinetics

PK & PD of protein therapeutics

Protein therapeutics Which of the following types of antibodies can produce the most serious effect in humans? A. Neutralizing antibodies B. Non-neutralizing antibodies C. Cross-reactive antibodies D. Sustaining antibodies C. Cross reactive also neutralizes biological therapeutic AND the biological function of the endogenous protein

Protein therapeutics What are some key differences between small molecule drugs and biologics? Production process Administration Transport What are examples of methods of elimination of proteins? What are two ways that biologics can move across vasculature? Biologic drugs often exhibit high or low volume of distribution? Explain your answer. Biologics are: Dependent on the production process Cannot be given orally (low permeability and high GI protease activity). Should be given parenterally (IV, IM, SC) Small molecules= diffusion. Biologics: convective extravasation Proteolysis! Major sites= liver, GI tract, lung, skin, RES. Also, target mediated. Transcellular or Paracellular Low Vd (largely confined to vascular space) Dose-dependent non-linear PK (because it is saturable)

Clearance

Protein therapeutics For target-mediated drug disposition, what happens to CL when there’s an increased concentration of drug? A. Increases B. Decreases C. Nothing The more _________ the biologic, the ___________ the immunogenicity. A. Humanized, more B. Non-human, less C. Humanized, less B (Dose-dependent non-linear PK (because it is saturable) C

PK/PD

Pk/pd When do we need PD monitoring? What does EC50 measure? What about Emax? Drug A EC50= 14. Drug B EC50=200. Which is more potent? If concentrations are not predictive of the effect and when PD variability is much higher than PK variability. Potency Intrinsic ability A

Pk/pd Which of the following are characteristics that may mean the drug should be monitored using Pharmacodynamics instead of Pharmacokinetics? A. The drug concentrations are predictive of the effect B. When pharmacokinetic variability is much bigger than pharmacodynamic variability C. When pharmacodynamic variability is much bigger than pharmacokinetic variability D. Both A and D C

Pk/pd

Pk/pd Calculate the loading dose to produce and maintain 90% of Emax. V=40 L, CL=2 L/h, EC50=4mg/L LD=Ec50X Vd=160 mg 90/(100-90)*160 mg=1440 mg 1440

Pk/pd Describe: Phase 3 Phase 2 Phase 1 Region 3: CONSTANT phase (C>>EC50). No further increase in effect by increasing dose. Also note that even though the concentration is decreasing, as long as it is still>>EC50, the effect is the same! Region 2: Effect is between 20% and 80% of the Emax, it follows a log-linear relationship, where the effect is proportional to the ln of concentration Region 3: LINEAR phase (C<<<EC50)

Pk/pd Follow up question: How can the effect remain constant if the concentration is declining rapidly? Concentration is constant (phase 3) if C is still >>>EC50.

PK/PD For a sigmoid Emax model, what happens when you increase n? (Number 2 on recitation) A. Increase the Emax and increase the range of concentrations associated with 20 to 80% maximal effect B. Have NO effect on Emax and decrease the range of concentrations associated with 20 to 80% maximal effect C. Increase the Emax and decrease the range of concentrations associated with 20 to 80% maximal effect D. Have NO effect on Emax and increase the range of concentrations associated with 20 to 80% maximal effect E. None of the above B

Pk/pd

Pk/pd 6.1: D50=Ec50XVd D50=11*33=360 mg 6.2: DR50=EC50XCL DR50=11X2.64=29 6.3: 58/(100-58)*360 200/(344-200)*360=500mg MD= 58/(100-58)*29=40 mg/hr Fc= Css, max/Css, min Fe=Css,max/Css, min (EC50 + Css,min/(EC50 + Css, max)

Pk/pd In comparing the fluctuation of concentration (Fc) to the fluctuation of effect (Fe), which is true? A. Fc is always less than Fe B. Fe is less than Fc C. Neither B

Pk/pd Hysteresis: which causes counterclockwise or clockwise or neither Indirect link? Functional tolerance? Metabolic tolerance? Sensitization?

Pk/pd

Things to know Understand each phase of the curve Be able to calculate: D/DR50, or any % for D/DR50, Fc, Fe, Concentration Which things are counterclockwise/clockwise

5. EC50=1.8 mmol/L Emax=114 mm Hg N=3.79 What potassium level is necessary to maintain at least 80% of maximum muscle strength? E=0.8*114=91.2=Emax X C^n/(Ec50^n + C^n) 91.2=114X C^3.79/(9.3 + C^3.79) 846 +91.2C^3.79=114C^3.79 846=C^3.79 (114-91.2) 846=C^3.79 (22.8) 37.2=C^3.79

Questions?