Transcript Feb1
Dosing Regimen Concepts: 2-C, MM, Individualization principles Applications Practice Problems Discussion Two Compartment Concepts Infusion rate calculation ? Same as for the one-compartment case: Ko = CL x Cp,ss,desired Ko Loading dose calculation ? k12 V1 k21 k10 V2 k12 V1 Duration of infusion k21 k10 10.0 bolus 8 hr infusion 75 hr infusion Cp [mg/L] 1.0 0.1 0.0 0 5 10 15 Time [h] 20 25 30 V2 Saturable metabolism FDM/ Ko Vmax C ss Ko K M C ss Cp,ss CL K M Ko C ss Vmax K o Saturable metabolism CLlin = 1L/h Db dC p dt Vmax C p KM Cp CLlin C p CLsat KM = 2.22 mg/L Vmax = 100 mg/h Fraction of dose eliminated by the saturable pathway as dose increases ? CL = CLlin + CLsat When Cp << KM, CL = 100/2.22 + 1 = 46 L/h When Cp >> KM, CL 1 L/h Saturable metabolism: Practice problem #3 kr = 0.15 h-1 Db ksat a. above what body level does the t1/2 become dose dependent ? b. What is the minimum half life ? KM = 100 mg Vmax = 25 mg/h kr = 0.15 h-1 c. What would be the rate of elimination when the body level was 150 mg ? dDb Vmax Db k r Db dt K M Db DR Individualization principles DRusual generally based upon population average values for PK parameters and boundaries of the therapeutic window: FDM/ Ko = CLusual x Cp,ss,desired usual For a patient having CLunusual, make a proportional adjustment in the DR: FDM/ Ko = unusual CLunusual FDM/ CLusual Ko usual CL Determinants - Hepatic C ss K o Q f upCLint, u Q f upCLint, u C ss ,u K o Q f upCLint, u Q CLint, u Css Css,u Low E parenteral all E enteral Ko f upCLint, u Ko CLint, u High E parenteral: Ko Q f up K o Q High E, parenteral administration fup Total Cp Free Time Oral administration Total Cp Free fup Time Oral administration Total Cp Clint,u Free Time For the situation described, indicate with an arrow whether the listed parameters would increase, decrease, or not change. CL [mL/min] fup fe A 300 0.5 0.2 renal disease reduces GFR to 25% of normal B 500 0.05 0.05 competitive displacement increases fup to 0.25 Drug CL V t1/2 fe FFP DR p.o. A B or Drug Situation For the situation described, indicate with an arrow whether the listed parameters would increase, decrease, or not change. Drug CL [mL/min] V [L] fup fe Situation A 100 75 0.5 0.6 renal disease reduces GFR to 25% of normal B 50 100 0.05 0.05 t1/2 fe FFP A B V DR p.o. CL Drug competitive displacement increases fup to 0.15 For a drug eliminated by hepatic metabolism and administered orally on a multiple dose regimen, the dosing rate should be changed when: a. plasma protein binding is changed. b. hepatic blood flow is changed. c. the intrinsic unbound metabolic clearance is changed. d. the volume of distribution is changed. e. all of the above. For which one of the following would it be appropriate to lower the therapeutic window (based on total Cp) for an hepatically eliminated drug administered p.o. a. high E drug and QH is abnormally low. b. low E drug and QH is abnormally low. c. low E drug and fup is elevated. d. low E drug and CLint,u is elevated. e. high E drug and CLint,u is elevated. The CLH value of this drug is 5 L/h and fup = 0.025. Indicate with arrows the changes that would result from the change indicated. CLH Css,av Css,u,av DR Q CLint,u fup fup DR CLint,u Css,u,av CLH Q Css,av The CLH value of this drug is 45 L/h and fup = 0.025. Indicate with arrows the changes that would result from the change indicated. Route is i.m.