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 V1 V2 k10 k12 k21 Ko Loading dose calculation ?

V1 V2 k10 k12 k21 Duration of infusion

Saturable metabolism FDM/ Ko Cp,ss CL

Saturable metabolism CLlin = 1L/h Db CLsat Fraction of dose eliminated by the saturable pathway as dose increases ? KM = 2.22 mg/L Vmax = 100 mg/h 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 Db kr = 0.15 h-1 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 ?

DR Individualization principles DRusual generally based upon population average values for PK parameters and boundaries of the therapeutic window: FDM/ Ko = CLusual x Cp,ss,desired usual For a patient having CLunusual, make a proportional adjustment in the DR: FDM/ Ko unusual CLunusual CLusual usual =

CL Determinants - Hepatic Css Css,u Low E parenteral all E enteral High E parenteral:

High E, parenteral administration fup Total Cp Free Time

Oral administration Total Cp fup Free 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. Drug CL [mL/min] fup fe Situation A 300 0.5 0.2 renal disease reduces GFR to 25% of normal B 500 0.05 competitive displacement increases fup to 0.25 Drug CL V t1/2 fe FFP DR p.o. A B           or   

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 0.05 competitive displacement increases fup to 0.15 Drug CL V t1/2 fe FFP DR p.o. A B            

For a drug eliminated by hepatic metabolism and administered orally on a multiple dose regimen, the dosing rate should be changed when: plasma protein binding is changed. hepatic blood flow is changed. the intrinsic unbound metabolic clearance is changed. the volume of distribution is changed. 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. high E drug and QH is abnormally low. low E drug and QH is abnormally low. low E drug and fup is elevated. low E drug and CLint,u is elevated. high E drug and CLint,u is elevated.

The CLH value of this drug is 5 L/h and fup = 0. 025 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            

The CLH value of this drug is 45 L/h and fup = 0. 025 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. CLH Css,av Css,u,av DR Q  CLint,u  fup            