1. Dosage Regimen Design in Patients with Renal Insufficiency Cont’d Pharmacy 732 Winter, 2001

2. Q Factor: Assumptions Know fe (normal renal function)  Cl R   GFR (i.e. CrCl) *No change in Cl NR First-order kinetics *One compartment model Metabolites not active/toxic

3. Q Factor: Where…? Eq. 1* Eq. 2* Eq. 3 * If Cl NR-RF  Cl NR-N, then Eq. 1 is NOT valid, and Eq. 2 is not particularly helpful.

4. Instead... (Eq. 3) Cl T-RF = Cl NR-RF + Cl R-RF AND

5. Instead... How can we predict Cl NR-RF ? 1. Medical Literature 2. PK Theory - less common

6. What About Dosing a Multi-Compartment Drug? As previously defined: Also (formerly) defined:

7. Calculation of “Q” by direct comparison of drug Cl: –does NOT require the assumption of a one-compartment model –drug Cl is physiologically independent PK parameter Calculation of “Q” by comparison of elimination rate constants or half-life: –DOES require a one-compartment model –for multiple-compartment drugs, the terminal elimination rate constant (  ) is not a physiologically independent PK parameter (V  influenced by Cl)

8. Other PK Parameters Renal insufficiency may influence other aspects of drug disposition and metabolism in addition to reducing renal Cl. –Absorption –Distribution –Non-renal Metabolism

9. Absorption Drug absorption may be  or  by: –changes in GI transit time (food, medications, diseases) –edema of the GI tract; vomiting and diarrhea (severe renal insufficiency) –changes in pH (antacid administration) Alterations in drug absorption will affect oral bioavailability (F = fab*ffp*fgw)

10. Distribution Distribution may be  or  by –pathophysiologic changes in body compositon (volume overload) –increased or decreased plasma protein binding (nutritional status, medications, diseases) –altered tissue binding (may be difficult to quantify) Alterations in distribution (Vd) will affect C peak (may require adjustment of LD and  )

11. Non-renal Metabolism Metabolism may be altered by increased or decreased plasma protein binding (nutritional status, medications, diseases) Alterations in metabolism may require adjustment of DR or “resetting” of tx range (depends on E of drug)

12. “Physicians (and pharmacists) who rely blindly on nomograms and cookbook guidelines for dosing should have no business administering potentially toxic drugs to patients with impaired renal function.” Maher JF. Pharmacokinetics in patients with renal failure. Clinical Nephrology 1984;21:39-46. paraphrasing G. Levy, 1977.