Pharmacokinetics - Repeat Dose Administration Notes

Recap of PK Parameters

• Key PK parameters: K{el}, t{1/2}, F, V, CL; determined after a single dose.

Steady State Concentration (Css)

• Steady state: drug entering plasma equals clearance from plasma.

• Therapeutic window: Plasma drug concentration between MEC and MTC.

Continuous Dosing Methods

• Repeat oral administration & Constant rate IV infusion.

Constant Rate IV Infusion

• Predict Desired Css and Time to reach Css.

• CSS = \frac{MDR}{CL}; MDR = maintenance dose rate.

• Time to steady state: 3-5 half-lives.

• Loading dose (DL): DL = Css \times V

Repeat Oral Administration

• CSS = \frac{F \times MDR}{CL}, F = absolute oral bioavailability.

• Dosing interval (\tau) determines concentration variation between C{max ss} and C{min ss}.

• C*{max} = \frac{Dose \times F}{V}

Equations

• C{max ss} = \frac{F \cdot Dose}{V \cdot (1-e^{-K{el} \cdot \tau})}

• C{min ss} = C{max ss} \cdot e^{-K[el} \cdot \tau}

• Css = mean : of : C{min ss} : and : C{max ss}

General Rules for Dosing Regimens

• t[1/2} < 30 min: difficult to maintain therapeutic concentrations.

• t[1/2} 30 min - 8 h: dosing based on therapeutic window and convenience.

• t[1/2} 8 h - 24 h: dose every half-life.

• t[1/2} > 24 h: once per day or several days dosing feasible, but delayed Css.

Pharmacist’s Perspective

• Pharmacists select from manufacturer supplies, applying dosing principles.

• Drug strengths affect Css, and dosing period impacts drug concentrations.

Summary of PK Parameters

• t[1/2}: time to reach steady state.

• CL: concentration at steady state (Css).

• V: loading dose and first oral dose.

• F: with CL, Css following oral dosing.

• K{el}: variability in concentrations; C{max} relative to therapeutic window.

Design of Oral Dosing Regimens

• Balances t[1/2}, therapeutic window, drug concentration variability, time to steady state, and dosing period convenience.