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Dosing Regimen Design

Dosing Regimen Design. Two-Compartment Model Infusion Multiple Dosing. Assessment of PK parameters. CL: CL/F = (DM/ )/C ss,av and C ss,av = AUC ss, /. Relative F:. CL R :

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Dosing Regimen Design

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  1. Dosing Regimen Design Two-Compartment Model Infusion Multiple Dosing

  2. Assessment of PK parameters CL: CL/F = (DM/)/Css,av and Css,av = AUCss,/ Relative F: CLR: CLR = (Ae,ss/ x Css,av) where Ae,ss is the amount of drug excreted in the urine over one .

  3. k12 Cp V2 V1 k21 k10 C2 Ko Infusion dX1/dt = Ko + k21X2 – k10X1 – k12X1 dX2/dt = k12X1 – k21X2 X1,ss = Kok21/ = Ko/k10 X2,ss = Kok12/ X1,ss/X2,ss= k21/k12 = V1/V2 Cp,ss = Ko/CL = C2,ss

  4. Infusion rate calculation Same as for the one-compartment case: Ko = CL x Cp,ss,desired

  5. k12 V2 V1 k21 k10 Post-Infusion Profile

  6. k12 V2 V1 k21 k10 Short Infusion

  7. k12 V2 V1 k21 k10 Duration of infusion

  8. Getting model parameter values 1. Semilog graph of Cp,t values. Cp = A’e-t + B’e-t 2. Add line to log linear phase. 3. Subtract line from the Cp,t values. 4. Use slopes and intercepts of the two lines to calculate PK parameter values.

  9. V2 = V1(k12/k21) Vss = V1 + V2 V = V1(k12 + k21 - )/(k21 - ) V = V1k10/ V1 = Xo/(A + B) k21 = (A + B)/(A + B) CL = k10V1 = V k10 = /k21 t1/2, = ln 2/ k12 =  +  - k21 - k10 t1/2, = ln 2/ Getting model parameter values Xo = Ko  = infusion time Use A’, B’, , and : A = A’ / (1 - e-) B = B’ / (1 - e-)

  10. Multiple Dosing: i.v. bolus

  11. One-Compartment

  12. Gentamicin accumulation Rowland and Tozer, Fig. 19-12, p. 330.

  13. AUC and Css,av relationships AUC0- = AUC0-,single dose = A/ + B/ FDose/ = CL  Css,av Css,av = FDose / CL  

  14. k12 V2 V1 k21 k10 Loading Dose: lidocaine example Rowland and Tozer, Fig. 19.10, p. 329.

  15. Lidocaine LD: multiple bolus w/ 2.1, 3.0, 4.4 mg/min infusion Applied Pharmacokinetics, 2nd Ed., p. 659, Fig. 20.2

  16. Lidocaine LD Applied Pharmacokinetics, 2nd Ed., p. 660, Fig. 20.3

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