PHA 5127 Dose Optimization I Case Study II 1. Two patients (A and B) were given a same drug through IV bolus, and this drug is 40% bound to plasma proteins in both two patients but has different tissue binding. There is 70% and 80% tissue binding in patient A and patient B, respectively. In order to reach same initial total plasma concentration of 2mg/L in both two patients, which doses should be given to them? For patient A: fu=1-40%=60%, fuT=1-70%=30% Vd=Vp+ VT*(fu/fuT)=3L+38L*(60%/30%)=79L Dose= C0*Vd=2mg/L *79L=158mg For patient B: fu=1-40%=60%, fuT=1-80%=20% Vd=Vp+ VT*(fu/fuT)=3L+38L*(60%/20%)=117L Dose=C0*Vd=2mg/L*117L=234mg 2. The plasma protein binding of drug A and drug B is 5% and 98% respectively. If the protein bindings of both drugs decreased 50% in one patient, what percentage of change will happen in Vd (volume of distributions) and initial free drug concentration? (Assume IV bolus application, fuT=0.1, Vp=3L, VT=38L for both two drugs)? For drug A: f u,old=1-5%=95%, Vd,old=Vp+ VT*(fu,old/fuT)=3L+38L*(0.95/0.1)=364L f u,new=1-5%*50%=97.5%, Vd,new=Vp+ VT*(fu,new/fuT)=3L+38L*(0.975/0.1)=373.5L Vd,new/Vd,old=373.5L/364L=1.026. Hence, Vd for drug A increased by 2.6%C0,new/C0,old=oldfuoldvdDosenewfunewVdDose,*),/(,*),/(=×newvdoldVd,,oldfunewfu,,=(364L/373.5L)*(0.975/0.95)≈100%, so the initial free concentration will not change. C0,new/C0,old= For drug B: f u,old=1-98%=2%, Vd,old=Vp+ VT*(fu,old/fuT)=3L+38L*(0.02/0.1)=10.6L f u,new=1-98%*50%=51%, Vd,new=Vp+ VT*(fu,old/fuT)=3L+38L*(0.51/0.1)=196.8L Vd,new/Vd,old=196.8/10.6=18.57, so Vd for drug A increased by 1756.6% oldfuoldvdDosenewfunewVdDose,*),/(,*),/(=×newvdoldVd,,oldfunewfu,,=(10.6/196.8)*(0.51/0.02)≈1.37, so the initial free concentration will increase by 37%. 3. TRUE (T) or FALSE (F) To determine the loading dose, volume of distribution is an important factor. T F Drug A has 3% protein binding and has a narrow therapeutic window. Small differences in protein binding are not so important since 97% drug is free and available for receptors. T F For a drug with high tissue binding, the volume of distribution will be always very high. T F Apparent volume of distribution (Vd) will never excess the total body volume. T FLipophilic drugs are generally taken up fast by highly perfused organs T F The uptake of a hydrophilic drug into tissue can be increased significantly by increasing the blood flow through the tissue. (Assume permeability limited distribution) T
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