GSN. Koteswara Rao, Pham, DDD, DCT, (PAD) (MBA) Asst. Professor, RAGHU College of Pharmacy, Visakapataaae Pharmacokinetics Solved Problems sewvesaghapharmacycomt sor pinrmainasneogdowalonds Pharmacokinetics Oey eras tae) rows Cee 1. V. Bolus Administration] Solved Problems - a . ty G.S.N.K.Rao {Eswar} x OM At 4mw\ If the plasma concentration of viomycin after iv, bolus administration was fotfhidh to be 10.0 and 5.5 PROBLEM-1: a. the half-life of the drug b. the concentration of drug in plasma at zero time, c. the Vg, if dose administered was 300 mg, d._ the total systemic clearance, Clr © . the renal clearance, Cl if fraction ex¢ changed in urine is 0.8 SOLUTION-1: a, Calculate the half-life of the drug? Data given: C) = 10.0 pg/ml at t) = %hours ° gil at ts it = AEO3MK Kx = Elimination rate constant So, to calculate tia we. chayg 1YGrstBetermine Kg with the help of given data. Kz can be determined fda the slope of a line obtained by plotting log concentration on y-axis vs time on x-axis. (Jog@Vs time is plot for first order kinetics). Ke= oe eB 10=1 ree log @p= log 5.5 = 0.74 Slopebtith€ straight line of log C vs tis Yi 074 — 0.26 “MX = 2-4 2 O18 slope x 2.303 = — (— 0.13) x 2.303 = 0.299 hr! Then, tin = 0.693/Ky: = 0.693/0.299 hr! = 2.32 hours. Half-life of the given drug, tia is 2.32 hours. www.pharmainfo.neveswar Page 1 of 9 eswar@ pharmainfo.netGSN. Koteswara Rao, Pham, DDD, DCT, (PAD) (MBA) Asst. Professor, RAGHU College of Pharmacy, Visakhapatnam. Pharmacokinetics Solved Problems www saghupharmacy.com Log C vs time plot 14 42 Slope =-K,/2.303 oe yeti 126 06 Jog Come. eo oa 02 ° 1 2 a 4 5 Time (hours) b. Calculate the concentration of drug in plasma at mn iigy) Cy is the plasma drug concentration at zero time after Aynin or initial plasma drug concentration. This can be obtained from the graph (log cane, vs time) By extrapolating the straight line and finding the Y-intercept which is equal to log Co. ON From graph, log C. = 1.26 ¢ fas 2. Co= Anti-log 1.26 = 18.2 ug/ml c. Calculate the Va, if dose frinistered ‘was 300 mg Volume of distribution, Vg of « dnt WHEMdministered iv. is given by, Formula: Va = Xo/Co Where, Xo = Dose admintyjered inthi?Venously and \ @ Co = Plasi a zero time after administration Xs 300x 100042 300x 1000ml__ 300s “Va= 6, 7 18.2 pg/ml 182 132 7 165 lts [NOTE: conctangatieuits may be used either wp/ml or mg/liter because mg = 1000 and 1 ite 1000 mh} ~” |. Calulafé the total systemic clearance, Chy Totfgystemie Clearance, Chis given by the formula, Clr= Ke Vs o. Cl= Ky Vu = 0.299 hr! x 16.5 Its 299/60 mins x 16.5 x 1000 ml (4933.5/60) ml/min = 82.23 ml/min [NOTE: If Ky, is not available then you can use 0.693/ty in place of Ky, based on half-life relation] www.pharmainfo.neveswar Page 2 of 9 eswar@ pharmainfo.netGSN. Koteswara Rao, Pham, DDD, DCT, (PAD) (MBA) Asst. Professor, RAGHU College of Pharmacy, Visakhapatnam. Pharmacokinetics Solved Problems www saghupharmacy.com e. Calculate the renal clearance, Clk if fraction excretion unchanged in urine is 0.8 Renal Clearance, Clk can be given by the formulae: Formula 1: Cl, = F x Clr ; where P= Fraction excreted unchanged in urine (or) Formula 2: Cly = Ke x Va where K, = excretion rate constant (or) Formula 3: Cly = Rate of elimination by kidney /C We can use either formula | or formula 2 to calculate Clk of Using formula 1: Cly =F x Chr = 0.8 x 82.23 mV'min = 65.78 ml/min. Using formula 2: Cle =Ke x Va ¢ ae First we have to caleulate Ke and substitute that value in formula 2. Ke= Fx Ke=0.8 x 0.299 he! nogvoam aaa soaome' pS Cle = Ke x Va = 0.003986 / min x 16.5 Its = 0.003986 x 16506Gpdmin = 65.78 ml/min \ } “e,, www.pharmainfo.neveswar Page 3 of 9 eswar@ pharmainfo.netGSN. Koteswara Rao, Pham, DDD, DCT, (PAD) (MBA) Asst. Professor, RAGHU College of Pharmacy, Visakhapatnam. Pharmacokinetics Solved Problems www saghupharmacy.com PROBLEM-2: ‘The equation that best fits the plasma level time curve of azlocillin after an i.v. bolus dose of 2000 mg (assuming one-compartment kinetics) is C=143e ~°*7'. Calculate: ivy. bolus? NZ SOLUTIO? Given data: i.v. bolus dose, C=143e ~"*7" best fits for one-compartme On comparison, Cy = 143 ng/ml and Kr = 08 apparent Vs elimination tye of the drug plasma drug concentration after 6 hours - the amount of drug that will be left in the body after 6 hours -~\ when should the next dose be administrated if the drug becomes ineffective ee level falls below 50 jig/ml? the therapeutie index ofthe drug if the therapeutie range is 50 10 $00 pg ee of 500 how much dose should be administrated to attain an instantang oe ug/ml for how long will the plas i level lic in the therapeutig wil a. Calculate apparent Va cS ¢ Xp = 2000 mg. indhics (U8 order equation Apparent Volume of distributionyVqis given by the formula, 1 Vye Xe = —2000 mg x #2 _ 2000 1000ml__ _2000ts__ yy, ONS Co 148 nahh, Bygiml 143) oa [NOTE: Concentration units May besused either jig/ml or mg/liter: because | mg = 1000 wg and 1 It = 1000 ml] ae b. Calculatesttpintion typ of the drug Formulas.ty 6931 Ky Givgn, Kg st ir’, ee © 0.693/0.87hr™ 0.8 hours. Calculate plasma drug concentration after 6 hours Substitute t=6 hours in given equation C=143¢ -087"; ost C=143e = 143 x 0.0054 = 0.77 pg/ml. www.pharmainfo.neveswar Page 4 of 9 eswar@ pharmainfo.netGSN. Koteswara Rao, Pham, DDD, DCT, (PAD) (MBA) Asst. Professor, RAGHU College of Pharmacy, Visakhapatnam. Pharmacokinetics Solved Problems www saghupharmacy.com d. Calculate the amount of drug that will be left in the body after 6 hours The term °C” represents plasma drug concentration whereas the term *X” represents the drug content in the body. Hence the below two equations are similar C= Ce“ and X= Xoo Where, Xp = amount of drug injected and X = amount of drug left in the body at time, t. So, substitute t=6 in the above equation. =~ X= Xie ** = 2000 x e°*7** = 2000 x 0.0054 = 10.8 mg } eo \ So, after 6 hours of administration of drug, 10.8 mg will be left in the body y ! \ e. Calculate, when should the next dose be administrated if the dui Bees ineffective when the plasma level falls below 50 g/ml? Cc SD : Here, we have to calculate the time of next dose where C = 50 gloat log C = log 143 — 0.872.303 [ similar to log C = log C.~ kt/2.3 By applying log terms to the given equation C=143e ~°*" we ee \ ? «Substitute C=50 in above equation; es) 4 log 50 = log 143 — 0.871/2.303 143 - log 50 o> . = 0.870 2.30; _ {log 143 - log50) x 2.303 Nx 2.303 _ | 5, ate Ee oar = 1.24 hours 4 > e £. Calculate the therapeuffejndes-gfthe drug if the therapeutic range is 50 to 500 ng/ml 500 = 30 =10 & Caleufie fhuch dose should be administrated to attain an instantaneous plasma concentration of $00 g/ml a Forpptfla: X= GV = 500 x 14. = 7000 me. h, "Calculate, for how long will the plasma level lie in the therapeutic window if the above dose is given as iv, bolus? Formula; log C = log Cy ~ kt/2.303 log 50 = log 500 ~ 0,87 12.303 _, _ log 500 logS0) x2.303__(log 500/50) x 2.303 = log 10.x2.303 _ ots 0.87 = 087 ORF =2.65 hours www.pharmainfo.neveswar Page 5 of 9 eswar@ pharmainfo.netGSN. Koteswara Rao, MPhsim. DDD. DCT. (PD), (488) Asst. Professor, RAGHU College of Pharmacy, Visakhapatnam. Pharmacokinetics Solved Problems www raghapharmacy.com PROBLEN-3: ‘The half-life of propranolol in a 60 kg patient is 4 hours and Vs is 5.5 liter/kg. Determine a. The total systemic clearance of drug b. What will be the renal clearance if fraction excreted unchanged in urine is 0.047? c. If the drug is eliminated only by hepatic and renal routes, what will be the hepatic extraction ratio if blood flow to liver is 1.5 liter/min? - he d. If the blood flow rate to the liver reduces to 0.8 It/min in situations of CCF, whi Rill be . ) new hepatic and total systemic clearance values? NY (Oe e. What will be the % decrease in overall clearance of drug? SOLUTION-3: a, Determine the total systemic clearance of drug Given, ty = 4 hours and Va = 5.5 liters/kg For 60 kg patient, Vg will be 60x 5.5 lite Formula NZ 0.693 0.693 Ch= = = — 0.693 _ 5 2 Ch=KeV, tie *¥!= Fxe0min *OO% er ml/min ¢ b, What will be the renal clearance i Renal Clearance, Cl, can be given by the fo reted unchanged in urine is 0.047? Formula 1: Cla = Fx Clr : where FafFraction ( e jon rate constant (or) Formula 2: Cla = Ke x Va: wher Ks, Formula 3: Cly = Rate ae ninatioMpy kidney / C Cla = F x Clr = 0.047. 9338 nlfmin = 44.8 mi/min feted unchanged in urine (or) If thes@Pag is elit ated only by hepatic and renal routes, what will be the hepatic crab if blood flow to liver is 1.5 liter/min? HepatietBxtractiotwRatio, ERu is given by the e 7 Hepatic Clearance, Cly ince, Chr= For oa ERS Blood flow, On [ Since, Chr = Qu x ERu] Blood flow to liver, Qu is given as 1.5 liter/min So, determine Cly and substitute its value in the formula to get ERu, We know, Clr = Cl + Cli Cla = Clr - Cl= (952.8 ~ 44.8) ml/min 108 ml/min www.pharmainfo.neveswar Page 6 of 9 eswar@ pharmainfo.netGSN. Koteswara Rao, Pham, DDD, DCT, (PAD) (MBA) Asst. Professor, RAGHU College of Pharmacy, Visakhapatnam. Pharmacokinetics Solved Problems www saghupharmacy.com __Hepatie Clearance. Chy 908 m/min v ERH= "Blood flow, Qi Sx 1000 mifmin ~ 6055 4. If the blood flow rate to the liver reduces to 0.8 It/min in situations of CCF, what will be the new hepatic and total systemic clearance values? Clu = Qu x EI Clp= Cl + Ch = (44.8 + 484.24) ml/min = 529 ml/min 0.8 It/min x 0.6053 = 8000 ml/min x 0.605 484.24 ml/min e. What will be the % decrease in overall clearance of drug? __Initial Clr Final Clr = 92848 yay “be decrease = Initial Clr xim=“ons - - www.pharmainfo.neveswar Page 7 of 9 eswar@ pharmainfo.netGSN. Koteswara Rao, Pham, DDD, DCT, (PAD) (MBA) Asst. Professor, RAGHU College of Pharmacy, Visakhapatnam. Pharmacokinetics Solved Problems www saghupharmacy.com PROBLEM-4: A dose of 325 mg of a new drug is injected intravenously to a healthy volunteer and the following blood data was obtained. Assume that the drug follows one compartment open model and calculate all possible pharmacokincties parameters. Time (hrs) Plasma drug concentration, C (mit) ~ 2 18.3 . ~ 4 10.1 ~ \ 6 53 or)? ‘ 8 33 4 33 VJ 10 18 AN 12 10 od 16 O31 GA 20 0.21 ow i SOLUTIO! Given data: pde vs time profile and assumed to follow one-one open model and follows first order kinetics. Pharmacokinetic parameters that can be assasged for this profile are: Ky, ty. Co, Vis Clr and AUC. (( ‘ Elimination rate constant, Ky: Hence a plot of log C vs time gives straight li weds is Kg = — slope x 2.303 . Jog Cy = log 18.3 = 1.2625 > log Cy = log 5. Slope of the straight tm oe offog CWS ~ =) a =lae'18.3_ __0.7634- 1.2625 Slope= ya = 7 0.125 2. Ky =~ slope x 2.303% (0. =) 2.303 = 0.288 hr! Biological half-lifepty:@ Then, ty = 0.693/Ky# 0.693/0.288 hr’! = 2.41 hours, ~ Halffife oa given drug, typ is 2.41 hours. Inittal Plasinge drug concentration, Co: Fro -pfot of log C vs time, extrapolate the straight line towards y-axis. The y-intercept is equal to log Co log Co = 1.4955 Co= Antilog 1.4955 = 31.3 mg/t or g/ml Volume of distribution, Ve: Va= XolCo = 325 mg/31. = 10.38 Its www.pharmainfo.neveswar Page 8 of 9 eswar@ pharmainfo.netGSN. Koteswara Rao, Pham, DDD, DCT, (PAD) (MBA) Asst. Professor, RAGHU College of Pharmacy, Visakhapatnam. Pharmacokinetics Solved Problems www saghupharmacy.com log C vs time 2.0000 1.5000 1.0000 © 0.5000 —elog Cvs _ 2 0.0000 “te Extrapolated % 0.5000 SS —Linear (log Cvst} “Ny ) y= 122K +1498 1.0000 / 1.5000, Me ‘time (hrs) LF pdc vs time: Semilog plot 100 + te pdevstime —m- Earapolated 3 — Expon. (pdc vs time) S y= 31.2deo 25 time (hrs) Total Systemic Cle Clr=Kex Wy=0. =e, its = 2.989 Itshhr or 16.48 ml/min Area Under the-urve, A Here, we hae fouremember that AUC for a plot obtained by values of a drug administered inravenouly culated by using the simple equation: i hg. ma AUC calculated from Trapezoidal rule will also give the same answer here for an int iSly administered drug kinetic profile] Cy _ 313 agg 710868 me. hrft or 108.68 jg, him 600D LucK «(Auch Reference: Bio-Pharmaceuties and Pharmacokinetics by: Brahmankar V. Venkateswarlu www.pharmainfo.neveswar Page 9 of 9 eswar@ pharmainfo.net