Docstoc

Supplementary Information for

Document Sample
Supplementary Information for Powered By Docstoc
					Additional Information for:
"The Pharmacokinetics of the Interstitial Space in Humans" by David G. Levitt PKQuest Maple worksheets for all solutes. > edta_elia:=proc() IV data of Ellia et. al (Clincial Science, 1987, 73: 197) - Concentration in units of fracton of dose/liter - assume dose = 1 mmol - Average value of 7 normal subjects - average weight 70.9 kg, height 178 (this is for a larger population then the 7 used here - assume representative). No information about time course of injection - assume 1 minute. > local i,datafile,tdata,Kp,xscale; > defaultpar(): > Wtot:= 70.9; > standardhuman2(Wtot); > Fat:=0.18;# Value of 70.9 Kg, 178 cm males > cunit:= "millimoles"; > concunit[vein] :=4;#plasma conc > mecf:=1; #distributes in ECF > rclr:=0.100; > pdata:=1; > data[1]:=[[30, 0.05], [120,0.0249], [240,0.0122],[360,0.006], [480,0.0034]]; Infuse 11 mmol as bolus IV as (assumed) 1 minute injection > ninput:=1; finput[1]:= table([organ=0,type=1,rate=1,tbeg=0,tend=1,csteady=0,padjus t=0]); > print("data=",data[1]); end proc: > mannitol_elia:=proc() IV data of Ellia et. al (Clincial Science, 1987, 73: 197) - Concentration in units of fracton of dose/liter - assume dose = 1 mmol - Average value of 7 normal subjects - average weight 70.9 kg, height 178 (this is for a larger population then the 7 used here - assume representative). No information about time course of injection - assume 1 minute. > local i,datafile,tdata,Kp,xscale; > > > defaultpar(): Wtot:= 70.9; standardhuman2(Wtot);

> Fat:=0.18;# Value of 70.9 Kg, 178 cm males > cunit:= "millimoles"; > concunit[vein] :=4;#plasma conc > mecf:=1; #distributes in ECF > rclr:=0.094; > pdata:=1; > data[1]:=[[30, 0.0512], [120,0.0267], [240,0.0118],[360,0.0069], [480,0.0039]]; Infuse 11 mmol as bolus IV as (assumed) 1 minute injection > ninput:=1; finput[1]:= table([organ=0,type=1,rate=1,tbeg=0,tend=1,csteady=0,padjus t=0]); > print("data=",data[1]); end proc: > mannitol_ml_laker:=proc() IV data of Laker et. al. (European J. clin. Invest. 1982 12: 485) - 11 mmol bolus injection (no details published), no body weight info. Personal communication from Mike Laker: Weight = 158 lbs, = 71.66 Kg, Ht = 5' 8 = 172 cm. - 1 to 2 minute injection > local i,datafile,tdata,Kp,xscale; > defaultpar(): > Wtot:= 71.66; > standardhuman2(Wtot); > Fat:=0.20;# based on 71.66 Kg and 172 cm > cunit:= "millimoles"; > concunit[vein] :=4;#plasma conc > mecf:=1.0;rclr := .14;#Minimum error=.0542 > pdata:=1; > data[1]:=[ [15., .5774715], [30., .450227], [60., .3393307], [90., .2259966], [120., .172582], [150., .1416132], [210., .9410623e-1], [270., .671826e-1], [375., .3983372e-1]]; > print("data=",data[1]); Infuse 11 mmol as bolus IV as (assumed) X minute injection > X:=1.5; > ninput:=1; finput[1]:= table([organ=0,type=1,rate=11/X,tbeg=0,tend=X,csteady=0,pad just=0]); end proc:

Inulin data from Odeh et. al Clin. Phar. and Ther. 53:419 Illustrates application to solute with significant capillary permeability limitation, distribution only in ECF and renal clearance. Initially found the value of mecf that gave best fit to data. Then adjusted the values in standardhuman so that this became the default value, and then set mecf = 1. Set renal clearance = 10% of renal plasma water flow - literature value. Adjusted capillary muscle clearance (fclear[muscle]) to get optimum fit. > with (gensolve); > inulin_odeh:=proc() Data from odeh et. al Clin. Phar. and Ther. 53:419 > local i,datafile; > defaultpar(): > Wtot:= 87.3; #Body weight Based on data of 87.3 Kg and 173 cm standardhuman2(Wtot); > Fat:=0.28;# Fat by weight based on 162 cm height and standard chart. > mecf := .4208; fclear[muscle]:= .409;#error = 0.0195 > rclr:=0.1001; > cunit:="milligrams"; > concunit[vein] :=4;# venous plasma concentration findabs:=0; ninput :=1; finput[1]:=table([organ=vein,type=1,rate=800,tbeg=0, tend=5,csteady=0,padjust=0]);#4 gms over 5 minutes > data[1]:=[[7., 652.6531], [10.79412, 477.4343], [16.48529, 364.829], [21.54412, 317.7595], [27.23529, 284.9295], [30.39706, 248.1684], [45.57353, 205.4253], [60.75, 175.0616], [77.19118, 145.9672], [91.10294, 126.2139], [121.4559, 90.99627], [151.1765, 73.16463], [181.5294, 53.52201], [240.9706, 36.94064], [301.6765, 21.72768], [360.4853, 16.24489], [420.5588, 9.765577], [480., 6.939042]];# [time (minutes), concentration (mg/lit)] > pdata:=1; > end proc:

> morphine6G_penson:=proc() Data from Penson et. al. (Br. J. Clin Pharmacol. 2002, 53:374) IV dose of 2 mg M6G as 2 min bolus - units in nmole/liter)

Subjects: 4 female, 6 male, age 31 (24-42) weight 71 Kg and GFR or 109 ml/min > local i,datafile,tdata,Kp,xscale; > defaultpar(): > Wtot:= 71.0; # standardhuman(Wtot); > standardhuman2(Wtot); > Fat:=0.26;# Guess for English subjects -male and female > cunit:= "nanomoles"; > concunit[vein] :=4;#plasma conc > pdata:=1; > ninput:=1; > rclr:=0.154; > mecf:=1;#standard ecf space rclr := .154;#glomerular filtration Infuse 2 mg (= 4307 nanomoles) in 2 minutes > data[1]:=[[5., 391.], [10., 334.1185], [15., 263.4208], [30., 199.6141], [45., 153.274], [60., 130.8081], [90., 91.57122], [120., 66.69478], [150., 50.53973], [180., 37.29939], [210., 31.41463], [240., 25.09675], [300., 15.39503], [360., 9.319814], [480., 5.793037], [600., 5.143764]];#Delete 0 time point and 2 minute time point (cannot time) > X:=2; #2 min bolus > finput[1]:= table([organ=0,type=1,rate=4307/X,tbeg=0,tend=X,csteady=0,p adjust=0]); > print("data=",data[1]); > end proc:

> morphine6G_lotsch:=proc() IV data of Morphine-6-glucluride data of Lotsch (Clin. Parm. Ther. 1998v. 63: 629) input of 0.044 mg/kg as bolus plus 0.022mg/kg/hr for 4 hours > local i,datafile,tdata,Kp,xscale; defaultpar(): Wtot:= 70.0; standardhuman2(Wtot); > Fat:=0.2;# estimate for men > cunit:= "nanomoles"; > concunit[vein] :=4;#plasma conc > mecf:=1.0;#Standard ecf space rclr := .139;#glomerular filtration rate > >

IV

> pdata:=1; > #datafile:="C:/Documents and Settings/DLevitt/My Documents/pkquest_prog/Morphine/IV_MP6_lotsch.tab"; #data[1]:=readtab(-1,datafile); > data[1]:=[[0., 0.], [10., 572.2689], [20., 471.4286], [30., 428.5714], [40., 408.4034], [50., 390.7563], [60., 380.6723], [90., 363.0252], [120., 365.5462], [150., 365.5462], [180., 373.1093], [210., 373.1093], [240., 365.5462], [270., 277.3109], [300., 199.1597], [330., 166.3866], [360., 126.0504], [420., 85.71429], [480., 57.9832]]; Infuse 0.044 mg/kg as bolus in X minutes (=6640 nanomoles/70kg) plus .022 mg/kg/hr for 4 hours (=55.44 nanomoles/min/70kg) > ninput:=2; X:=2.5; #In 12 minutes = 0.2 hour (in paper Lotsch et. al. Anethesiology 95:1329 X:=5; #In 12 minutes = 0.2 hour (in paper Lotsch et. al. Anethesiology 95:1329 finput[1]:= table([organ=0,type=1,rate=6640/X,tbeg=0,tend=X,csteady=0,p adjust=0]); finput[2]:= table([organ=0,type=1,rate=55.44,tbeg=0,tend=240,csteady=0, padjust=0]); print("data=",data[1]); end proc:

> morphine3G_penson:=proc() IV data of Penson et. al. (J. Pharm. Sci. 2001, V. 90: p. 1810) - measured plasma morphine-3-glucuronide concentration (units of ng/ml) after a 2 minute IV bolus input of 30 mg/70 Kg. Fits data using two ECF muslce compartments - one with a slow exchange > local i,datafile,tdata,Kp,xscale; > defaultpar(): > Wtot:= 70.0; # standardhuman(Wtot); > standardhuman2(Wtot); > Fat:=0.16;# Guess for English subjects > cunit:= "nanomoles"; > concunit[vein] :=4;#plasma conc > pdata:=1; > ninput:=1; > xscale:= 2.155; #convert from nanogram/ml to nanomole/liter (mol. wt = 464)

> mecf:=1;#Standard ecf > X:=3;#3 minute constant infusion > rclr:= .122;#renal glomerular clearance > if true then Infuse 30 mg (= 64,600 nanomoles) in 2 minutes > data[1]:=[[3., 8942.894425], [6., 6979.26920], [10., 5403.287530], [15., 4459.354430], [30., 3316.299330], [45., 2369.59490], [60., 1805.002356], [90., 1500.802124], [120., 1237.948801], [150., 1054.316079], [180., 689.6836140], [210., 672.8925005], [240., 529.043880], [300., 619.9555720], [360., 263.1871330], [480., 230.9653575], [600., 118.6290003], [720., 46.42923795]];#Delete 0 time point > finput[1]:= table([organ=0,type=1,rate=64600/X,tbeg=0,tend=X,csteady=0, padjust=0]); end if; > if false then Infuse 15 mg (= 32,300 nanomoles) in 2 minutes (Xmin) > data[1]:=[[2., 4424.697720], [5., 3317.661290], [10., 2448.019660], [15., 2223.477280], [30., 1640.009306], [45., 1310.269954], [60., 913.7934855], [90., 678.9838235], [120., 492.5543425], [150., 472.6774845], [180., 326.8333340], [210., 294.2187020], [240., 236.8118725], [300., 168.8595505], [360., 116.6219195], [479.7698, 65.26814020], [600.2018, 51.5129045]]; > finput[1]:= table([organ=0,type=1,rate=32300/X,tbeg=0,tend=X,csteady=0, padjust=0]); > end if; > print("data=",data[1]); > end proc:

> amoxicillin_sjovall:=proc() > local i,datafile,tdata,Kp,xscale; > defaultpar(): > Wtot:= 74.7; # standardhuman(Wtot); > standardhuman2(Wtot); > Fat:=0.2;# estimate for young chilian men (7) and women (2) > cunit:= "mg"; > concunit[vein] :=4;#plasma conc

> mecf:=1; > kProt:= -2; #this turns on use of cProt[i] to determine fw[i] > fw[vein]:= 0.83;# fraction free in vein > Tclr[kidney]:= .447;#error = 0.024 > pdata:=1; > data[1]:=[[0., 0.], [20., 181.7585], [30., 117.2842], [40., 95.12166], [50., 78.67], [65., 65.1], [95., 35.36592], [125., 22.82072], [170., 13.94241], [230., 8.040628], [290., 4.381039], [350., 2.625137], [410., 1.514265], [470., 1.017644], [530., .6970699], [650., .3737633]]; > print("data=",data[1]); Infuse 2.5 gm per 1.73 M^2 over 20 minutes - These subjects have surface area of 1.94 M^2 - thus dose = 2.80 g > ninput:=1; X:=20; finput[1]:= table([organ=0,type=1,rate=2800/X,tbeg=0,tend=X,csteady=0,p adjust=0]); end proc:

> amoxicillin_arancibia_IV:=proc() > local i,datafile,tdata,Kp,xscale; > defaultpar(): > Wtot:= 66.4; # standardhuman(Wtot); > standardhuman2(Wtot); > Fat:=0.20;# estimate for young chilian men (7) and women (2) > cunit:= "nanomoles"; > concunit[vein] :=4;#plasma conc > mecf:=1; kProt:= -2; #this turns on use of cProt[i] to determine fw[i]; > fw[vein]:=0.83; > Tclr[kidney]:= .388;#antecubital concentration error = 0.434 > pdata:=1; > data[1]:=[[10., 31.25619], [20., 22.40934], [30., 18.77042], [45., 14.30196], [60., 11.29147], [90., 7.771161], [120., 5.083484], [180., 2.625109], [240., 1.208733], [300., .728815]];

> print("data=",data[1]); Infuse 500mg as bolus IV as 0.2 minute bolus > ninput:=1; finput[1]:= table([organ=0,type=1,rate=2500,tbeg=0,tend=0.2,csteady=0,p adjust=0]); end proc:

> piperacillin_lode:=proc() V Data from Lode et. al. (Antimicrob. Agents and Chem. 25: 105; 1984 Constant 15 minute infusion of 2 gms to normal subjects: Wt 68.1 Kg, surface area = 1.8 M^2 - corresponds to ht = 170 cm, Fat = 0.2 Also measured binding: 0.48 > local i,datafile,tdata,Kp,xscale; > defaultpar(): > Wtot:= 68.1; > standardhuman2(Wtot); > Fat:=0.16;# > cunit:= "milligram"; > concunit[vein] :=4;#plasma conc > mecf:=1.0; > Tclr[kidney]:= .50734; fclear[muscle]:= .84731;#error =0.061 > Tclr[kidney]:= .4;#error = 0.076 kProt:= -2; #this turns on use of cProt[i] to determine fw[i]; > fw[vein]:=0.52; > pdata:=1; > #data[1]:=[[0., 0.], [15., 132.1508], [20., 118.6138], [25., 101.9239], [35., 89.49306], [45., 69.76633], [60., 55.59287], [75., 43.36742], [105., 29.07748], [134., 19.93309], [195., 10.32338], [255., 4.955894], [375., .9393548]]; Remove last point - way too small > data[1]:=[[0., 0.], [15., 132.1508], [20., 118.6138], [25., 101.9239], [35., 89.49306], [45., 69.76633], [60., 55.59287], [75., 43.36742], [105., 29.07748], [134., 19.93309], [195., 10.32338], [255., 4.955894]]; > print("data=",data[1]); > nfuse 2000 mg as IV for 15 minutes

> ninput:=1; finput[1]:= table([organ=vein,type=1,rate=2000/15,tbeg=0,tend=15,cstead y=0,padjust=0]); end proc: > > > cefatrizine_pfeffer:=proc() Data from Pfeffer et. al. 1983 (Antimicrob. Agents and Chem. 24: 915)30 min constant infusion of 260, 527 and 1037 mg - nearly identical results - linear system. This data is for the 1037 mg dose. - Subjects:: Males Age 32 Ht 170 Wt 67 Kg Surface Area = 1.78 M^2 - 20 % fat Binding was measured: 62% > local i,datafile,tdata,Kp,xscale; defaultpar(): Wtot:= 67; standardhuman2(Wtot); Fat:=0.16;# cunit:= "milligram"; concunit[vein] :=4;#plasma conc #mecf:=1.2; mecf:=1.0; > fclear[muscle]:=0.73;Tclr[kidney]:= .77183;#error =0.052 > Tclr[kidney]:= .77566;#flow limited, error = 0.106 kProt:= -2; #this turns on use of cProt[i] to determine fw[i]; > fw[vein]:=0.38; > pdata:=1; > data[1]:=[[5,26],[10., 44], [20., 65], [30., 75], [35.,57], [50., 34], [60., 28], [90., 18], [120., 11], [210., 3.8], [270,2],[390,1]]; Remove last point - much to high.- suggests impurity interfering with low concentrations. > data[1]:=[[5,26],[10., 44], [20., 65], [30., 75], [35.,57], [50., 34], [60., 28], [90., 18], [120., 11], [210., 3.8], [270,2]]; 527 mg dose > #data[1]:=[[5,13],[10.,22], [20., 30], [30., 37], [35.,26], [50., 17], [60., 13], [90., 7], [120., 5], [210., 1.8], [270,0.77],[390,.26]]; > #for i from 1 to nops(data[1]) do > > > > > > >

# data[1][i][1]:=data[1][i][1]-1; #add 1 minute sampling delay #end do;; > print("data=",data[1]); > nfuse 1037 mg as IV for 30 minutes > ninput:=1; finput[1]:= table([organ=0,type=1,rate=1037/30,tbeg=0,tend=30,csteady=0 ,padjust=0]); nfuse 527 mg as IV for 30 minutes #input[1]:= table([organ=0,type=1,rate=527/30,tbeg=0,tend=30,csteady=0, padjust=0]); end proc:

Data from Pfeffer et. al. (J. Pharm. Sci. 69: 398) 1980 Constant IV infusion of 1132 or 2264 mg for 30 min. Total for male subjects- Wt 72.5 Kg Surface area of 1.9 M^2 - 4 of these subjects used for 1132 study, 6 for 2264 study with(gensolve); ceforanide:=proc() > local i,datafile; > defaultpar(): > Wtot:= 72.5; standardhuman2(Wtot); > Fat:=0.16; > mecf:=1.0; > kProt:= -2; #this turns on use of cProt[i] to determine fw[i] > fw[vein]:= 0.18;# fraction free in vein > Tclr[kidney]:= .275; fclear[muscle]:= .518;# error=0.0431 PSmuscle = 0.047 #fclear[muscle]:=1;Tclr[kidney]:= .247;#error = 0.0869 > cunit:="milligrams"; > concunit[vein] :=4; findabs:=0; ninput :=1; #Constant 30 minute infusion of 2 grams > pdata:=1; Infuse 1132 mg over 30 minutes finput[1]:=table([organ=vein,type=1,rate=1132/30,tbeg=0, tend=30,csteady=0,padjust=0]);

data[1]:=[[0., 0.], [15., 82.85265], [30., 136.9206], [44., 100.7792], [60., 86.44002], [90., 69.91042], [150., 46.74141], [240., 34.79965], [360., 20.97259], [540., 12.63875], [720., 5.972182]]; print("data[1]=",data[1]); > end proc: with(gensolve); flucloxacillin_wise:=proc() This uses new version - gensolve108 - in which ps[i] is defined in defaultpar and only f[muscle] needs to be defined. This uses new version - gensolve134 - new set of ecf values This assumes 100% renal excretion.. > local i,datafile; > defaultpar(): > Wtot:= 75.0; standardhuman2(Wtot); > Fat:=0.2; mecf:=1; kProt:= -2; #this turns on use of cProt[i] to determine fw[i] > fw[vein]:= 0.07;# fraction free in vein fclear[muscle]:= .344;Tclr[kidney]:= 3.205;#error = 0.064, PS = 0.0701 #fclear[muscle]:=1;Tclr[kidney]:= 3.627;#error = 0.11 > cunit:="milligrams"; > concunit[vein] :=4; findabs:=0; ninput :=1; finput[1]:=table([organ=vein,type=1,rate=2000.0/30,tbeg=0, tend=30,csteady=0,padjust=0]);#Constant 30 minute infusion of 2 grams > pdata:=1; Infuse 1000 mg over X minutes > X:=3; > ninput :=1; finput[1]:=table([organ=vein,type=1,rate=1000.0/X,tbeg=0, tend=X,csteady=0,padjust=0]); data[1]:=[[10., 139.], [20., 65.52247], [30., 55.26123], [45., 36.51656], [60., 26.55441], [90., 15.34426], [120., 9.196795], [180., 3.800858], [240., 1.991055], [300., 1.019963], [360., .6715082]];# leave out t=0 point print("data[1]=",data[1]);  end proc:

with(gensolve); dicloxacillin_male:=proc() This uses new version - gensolve108 - in which ps[i] is defined in defaultpar and only f[muscle] needs to be defined. This uses new version - gensolve134 - new set of ecf values This assumes 100% renal excretion.. > local i,datafile; > defaultpar(): > Wtot:= 75.0; > #Wtot:= 70.0; standardhuman2(Wtot); > Fat:=0.2; > mecf:=1; > #Tclr[kidney]:= 3.150; fclear[muscle]:= .2539;#error =0.12 PS=0.113 > fclear[muscle]:=1;Tclr[kidney]:= 3.602;# error = 0.18 kProt:= -2; #this turns on use of cProt[i] to determine fw[i] > fw[vein]:= 0.03;# fraction free in vein > cunit:="milligrams"; > concunit[vein] :=4; findabs:=0; ninput :=1; finput[1]:=table([organ=vein,type=1,rate=2000.0/30,tbeg=0, tend=30,csteady=0,padjust=0]);#Constant 30 minute infusion of 2 grams > pdata:=1; > data[1]:=[[0., 0.], [10., 142.4516], [20., 210.5457], [30., 268.2141], [45., 209.8305], [60., 153.5333], [90., 102.7835], [120., 64.88918], [240., 14.76571], [360., 5.992287], [480., 2.083122]];# time, concentration (mg/liter) > end proc: