760
KLINICKÁ341804301074588109168189242288347
FARMAKOLOGIE708804301074392139212266313373416475534555599
A13288043010753
FARMACIE1402804301074292139211266317337381
/18048043010757
Klin1880804301077091109157
Farmakol2057804301074278105179220258305325
Farm2402804301074178104179
2020;2601804301074386128171187
34(4):2807804301074489113155176191
152–1573017804301074482124167206243285
/33228043010757
www.klinickafarmakologie.cz4568804301076513320121425327329234035839843647950254457164568672477179183988990895196610061045
1561308026012657110168
ORIGINÁLNÍ341207012673138172244278352422476549582
PRÁCE944207012661125197257315
Comparison34136501063271125160197232250282323365
of72036501063970
DOS80536501063980112
and93236501063980120
Windows106736501065876117156197256289
version137136501063768104139155196238
of162436501063970
the170836501063172104
MwPharm1827365010653112147187227263317
–2159365010646
a2220365010639
pharmacokinetic227436501063374114149204245278317353371412443477495529
software281836501063272103137199236271303
for313636501062971107
PK/PD32573650106346997132171
monitoring344336501065393135152184223259277318357
of381536501063970
digoxin39003650106385695136171189230
evaluation.340257301194892137157208252280300352404421
Pearson’s782257301195298141169205257310325358
coefficient1161257301194797146171200220264283330382410
of1592257301195681
rank1694257301193277128169
co‑1884257301194797128
rrelation340271301192958104124167196215267319
was6802713011967112147
calculated.848271301194084103147198217261289335389405
%PE12742713011969117161
was14562713011967111147
calculated1623271301194185104147199218262290336389
as340285301194683
the445285301193892141
difference608285301196282108138187216263317362409
between10392853011963113144219267317371
predicted1432285301196392140196216261294341397
and18512853011953106161
the340299301193183131
measured4922993011988136179215265293340394
value907299301195196116167214
(formula1142299301193356108136217269288332
1)1495299301195573
and15892993011951103157
as1767299301195187
the1875299301193789137
difference34031330119547296125170197242293336380
between740313301195097126198244291342
bothmodels11023133011949101129180276327380427446480
(formula160231330119214394121201251270312
2).193431330119446678
RMSE3403273011950126170213
was5743273011967111146
calculated740327301194084103146197216259287332386
according1146327301194184125175203254273324377
to1543327301192676
formula1639327301192272100181231251294
3.1953327301194459
%PE4803413011974124168
=6703413011960
(1)75234130119267089
%PE8633413011973123168
=10533413011960
(2)113434130119277498
RMSE12543413011951128174219
=14953413011960
(3)157634130119277497
Statistical340367501435690145181206249288313366421446
analysis8143675014356120174199252297321364
Statistical480383301194675120149169205236256300346366
analysis867383301194295139159203240259295
of1183383301195076
all128038330119426282
data1384383301195195124169
was15753833011968113150
perfor‑17463833011952101129159211240266
med3403973011982130185
using547397301194985105157211
Prism78039730119477595131211
8.3.01013397301194563112129177
(GraphPad1212397301192382111157211265314358412
Software,1646397301194396122156230276304351367
San340411301194794148
Diego,510411301197495144201255272
CA,8044113011965126146
USA)9734113011971116174200
and11964113011954108163
MedCalc13824113011986136193251298319364
18.2.1.17694113011957101119170188231243
(MedCalc340425301192699146200256300319362
Software,723425301194193118152224268296342356
Ostend,1100425301196298128174225278294
Belgium).1415425301194592112165184235314336349
All178542530119547392
va‑1898425301194185114
lues340439301192173122159
are521439301194372119
presented662439301195382130167215268298344400
as1084439301194379
median11854393011980128184204248301
(interquartile150843930119244497126173202255307352381415436456504
range).340453301192975127181229252266
For628453301194294123
comparison772453301194192173227273301322357410463
of1257453301194975
repeated1353453301192673127176220249296350
measu‑17254533011978126170206257287
rements340467301192976157205258287325
of687467301194975
SDC’s7844673011943105162178212
the1018467301192780128
Wilcoxon11684673011978100120164215256308361
signed‑rank1550467301193454107160208263293323369421462
test340481301193178115146
was5084813011973118155
used.685481301195389138193210
To480495301194693
make5954953011988133175222
the839495301193790139
point10004953011961115136189218
that1240495301193790135164
methods14264953011988137167221274329365
used1813495301195996144199
to340509301193182
measure4445093011989137182218270299346
chosen8125093011951104157194243296
parameters11305093011962107136182263312343389418456
had16085093011960105159
good17895093011961114168224
correlation3405233011946100132163213236283315337393450
when8135233011989146197253
a10905233011961
set11755233011953104137
of1335523301197098
samples14575233011953101186244267318357
had18385233011970117175
been3405373011956106156210
chosen,5725373011953107161198248302319
the913537301193993142
Bland1078537301195880125179234
and13355373011953107162
Altman1519537301196788119202248301
plot1843537301196385139169
was3405513011974121159
used.522551301196299149206225
Correlations7695513011966119150181230252298329350405460498
between12895513011965116147224273324379
calcula‑16915513011953100122168222244290321
ted340565301193178133
SDC’s4955653011953116174190225
in741565301192981
both8445653011963117147200
models10665653011989143198246267303
were13915653011980127156204
evaluated16175653011955100146166219264293340395
by340579301195598
Pearson’s4605793011954100144173211264318333368
correlation850579301194798128158205226271300321374427
as1299579301194985
appropriate.14065793011949103158188240295324345390419466482
All1910579301196282103
data340593301195498127171
were5335933011967114143189
analyzed743593301194193137157200242289343
on11075933011949102
an1230593301194193
intention‑to‑treat134559330119176897143195224244295348378408459490520549595639667
basis3406073011955101138157193
and555607301194497151
for728607301192577107
each857607301194791135188
test,1067607301192976113145162
a12516073011944
P13176073011949
value1388607301194389109162210
<0.0516206073011958105122171218
was18606073011970116153
considered340621301194596149186206260308337384440
statistically802621301193769114144164200232252297342363383427
significant.1251621301193757111164184211232276322375404422
Results3406470014768131181250281324375
The4806633011946100149
baseline650663301195197133181201221273321
demographic,993663301195098179232286315360414467487530547
clinical156266330119416180133152196241261
cha‑1845663301194193137167
racteristics340677301192975120153200229250286317338382420
laboratory782677301191863118172201247277328357405
findings120967730119234497151172224279315
of1546677301195076
the1644677301192780129
study1795677301193466119173217
cohort340691301194495147200228262
are623691301194169116
listed76069130119173772103149203
in985691301191768
Table1075691301194279133154202
1.1298691301194456
The1375691301194296144
final154069130119234495139159
analysis1721691301194193137157200237256291
included340705301192174118139191245294349
29711705301194996
patients.8297053011955101131151199252282320338
All480719301195980100
pharmacokinetic6037193011963117162191274319365416459482535584615636680
parameters13067193011963109138184266316346394423461
of1789719301196188
di‑1899719301196283113
goxin3407333011953105146166217
-5787333011925
populational6247333011951103157209228272300320371423467486
and1131733301194192145
individualized1297733301191768121141184205257308351371390429475529
data1847733301194993121165
are340747301194574122
summarized483747301193789170251296325346386434489
in994747301192073
Table1089747301194684139160209
2.1319747301194965
WIN14067473011982103166
uses1594747301195389137174
lower1790747301192174146194222
absorption3407613011946101139193223279310331385439
rate802761301193784114161
constant9867613011952105159196228274328358
(ka)1367761301193477144676860702714727613011927
(0.61152176130119348299149191
vs1735761301195391
2.5),1848761301195774124149164
and340775301194598153
absolute515775301194297134187208261291338
bioavailability875775301195273126172216261282302347401422443463493540
(F)143777530119246996
(0.65155577530119247187136183
vs1760775301194280
0.7),1861775301194663110137152
compared2140383301194495175229274302349403
to2564383301192778
DOS.26633833011961127172189
Further2873383301194392120154206254282
differences317738330119507095124172200246298342388425
were36233833011968115143190
observed21403973011953108145194223271319374
between25363973011958108138213261310363
total2921397301193485115161181
plasma3124397301195980125161242287
clearance3433397301194868116161189235288333379
(CL)2140411301192681125151
(6.11231341130119287492134172
vs2507411301194785
6.452613411301195169117162
L/h)2797411301194786140164
and29824113011948101155
extrarenal3159411301195195128158203232280333377398
fracti‑3579411301192859105149182203233
on21404253011953107
(fe)2269425301192852232143260702823484253011926
(0.771239642530119297692140188233
vs2651425301194784
0.783).2757425301195167115161208231245
Changes30244253011959112157210264313350
in3396425301192375
ka349342530119453539432607026
and3590425301194598153
F37654253011948
manifested21404393011982127180200226274311343390446
in2607439301192982
minor27104393011990110163216246
differences2978439301196282108138186215263316360407444
between34444393011963112143218266315368
minimal21404533011982102155175256301322
(Cmin)24834533011926802563460607048619226544533011926
and2702453301194497152
maximal28764533011980125169190271316336
(Cmax)323445330119258033134606070487510234164533011926
concent‑3464453301194495149193240293322349
ration2140467301193075105125178232
-23944673011932
narrowing24484673011956101130160211283304357411
of2881467301195682
the2985467301193386135
curve,31424673011947100128177224240
as3404467301194884
evident3510467301195196117171220273302
from2140481301192757110193
the2356481301193993142
graphic2521481301196292138194248269314
output28574813011962116147203257289
of3168481301196289
both32794813011963118149203
models35044813011991145201251272309
-21404953011930
for2192495301192577106
DOS23204953011964132177
(Fig251949530119257090144
1a)2685495301194786110
and2817495301194497151
for2990495301192578107
Windows31194953011981102155209263334371
(Fig351249530119257191145
1b).3679495301194796119133
It2140509301192153
was22155093011981127165
obvious24025093011962118163185239293330
that2755509301193993139169
WIN29475093011992116182
predicted3153509301196393142198219264298346402
lower3578509301192983156205234
values2140523301194590110161209245
of2407523301194974
pharmacokinetic25035233011951104148176257301345396437459511559589609652
parameters3177523301195196124169249297327373402439
than3637523301192779123176
DOS,21405373011966135181199
but23615373011964118150
there2533537301193993143173221
were27775373011980129159207
no30075373011962116
significant3146537301194566121175196222245290337391421
diffe‑3589537301196384111142190223
rences2140551301193077130175222259
between24215513011962112142217265314368
measured28105513011990139183219271300348403
and32355513011953106160
predicted3417551301196392140195215260293340395
values2140565301194591112164212249
by2411565301195599
both25325653011955109139192
versions2746565301194593122159179232286322
(Table3090565301192676114169191239
3).335156530119497286
The22805793011948106158
distribution2462579301197698137171203226284340374397453510
of29965793011974103
error31235793011969101133188220
on33675793011975132
Bland­3523579301197195142199256289
‑Altman2140593301192985105135214258309
analysis2470593301194193136156198235253288
of2779593301194974
measured28745933011976124167202252280326380
and3274593301194193146
predicted3441593301195079124178197240273318372
SDC21406073011946109167
is2329607301192258
given2409607301195575121168221
in2652607301192275
Fig2749607301194767121
2a2892607301195094
(for3008607301192852104134
DOS)31646073011965133179204
and33906073011947100154
Fig3566607301194767121
2b37096073011950103
(for2140621301192751103133
Windows).22946213011983105158212265337374397411
The27276213011948102151
distribution2900621301195576111143173194248301332353406459
of3381621301195480
errors3483621301195079108160190227
of3732621301195481
predicted2140635301195585132187208252285332387
SDC25496353011954117175
in2746635301192881
both28486353011963117147200
models30706353011989143198247268303
is3395635301192964
given3481635301196282127175228
in3731635301192881
Fig2140649301194666120
2c.2282649301194788106
As2410649301195695
it2527649301191849
is2598649301191955
shown,2674649301193688142213267284
most29806493011979133170201
points32036493011953108128181210249
lie347464930119193887
inside3583649301191871107127181230
the2140663301193183131
limits2292663301191837117137167205
which25186633011968121141184236
indicates2776663301191769123142186231260306342
that3140663301192779123152
there3314663301192779127156202
is3538663301191752
agre‑3611663301194295124170201
ement21406773011949130179232261
between24236773011955105135210258307360
the2805677301193184133
models.29596773011982136191240261296314
Comparison22806913011956106187240285313333368420472
of2773691301194974
measured28686913011977125168204254282328382
and3271691301194193146
predicted3438691301195180126180199242275320374
values2140705301194592112165214251
of2413705301196188
SDC25237053011954117175
is2720705301192965
given2807705301196283128176230
in3059705301192881
Fig3162705301195474129
3a33137053011956101
(for3437705301193458111140
DOS)36007053011972140186212
and21407193011946100155
Fig2317719301195575130
3b24697193011957112
(for2603719301193459112142
WIN).27687193011990112176202217
Comparison30077193011965118201256303332353390444499
of3528719301196188
pre‑3638719301196494142174
dicted2140733301195475119152199254
values2416733301194894115167215252
of2690733301195683
SDC27947333011950113170
in2986733301192477
both30857333011958112142195
models33027333011985138194242263299
is3623733301192460
gi‑3704733301195878108
ven2140747301194593146
in2308747301192072
Fig2402747301194666120
3c.2544747301194891109
There26757473011946100149178225
was29227473011971117154
a30977473011945
close3164747301194464117154203
correlation3389747301194395124154201222267296317370423
between21407613011957108140216266317372
predicted2535761301196495144201222268303351408
and29667613011954109166
measured31547613011992143188226280310359416
SDCs35937613011955120180219
(the2140775301192655107156
Pearson’s2317775301194792136165202255308323357
coefficient2696775301194191140166196217261281328381410
of3128775301194975
correlation3224775301194192121151197218262292312364417
was36637753011968113149
0.0083940383301194965114164214
for4176383301192375104
DOS43023833011962129175
vs4499383301194178
0.3144599383301194662112154197
for4818383301192375105
WIN49443833011979100164
model,51293833011979132188236257273
both54243833011952106136189
P<0.0001)39403973011950104151167216266317360379
and4341397301194295149
between45123973011952101132206254303356
SDCs48903973011943106163201
predicted5113397301195281129184204248281328383
by5518397301195295
both39404113011955109139192
models41544113011982136191239260296
(0.013,447241130119277390139183224240
P<0.0001).47334113011951104151168217267318362380395
Discussion39404370014782114164219287338388419487556
To4080453301194792
our41934533011959110137
knowledge,43514533011948101153223243290344397444458
this4829453301193688107141
study4990453301194373125178221
is5231453301192660
the5312453301193688135
first546745330119325279115145
one39404673011953105151
evaluating4111467301194991135154204247274293344396
quality45274673011954104147166184212257
of4804467301195377
the4901467301193182129
long‑term5050467301192172123176204233278305385
pre‑5455467301195582128157
diction3940481301195473115146164215266
of4226481301194872
serumdrug4318481301193278105157236304331382435
levels4773481301191562104150169202
achieved4995481301194083133151198240286339
by5353481301195091
two5464481301192698149
different394049530119547397125171198243294321
versions4281495301194490117152170221272307
of4608495301195175
the4703495301193081128
same4851495301193579159205
TDM50764953011945109184
software5280495301193687112144217260287333
package.39405093011957103148189236291340355
We43175093011993139
demonstrated44785093011965113196250304340372401447476523579
that5078509301194195140169
formerly5268509301193689118202251280300345
popular,39405233011955107161212230273300310
long‑term4270523301192677129181210239283310390
used,4680523301195892139192207
but49075233011960111140
in5067523301192576
these5163523301193586133168215
times5398523301193554133179214
unsupported39405373011953104138188241294346374406450504
DOS44635373011969135178
version4661537301195095122158176226278
of4959537301195781
the5060537301193587133
MwPharm52135373011982151199250292319399
software3940551301193789113145218262288334
can4294551301194488138
be44525513011955103
used4575551301195287133187
for4781551301192677104
TDM49055513011946110185
of5110551301195377
digoxin5207551301195473125176216235286
in‑5512551301192172100
terchangeably3940565301193176104145197240291344391434487507549
with4509565301197898127179
actually4708565301195194126177220239258300
used5028565301195994141195
Windows52435653011988108159212264334370
version3940579301194591118154172223275
-42355793011935
dosing42905793011959111146164215267
advice45775793011951104147166209254
will4851579301197796115133
not50045793011959110138
be51625793011961109
affected5291579301195074102148192223268322
regardless3940593301193075128171198249267314349383
of4343593301195176
the4438593301192981127
chosen4585593301194394145180226277
version.4882593301194489116152170220272288
TDM40806073011947110186
of4286607301195579
digoxin4385607301195775127178218237288
has4693607301195598133
been48466073011957105152203
used5069607301195589136189
for5278607301192879106
more54046073011984136163209
than3940621301193184128180
5041416213011955101
years4263621301195097140168205
[10].4488621301193377119142157
Based46656213011957102138186240
on49266213011959112
the5059621301193789137
published52176213011962114168188207242294341396
studies,3940635301193869122176195243280296
it4257635301192757
is4335635301192762
considered44186353011951102156191210264312340387442
appropriate48816353011952107162190242297326346389418465
to5367635301193788
tar‑5476635301193783111136
get39406493011954101129
a40896493011948
SDC41576493011949110166
in4343649301192374
the4437649301193485131
therapeutic4588649301193485132159203255303353382401443
range5051649301193276127179226
of5296649301195681
0.55396649301195266114
to5530649301193382
239406633011949
μg/l,4009663301194799133153167
but41966633011958109138
there4354663301193384131158203
is4577663301192357
a46546633011948
large472266330119246693144191
interindividual4933663301192374101146173192242295313356375428478521539
va‑5492663301194891120
riability394067730119304992146165184202232277
[15].4238677301193275115140154
The44136773011952106153
risk458767730119355489129
of4736677301196084
digitalis4841677301196079132150180224243262296
intoxication5157677301192779106157197217260304332351403455
(ADRs)3940691301192782144193229250
increases4210691301192576118145190233267314349
at4579691301194977
serum4676691301194188115166246
concentrations4941691301194999150193237289316343387415433484536570
of5531691301195781
≥2.039407053011959104119165
μg/l4125705301194799132152
[10].4297705301192163104127140
The4457705301194193140
purpose46167053011950101128181233267313
of4949705301194872
blood5041705301194968119171224
concent‑5284705301194089140182227277304328
rationmonitoring394071930119297299117168218313364415433461509536555605656
of4616719301194770
digoxin4706719301194866117168207225275
is5001719301191548
the5069719301192575121
prevention5209719301194976121163208258285303353404
of3940733301195480
ADRs,40407333011966130180217233
especially4294733301195591145194239258302321340384
extracardiac4698733301195699131160205249294322375394437481
ADRs,52007333011966130180217233
and54547333011952104158
digoxin3940747301195473125176216235285
should4245747301193383135186204256
be4521747301195098
administered4639747301194093172190241259293323367394440493
at5152747301194068
minimum5240747301197695145164243293372
effective3940761301194972100146190221239283328
concentrations.4288761301194696147190234285313340384412430481533567583
SDC48917613011948109164
at5075761301194775
0.5–0.95170761301195065112160210225269
μg/l5459761301194799133153
reducesmortality3940775301192973125173215258292386436462493535553570598641
andhospitalizations4600775301193988139205255289339357385427445462499542569587636686719
in5338775301191564
all542177530119395774
HF5514775301195698
Tab.2140258201124992147170
3.2328258201125074
Plasma2447258801074360105135205250
levels271325880107195796133151180
(SDC)2910258801072361115165189
of3115258801074568
digoxin3199258801074564109154190208254
Parameter217127250984585115156225267296338367
measured3268272509868110152186232261303351
predicted403127250984776118166187224255296344
(DOS)439127250982579137178202
predicted490127250984776118166187224255296344
(WIN)526127250982596118173197
SDC217128480953788135
(μg/L)232428480952164108138174196
0.8632022848095395394134
(0.60–1.16)33532848095226074114154197232242277312332
0.8840662848095395394134
(0.60–1.05)42172848095226074114154197232242282320341
0.8349442848095395394132
(0.57–1.19)50942848095215973113151187222232267301321
%PE2171296809559100136
(1)23252968095215773
(%)24152968095217999
-1.341032968095245969109
(-6.442302968095214385100139
–7.1)43872968095407582117133
-3.249612968095246074115
(-11.8–7.2)50942968095214378109120160202238244285305
%PE2171308809559100136
(2)23253088095215979
(%)24223088095217998
-0.449503088095246680119
(-10.2–8.6)50863088095224479114128169208249264304324
RMSE2171320809540103141177
(%)23663208095217998
1.241293208095394990
(0.2–1.3)42373208095215973114153187198238257
25020320809539
(0.6–2.9)50773208095215973113156191205243263
%PE217133280955795129
was231533280955595122
calculated24513328095347390123164180221244277318
as278333280954067
a2865332809540
difference29193328095415778101134157190232266298
between32323328095407598156190224265
predicted35123328095406497137154187212245286
and381233280954182123
measured394933280956398138165205228261302
values42653328095347390131165193
(1),4472332809521557183
and457033280954081122
as470633280954068
a4788332809540
difference48433328095405677100134157190231265298
between51553328095407599156190224266
both543533280954081105146
models2171342809564104145180196223
(2).2408342809522577788
Individualized25113428095165898115149166206247287304321352385426
data295134280954181104143
are31083428095416497
presented32193428095416497125159200223256297
as353034280954067
a3612342809540
median366634280956498139156196237
(interquartile39183428095213778101134157196236277300325342358392
range).432534280952361103143177197209
%PE:217135280955795129143
percentage23293528095407598130163204227266306341
prediction26843528095406497138154188213229269311
error;30103528095335780119143157
RMSE:318235280953999133167181
root337835280952362103127
mean351935280956498139180
square371335280952868109149172205
error;39333528095345780119143158
SDC:410535280953584128143
serum42623528095286285126189
digoxin44663528095405797138170187228
concentration;470835280953372114147180222244267306329345386428441
Fig.33462501124771125149
3.50162501124872
Comparison61863001074891163209254280298328372418
of105363001074366
measured1135630010770108153183227253290335
and148663001074490135
predicted163863001074369106151170207234271316
SDC197163001073792141
values21286300107368098144182213
in235763001071763
DOS2436630010754113151
modela,2603630010770115161199218263279
inWindows289863001071763150168214259305367398
modelb,3312630010770115161199218263277
inWIN360663001071662149167222
and384463001074490135
DOS3996630010754113151
modelc.4163630010769114161199217255271
The445063001073885123
full45906300107216785104
line47106300107163581119
represents484563001072461107133169200238284309341
linear52026300107163581119164190
regression,5408630010724611061321683347400107316178124170186
while536740010762108127145183
the73574001072672110
dashed86274001074590120165203249
line11277400107183783121
is126474001071948
the132874001072772111
line14557400107183783121
of159274001074568
identity167674001071964102149174192218257
(y=x)194974001072459113147170