Pharmakokinetische Grundlagen und Pharmakodynamik beim ... · Pharmakokinetische Grundlagen und Pharmakodynamik beim Schwerkranken Fritz Sörgel Institut für Biomedizinische und

Pharmakokinetische Grundlagen und Pharmakodynamik beim Schwerkranken

Fritz SörgelInstitut für Biomedizinische und

Pharmazeutische ForschungNürnberg-Heroldsberg

Dose

Effect

Plasma Concentration

BLACK BOX

U

Pharmakokinetik Pharmakokinetik von Antibiotikavon Antibiotika

Zeit

Kon

zent

ratio

n

T 1/2


Zeit

Kon

zent

ratio

n

T 1/2

AUC


Zeit

Kon

zent

ratio

n

T 1/2

AUC

Clearance = Dosis : AUC


Zeit

Kon

zent

ratio

n

T 1/2

AUC

Clearance = Dosis : AUC Verteilungsvol.

SEPSISSEPSIS

IncreasedCardiac Index

IncreasedClearances

Low Serum DrugConcentrations

Low Serum DrugConcentrations

IncreasedPermeabillityFluid Shifts

IncreasedVolume ofDistribution

End OrganDysfunction

Increased Drug Half-

Lives

DecreasedClearances

High Serum DrugConcentrations

High Serum DrugConcentrations

Antimicrobial Creatinine clearance

> 80 ml/min 80-50 ml/min 50-10 ml/min < 10 ml/min

Cefotaxime 2-3g/6-8h 1-2g/6-8h 1-2g/8h 1-2g/24hVancomycin 15-25 mg/kg/12h 1g/24h 1g/3-5 days 1g/7 daysImipenem/ccilastatin 0.5-1g/6-8h 0.5-1g/8h 0.5-1g/12h 0.5-1g/24hAmoxicillin/clavulanic acid 1-2g/100-200mg/6-8h 1-2g/100-200mg/6-8h 1-2g/100-200mg/12h 1-2g/100-200mg/24hTobramycin 3-5mg/kg/24h 3-5mg/kg/24h 1-3mg/kg/24h 0.5-1mg/kg/24hCiprofloxacin 200-400mg/8-12h 200-400mg/8-12h 200-400/8-12h 250-500mg/12hCeftazidime 1-2g/8-12h 1-2g/8-12h 1g/12-24h 0.5g/24hErythromycin 30-50mg/kg/24h 30-50mg/kg/24h 30-50mg/kg/24h 30-50mg/kg/24hCeftriaxone 2-4g/24h 1-2g/24h 1-2g/24h 0.5-1g/24hPiperacillin/tazobactam 4g/0.5g/6h 4g/0.5g/6h 4g/0.5g/8h 4g/0.5g/12hMeropenem 1-2g/8-12h 1-2g/8-12h 0.5-1g/8-12h 1g/24hPiperacillin 4g/6h 4g/6h 4g/8h 4g/12h

The first 3 doses every 12 hours.Maximum 600 mg if bodyweight >50kg and 450mg if bodyweight <50kg.

Amikacin

Pyelonephritis

6 DaysAminoclycosides 3 Weeks

Relaps Discharge

1.0 l / kg

0.19

0.55

0.2

Jeliffe, 1998

Plasma Concentration Vs Time

0

2

4

6

8

10

12

0 5 10 15 20 25 30Time (hrs)

Plas

ma

Con

c (m

cg/m

L)

Subject 1Subject 2Subject 3Subject 4Subject 5Subject 6Subject 7Subject 8Subject 9Subject 10Subject 11Subject 12Subject 13Subject 14Subject 15Subject 16Subject 17Subject 18Subject 19Subject 20

Plasmakonzentrations- Zeitkurven nach 500 mg Levofloxacin bei 20 schwerstkranken Patienten einer Intensivstation (Apache II-Score > 20)

AUC: 25.414.140.239.232.7

194.7

MIC90=1µg/ml

PD Dr. Barth, 2003

Intermittent treatment group

(n = 10)

Continuous infusion treatment group

(n = 10) Sex (f / m) 5 / 5 4 / 6 Age [years] 59 ± 16 (38-78) 62 ± 16 (34-80) Height [cm] 170 ± 7 (158-184) 171 ±8 (160-180) Weight [kg] 78 ± 14 (60-105) 73 ± 8 (60-90) BSA [m²] 1.89 ± 0.16 (1.60-2.13) 1.84 ± 0.14 (1.60-2.09) SAPS II- Score 43 ± 12 (22-62) 44 ± 14 (28-77) APACHE II- Score 28 ± 5 (20-33) 26 ± 6 (18-36) SOFA- Score 6 ± 3 (1-10) 7 ± 2 (4-10) Creatinine clearance [mL / min] 128 ± 35 (91-187) 122 ± 33 (75-177) ICU-LOS at study begin [d] 12 ± 7 (4-24) 14 ± 8 (7-35) Outcome (survivor / non-survivor)

8 / 2 9 / 1

PK/PD of imipenem / cilastatin in critically ill patients with normal renal function

Intermittent infusion group: 1g/1g IMI/CIL tid, as 40-min infusionContinuous infusion group: 2g/2g IMI/CIL daily + loading dose

Average ±±±± SD plasma concentrations of imipenem

0

5

10

15

20

25

0 8 16 24 32 40 48 56 64 72

Time after start of first dose (h)

Imip

enem

con

cent

ratio

n (m

g/L) Continuous treatment group

Intermittent treatment group

Median, 90% and 50 % prediction intervals derived from 10,000 simulated ICU patients for imipenem

0

10

20

30

40

50

60

0 6 12 18 24 30 36 42 48 54 60 66 72

Time after first dose (h)

25 % percentile

5 % percentile

50 % percentile

75 % percentile

95 % percentile

Raw data0

10

20

30

40

50

60

0 6 12 18 24 30 36 42 48 54 60 66 72

Time after first dose (h)

1g imipenem tid for 3 days as 40-min iv infusionLoading dose: 1g IMI

as 40-min infusion;Maintenance dose: 2g/day as continuous infusion starting at 4-h

Probability for target attainment for imipenem in critically ill patients

Target = bacteriostasis Target = maximal kill

Intermittent treatment:1g imipenem tid for 3 days as 40-min iv infusionContinuous treatment:Loading dose: 1g IMI as 40-min infusion;Maintenance dose: 2g/day as continuous infusion starting at 4-h

0.0

0.2

0.4

0.6

0.8

1.0

0.125 0.25 0.5 1 2 4 8 16 32 64MIC (mg/L)

Continuous

Intermittent

0.0

0.2

0.4

0.6

0.8

1.0

0.125 0.25 0.5 1 2 4 8 16 32 64MIC (mg/L)

Continuous

Intermittent

Einfluß von geändertenEinfluß von geänderten PlasmakonzentrationenPlasmakonzentrationenaufauf die Pharmakodynamik die Pharmakodynamik eines Antibiotikumseines Antibiotikums

1*Conc

10,731750,54205,407718,312421,244646,1962820,16161,136602,118419,105058,095109,087578,081763,077171,0734520,07036,067722,065415,063353,061474,059734,058103,056558,055084,053669

Zeit

Ko

nze

ntr

atio

n

MHKMHK

Normalwerte


1*Conc

10,731750,54205,407718,312421,244646,1962820,16161,136602,118419,105058,095109,087578,081763,077171,0734520,07036,067722,065415,063353,061474,059734,058103,056558,055084,053669

Zeit

Ko

nze

ntr

atio

n

MHKMHK

Normalwerte + Interaktion/ Erkrankung


1*Conc

10.731750.54205.407718.312421.244646.1962820.16161.136602.118419.105058.095109.087578.081763.077171.0734520.07036.067722.065415.063353.061474.059734.058103.056558.055084.053669

Zeit

Ko

nze

ntr

atio

n

MHKMHK

Normalwerte + Interaktion/ Erkrankung

- Interaktion

Individualisierung der AntibiotikatherapieIndividualisierung der AntibiotikatherapieIndividualisierung der AntibiotikatherapieIndividualisierung der AntibiotikatherapieOderOderOderOder

ONE SIZE FITS ALL ?ONE SIZE FITS ALL ?ONE SIZE FITS ALL ?ONE SIZE FITS ALL ?

The Therapeutic OrphanThe Therapeutic Orphan

NEWBORN RENAL FUNCTION

Very low Glomerular Filtration Rate (GFR)Delicate balance between vasoconstrictor and

vasodilatory renal forcesLow mean arterial pressure and high intrarenal

vascular resistanceLimited postnatal renal functional adaptation to

endogenous or exogenous stress

Neonates No. of Gestational Weight Crown heel CLCRFemales age length/ Males (weeks) (kg) (cm) (ml/min/1.73 m2)

Pre-Term 10 / 13 32 +/- 2 1.87 +/- 0.53 42.7 +/- 3.4 23.2 +/- 6

Full-Term 5 / 9 39 +/- 1 3.17 +/- 0.487 49 +/- 3 43.4 +/- 10.7

Pharmacokinetics of meropenem in neonates

� Single dose of meropenem as a 30-min iv infusion.

� Pre-term and full-term infants subdivided into 3 subgroups each:

� Subgroup 1: 10 mg/kg meropenem� Subgroup 2: 20 mg/kg meropenem� Subgroup 3: 40 mg/kg meropenem

0.1

1

10

100

0 2 4 6 8 10 12 14 16 18 20 22 24Time (h)

Con

cent

ratio

n (µ

g/m

L) 10 mg/kg20 mg/kg40 mg/kg

0.1

1

10

100

0 2 4 6 8 10 12 14 16 18 20 22 24Time (h)

Con

cent

ratio

n (µ

g/m

L) 10 mg/kg20 mg/kg40 mg/kg

Meropenem plasma concentrations in neonates after a 30-min intravenous infusion

Pre-term neonates Full-term neonates

Meropenem clearance vs.

Creatinine clearanceTotal body weight

Prob

abili

ty o

f ta

rget

atta

inm

ent

MIC (mg/L) MIC (mg/L)

Probability of target attainment of meropenem for bacteriostasis (black curve) and

maximal bacterial kill (red curve)Pre-term neonates Full-term neonates

At a dose of 20 mg/kg tid robust (>90%) probability of maximal kill:- for MICs ≤ 8 mg/L for pre-term neonates and - for MICs ≤ 4 mg/L for full-term neonates

Meropenem gestational age vs. clearance totalMeropenem gestational age vs. clearance total

y = 0.7301x - 19.519R2 = 0.6652

0

2

4

6

8

10

12

14

16

27 29 31 33 35 37 39 41 43

Gestational age (weeks)

CLto

t (m

L/m

in)

y = 0.7301x - 19.519R2 = 0.6652

0

2

4

6

8

10

12

14

16

27 29 31 33 35 37 39 41 43

Gestational age (weeks)

CLto

t (m

L/m

in)

Meropenem creatinine clearance vs. clearance total

Meropenem creatinine clearance vs. clearance total

y = 0.2204x - 0.9009R2 = 0.6701

0

2

4

6

8

10

12

14

16

0 10 20 30 40 50 60 70

CLCR (mL/min/1.73 m2)

CLto

t (m

L/m

in)

y = 0.2204x - 0.9009R2 = 0.6701

0

2

4

6

8

10

12

14

16

0 10 20 30 40 50 60 70

CLCR (mL/min/1.73 m2)

CLto

t (m

L/m

in)



Die Pharmakokinetik von X - Floxacin ist unabhängig vom Geschlecht

Die Pharmakokinetik von X - Floxacin ist geschlechtsunabhängig

Die Pharmakokinetik von X - Floxacin ist unabhängig vom Alter

Die Pharmakokinetik von X - Floxacin ist geschlechtsunabhängig

Die Pharmakokinetik von X - Floxacin ist unabhängig vom Alter

Die Pharmakokinetik von X - Floxacin ist unabhängig vom Gewicht

AUCAUC--Werte nach Gabe von Werte nach Gabe von 600 mg 600 mg Grepafloxacin imGrepafloxacin im SteadySteady--State (Mean State (Mean ±±±±±±±± SD)SD)

Altersgruppen (in Jahren)Alter (a) 40 - 49 50 - 59 60 - 69 > 70

Männer (n=6) 44.0 ±±±± 2.2 53.8 ±±±± 3.4 64.2 ±±±± 3.4 74.5 ±±±± 3.3Frauen (n=6) 44.5 ±±±± 1.8 54.5 ±±±± 3.3 64.5 ±±±± 2.7 72.7 ±±±± 1.9

Gewicht (kg)

Männer (n=6) 89.8 ±±±± 9.0 81.1 ±±±± 13.5 79.3 ±±±± 6.4 75.8 ±±±± 9.1Frauen (n=6) 70.7 ±±±± 11.1 65.9 ±±±± 10.3 67.7 ±±±± 5.3 65.4 ±±±± 8.7

AUCss24h (mg�h/L)

Männer (n=6) 24.6 ±±±± 7.2 29.9 ±±±± 5.1 30.7 ±±±± 12.6 28.7 ±±±± 6.2Frauen (n=6) 35.3 ±±±± 5.2 35.5 ±±±± 8.1 37.3 ±±±± 9.8 41.3 ±±±± 10.2

C. Efthymiopoulos et al. Clin. Pharmacokinet. 1997; 33 Suppl. 1

AUCAUC--Werte nach Gabe von Werte nach Gabe von 600 mg 600 mg Grepafloxacin imGrepafloxacin im SteadySteady--State (Mean State (Mean ±±±±±±±± SD)SD)

Altersgruppen (in Jahren)

Alter (a) 40 - 49 50 - 59 60 - 69 > 70

Männer (n=6) 44.0 ±±±± 2.2 53.8 ±±±± 3.4 64.2 ±±±± 3.4 74.5 ±±±± 3.3Frauen (n=6) 44.5 ±±±± 1.8 54.5 ±±±± 3.3 64.5 ±±±± 2.7 72.7 ±±±± 1.9

Gewicht (kg)

Männer (n=6) 89.8 ±±±± 9.0 81.1 ±±±± 13.5 79.3 ±±±± 6.4 75.8 ±±±± 9.1Frauen (n=6) 70.7 ±±±± 11.1 65.9 ±±±± 10.3 67.7 ±±±± 5.3 65.4 ±±±± 8.7

AUCss24h (mg�h/L)

Männer (n=6) 24.6 ±±±± 7.2 29.9 ±±±± 5.1 30.7 ±±±± 12.6 28.7 ±±±± 6.2

Frauen (n=6) 35.3 ±±±± 5.2 35.5 ±±±± 8.1 37.3 ±±±± 9.8 41.3 ±±±± 10.2


AUCAUC--Werte nach Gabe von Werte nach Gabe von 600 mg 600 mg Grepafloxacin imGrepafloxacin im SteadySteady--State (Mean State (Mean ±±±±±±±± SD)SD)Alter (a) 40 - 49 50 - 59 60 - 69 > 70

Männer (n=6) 44.0 ±±±± 2.2 53.8 ±±±± 3.4 64.2 ±±±± 3.4 74.5 ±±±± 3.3

Frauen (n=6) 44.5 ±±±± 1.8 54.5 ±±±± 3.3 64.5 ±±±± 2.7 72.7 ±±±± 1.9

Gewicht (kg)

Männer (n=6) 89.8 ±±±± 9.0 81.1 ±±±± 13.5 79.3 ±±±± 6.4 75.8 ±±±± 9.1

Frauen (n=6) 70.7 ±±±± 11.1 65.9 ±±±± 10.3 67.7 ±±±± 5.3 65.4 ±±±± 8.7

AUCss24h (mg�h/L)

Männer (n=6) 24.6 ±±±± 7.2 29.9 ±±±± 5.1 30.7 ±±±± 12.6 28.7 ±±±± 6.2

Frauen (n=6) 35.3 ±±±± 5.2 35.5 ±±±± 8.1 37.3 ±±±± 9.8 41.3 ±±±± 10.2


Clearance von Grepafloxacin

(normiert nach verschiedenen Verfahren)

CL/F CL/F/BW CL/F/BSA CL/F/LBM

(ml/min) (ml/min/kg) (ml/min/m2) (ml/min/kg)

Männer(M) 378 ±±±± 110 4.66 ±±±± 1.21 190 ±±±± 49 6.4 ±±±± 1.69

Frauen (F) 279 ±±±± 60 4.17 ±±±± 0.77 160 ±±±± 30 6.36 ±±±± 1.17

Ratio M/F 1.35 1.12 1.19 1.01

Die Pharmakokinetik von X-Floxacin ist im Alter, bei Frauen oder bei niedrigem

Gewicht nicht verändert

PlasmaspiegelDen Kliniker interessieren die

unkorrigierten Konzentrationen

Mechanismus der AusscheidungFür den Pharmakokinetiker interessant,

mL/min/kg

Die Pharmakokinetik von X-Floxacin ist nicht verändert - also keine Dosisänderung-

Plasmaspiegel vs. Pharmakodynamik

1*Conc

10,731750,54205,407718,312421,244646,1962820,16161,136602,118419,105058,095109,087578,081763,077171,0734520,07036,067722,065415,063353,061474,059734,058103,056558,055084,053669

Zeit

Konz

entra

tion

MHK

Toxizität

70 % des Gewichtes

�Normalgewicht�

Sollen beide die gleiche Dosis bekommen ?

�One size fits all�

U

Individualisierung der AntibiotikatherapieIndividualisierung der AntibiotikatherapieIndividualisierung der AntibiotikatherapieIndividualisierung der Antibiotikatherapie

No Effect of Body Weight on PEG-INF alpha 2aClearance in Healthy Subjects

Pooled Data Basic Model

0

50

100

150

200

250

40 50 60 70 80 90 100 110Weight (kg)

CL

(mL/

h)

N = 285, 3 N = 285, 3 ClinClin PharmPharm StudiesStudies

55

60

65

70

75

80

85

90

95

100

Vert

eilu

ngsv

olum

en (L

)HCV Woche 1

Gesunde

Gesunde 70-74 Jahre HCV Woche 4

NI vor HD

NI 10-29NI 50-78NI 30-49

Gesunde 65-69 JahreGesunde 20-45 Jahre NI nach HDGesunde 75-80 Jahre Gesunde

Verteilungsvolumen von Interferon alpha 2b in den FDA-Studien

0

5

10

15

20

25

Vert

eilu

ngsv

olum

en (L

)HCV 180µg sc SD

HCV 180µg sc MDHCV zirrh. 90µg sc SD

HCV zirrh.180µg sc SD

NI 60-80

NI 40-60NI 20-40

Gesunde 180µg sc >60 Jahre

HCV 270µg sc SDNI 80-100

HCV 45µg sc MD

Gesunde 180µg sc 18-25 JahreGesunde 180µg sc

HCV 135µg sc MDHCV 270µg sc MDHCV 180µg sc MDHCV 90µg sc MDGesunde

HCV 180µg sc SDHCV zirrh. 90µg sc MD

Gesunde 90µg ivHCV 135µg sc SDHCV 45µg sc SDGesunde 180µg sc

HCV 180µg sc SDGesunde Männer 180µg sc

HCV 90µg sc SD Gesunde Frauen 180µg sc

Gesunde 90µg iv

Verteilungsvolumen von Interferon alpha 2a in den FDA-Studien

0

10

20

30

40

50

60

70

80

90

100Ve

rteilu

ngsv

olum

en (L

)

Interferon alpha 2b

Interferon alpha 2a

Verteilungsvolumen von Interferon alpha 2a und 2b in den FDA-Studien

Kritik der reinenNorm

Klinische Forschung hilft vor allem StandardpatientenVon Harro Albrecht

Ausgabe 2, 2005

Summerskill W.Evidence-based practice and the individual.

Lancet. 2005 Jan 1;365(9453):13-4.

Response by Body Weight in Non-US Centres: PEGASYS® + COPEGUS® SVR (95% CIs)

SVR

(%)

73

6762 61

40

30

50

60

70

80

Weight (Kg)

Data presented to FDA

< 64 < 74 75-85 85 - 98

PEGASYS® 180 µg + COPEGUS® 1000�1200 mg

Response by Body Weight in Non-US Centres:

PEG-IFN alfa-2b (12KD) + RBV SVR (95% CIs)

Data presented to FDA

40

30

50

60

70

80

SVR

(%)

Weight (Kg)

55

69

5552

≤≤≤≤ 64 >64 ≤≤≤≤ 74 >74 ≤≤≤≤ 84 >84

Peginterferon alfa-2b 1.5 µg/kg + RBV 800 mg

Site of infectionSite of infection

Healthy volunteers

Intensive care patients

Brain

MicrodialysisBrain pressure probe

Lung

Skin incision

Probe entering lung tissue

0 50 100 150 200 250

1

10

100

free serum musclepi

pera

cilli

n co

ncen

tratio

n (µ

g/m

l)

time (min)0 50 100 150 200 250

1

10

100

intensive care patientshealthy volunteers

free serum muscle

time (min)

Penetration of Piperacillin into soft tissues

Brunner et al. (1999)

Lung

Skin incision

Probe entering lung tissue

Macrolides and quinolones accumulate inside Macrolides and quinolones accumulate inside cells. Key pathogens are outside the cells.cells. Key pathogens are outside the cells.

Bacteria, such as Streptococcuspneumoniae, form in clusters in the interstitial space

Macrolides and quinolones antibiotics accumulatelargely inside cells

β-lactam antibiotics are located largelyin the interstitial space

Cars. Diagn Microbiol Infect Dis 1997;27:29�34

DISTRIBUTION OF DRUGS IN THE HUMAN BODY

Blood

Flow

Extracellular Water

IntracellularWater

Plasma Proteins

EndothelialMembrane

Cell

Drug Molecule

Kon

zent

ratio

n (m

g/l b

zw.

mg/

kg)

Zeit (h)15

Serum

24930

11

9

7

5

3

1

2118126

Lungengewebe

Einzeldosis 500 mg Levofloxacin p.o.

Konzentration am Infektionsort

Lee LJ et al (1996), ASHP; Isaacson DM et al (1997), Recent Res Dev Antimicrob Agents Chemother

MHK90 (mg/l)S. pneumoniae 1.0M. catarrhalis 0.06

H. influenzae 0.01S. aureus 0.25K. pneumoniae 0.25E. coli 0.12C. pneumoniae 0.5M. pneumoniae 0.5L. pneumophila 0.03

MHK

Lunge als ganzes Stück

Stück im

Reagenzglas

mit Puffer Beim Ultraturrax

Homogenisiert Zentrifugiert

Kon

zent

ratio

n (m

g/l b

zw.

mg/

kg)

Zeit (h)15

Serum

24930

11

9

7

5

3

1

2118126

Lungengewebe

Einzeldosis 500 mg Levofloxacin p.o.

Konzentration am Infektionsort

Lee LJ et al (1996), ASHP; Isaacson DM et al (1997), Recent Res Dev Antimicrob Agents Chemother

MHK90 (mg/l)S. pneumoniae 1.0M. catarrhalis 0.06

H. influenzae 0.01S. aureus 0.25K. pneumoniae 0.25E. coli 0.12C. pneumoniae 0.5M. pneumoniae 0.5L. pneumophila 0.03

MHK

InfektionsortInfektionsort

Lower Respiratory SystemLower Respiratory System

Penetration of Drugs Into Tears, Sweat, Nasal Secretions, Liquor

Blister Fluid, Epithelial LiningFluid Microdialysis

Blood Membrane

Drug

ELF

Penetration of Drugs Into Tears, Sweat, Nasal Secretions,

LiquorBlister Fluid, Epithelial Lining Fluid

Microdialysis

Blood Membrane

Drug

ELF

Bronchial Mucosa

Penetration of Drugs Into Tears, Sweat, Nasal Secretions,

LiquorBlister Fluid, Epithelial Lining Fluid

Microdialysis

Blood Membrane

Drug

ELF

Suck it ?


Blister Fluid, Epithelial Lining FluidMicrodialysis

Blood Membrane

Drug Drug

Warm Saline> 50 mL

BAL


Blister Fluid, Epithelial Lining FluidMicrodialysis

Blood Membrane

Drug

DrugConcentration low

BioanalyticalProblem

Which dilution do we have ?

Warm Saline> 50 mL

BAL

Calculation of drug concentrations in ELF

Drug Concentration in ELF =

Drug conc. in BAL x urea conc in plasmaurea conc in BAL

Urea - Method of Analysis

Previously: Enzymatic methods

Urea + H2O + urease →→→→ 2 NH3 + CO2

GLDH2-Oxoglutarate + NADH + NH4

+ L-Glutamate + NAD+ + H2O

NADH consumption in an enzymatic reaction correlates with ammonia

Previously: Enzymatic methods

Values for urea in BAL vary quite significantly

From 1µg/mL to 40µg/mL

We failed to construct a standard curve in the range where concentration of urea in BAL were expected.

We found one publication in which the lowest measure of the concentration was claimed to be as little as 60 ng/mL. It is very unlikely that simple UV-photometry can pick up such low levels of urea in a complex matrix.

Urea - Method of Analysis

DerivatisationDerivatisation of Ureaof Urea

C NH2

OH2N + C C O C C

FF

F

OOFF

F

C N H

OH2N C C

FF

F

O

C CF

FF

O

HO+

Analyte

Reaction of Internal Standard (IS)Reaction of Internal Standard (IS)

C NH2

OH2N + C C O C C

FF

F

OOFF

F

C N H

OH2N C C

FF

F

O

C CF

FF

O

HO+

IS

***

***

urea-13C-15N2

IN T R A P U L M O N A R Y C O N C E N T R A T IO N S O F B E T A -L A C T A M A N T IM IC R O B IA L A G E N T S

B ro n c h ia l A lv e o la r T im e P o s t D o s e (h ) S e ru m M u c o s a E L F M a c ro p h a g e D ru g D o s e (n u m b e r o f d o s e s ) (µµµµ g /m L ) (µµµµ g /g ) (µµµµ g /m L ) (µµµµ g /m L ) A m o x ic illin 5 0 0 m g 1 -2 (1 ) 6 .9 0 2 .9 9 0 .8 9 0 A m o x ic illin 5 0 0 m g Q 8 h ? (1 3 ) 4 .1 3 2 .6 8 C e fd in ir 3 0 0 -6 0 0 m g 4 (1 ) 2 .0 -4 .2 0 .7 8 -1 .1 4 0 .2 9 -0 .4 9 0

C e f ix im e 2 0 0 -4 0 0 m g /d a y 4 (> 1 ) 3 .9 -6 .6 1 .5 -2 .4 C e fu ro x im e 5 0 0 m g 6 (1 ) 1 .1 0 0 C e fp o d o x im e 2 0 0 m g 3 -6 (1 ) 1 .8 5 -1 .4 0 0 .8 9 -0 .8 4 0 .2 2 -0 .1 2 C la v u la n ic a c id 2 5 0 m g 1 -2 (1 ) 5 .2 5 1 .6 5 0 .9 6 0 .7 6 P ip e ra c illin 2 -4 g Q 6 h 0 .5 -0 .7 4 (4 ) 8 5 .2 -1 9 6 2 5 .4 -9 7 .7

D . N ix , In f . D is . C lin . N o rth A m e ric a 1 2 (3 ), 1 9 9 8

Linezolid (M) > 1Telithromycin 4.8 ( 2h ) to 14.8 (24 h ) Trovafloxacin 2.75 ( Study by us )Gemifloxacin 1.99 ( Study by us )Ceftidoren 0.3 ( Study by us )Meropenem close to 1 (in a VAP - study)

FlüssigFest

HPLC Chromatograph 10-50 µL

10 �300 mg

4 - 24 Stunden schütteln

Penetration of Betalactams into bone 1h after administration

0

20

40

60

80

100

120

140

160

180

200

Fluclox

acillin

Pen G

Dicloxa

cillin

Amoxici

llinAmpic

illinMez

locillin

Oxacil

linPipe

racillin

Ticarci

llinCefu

roxim

e

Cefu. (i

nfecte

d bon

e)Cefa

mandole

Cefo

tiam

Clavulan

ic ac

id*Taz

obacta

mSulb

actam

Pen

etra

tion

(%)

minimummaximumnot measurableone value

Penetration of Betalactams into bone 1h after administration

0

20

40

60

80

100

120

140

160

180

200

Fluclox

acillin

Pen G

Dicloxa

cillin

Amoxici

llinAmpic

illinMez

locillin

Oxacil

linPipe

racillin

Ticarci

llinCefu

roxim

e

Cefu. (i

nfecte

d bon

e)Cefa

mandole

Cefo

tiam

Clavulan

ic ac

id*Taz

obacta

mSulb

actam

Pen

etra

tion

(%)

minimummaximumnot measurableone value

Umfrage

0

20

40

60

80

100

120

1

[% ]

FastingAdministration 5 min before French BreakfastAdministration 5 min after FDA Breakfast

French Breakfast: 2 slices of toast, 1 peace of butter, 1 slice of ham, 1 slice of cheese, 240 mL orange juice.

FDA Breakfast: 2 slices of toast with butter, 2 eggs fried in butter, 2 strips of bacon, 113 g hash brown potatoes, 240 mL whole milk.

Influence of Food on AUC of Clavulanic acid



MEROPENEM IN PRETERM NEONATES

Mean (SD) Min Max

Cmax (µg/mL) 20.5 (3.45) 15.2 25.6tmax (h) 0.62 (0.12) 0.50 1.05t1/2 (h) 3.22 (0.69) 2.13 4.47Vdss (l) 0.90 (0.43) 0.3991.57CLtot (mL/min) 3.80 (1.67) 1.69 6.20

Van den Anker, Martinkova, Kinzig-Schippers, Pokorna, De Groot, Drusano, Sörgel 2004: in preparation

MEROPENEM IN TERM NEONATES

Mean (SD) Min Max

Cmax (µg/mL) 21.7 (4.51) 17.5 28.5tmax (h) 0.50 (0.00) 0.50 0.50t1/2 (h) 2.46 (0.74) 1.34 3.15Vdss (l) 1.64 (0.39) 1.20 2.23CLtot (mL/min) 8.88 (3.46) 4.88 13.8

Documents

Pharmakokinetische Grundlagen und Pharmakodynamik beim ... · Pharmakokinetische Grundlagen und Pharmakodynamik beim Schwerkranken Fritz Sörgel Institut für Biomedizinische und