Kairo Vortrag Engl.
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Transcript of Kairo Vortrag Engl.
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Plasma Concentrations of Sulfadiazine and
Pyrimethamine in Pregnants with Primary
Toxoplasmosis and Patients with Ocular
Toxoplasmosis: A Comparison
Cairo 2012 10.10.2012
Harald Hlobil, Justus G. Garweg, Martin Enders,Ute Klarmann, Ingrid Reiter-Owona
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Toxoplasmosis
Self limiting disease,
treatment not necessary
Immunodeficiency:
tachyzoite replication unlimitedlethal without treatment
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6-17 h (mean 10 h)
parasitostatic
46-150 h (mean 100 h)
parasitocidal
Standard Therapy
Elimination half-life
Synergistic activity !
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Sulfadiazine
50 mg/kg, max. 4.0 g
Effective target values:
(50-150 mg/l)
(50-150 g/ml)
Period: 4 weeks
Pyrimethamine
25 mg/day
Effective target values:
(7001300 g/l)
(0.7-1.3 g/ml)
Standard Treatment
In pregnancy (>15th week) and ocular toxoplasmosis
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Study Groups (Outdoor)
Sex: female No.: 21
Age: 17-39 years
Median age 27 years
Treatment 15th week o.p.
I. Ocular Toxoplasmosis II. Pregnant Women
Group IIa No.: 89
Age: 18-42 yearsMedian 30 years
Group IIb No.: 10 Age: 26-38 years
Median 30 years
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Blood Sampling:14 days after onset of therapy
Measurement of Drug Serum Concentrations
Evaluation:Statistics SPSS 20.0
Method:Liquid ChromatographyMass Spectrometry
(LC-MS/MS, AB Sciex, Germany).
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Patients with ocular toxoplasmosis (n = 28)
Serum levels at various intervals after dosage
Effective target values
Steady-state at day 14 after dosage
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Results Pyrimethamine
P < 0.001*
OT PW
MW SD 1680 1323 838 434
Min - Max 29 - 6160 29 - 2550
*Mann-Whitney-U test
Effective target values700-1300 g/l
Ocular Toxoplasmosis Pregnant Women
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Pyrimethamine target values
Below targetWithin targets
Above target
OcularToxoplasmosis
PregnantWomen
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Results Sulfadiazine:
OT PW
MW SD 67.1 43.8 44.5 25.9
Min - Max 9 - 166 9 - 137
P = 0.012*
*Mann-Whitney-U test
Ocular Toxoplasmosis Pregnant Women
Effective target values50-150 mg/l
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Sulfadiazine - target values
Does
preganancy
influence the
serumconcentration?
Below target
Within targets
Above target
OcularToxoplasmosis
PregnantWomen
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Pregnancy and pharmacokinetics
Body volume and weight is increasing
Absorption is decreased
Decreased protein binding capacity
Clearance is increased
glomerular filtration rate ( 50%)
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Body Weight and Pyrimethamine Plasma Concentration
(Group IIb; Dosage 25 mg/day)
Pyrimethaminspiegelverlauf bei 10 Schwangeren in Abhngigkeit der
Zeit nach Therapiebeginn (n=40 Seren - Zeitraum 1/2010-11/2011)
Normwert - : 700-1300 g/l
0
200
400
600
800
1000
1200
1400
1600
1800
0 7 14 21 28 35 42 49 56 63 70 77
Zeit nach Therapiebeginn (d)
Pyrim
ethamin(g/l)
Nr.3-100kg
Nr.18-68 kg
Nr.27-73 kg
Nr.32-72 kg
Nr.34-97 kg
Nr.51-62 kg
Nr.63-120 kg
Nr.100-82 kg
Nr.101-69 kg
Nr.105-86 kg
Green: 62-72 kg Blue : > 80 -120 kg
Serum levels at various intervals after dosage in 10 pregnant women
Time after initiation of therapy (d)
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Sulfadiazinspiegelverlauf bei 10 Schwangeren in Abhngigkeit derZeit nach Therapiebeginn (n=40 Seren - Zeitraum 1/2010-11/2011)
Normwert - : 50-150 mg/l
0
20
40
60
80
100
120
140
160
0 7 14 21 28 35 42 49 56 63 70 77
Zeit nach Therapiebeginn (d)
Sulfadiazin(mg/l)
Nr.3-100 kg
Nr.18-68 kgNr.27-73 kg
Nr.32-72 kg
Nr.34-97 kg
Nr.51-62 kg
Nr.63-120 kg
Nr.100-82 kg
Nr.101-69 kg
Nr.105-86 kg
Initial dosis 3000 mg, thereafter 4000 mg/day
Body Weight and Sulfadiazine Plasma Concentration
(Dosage per kg of BW)
Time after initiation of therapy (d)
Serum levels at various intervals after dosage in 10 pregnant women
Green: 62-72 kg Blue : > 80 -120 kg
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Pregnancy and decrease of Py/SD serum
concentrations
No data published on pharmacokinetics of sulfadiazine andpyrimethamine in Toxoplasma-infected pregnant women!
Treatment study in Rhesus Monkeys (Schoondermark et al.,1995)
CmaxMean values
Nonpregnant (n=2) Pregnant (n=2)160/165*
Pyrimethamine 0.22 g/ml 0.25 g/ml
Sulfadiazine 58.7 g/ml 5.8 g/ml
*days of pregnancy
Sulfadiazine: increased clearance (glomerular filtration)!
Median half-life shorter?
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Inhibitory effect of PY combined with SD(in vitro)
Concn of
sulfadiazine (g/ml)
OD value (103) at the indicated concnapyrimethamine (g/ml)
0 0.01 0.05 0.5
0 83860 85565 67970 7323
0.02 75674 81932 23351* 4227
0.2 39354 14039* 2614* 1514*
2 379 1811 1413 146
a Mean standard deviation; each value represents the results from 8 to 12
replicate wells from 2 or 3 replicate plates. P values were calculated for the
interaction effect. *, P < 104.
Antimicrob. Agents Chemother. September 2000 vol. 44 no. 9 2575-2577
http://aac.asm.org/content/44/9/2575/T1.expansion.htmlhttp://aac.asm.org/content/44/9/2575/T1.expansion.html -
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Effective plasma concentrations during
pregnancy?
Pyrimethamine
(g/ml)
Sulfadiazine
(g/ml
Ratio Literature
Mice 0.1 25 1: 250 Weis et al., 1992
Newborn 1.3-2.2 44 - 86 Ca. 1:35 Schmidt et al., 2006
HIV+, male
AIDS, male
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0.4-1.8
56.8 - 84.9
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Jordan et al., 2004
Klinker et al., 1996
OT MV 1.68 (0.03-6.16) MV 67.1 (9-166) 1:40 Hlobil et al.
PW MV 0.84 (0.03-2,5) MV 44.5 (9-137) 1:53
Problem: Effective drug concentration in
immunocompetent individuals is not yet proven
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Conclusions
Pregnancy signifigantly reduces the serum
concentration of SD and PY
Dose-optimation studies are necessary for
different patient groups
The relationship between drug levels and
the therapeutic response needs definition
Measurement of the drug serum concen-
tration is necessary during pregnancy
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Harald Hlobil
Laborrzte Sindelfingen
Vogelhainweg 4 - 671065 Sindelfingen
Justus Garweg
Bremgartenstrasse 119
CH - 3012 Bern
Martin Enders
Veronika Rilling
Rosenbergstrae 85
70193 Stuttgart
INSTAND e.V.
Gesellschaft zur Frderung der
Qualittssicherung in
medizinischen Laboratorien e.V.
Acknowledgment
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Therapie: Fansidar 1x (500mg SDOX und 75 mg PYR)
Plasma concentrations od SDOX and PYR were significantlylower in pregnant women!
Karunajeewa HA, et al. 2009. Pharmacokinetic properties of sulfadoxine-pyrimethamine in
pregnant women. Antimicrob. Agents Chemother. 53:43684376.