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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

-

0.4-1.8

56.8 - 84.9

-

-

-

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.