PRAZIQUANTEL DOSING FOR YOUNG
CHILDREN,
WHAT DO WE NEED TO GET IT RIGHT ?
Amaya Bustinduy
Paediatric Infectious Diseases
Research Group
Institute of Infection and Immunity
St George’s University of London
Russell Stothard
William Hope
Steve Ward
Narcis Kabatereine
David Waterhouse
Jose Sousa Figueiredo
Janet Scott
Govert Van Damm
Outline
•  Praziquantel in young children- what is the evidence for
safety and efficacy.
•  First pharmacokinetic study in children conducted in a Sm
endemic area (Uganda).
•  Controversies regarding active component of PZQ- R/S
enantiomer conundrumà is it a species dependent effect?
•  Needed future studies
Schistosomiasis in preschool children
Current Mass Drug Administration Programmes DO NOT target preschool
children. Why?
Exposure (water contact) during childhood
passive
infant (1 yr) toddler (1-­‐3yrs) active
pre-­‐school (< 5 yrs) First treatment for the under-fives is delayed until school entry translating as
6 years of accumulating morbidity
PRAZIQUANTEL
•  Praziquantel (PZQ) is the only approved drug for the treatment
of all types of schistosomiasis. ( exception: Oxaminiquine in
Brasil for S. mansoni)
•  WHO recommended Pediatric doses (40 mg/kg-60 mg/kg)
extrapolated from adult data.
•  Out of the two PZQ enantiomers (R-PZQ and S-PZQ) R-PZQ
is thought to be the biologically ACTIVE component with less
bitter taste.
•  Used safely in preschool children
•  S. haematobium (Mutapi F et al. PLNTD, 2011)
•  S. mansoni - Documented poor cure rates of PZQ in Uganda in
Preschool children. (Sousa-Figueiredo et al. Plos NTD (2012))
schistosomule
Praziquantel
PRAZIQUANTEL ENANTIOMERS ( R-, S-)
Species
S.japonicum
S.japonicum
Type of study
Active
Reference
enantiomer
Rabbits
R-PZQ
Liu YH,for
(Chinese medical
What
is the evidence
journal ,1986 )
S.
haematobium?
In vitro,
Murine
R-PZQ
Liu YH, Chinese medical
journal 1993)
S.japonicum
Human study
(Levo, racemate)
R-PZQ
Wu MH, (Chinese medical
journal 1991)
S. mansoni
Murine
R-PZQ
Xiao SH, Catto, (JID,1989)
S. mansoni
In vitro/Murine
R-PZQ
Meister et al. (AAC, 2014)
S. mansoni
Are
all
species
the
Murine
S-PZQ
Irie et al. (AJTMH, 1989)
sameS-PZQ
?? Tanaka et al (AJTMH,1989)
Murine
S. mansoni
PK/PD- Human
S-PZQ
Bustinduy et al.
(submitted)
S. mansoni
The PK/PD study- (Schistosoma mansoni)
Lake Albert-­‐Uganda Schistosomiasis hot
spot
Prevalence > 60-70 %
Methods
60 children included
S. mansoni positive
Praziquantel
40 mg/kg
N=30
Praziquantel
60 mg/kg
N=30
Blood draws:
Baseline, 1h, 2h, 4h, 6h, 12 h, 24 h post PZQ
N=1
Unwell -excluded
PK: Pharmacokinetic analysis
(LC/MS)
N=59
N=2
lost to follow up
PD: Pharmacodynamic analysis
24 day parasitology follow up
N=58
Results - Individual PK distribution
S-PZQ
40
40
R-PZQ
mg/kg
mg/kg
60
60
mg/kg
mg/kg
4500.0
4000.0
4000.0
3500.0
3500.0
3000.0
3000.0
Concentration (ng/ml)
Concentration (ng/ml)
4500.0
2500.0
2000.0
1500.0
1000.0
2500.0
2000.0
1500.0
1000.0
500.0
500.0
0.0
0
4
8
12
Time (Hours)
16
20
24
0.0
0
4
8
12
Time (Hours)
16
20
24
Results -PD- S. mansoni egg clearance
Egg reduction
rate
(ERR)
Cure rate
(CR)
40 mg/kg
82(79-84)
68 (49-85)
60 mg/kg
91(89-94)
82(63-94)
P value
< 0.0001
0.3578
Results - CCA and CAA
Individual CAA levels
60 mg/kg
200000
150000
P < 0.05
100000
PZQ mg/ml
60
50000
0
40
CAA base
CAA 4h
CAA 24 h
CAA 24 days
Individual CAA levels
40 mg/kg
20
250000
0
200000
Cured
Non-Cured
Urine CCA
150000
100000
50000
0
CAA base
CAA 4h
CAA 24 h
CAA 24 days
PK and PD relationship
Mean AUC: 2.7 mg.h/L
value
Female
Total AUC
OR
95 % CI
3.67
1.94
(1.2-14.7)
(1.05-3.5)
P
0.015
0.033
PK and PD relationship
S-AUC
R-AUC
OR
4.72
0.02
95 % CI
(1.5-14.8)
(0.0003-1.1)
P value
0.007
0.058
Monte Carlo simulation N=5,000
Preschool (5yo)
Girls 80 mg/kg
Boys 80 mg/kg
Boys 80 mg/kg
PZQ mg/kg
Girls 80 mg/kg
Girls 60 mg/kg
Boys 60 mg/kg
Girls 60 mg/kg
Boys 60 mg/kg
Girls 40 mg/kg
Boys 40 mg/kg
Boys 40 mg/kg
0.
0
0.
1
0.
2
0.
3
0.
4
0.
5
0.
6
0.
7
0.
8
0.
9
1.
0
Girls 40 mg/kg
0.
0
0.
1
0.
2
0.
3
0.
4
0.
5
0.
6
0.
7
0.
8
0.
9
1.
0
PZQ mg/kg
Preschool (3 yo)
Individual Cure rate
Individual Cure rate
School age (8 yo)
Girls 80 mg/kg
Boys 80 mg/kg
Boys 80 mg/kg
PZQ mg/kg
Girls 80 mg/kg
Girls 60 mg/kg
Boys 60 mg/kg
Girls 60 mg/kg
Boys 60 mg/kg
Girls 40 mg/kg
Boys 40 mg/kg
Boys 40 mg/kg
Individual Cure rate
0.
0
0.
1
0.
2
0.
3
0.
4
0.
5
0.
6
0.
7
0.
8
0.
9
1.
0
Girls 40 mg/kg
0.
0
0.
1
0.
2
0.
3
0.
4
0.
5
0.
6
0.
7
0.
8
0.
9
1.
0
PZQ mg/kg
School age (6 yo)
Individual Cure rate
Conclusions of the Ugandan PK/PD study
•  The recommended WHO PZQ dosing of 40 mg/kg was
sub-optimal for all ages, particularly preschool children.
•  60 mg/kg PZQ appears acceptable for school age
children.
•  Higher doses of 80 mg/kg may be necessary for preschool
children.
•  S-PZQ was the biologically active PZQ enantiomer in this
setting.
Schistosomiasis in preschool children
Exposure (water contact) during childhood
passive
active
infant (1 yr) toddler (1-­‐3yrs) pre-­‐school (< 5 yrs) First
Treatment
treatment
for the
for the
under-fives
under-fives
is given
is delayed
beforeuntil
school
school
entry
entry
translating
translating
as as
66years
yearsof
ofaccumulating
preventing morbidity.
morbidity.
At the adequate dosing and interval
Future studies
•  Different doses need to be tested across age groups- need to
include 60 and 80 mg/kg.
•  School age
•  Preschool
•  Praziquantel enantiomers (R/S) need to be measured across
Schistosoma species and in clinical settings.
•  Establish MIC ( Minimum Inhibitory Concentration) for PZQ.
•  More refined morbidity tools need to be implemented to stage
clinical schistosomiasis more effectively.
Acknowledgments
Vector Control Division-MoH
Russell Stothard
David Waterhouse
Stephen Ward
Raman Sharma
Jose Sousa-Figueireido
Michelle Stanton
Narcis Kabatereine
Edridah Tukahebwa
Aida Wamboko
Moses Arianitwe
Moses Adriko
Gerald Msewige
Aaron Atuhaire
Fiddi Rugianna
Community mobilizers
-Buliisa district
William Hope
Janet Scott
Govert Van Damm
To all the children that participated in the
study
Thank you
Questions?