Antimicrobial Pharmacokinetics and Pharmacodynamics: Critical Tools for Optimising Clinical Care in Neonates
William Hope
University of Liverpool
July2012
Neonatal Haematogenous Candida Meningoencephalitis (HCME)
• Widespread involvement of the CNS by Candida in premature neonates
• Associated with: – Significant short-term
mortality
– Long term neurodevelopmental abnormalities
– Low IQ scores
Shenvi et al BMJ Case Reports 2011
HO
O
NH
O
HO
OH
HN
O
N
HO
H2N
O
H3C
HO
NH
O
HN
CH3
OH
N
O
O
OH
O
NH
O
O
N
HO OH
O
H3C
S
OH
O
O
• Echinocandins
– Caspofungin, micafungin, anidulafungin
– Large molecules, ~ 1200 Daltons
– Water soluble
– Dogma = don’t penetrate the CNS
• EMA offers patent extensions for initiation of Paediatric Investigational Programmes (PIP)
• But, immediate question is what is an appropriate dosage for study in clinical trials?
Anidulafungin is licensed in the UK, and it works in adults…
Reboli et al NEJM 2007
And, we know the dose: 200 mg load then 100 mg/day
Question posed to us by Pfizer
• What is likely to be an efficacious dosage of anidulafungin for human neonates with HCME?
• A problem that can not be easily addressed clinically
– Relatively rare, but serious disease
– Endpoint difficult to measure
– If dosage wrong, many neonates will potentially do very poorly, and an otherwise useful agent will be abandoned
• But, the problem can be addressed using a PK-PD approach with bridging
Rabbit model of neonatal HCME • Male New Zealand White rabbits
• Non-neutropenic model
• Inoculum 1 × 106 organisms per rabbit
• Central silastic venous catheter permits repeated atraumatic venous access
Groll et al J Infect Dis 2000
Rabbit model of neonatal HCME
inoculum
48 72 96 0
Sacrifice 96 hours
Anidulafungin therapy
Modified from Groll et al J Infect Dis 2000 and Hope at al JID 2008
Days
Structural Mathematical Model
Central compartment
Peripheral compartment
i.v. injection
clearance Cerebrum
CFU
bra
in
Time
dX1/dt=R(1)-(Kcp+(SCLstd*(weight/70)0.75/Vstd*(weight/70))*X1+Kpc*X2 Equation 1
dX2/dt=Kcp*X1-Kpc*X2 Equation 2
3 mg/kg loading followed by 1.5 mg/kg/day: comparable AUCs to adults
Allometric Population PK model
Adult AUC Equivalent
Summary
• Significantly higher dosage than that studied required for neonatal HCME
– 9 followed by 4.5 mg/kg likely regimen
• Basis for further PK and safety studies of higher dosages
• Basis for definitive clinical trial
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