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