Summary:
Objectives: To investigate intact blood-brain-barrier (BBB) penetration by
doripenem (DRP) and characterize DRP pharmacokinetics (PK) in cerebrospinal
fluid (CSF), using a NONMEM 7.2 population PK-model.
Patients and Methods: 36 neurological patients with no active neurological
disease or CNS infection received a single 500mg DRP dose before pump
implantation surgery, or lumbar puncture, for intrathecal baclofen
administration. In most cases one CSF and blood samples were collected per
patient and analysed for DRP with HPLC. A two-stage PK analysis was performed
to estimate: 1)Empirical Bayesian Estimates (EBE) of individual DRP plasma PK
parameters, using plasma DRP concentrations and literature population priors,
for a two-compartment model, 2)DRP CSF PK parameters using EBE of plasma PK
parameters as covariates. The mean values of the structural model parameters,
kCSF (distribution rate constant) and PC (CSF/plasma partition coefficient),
and the residual variability were estimated. The model was validated internally
using visual predictive check (VPC) and bootstrap.
Results: VPC of the plasma PK model and plasma data showed that the model
describes data reasonably. The mean estimates of the parameters were
kCSF=0.053h-1, PC=0.099, corresponding to mean steady state DRP CSF
concentration, CSSCSF=0.46mg/L (3500mg daily dose) and mean equilibrium
half-life t1/2=13hrs. Simulating various dosing scenarios and comparing CSSCSF
to different MIC values, showed that the pharmacodynamic index T>MIC=100%, with
any daily dose 3500mg.
Conclusion: The present NONMEM analysis of DRP CSF data shows that DRP crosses
intact BBB significantly and suggests drug’s usefulness to treat certain CNS
infections, since drug penetration through BBB is enhanced by meningeal
inflammation.
