title: Pharmacokinetics of doripenem in CSF of patients with non-inflamed meninges.
abstract: OBJECTIVE
  To investigate intact blood-brain barrier (BBB) penetration by doripenem and characterize doripenem pharmacokinetics in CSF using a pharmacokinetic model.
  
  
  METHODS
  Thirty-eight neurological patients with no active neurological disease or CNS infection received a single 500 mg doripenem dose before pump implantation surgery, or lumbar puncture, for intrathecal baclofen administration. In most cases single CSF and blood samples were collected per patient and analysed for doripenem with HPLC. A two-stage pharmacokinetic analysis was performed to estimate: (i) empirical Bayesian estimates (EBEs) of individual doripenem plasma pharmacokinetic parameters, using plasma doripenem concentrations and literature population priors for a two-compartment model; and (ii) doripenem CSF pharmacokinetic parameters using simulated plasma concentrations from stage (i) as a forcing function. The mean values of the structural model parameters, k(CSF) (distribution rate constant) and PC (CSF/plasma partition coefficient), and the residual variability were estimated.
  
  
  RESULTS
  The mean estimates of the parameters were k(CSF)= 0.105 h(-1) and PC= 0.053, corresponding to mean steady-state doripenem CSF concentrations of 0.20 mg/L and 0.40 mg/L for regimens of 3 × 500 mg daily and 3 × 1000 mg daily, respectively, and a mean equilibrium half-life of 6.6 h. The model was validated internally using a visual predictive check (VPC) and bootstrap. Simulating two dosing scenarios gave doripenem levels in the CSF above or close to the literature MIC values.
  
  
  CONCLUSIONS
  The present NONMEM software analysis shows that doripenem crosses intact BBB significantly and suggests that the drug should be further evaluated as a candidate to treat certain CNS infections, since drug penetration through BBB is enhanced by meningeal inflammation.
authors.affiliation: Laboratory of Biopharmaceutics & Pharmacokinetics, Faculty of Pharmacy,  National & Kapodistrian University of Athens, Athens,  Greece.
authors.forename: R
authors.initials: R
authors.lastname: Nalda-Molina
authors.forename: A
authors.initials: A
authors.lastname: Dokoumetzidis
authors.forename: G
authors.initials: G
authors.lastname: Charkoftaki
authors.forename: E
authors.initials: E
authors.lastname: Dimaraki
authors.forename: K
authors.initials: K
authors.lastname: Margetis
authors.forename: H
authors.initials: H
authors.lastname: Archontaki
authors.forename: S
authors.initials: S
authors.lastname: Markantonis
authors.forename: N
authors.initials: N
authors.lastname: Boutos
authors.forename: D
authors.initials: D
authors.lastname: Sakas
authors.forename: E
authors.initials: E
authors.lastname: Vryonis
authors.forename: A
authors.initials: A
authors.lastname: Skoutelis
authors.forename: G
authors.initials: G
authors.lastname: Valsami
mesh_terms: D000328:Adult; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D015780:Carbapenems / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002555:Cerebrospinal Fluid / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid; D000077726:Doripenem; D006801:Humans; D015233:Models, Statistical; D010949:Plasma / Q000737:chemistry
chemical_list: D000900:Anti-Bacterial Agents; D015780:Carbapenems; D000077726:Doripenem