Penetration of Intact Blood-Brain Barrier by Doripenem

Margetis, Konstantinos; Dimaraki, E.; Charkoftaki, Georgia; Vryonis, Evangelos; Markantonis, S; Boutos, N.; Archontaki, Helen; Sakas, Damianos E.; Valsami, Georgia; Skoutelis, Athanasios

doi:10.1128/aac.01634-10

Cited by 5 publications

(8 citation statements)

References 12 publications

(6 reference statements)

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“…Doripenem levels in CSF after single-dose administration of 500 mg ranged from 0.05 to 0.50 mg/L, depending on the time of CSF sampling after the end of drug infusion (Figure 1), while the respective plasma levels measured were between 0.2 and 22 mg/L for the same time interval. These results confirm our preliminary results 17 based on measurements from five neurological patients with non-inflamed meninges, where doripenem was found to enter the CSF to a measurable extent.…”

Section: Discussionsupporting

confidence: 81%

“…However, we have shown previously that doripenem penetrates the intact human BBB to a small but measurable extent. 17 The lack of relative pharmacokinetic studies has probably inhibited the study of the clinical effectiveness of doripenem in bacterial meningitis, despite the fact that its broad spectrum of antimicrobial activity would make it a highly promising agent for this indication.…”

Section: Introductionmentioning

confidence: 99%

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Pharmacokinetics of doripenem in CSF of patients with non-inflamed meninges

Nalda-Molina¹,

Dokoumetzidis²,

Charkoftaki³

et al. 2012

Journal of Antimicrobial Chemotherapy

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Objectives: To investigate intact blood-brain barrier (BBB) penetration by doripenem and characterize doripenem pharmacokinetics in CSF using a pharmacokinetic model. Patients and 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 ¼ 0.105 h 21 and PC ¼ 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.

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Section: Discussionsupporting

confidence: 81%

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics of doripenem in CSF of patients with non-inflamed meninges

Nalda-Molina¹,

Dokoumetzidis²,

Charkoftaki³

et al. 2012

Journal of Antimicrobial Chemotherapy

Self Cite

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“…1. Plasma concentrations were in agreement with those obtained in previous studies [6,7]. Unbound doripenem concentrations in the interstitium of brain parenchyma were substantially below plasma values in all patients, as indicated by ratios of the maximum concentration in brain to that in plasma (C max brain /C max plasma ) of 0.007, 0.203, 0.003, 0.004 and 0.004 for Patients 1-5, respectively.…”

Section: Resultssupporting

confidence: 89%

“…None the less, penetration of doripenem into CSF as previously described [7] and into brain parenchyma in the present study appears particularly low. However, brain concentrations and AUC brain /AUC plasma ratios of antibiotics depend not only on their physicochemical properties but may also be affected by inflammation of the brain or affinity to active transport systems [1,12].…”

Section: Resultsmentioning

confidence: 36%

“…and Acinetobacter baumannii [6]. However, data on the penetration of doripenem into brain tissue are restricted to a recent study where single point measurements of CSF concentrations were made [7]. Against this background, the present observational study set out to evaluate the distribution of doripenem in cerebral tissue in neurointensive care patients undergoing microdialysis for neurointensive monitoring.…”

Section: Introductionmentioning

confidence: 97%

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Penetration of doripenem in human brain: an observational microdialysis study in patients with acute brain injury

Poeppl

Zeitlinger

Donath

et al. 2012

International Journal of Antimicrobial Agents

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Cerebral microdialysis in clinical studies of drugs: pharmacokinetic applications

Shannon

Carpenter

Guilfoyle

et al. 2013

J Pharmacokinet Pharmacodyn

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The ability to deliver drug molecules effectively across the blood–brain barrier into the brain is important in the development of central nervous system (CNS) therapies. Cerebral microdialysis is the only existing technique for sampling molecules from the brain extracellular fluid (ECF; also termed interstitial fluid), the compartment to which the astrocytes and neurones are directly exposed. Plasma levels of drugs are often poor predictors of CNS activity. While cerebrospinal fluid (CSF) levels of drugs are often used as evidence of delivery of drug to brain, the CSF is a different compartment to the ECF. The continuous nature of microdialysis sampling of the ECF is ideal for pharmacokinetic (PK) studies, and can give valuable PK information of variations with time in drug concentrations of brain ECF versus plasma. The microdialysis technique needs careful calibration for relative recovery (extraction efficiency) of the drug if absolute quantification is required. Besides the drug, other molecules can be analysed in the microdialysates for information on downstream targets and/or energy metabolism in the brain. Cerebral microdialysis is an invasive technique, so is only useable in patients requiring neurocritical care, neurosurgery or brain biopsy. Application of results to wider patient populations, and to those with different pathologies or degrees of pathology, obviously demands caution. Nevertheless, microdialysis data can provide valuable guidelines for designing CNS therapies, and play an important role in small phase II clinical trials. In this review, we focus on the role of cerebral microdialysis in recent clinical studies of antimicrobial agents, drugs for tumour therapy, neuroprotective agents and anticonvulsants.

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Penetration of Intact Blood-Brain Barrier by Doripenem

Cited by 5 publications

References 12 publications

Pharmacokinetics of doripenem in CSF of patients with non-inflamed meninges

Pharmacokinetics of doripenem in CSF of patients with non-inflamed meninges

Penetration of doripenem in human brain: an observational microdialysis study in patients with acute brain injury

Cerebral microdialysis in clinical studies of drugs: pharmacokinetic applications

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