Pharmacokinetic quantification of the exchange of drugs between blood and cerebrospinal fluid in man

Nau, Roland; Zysk, Gregor; Thiel, Andreas; Prange, Hilmar

doi:10.1007/bf00315520

Cited by 41 publications

(33 citation statements)

References 41 publications

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“…This difference is constructed as AUC CSF /AUC plasma ratio integrates the entire dosing interval. The ratio of the AUCs estimates more accurately the penetration into the central nervous system than only a CSF/plasma ratio obtained with plasma and CSF concentrations (30). A penetration of at least 20% of the AUC plasma into the CSF may be used as a benchmark for comparison with other agents with a presumed activity in the CSF.…”

Section: Discussionmentioning

confidence: 99%

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Plasma and Cerebrospinal Fluid Population Pharmacokinetics of Temozolomide in Malignant Glioma Patients

Ostermann

Csajka

Buclin

et al. 2004

Clinical Cancer Research

430

324

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Purpose: Scarce information is available on the brain penetration of temozolomide (TMZ), although this novel methylating agent is mainly used for the treatment of malignant brain tumors. The purpose was to assess TMZ pharmacokinetics in plasma and cerebrospinal fluid (CSF) along with its inter-individual variability, to characterize covariates and to explore relationships between systemic or cerebral drug exposure and clinical outcomes.Experimental Design: TMZ levels were measured by high-performance liquid chromatography in plasma and CSF samples from 35 patients with newly diagnosed or recurrent malignant gliomas. The population pharmacokinetic analysis was performed with nonlinear mixed-effect modeling software. Drug exposure, defined by the area under the concentration-time curve (AUC) in plasma and CSF, was estimated for each patient and correlated with toxicity, survival, and progression-free survival.Results: A three-compartment model with first-order absorption and transfer rates between plasma and CSF described the data appropriately. Oral clearance was 10 liter/h; volume of distribution (V D ), 30.3 liters; absorption constant rate, 5.8 h ؊1 ; elimination half-time, 2.1 h; transfer rate from plasma to CSF (K plasma3 CSF ), 7.2 ؋ 10 ؊4 h ؊1 and the backwards rate, 0.76 h ؊1 . Body surface area significantly influenced both clearance and V D , and clearance was sex dependent. The AUC CSF corresponded to 20% of the AUC plasma . A trend toward an increased K plasma3 CSF of 15% was observed in case of concomitant radiochemotherapy. No significant correlations between AUC in plasma or CSF and toxicity, survival, or progression-free survival were apparent after deduction of dose-effect.Conclusions: This is the first human pharmacokinetic study on TMZ to quantify CSF penetration. The AUC CSF / AUC plasma ratio was 20%. Systemic or cerebral exposures are not better predictors than the cumulative dose alone for both efficacy and safety.

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Section: Discussionmentioning

confidence: 99%

“…Because plasma concentrations decreased more quickly than in the CSF, the CSF/plasma ratio increased across the dosing interval (median, 30.1%; range, 2.1-65.2%). The CSF curve was essentially flat at approximately 1 g/ml, likely attributable to slow influx and efflux rates from the CSF compartment (30).…”

Section: Demographicsmentioning

confidence: 97%

Plasma and Cerebrospinal Fluid Population Pharmacokinetics of Temozolomide in Malignant Glioma Patients

Ostermann

Csajka

Buclin

et al. 2004

Clinical Cancer Research

430

324

View full text Add to dashboard Cite

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“…For this purpose, CSF and serum concentrations at different intervals between the infusion and the lumbar puncture have to be studied with a relative large cohort of patients in order to extrapolate concentration-versus-time curves in CSF. Measurement of CSF concentrations at a single time point after a drug injection or short-duration infusion can lead to wrong conclusions depending on the interval between drug infusion and CSF withdrawal: because of the lag of the concentration-time curve in CSF compared to the respective curve in serum, CSF-to-serum concentration ratios at individual time points strongly depend on the interval between drug administration to the systemic circulation and CSF and serum sampling (179) (Fig. 2A and B Table S1 in the supplemental material, absolute CSF concentrations only and not concentration ratios are reported, unless the original study clearly documented the attainment of steady state.…”

Section: Methods To Study Drug Concentrations In the Cns In Humansmentioning

confidence: 99%

Penetration of Drugs through the Blood-Cerebrospinal Fluid/Blood-Brain Barrier for Treatment of Central Nervous System Infections

2010

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SUMMARY The entry of anti-infectives into the central nervous system (CNS) depends on the compartment studied, molecular size, electric charge, lipophilicity, plasma protein binding, affinity to active transport systems at the blood-brain/blood-cerebrospinal fluid (CSF) barrier, and host factors such as meningeal inflammation and CSF flow. Since concentrations in microdialysates and abscesses are not frequently available for humans, this review focuses on drug CSF concentrations. The ideal compound to treat CNS infections is of small molecular size, is moderately lipophilic, has a low level of plasma protein binding, has a volume of distribution of around 1 liter/kg, and is not a strong ligand of an efflux pump at the blood-brain or blood-CSF barrier. When several equally active compounds are available, a drug which comes close to these physicochemical and pharmacokinetic properties should be preferred. Several anti-infectives (e.g., isoniazid, pyrazinamide, linezolid, metronidazole, fluconazole, and some fluoroquinolones) reach a CSF-to-serum ratio of the areas under the curves close to 1.0 and, therefore, are extremely valuable for the treatment of CNS infections. In many cases, however, pharmacokinetics have to be balanced against in vitro activity. Direct injection of drugs, which do not readily penetrate into the CNS, into the ventricular or lumbar CSF is indicated when other effective therapeutic options are unavailable.

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“…A different study design, incorporating multiple plasma and CSF samplings from neurosurgical devices, would provide more pharmacokinetic data (18). Data on rufloxacin penetration into body fluids after a single oral administration have demonstrated a mean time to maximum drug concentration in plasma Ϯ standard deviation of 3.83 Ϯ 2.62 h (12) and mean times to maximum drug concentration in the extravascular compartment ranging from 3.5 to 11.8 h (26,28).…”

Section: Discussionmentioning

confidence: 99%

Penetration of Rufloxacin into the Cerebrospinal Fluid in Patients with Inflamed and Uninflamed Meninges

Moretti

Pauluzzi

Cesana

2000

Antimicrob Agents Chemother

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Forty-four patients scheduled for lumbar puncture (LP) were recruited to determine the level of penetration of orally administered rufloxacin into cerebrospinal fluid (CSF). The patients were divided into three clinical groups: those with normal CSF (groups A 1d and A 7d ), those with aseptic meningitis (group B), and those with bacterial meningitis (group C). Members of group A 1d received a single 400-mg rufloxacin dose, while group A 7d , B, and C constituents had a multiple-dose regimen (one 400-mg dose, followed by one 200-mg dose daily for 6 days). LP was performed on group A 1d members 5 h after they had received treatment, while for group A 7d it was undertaken 5 h after administration of the last dose. For group B, LP was performed 5 h after the first and the last doses, whereas for group C it was undertaken after the first, fourth, and last doses. Concentrations of rufloxacin in simultaneously collected CSF and plasma samples were determined. Mean CSF/plasma rufloxacin concentration ratios ranged from 0.57 to 0.84, depending on the study group. A higher, but not statistically significant, degree of penetration into CSF was observed in patients with bacterial meningitis than in those with normal CSF or aseptic meningitis. These data indicate that rufloxacin diffuses efficiently into the CSF of patients with either inflamed or uninflamed meninges.Although the introduction of antibiotics made bacterial meningitis curable, the morbidity and mortality associated with this disease remain unacceptably high. In a recent review of 493 episodes of bacterial meningitis in adults, the overall case fatality rate was 25% (6).The penetration of an antibacterial drug into the cerebrospinal fluid (CSF) is an important characteristic in terms of its potential use in central nervous system (CNS) infections. In the presence of inflamed meninges, therapeutic concentrations of many antibiotics can be attained in CSF (2). However, in some persons with brain abscesses, early meningitis, or latestage meningitis, only minor impairments of the blood-CSF barrier occur. Dexamethasone, recommended for use in adjunctive therapy for bacterial meningitis, reduces meningeal inflammation (25) and thereby decreases drug penetration into CSF (2, 23). To ensure successful therapy and to prevent relapses, therapeutic concentrations of any antibiotic proposed for the treatment of CNS infections should be achieved even in the presence of uninflamed meninges.Fluoroquinolones are broad-spectrum antimicrobial agents with in vitro and in vivo bactericidal activity against susceptible organisms (10). The individual fluoroquinolones differ in their physiochemical properties, pharmacokinetic characteristics, and body fluid penetration abilities (10,14). Their lipophilicity (octanol-buffer partition coefficient ϭ 0.37 at pH 7) (1, 7) and the high apparent volume of distribution of 130 to 150 liters (12,15,26,28) account for their high degree of penetration into CSF. However, analysis of comparative data on CSF transport and disposition of quinolones ...

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Pharmacokinetic quantification of the exchange of drugs between blood and cerebrospinal fluid in man

Cited by 41 publications

References 41 publications

Plasma and Cerebrospinal Fluid Population Pharmacokinetics of Temozolomide in Malignant Glioma Patients

Plasma and Cerebrospinal Fluid Population Pharmacokinetics of Temozolomide in Malignant Glioma Patients

Penetration of Drugs through the Blood-Cerebrospinal Fluid/Blood-Brain Barrier for Treatment of Central Nervous System Infections

Penetration of Rufloxacin into the Cerebrospinal Fluid in Patients with Inflamed and Uninflamed Meninges

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