Cerebrospinal Fluid Penetration Research Articles

High dose oral and intravenous rifampicin for improved survival from adult tuberculous meningitis: a phase II open-label randomised controlled trial (the RifT study).

Background: Tuberculous meningitis (TBM) has 44% (95%CI 35-52%) in-hospital mortality with standard therapy in Uganda. Rifampicin, the cornerstone of TB therapy, has 70% oral bioavailability and ~10-20% cerebrospinal fluid (CSF) penetration. With current WHO-recommended TB treatment containing 8-12mg/kg rifampicin, CSF rifampicin exposures frequently fall below the minimal inhibitory concentration for M. tuberculosis. Two Indonesian phase II studies, the first investigating intravenous rifampicin 600mg and the second oral rifampicin ~30mg/kg, found the interventions were safe and resulted in significantly increased CSF rifampicin exposures and a reduction in 6-month mortality in the investigational arms. Whether such improvements can be replicated in an HIV-positive population remains to be determined. Protocol: We will perform a phase II, open-label randomised controlled trial, comparing higher-dose oral and intravenous rifampicin with current standard of care in a predominantly HIV-positive population. Participants will be allocated to one of three parallel arms (I:I:I): (i) intravenous rifampicin 20mg/kg for 2-weeks followed by oral rifampicin 35mg/kg for 6-weeks; (ii) oral rifampicin 35mg/kg for 8-weeks; (iii) standard of care, oral rifampicin 10mg/kg/day for 8-weeks. Primary endpoints will be: (i) pharmacokinetic parameters in plasma and CSF; (ii) safety. We will also examine the effect of higher-dose rifampicin onsurvival time, neurological outcomes and incidence of immune reconstitution inflammatory syndrome. We will enrol 60 adults with suspected TBM, from two hospitals in Uganda, with follow-up to 6 months post-enrolment. Discussion: HIV co-infection affects the bioavailability of rifampicin in the initial days of therapy, risk of drug toxicity and drug interactions, and ultimately mortality from TBM. Our study aims to demonstrate, in a predominantly HIV-positive population, the safety and pharmacokinetic superiority of one or both investigational arms compared to current standard of care. The most favourable dose may ultimately be taken forward into an adequately powered phase III trial. Trial registration: ISRCTN42218549 (24 th April 2018).

Standard-dose osimertinib for refractory leptomeningeal metastases in T790M-positive EGFR-mutant non-small cell lung cancer

Background:Osimertinib demonstrated promising efficacy for refractory leptomeningeal metastases (LM) in preclinical data and a clinical study at 160 mg, but there is limited data for the standard 80 mg dose.Methods:T790M-positive patients with suspected LM after classical epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) failure were enroled.Results:We investigated 13 patients (5 definitive and 8 possible LM cases). In two of the five definitive cases with T790M in and outside the central nervous system (CNS), osimertinib was effective for both lesions, with cerebrospinal fluid (CSF) clearance of cancer cells and sensitive/T790M mutations. In three definitive cases with extra-CNS T790M without CSF T790M, cancer cells and sensitive mutations in the CSF persisted after osimertinib initiation. The median progression-free survival of all 13 patients was 7.2 months. Osimertinib was generally well-tolerated despite poor performance status, but interstitial lung disease (grade 2) was confirmed in one patient. Based on 25 samples from 13 patients, the osimertinib CSF penetration rate was 2.5±0.3%.Conclusions:Osimertinib 80 mg is a useful therapeutic option for refractory LM after classical EGFR-TKI failure. It appears more effective in CSF T790M-positive cases.

Antibiotic Distribution into Cerebrospinal Fluid: Can Dosing Safely Account for Drug and Disease Factors in the Treatment of Ventriculostomy-Associated Infections?

Ventriculostomy-associated infections, or ventriculitis, in critically ill patients are associated with considerable morbidity. Efficacious antibiotic dosing for the treatment of these infections may be complicated by altered antibiotic concentrations in the cerebrospinal fluid due to variable meningeal inflammation and antibiotic properties. Therefore, doses used to treat infections with a higher degree of meningeal inflammation (such as meningitis) may often fail to achieve equivalent exposures in patients with ventriculostomy-associated infections such as ventriculitis. This paper aims to review the disease burden, infection rates, and common pathogens associated with ventriculostomy-associated infections. This review also seeks to describe the disease- and drug-related factors that influence antibiotic distribution into cerebrospinal fluid and provide a critical appraisal of current dosing of antibiotics commonly used to treat these types of infections. A Medline search of relevant articles was conducted and used to support a review of cerebrospinal fluid penetration of vancomycin, including critical appraisal of the recent paper by Beach et al. recently published in this journal. We found that in the intensive care unit, ventriculostomy-associated infections are the most common and serious complication of external ventricular drain insertion and often result in prolonged patient stay and increased healthcare costs. Reported infection rates are extremely variable (between 0 and 45%), hindered by the inherent diagnostic difficulty. Both Gram-positive and Gram-negative organisms are associated with such infections and the rise of multi-drug-resistant pathogens means that effective treatment is an ongoing challenge. Disease factors that may need to be considered are reduced meningeal inflammation and the presence of critical illness; drug factors include physiochemical properties, degree of plasma-protein binding, and affinity to active transporter proteins present in the blood-cerebrospinal fluid barrier. The relationship between cerebrospinal fluid antibiotic exposures in the setting of ventriculostomy-associated infection and clinical response has not been fully elucidated for many of the antibiotics commonly used in its treatment. More thorough and clinically relevant investigations are needed to better define blood pharmacokinetic/pharmacodynamics targets and optimal therapeutic exposures for treatment of ventriculostomy-associated infections. It is hoped that this future research will be able to provide clearer recommendations for clinicians frequently faced with dosing-related dilemmas when treating patients with these challenging infections.

Abstract 5040: The plasma and cerebrospinal fluid pharmacokinetics of pegylated liposomal doxorubicin after intravenous administration in non-human primates

Abstract Background: Pegylated liposomal doxorubicin (PLD) exhibits altered plasma pharmacokinetics (PK) compared to doxorubicin, with a longer half-life (55 hours), large area under the concentration-time curve (AUC), lower rate of clearance, and markedly smaller volume of distribution. The cerebrospinal fluid (CSF) PK of PLD are unknown. We evaluated the plasma and CSF PK of PLD in a non-human primate (NHP) model. Methods: PLD was given as single dose (1 mg/kg = low adult recommended dose of 20 mg/m2) intravenously over 60 minutes to 3 NHP with indwelling central venous catheters and central nervous system ventricular reservoirs or lumbar ports. Serial blood and CSF samples were obtained for 96 hours after completion of the infusion. The total doxorubicin concentration (liposome bound + protein bound + free) was quantified with a validated liquid chromatography/tandem mass spectrometry assay (lower limit of quantification plasma=0.29 ng/mL, and CSF=0.06 ng/mL). PK parameters were estimated using non-compartmental methods. CSF penetration was calculated from the AUCCSF:AUCplasma. Results: PLD was well tolerated. Total doxorubicin plasma concentration time curves were characterized by sustained PLD exposure, comparable to the exposure observed in humans at a similar dose. The terminal elimination phase was not captured. In CSF, doxorubicin was measurable and still present at the last time point in all animals, but the CSF penetration was limited (Table). Conclusions: Using a sensitive assay, we could quantify doxorubicin in CSF. However, the CSF penetration is limited in NHP with intact blood brain barrier. Our assay analyzed the total doxorubicin concentration in plasma. It is unknown if PLD can penetrate into the CSF, therefore we could not determine if the CSF penetration represents total versus free. Plasma and CSF PK of pegylated liposomal doxorubicin in NHPAnimalCmax Plasma(ng/mL)Tmax Plasma(h)AUC0-96h Plasma(ng*h/mL)Cmax CSF (ng/mL)Tmax CSF (h)AUC0-96h CSF (ng*h/mL)CSF Penetration (%)19396487.24E+051.84524.210.3323044901.76E+060.71618.750.113374670.081.91E+063.251036.410.2Mean25770161.46E+061.93726.460.21 Citation Format: Christine Higham, Robert Murphy, Cynthia McCully, Katherine Warren, Brigitte Widemann. The plasma and cerebrospinal fluid pharmacokinetics of pegylated liposomal doxorubicin after intravenous administration in non-human primates [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5040. doi:10.1158/1538-7445.AM2017-5040

Ponezumab in mild-to-moderate Alzheimer's disease: Randomized phase II PET-PIB study

IntroductionThe safety, pharmacokinetics, and effect on peripheral and central amyloid β (Aβ) of multiple doses of ponezumab, an anti-Aβ monoclonal antibody, were characterized in subjects with mild-to-moderate Alzheimer's disease treated for 1 year. MethodsSubjects were aged ≥50 years with Mini–Mental State Examination scores 16 to 26. Cohort Q was randomized to ponezumab 10 mg/kg (n = 12) or placebo (n = 6) quarterly. Cohort M was randomized to a loading dose of ponezumab 10 mg/kg or placebo, followed by monthly ponezumab 7.5 mg/kg (n = 12) or placebo (n = 6), respectively. ResultsPonezumab was generally well tolerated. Plasma concentrations increased dose dependently, but cerebrospinal fluid (CSF) penetration was low. Plasma Aβ increased dose dependently with ponezumab, but CSF biomarkers, brain amyloid burden, cognition, and function were not affected. ConclusionsBoth ponezumab dosing schedules were generally safe and well tolerated but did not alter CSF biomarkers, brain amyloid burden, or clinical outcomes.

Plasma and cerebrospinal fluid pharmacokinetics of doxil after intravenous administration in adults with primary CNS lymphoma.

e14067 Background: Doxil, a pegylated liposomal doxorubicin (PLD) has excellent CNS penetration in rodent brain tumor models and is active in patients with lymphoma. The CNS penetration of doxil in humans is unknown. We evaluated the plasma and cerebrospinal fluid (CSF) pharmacokinetics (PK) of doxil in adults primary CNS lymphoma (PCNSL) as a surrogate for CNS penetration. Methods: Adults with PCNSL enrolled on a NCI phase I study of ibrutinib and multi-agent immune-chemotherapy (NCT02203526) received doxil 50 mg/m2 IV over 1 hour on day 2 of 21-day cycles of chemotherapy. In 4 patients with indwelling Ommaya reservoirs serial blood and CSF samples were obtained prior to infusion and until a median of 345 hours, (range 72-477 hours) after doxil administration. Total doxorubicin concentration (liposome bound + protein bound + free) was quantified with a validated liquid chromatography/tandem mass spectrometry assay (lower limit of quantification plasma=0.29 ng/mL, and CSF=0.06 ng/mL). PK parameters were estimated using non-compartmental methods. CSF penetration was calculated from the AUCCSF:AUCplasma. Results:Total doxorubicin plasma concentration time curves were characterized by sustained drug exposure and a median terminal half-life of 64.5 hours. (range, 61.9-65.1 hours). Doxorubicin was measurable in CSF in all patients, but CSF penetration was low. The terminal half-life of doxorubicin in CSF could not be calculated due to persistently measurable concentrations throughout the sampling times. Conclusions: In patients with PCNSL doxorubicin was measurable in CSF for prolonged time periods after doxil administration, but CSF penetration is low. Clinical trial information: NCT02203526. [Table: see text]

Penetration of Vancomycin into the Cerebrospinal Fluid: A Systematic Review.

Infectious disease and pharmacokinetic textbooks indicate that vancomycin has poor penetration into the central nervous system due to its hydrophilic nature and high molecular weight. Recent literature suggests that penetration of vancomycin into cerebrospinal fluid (CSF) is higher than previously reported; therefore, we conducted a systematic review to assess the penetration of vancomycin into CSF. We searched the MEDLINE, EMBASE, and CENTRAL electronic databases for English-language human studies evaluating serum and CSF concentrations of intravenous vancomycin. In 13 identified studies, the CSF-to-serum ratio of vancomycin varied from 0.00 to 0.81. CSF penetration ranged 0.06-0.81 in patients with meningitis, 0.05-0.17 in ventriculitis, 0.00-0.36 in other infections, and 0-0.13 in patients without infection. Despite variable CSF penetration, 83% of patients with meningitis and 100% of patients with ventriculitis achieved clinical cure. No factor predicted vancomycin CSF penetration. Contrary to prior belief, studies included in our review did not show universally low penetration of vancomycin into CSF. CSF vancomycin levels were variable and did not predict clinical cure.

Plasma and cerebrospinal fluid pharmacokinetics of selumetinib in non-human primates (NHP).

e14070 Background: Selumetinib (AZD6244 hyd sulfate) is an orally bioavailable agent targeting mitogen-activated protein kinase (MEK) 1/2. Selumetinib has shown activity in children with NF1 plexiform neurofibromas and refractory low-grade gliomas. The central nervous system (CNS) penetration of selumetinib in humans is unknown. Methods: We analyzed selumetinib in the cerebrospinal fluid (CSF) of NHP as a surrogate for CNS penetration. Four adult male rhesus macaques were each given a single dose of selumetinib capsules 2.5 mg/kg (human equivalent dose 50 mg/m2) by mouth on an empty stomach. Selumetinib was quantified in serial paired plasma and CSF samples from 0 to 48 hours after administration by Covance Bioanalytical Services (lower limit of quantification 0.5 ng/mL). Free selumetinib was estimated at 2.3% of total based on reported plasma protein binding of 97.7% in NHP. Pharmacokinetic parameters including area under the concentration x time curve (AUC) of selumetinib were calculated using non-compartmental methods and CSF penetration was calculated from the ratio of AUC (CSF): AUC (plasma). Results: Selumetinib was detected in plasma in all four NHPs, but in the CSF of only one NHP (ZH60). The mean (± SD) AUC0-∞ and half-life (t1/2) in plasma were 3350 ± 489 ng•h/mL and 10.8 ± 2.5 hours, respectively. In ZH60, the CSF AUC0-48 hr was 10.6 ng•h/mL. The CSF penetration of total and free selumetinib in this animal was 0.4%, and 14%, respectively. The mean plasma AUC and t1/2 were comparable to that of children (2842 ng•h/mL and 6.9 hours, respectively) at a similar dose in a phase I trial. However, the average peak concentration in children occurred at approximately 1 hour with a Cmax of 841 ng/mL, while the Cmax in NHP plasma ranged from 1 – 4 hours and averaged 198.8 ng/mL. Conclusions: The CSF penetration of oral selumetinib is limited; in one NHP it was 0.4% and 14% when corrected for plasma protein binding of selumetinib. The fact that plasma AUC0-∞ and half-lives in NHP were similar to previously reported human plasma PK indicates that this model may accurately reflect human CSF penetration as well.

Multiple-dose ponezumab for mild-to-moderate Alzheimer's disease: Safety and efficacy

IntroductionMultiple intravenous doses of ponezumab, an anti-amyloid antibody, were evaluated in subjects with mild-to-moderate Alzheimer's disease (AD). MethodsIn part A, 77 subjects were randomized to ponezumab 0.1, 0.5, or 1 mg/kg (75 treated) and 26 to placebo (24 treated). In part B, 63 subjects were randomized and treated with ponezumab 3 or 8.5 mg/kg and 32 with placebo. Subjects received 10 infusions over 18 months and were followed for 6 months thereafter. ResultsPonezumab was generally safe and well tolerated. Most common adverse events were fall (16.7% ponezumab, 21.4% placebo), headache (13.8%, 21.4%), and cerebral microhemorrhage (13.8%, 19.6%). Plasma ponezumab increased dose-dependently with limited accumulation. Cerebrospinal fluid penetration was low. Plasma Aβ1–x and Aβ1–40 showed robust increases, but cerebrospinal fluid biomarkers showed no dose response. Ponezumab had no effects on cognitive/functional outcomes or brain volume. ConclusionsMultiple-dose ponezumab was generally safe, but not efficacious, in mild-to-moderate AD.

Pharmacokinetics and cerebrospinal fluid penetration of norvancomycin in Chinese adult patients.

Norvancomycin is an antibiotic that has been approved for the treatment of infections caused by antibiotic-resistant Gram-positive bacteria and has been used in China for more than a decade. However, the cerebrospinal fluid (CSF) penetration of norvancomycin has not been evaluated. The aims of the study were (i) to investigate the pharmacokinetics and CSF penetration of norvancomycin in meningitis and non-meningitis patients and (ii) to recommend favourable dosing regimens in meningitis patients. Twenty adult patients (ten with meningitis and ten without meningitis) requiring norvancomycin treatment were enrolled. All patients received a norvancomycin regimen of 800 mg every 12 h. Blood and CSF samples were consecutively collected up to 12 h after the end of the fourth 60-min infusion. Norvancomycin concentrations both in serum and CSF were measured using a high-performance liquid chromatography (HPLC) assay. CSF penetration of norvancomycin was evaluated by calculating the CSF/serum ratio. Mean norvancomycin serum trough levels were 9.9 ± 1.44 µg/mL in patients with meningitis and 10.08 ± 1.12 µg/mL in patients without meningitis (P > 0.05). In addition, norvancomycin penetrated into the inflamed meninges, with mean CSF concentrations of 3.93-10.52 µg/mL and mean CSF/serum ratios of 0.18-0.43, both of which were significantly higher than in patients without meningitis (P <0.05). These results suggest that norvancomycin has higher CSF penetration in patients with meningitis compared with other groups and that norvancomycin is effective in treating patients with purulent meningitis at a comparably low dose.

The effect of angiotensin receptor neprilysin inhibitor, sacubitril/valsartan, on central nervous system amyloid-β concentrations and clearance in the cynomolgus monkey

Sacubitril/valsartan (LCZ696) is the first angiotensin receptor neprilysin inhibitor approved to reduce cardiovascular mortality and hospitalization in patients with heart failure with reduced ejection fraction. As neprilysin (NEP) is one of several enzymes known to degrade amyloid-β (Aβ), there is a theoretical risk of Aβ accumulation following long-term NEP inhibition. The primary objective of this study was to evaluate the potential effects of sacubitril/valsartan on central nervous system clearance of Aβ isoforms in cynomolgus monkeys using the sensitive Stable Isotope Labeling Kinetics (SILK™)-Aβ methodology.The in vitro selectivity of valsartan, sacubitril, and its active metabolite sacubitrilat was established; sacubitrilat did not inhibit other human Aβ-degrading metalloproteases. In a 2-week study, sacubitril/valsartan (50mg/kg/day) or vehicle was orally administered to female cynomolgus monkeys in conjunction with SILK™-Aβ. Despite low cerebrospinal fluid (CSF) and brain penetration, CSF exposure to sacubitril was sufficient to inhibit NEP and resulted in an increase in the elimination half-life of Aβ1-42 (65.3%; p=0.026), Aβ1-40 (35.2%; p=0.04) and Aβtotal (29.8%; p=0.04) acutely; this returned to normal as expected with repeated dosing for 15days. CSF concentrations of newly generated Aβ (AUC(0–24h)) indicated elevations in the more aggregable form Aβ1-42 on day 1 (20.4%; p=0.039) and day 15 (34.7%; p=0.0003) and in shorter forms Aβ1-40 (23.4%; p=0.009), Aβ1-38 (64.1%; p=0.0001) and Aβtotal (50.45%; p=0.00002) on day 15. However, there were no elevations in any Aβ isoforms in the brains of these monkeys on day 16. In a second study cynomolgus monkeys were administered sacubitril/valsartan (300mg/kg) or vehicle control for 39weeks; no microscopic brain changes or Aβ deposition, as assessed by immunohistochemical staining, were present. Further clinical studies are planned to address the relevance of these findings.

Oxytocin by intranasal and intravenous routes reaches the cerebrospinal fluid in rhesus macaques: determination using a novel oxytocin assay.

Oxytocin (OT) is a potential treatment for multiple neuropsychiatric disorders. As OT is a peptide, delivery by the intranasal (IN) route is the preferred method in clinical studies. Although studies have shown increased cerebrospinal fluid (CSF) OT levels following IN administration, this does not unequivocably demonstrate that the peripherally administered OT is entering the CSF. For example, it has been suggested that peripheral delivery of OT could lead to central release of endogenous OT. It is also unknown whether the IN route provides for more efficient entry of the peptide into the CSF compared to the intravenous (IV) route, which requires blood-brain barrier penetration. To address these questions, we developed a sensitive and specific quantitative mass spectrometry assay that distinguishes labeled (d5-deuterated) from endogenous (d0) OT. We administered d5 OT (80 IU) to six nonhuman primates via IN and IV routes as well as IN saline as a control condition. We measured plasma and CSF concentrations of administered and endogenous OT before (t=0) and after (t=10, 20, 30, 45 and 60 min) d5 OT dosing. We demonstrate CSF penetrance of d5, exogenous OT delivered by IN and IV administration. Peripheral administration of d5 OT did not lead to increased d0, endogenous OT in the CSF. This suggests that peripheral administration of OT does not lead to central release of endogenous OT. We also did not find that IN administration offered an advantage compared to IV administration with respect to achieving greater CSF concentrations of OT.

OA08.05 Efficacy and Cerebrospinal Fluid Concentration of Afatinib in NSCLC Patients with EGFR Mutation Developing Leptomeningeal Carcinomatosis

Afatinib (AFA) is an effective treatment in advanced non-small-cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR) mutation. However, there were few reports about the cerebrospinal fluid (CSF) penetration rate and the efficacy for central nervous system (CNS) metastasis. Therefore, we conducted the study to evaluate the CSF penetration rate and efficacy of AFA in NSCLC patients harboring EGFR mutation with leptomeningeal carcinomatosis (LC). Eligibility criteria included performance status (PS) 0-3, aged 20 years or older, pathologically proven NSCLC, harboring EGFR mutation, with LC, adequate organ function, and written informed consent. Patients received AFA (40mg/body every day). We analyzed the blood and CSF level of AFA before administrating AFA on the eighth day. The primary endpoint was the CSF penetration rate. Secondary endpoints included objective response rate (ORR), progression free survival (PFS), overall survival (OS), and safety profile. A total of 11 patients were enrolled. And we could analyze the blood level in 10 patients and the CSF level in 8 patients. Median patients-age was 66 years old. All patients were adenocarcinoma. In EGFR mutation status, 5 patients had exon 19 deletion, 3 had L858R and 3 had minor (exon18) mutation. The patients with PS 2 were 3 patients and PS 3 were 4 patients. Almost all patients received AFA after third-line or more line chemotherapy. The blood level was the Median 88.2 ng/ml (range: 30.4-373), the CSF level was Median 1.4 ng/ml (range: 0.39-2.85) and the CSF penetration rate was Median 1.65% (range: 0.1-9.25). The ORR is 27.3%, and two of three patients with exon 18 mutation showed the partial response. Median OS was 3.8 months (95%CI: 1.1-13.1) and median PFS was 2.0 months (95%CI: 0.6-5.8). Hematological toxicity was mild, however we have to take care of severe diarrhea and skin toxicities, especially in patients with poor PS. The median CSF penetration rate (1.65%) of AFA were higher than the penetration rate in previous case report. Although the efficacy for EGFR mutation positive patients with LC was moderate, the promising efficacy for the patient with LC harboring EGFR exon 18 mutation was demonstrated. And we have to take care of diarrhea and skin toxicities, especially in the patients with poor PS.

Is First-Line Vancomycin Still the Best Option to Treat Staphylococcus Health Care–Associated Meningitis?

Cerebrospinal fluid (CSF) penetration of vancomycin through the blood-brain barrier is poor but important inflammation improved it. Hence, vancomycin is recommended for the treatment of community meningitis. However, what about mild inflammatory health care-associated meningitis? The aim of this study was to evaluate the impact of vancomycin diffusion on CSF in Staphylococcus epidermidis health care-associated meningitis. This was a retrospective study of all consecutive patients with S.epidermidis CSF shunt-associated infection, which was treated by continuous intravenous vancomycin after standard of care (60 mg/kg/d after a loading dose of 15 mg/kg). Patient outcome, CSF protein level, and vancomycin concentration in CSF and serum were assessed. We report 6 consecutives cases. Clinical and biologic manifestations were of mild intensity. Meningeal permeability was moderately altered with low CSF protein levels. Despite appropriate vancomycin dosage resulting in high serum concentrations, CSF remained below the S.epidermidis minimal inhibitory concentration. We propose to reassess vancomycin use as first-line therapy when meningeal inflammation is mild-to-moderate in favor of antibiotics, which have a better CSF penetration.

White matter damage and glymphatic dysfunction in a model of vascular dementia in rats with no prior vascular pathologies

We investigated cognitive function, axonal/white matter (WM) changes and glymphatic function of vascular dementia using a multiple microinfarction (MMI) model in retired breeder (RB) rats. The MMI model induces significant (p < 0.05) cognitive decline that worsens with age starting at 2 weeks, which persists until at least 6 weeks after MMI. RB rats subjected to MMI exhibit significant axonal/WM damage identified by decreased myelin thickness, oligodendrocyte progenitor cell numbers, axon density, synaptic protein expression in the cortex and striatum, cortical neuronal branching, and dendritic spine density in the cortex and hippocampus compared with age-matched controls. MMI evokes significant dilation of perivascular spaces as well as water channel dysfunction indicated by decreased Aquaporin-4 expression around blood vessels. MMI-induced glymphatic dysfunction with delayed cerebrospinal fluid penetration into the brain parenchyma via paravascular pathways as well as delayed waste clearance from the brain. The MMI model in RB rats decreases Aquaporin-4 and induces glymphatic dysfunction which may play an important role in MMI-induced axonal/WM damage and cognitive deficits.

Evaluation of Meropenem Penetration into Cerebrospinal Fluid in Patients with Meningitis After Neurosurgery

Meropenem is important for management of postneurosurgical meningitis, but the data about its penetration into cerebrospinal fluid (CSF) are inadequate. This prospective, open-label study investigated the pharmacokinetic profile of meropenem in patients with postneurosurgical meningitis, especially its CSF penetration. A total of 82 patients with postneurosurgical meningitis were included to receive meropenem intravenously according to a regimen of 2 g every 8 hours, 1 g every 8 hours, or 1 g every 6 hours. After infusion of 4 doses, blood and CSF samples were collected simultaneously at predefined time points. The high-performance liquid chromatography ultraviolet method was used to determine the concentration of meropenem. The peak meropenem concentration in blood and CSF was 43.2 ± 5.3 and 2.4 ± 0.3 mg/L in the group who received 2 g every 8 hours; 28.9 ± 2.7 and 1.2 ± 0.2 mg/L in the group who received 1g every 8 hours; and31.5 ± 3.4 and 1.6 ± 0.2 mg/L in the group who received 1g every 6 hours. The maximal percent penetration into CSF was 17.6% ± 7.3%, 14.3% ± 1.7%, and 30.9% ± 24.2%, respectively. Dosing regimens of meropenem 1 g every 6 hours and 2 g every 8 hours provided higher CSF penetration than 1 g every 8 hours. A higher dose and shorter dosing interval of meropenem may be more useful for clearance of pathogens.

Penetration and distribution of gadolinium-based contrast agents into the cerebrospinal fluid in healthy rats: a potential pathway of entry into the brain tissue

ObjectiveSignal hyperintensity on unenhanced MRI in certain brain regions has been reported after multiple administrations of some, but not all, gadolinium-based contrast agents (GBCAs). One potential initial pathway of GBCA entry into the brain, infiltration from blood into the cerebrospinal fluid (CSF), was systematically evaluated in this preclinical study.MethodsGBCA infiltration and distribution in the CSF were investigated in healthy rats using repeated fluid-attenuated MRI up to 4 h after high-dose (1.8 mmol/kg) administration of six marketed and one experimental GBCA. Additionally, gadolinium measurements in CSF, blood and brain tissue samples (after 24 h) were performed using inductively coupled plasma mass spectrometry.ResultsEnhanced MRI signals in the CSF spaces with similar distribution kinetics were observed for all GBCAs. No substantial differences in the gadolinium concentrations among the marketed GBCAs were found in the CSF, blood or brain tissue. After 4.5 h, the concentration in the CSF was clearly higher than in blood but was almost completely cleared and lower than the brain tissue concentration after 24 h.ConclusionsIn contrast to the brain signal hyperintensities, no differences in penetration and distribution into the CSF of healthy rats exist among the marketed GBCAs.Key Points• Gadolinium-based contrast agents can cross the blood-CSF barrier.• Fluid-attenuated MRI shows GBCA distribution with CSF flow.• GBCA structure and physicochemical properties do not impact CSF penetration and distribution.• GBCA clearance from CSF was almost complete within 24 h in rats.• CSF is a potential pathway of GBCA entry into the brain.

Cerebrospinal fluid penetration of meropenem in neurocritical care patients with proven or suspected ventriculitis: a prospective observational study.

BackgroundVentriculitis is a complication of temporary intraventricular drains. The limited penetration of meropenem into the cerebrospinal fluid (CSF) is well known. However, ventricular CSF pharmacokinetic data in patients with ventriculitis are lacking. The aim of this study was to evaluate meropenem pharmacokinetics in the serum and CSF of neurocritical care patients with proven or suspected ventriculitis.MethodsWe conducted an observational pharmacokinetic study of neurocritical care patients with proven or suspected ventriculitis receiving meropenem. Multiple blood and CSF samples were taken and were described using nonparametric pharmacokinetic modelling with Pmetrics.ResultsIn total, 21 patients (median age 52 years, median weight 76 kg) were included. The median (range) of peak and trough concentrations in serum were 20.16 (4.40–69.00) mg/L and 2.54 (0.00–31.40) mg/L, respectively. The corresponding peak and trough concentrations in CSF were 1.20 (0.00–6.20) mg/L and 1.28 (0.00–4.10) mg/L, respectively, with a median CSF/serum ratio (range) of 0.09 (0.03–0.16). Median creatinine clearance ranged from 60.7 to 217.6 ml/minute (median 122.5 ml/minute). A three-compartment linear population pharmacokinetic model was most appropriate. No covariate relationships could be supported for any of the model parameters. Meropenem demonstrated poor penetration into CSF, with a median CSF/serum ratio of 9 % and high interindividual pharmacokinetic variability.ConclusionsAdministration of higher-than-standard doses of meropenem and therapeutic drug monitoring in both serum and CSF should be considered to individualise meropenem dosing in neurocritical care patients with ventriculitis.

Abstract 1411: Plasma and cerebrospinal fluid pharmacokinetics of tocilizumab in a nonhuman primate model

Abstract Background: Cytokine release syndrome (CRS) is a life-threatening complication of effective immunotherapies, particularly chimeric antigen receptor (CAR) T-cells. CRS is characterized by fever, hypotension, cardiac dysfunction, and at times end organ dysfunction and is mediated by elevated cytokines including IL-6, IFN-γ, and TNFα. A mainstay treatment for severe CRS is intravenous (IV) tocilizumab, a humanized, monoclonal antibody against membrane-associated and soluble IL-6 receptor. Most CRS symptoms resolve within hours of a single dose of IV tocilizumab in contrast to neurotoxicities, which are exacerbated or develop de novo after tocilizumab by a mechanism that is not well understood. IL-6 is elevated in the cerebrospinal fluid (CSF) of patients with CRS and neurotoxicity. The CSF penetration of tocilizumab is unknown. The objective of this study is to determine the CSF penetration of tocilizumab after IV administration in a nonhuman primate model. Methods: Four adult male rhesus monkeys (Macaca mulatta) each received 10 mg/kg tocilizumab IV (human equivalent dose of 8 mg/kg). The macaques have an implanted CNS ventricular reservoir for CSF collection and two central venous lines; one for drug administration and a second for sample collection. Serial, paired blood and CSF samples were collected 0-8 hours, 1-3 days, 5 days, &amp; 10 days post-infusion. A fluorescence bridging ELISA was used to determine serum and CSF levels of free tocilizumab (AbD Serotec). Results: Three of the four animals were evaluable. Mean serum Cmax = 1.55 μM (1.20-2.13) and mean CSF Cmax = 0.00065 μM (0.00037-0.00083). Mean serum and CSF Tmax were 10 hours and 48 hours, respectively. Mean serum and CSF half-life were 127 and 339 hours, respectively. Serum AUC (mean) = 63 μM/hour (25-130) while CSF AUC (mean) = 0.099 μM/hour (0.07-0.125). CSF penetration was low with mean CSF:plasma AUC ratio of 0.26%. All samples and standards were plated in triplicate and had a coefficient of variation less than 20%. In one animal, tocilizumab concentrations were markedly lower with no detectable tocilizumab in the serum after 4 hours; results from this study were considered unevaluable. Conclusion: Studies in this nonhuman primate model reveal low CSF penetration of tocilizumab and delayed time to maximum concentration in the CSF, potentially explaining the persistent neurologic toxicity observed in patients with CRS treated with tocilizumab. However, tocilizumab has a long half-life in the CSF, suggesting alternate means of delivery may be beneficial. Free tocilizumab concentrations were extremely low in one out of four animals and may have been due to preexisting inhibitors. Intranasal delivery of tocilizumab may result in significantly higher CSF exposure and provides a convenient route in patients that are otherwise critically ill. Studies of intranasal tocilizumab are ongoing and will be presented. Citation Format: Anandani Nellan, Nalini Jayaprakash, Cindy McCully, Brigitte C. Widemann, Daniel W. Lee, Katherine E. Warren. Plasma and cerebrospinal fluid pharmacokinetics of tocilizumab in a nonhuman primate model. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1411.

Ocular and Cerebrospinal Fluid Penetration of Antiretroviral Agents.

The ocular penetration of systemically administered antiretroviral drugs (ARVs), which is important in the clinical setting of HIV uveitis, is unknown. This study aimed to assess the ocular penetration of different antiretroviral drugs in an animal model. Twenty-five male New Zealand white rabbits were assigned to one of five treatment groups. Each group received a single oral dose of an antiretroviral drug (lamivudine, tenofovir, efavirenz, lopinavir, and raltegravir). These 5 drugs represent 4 different ARV drug classes [nucleoside reverse transcriptase inhibitors (NRTI), non-NRTI, protease inhibitors, and integrase inhibitors]. Serum, cerebrospinal fluid (CSF), and aqueous and vitreous humor samples were collected at the time of theoretical maximum serum concentration of each respective drug, for example, lamivudine 1 h, tenofovir 1 h, efavirenz 5 h, lopinavir 4 h, and raltegravir 3 h. The drug concentration in each sample was determined by means of high-performance liquid chromatography and mass spectrometry. After a single oral dose, measurable levels of all five ARVs administered could be detected in all 4 body compartments. The limit of detection based on a signal-to-noise ratio of 1:3 for the antiretroviral agents was as follows: 1 part per billion (ppb) for lamivudine, tenofovir, and efavirenz and 0.1 ppb for lopinavir and raltegravir. The IC50 (inhibitory concentration where 50% of viral replication is inhibited by a drug) was reached for all drugs in the serum and CSF. In the aqueous humor, lopinavir failed to reach IC50 and in the vitreous humor, only efavirenz and lopinavir attained IC50 levels. After a single oral dose, measurable levels of all 4 classes of ARVs could be detected in all 4 body compartments sampled. In the eye, IC50 levels were lower in the vitreous humor than in aqueous humor. IC50 levels in the serum were higher than in the CSF.