Drug Concentrations In Cerebrospinal Fluid Research Articles

Comparative analysis of post-mortem drug concentrations in cerebrospinal fluid and blood.

This study aimed to compare the concentration of various xenobiotics in both cerebrospinal fluid (CSF) and blood. We examined 175 autopsy cases covering a wide range of ages, causes of death, and drug ingestion histories, with cerebrospinal fluid and blood samples available for toxicological testing. Analytes studied included opioids, benzodiazepines, antidepressants, antipsychotics, and illicit substances such as cannabinoids, stimulants and new psychoactive substances, including synthetic cathinones and synthetic cannabinoids. We found that concentrations in CSF were generally lower than in blood. A significant correlation was observed between drug concentrations in CSF and blood for many analytes (p < 0.05). However, the strength and direction of the correlation varied considerably depending on the physicochemical properties of the drugs, suggesting that a 'one size fits all' model may not be applicable. The results indicate that cerebrospinal fluid (CSF) can be used to detect a variety of xenobiotics, particularly amphetamines, synthetic cathinones and synthetic cannabinoids, in cases where conventional biological materials are not available. Additionally, using the results obtained in the future can lead to a better understanding of pharmacokinetic processes and the effect of post-mortem redistribution. Further research is needed to refine our understanding of these relationships.

Validation of a quantitative liquid chromatography tandem mass spectrometry assay for linezolid in cerebrospinal fluid and its application to patients with HIV-associated TB-meningitis

Tuberculous meningitis treatment outcomes are poor and alternative regimens are under investigation. Reliable methods to measure drug concentrations in cerebrospinal fluid are required to evaluate distribution into the cerebrospinal fluid. A simple and quick method was developed and validated to analyse linezolid in human cerebrospinal fluid. Samples were prepared by protein precipitation followed by isocratic liquid chromatography and tandem mass spectrometry. The run time was 3.5 min. Accuracy and precision were assessed in three independent validation batches with a calibration range of 0.100–20.0 μg/mL. The method was used to analyse cerebrospinal fluid samples from patients with tuberculous meningitis enrolled in a clinical trial. Potentially infective patient samples could be decontaminated using Nanosep® nylon and Costar® nylon filter tubes under biosafety level 3 conditions before analysis. The filtration process did not significantly affect the quantification of linezolid. Linezolid concentration in cerebrospinal fluid obtained from tuberculous meningitis patients ranged from 0.197 μg/mL to 15.0 μg/mL. The ratio between average CSF and plasma linezolid concentrations varied with time, reaching a maximum of 0.9 at 6 h after dosing.

JAK Inhibition in Aicardi-Goutières Syndrome: a Monocentric Multidisciplinary Real-World Approach Study

The paradigm type I interferonopathy Aicardi-Goutières syndrome (AGS) is most typically characterized by severe neurological involvement. AGS is considered an immune-mediated disease, poorly responsive to conventional immunosuppression. Premised on a chronic enhancement of type I interferon signaling, JAK1/2 inhibition has been trialed in AGS, with clear improvements in cutaneous and systemic disease manifestations. Contrastingly, treatment efficacy at the level of the neurological system has been less conclusive. Here, we report our real-word approach study of JAK1/2 inhibition in 11 patients with AGS, providing extensive assessments of clinical and radiological status; interferon signaling, including in cerebrospinal fluid (CSF); and drug concentrations in blood and CSF. Over a median follow-up of 17 months, we observed a clear benefit of JAK1/2 inhibition on certain systemic features of AGS, and reproduced results reported using the AGS neurologic severity scale. In contrast, there was no change in other scales assessing neurological status; using the caregiver scale, only patient comfort, but no other domain of everyday-life care, was improved. Serious bacterial infections occurred in 4 out of the 11 patients. Overall, our data lead us to conclude that other approaches to treatment are urgently required for the neurologic features of AGS. We suggest that earlier diagnosis and adequate central nervous system penetration likely remain the major factors determining the efficacy of therapy in preventing irreversible brain damage, implying the importance of early and rapid genetic testing and the consideration of intrathecal drug delivery.

Multiple drug transporters contribute to the brain transfer of levofloxacin.

The aim of this study was to assess the influence of the major transporters at blood-brain barrier and blood-cerebrospinal fluid barrier on levofloxacin (LVFX) pharmacokinetics in rat. To explore the different effects of transporters on drug concentrations in cerebrospinal fluid (CSF) and brain extracellular fluid (ECF). High-performance liquid chromatography coupled with microdialysis was used to continuously and synchronously measure unbound concentrations of LVFX in rat blood, hippocampal ECF, and lateral ventricle CSF for comprehensive characterization of brain pharmacokinetics. The role of transporters in the brain efflux mechanism of LVFX was analyzed in the absence and presence of various transporter inhibitors. Following LVFX (50 mg/kg) administration, the unbound partition coefficient of LVFX in brain ECF and CSF (Kp,uu,ECF and Kp,uu,CSF ) were 34.0 ± 1.7% and 41.2 ± 2.4%, respectively. When probenecid was coadministered with LVFX, the AUC and the mean residence time (MRT) in rat blood increased significantly (p < 0.05). After MK571 intervention, 1.35-fold and 1.16-fold increases in Kp,uu,ECF and Kp,uu,CSF were observed, respectively (p < 0.05). Treatment with Ko143 increased the levels of LVFX in brain ECF. The difference in LVFX concentration in brain ECF and CSF was <3-fold with or without treatment with transporter inhibitors. Efflux of LVFX from the central nervous system (CNS) involves multidrug resistance-associated proteins (MRPs), breast cancer resistance protein (BCRP), and organic anion transporters (OATs). MRPs play an important role in mediating the brain/CSF-to-blood efflux of LVFX. LVFX concentrations in CSF can be used as a surrogate to predict the concentrations inside brain parenchyma.

Systemic hypertonic saline enhances glymphatic spinal cord delivery of lumbar intrathecal morphine

The blood-brain barrier significantly limits effective drug delivery to central nervous system (CNS) targets. The recently characterized glymphatic system offers a perivascular highway for intrathecally (i.t.) administered drugs to reach deep brain structures. Although periarterial cerebrospinal fluid (CSF) influx and concomitant brain drug delivery can be enhanced by pharmacological or hyperosmotic interventions, their effects on drug delivery to the spinal cord, an important target for many drugs, have not been addressed. Hence, we studied in rats whether enhancement of periarterial flow by systemic hypertonic solution might be utilized to enhance spinal delivery and efficacy of i.t. morphine. We also studied whether the hyperosmolar intervention affects brain or cerebrospinal fluid drug concentrations after systemic administration. Periarterial CSF influx was enhanced by intraperitoneal injection of hypertonic saline (HTS, 5.8%, 20 ml/kg, 40 mOsm/kg). The antinociceptive effects of morphine were characterized, using tail flick, hot plate and paw pressure tests. Drug concentrations in serum, tissue and microdialysis samples were determined by liquid chromatography-tandem mass spectrometry. Compared with isotonic solution, HTS increased concentrations of spinal i.t. administered morphine by 240% at the administration level (T13–L1) at 60 min and increased the antinociceptive effect of morphine in tail flick, hot plate, and paw pressure tests. HTS also independently increased hot plate and paw pressure latencies but had no effect in the tail flick test. HTS transiently increased the penetration of intravenous morphine into the lateral ventricle, but not into the hippocampus. In conclusion, acute systemic hyperosmolality is a promising intervention for enhanced spinal delivery of i.t. administered morphine. The relevance of this intervention should be expanded to other i.t. drugs and brought to clinical trials.

Sequential Cerebrospinal Fluid Sampling in Horses: Comparison of Sampling Times and Two Different Collection Sites

Analysis of the cerebrospinal fluid (CSF) is important as a complementary test in horses with neurologic diseases, and sequential analysis may provide information about the treatment response or evolution and quantitative measures of the CSF drug concentration during treatment. The aim of this study was to compare erythrocyte and nucleated cell counts and protein concentration in multiple CSF samples obtained sequentially from two different puncture sites in clinically healthy horses. Eight and 12 horses, with no evidence of neurologic disease, were subjected to CSF collection from the atlanto-occipital (AO) and C1–C2 spaces, respectively. Cytologic and chemical analyses were performed on the CSF obtained at five sampling times (T1, T2, T3, T4, and T5). Repeated measures models were used to compare the mean erythrocyte count, nucleated cell count, and total protein concentration between the AO and C1–C2 groups at each sampling time. C1–C2 CSF had a significantly higher total protein concentration at T1 and T4 than that of AO CSF. All total protein concentration values remained within the reference interval (<90 mg/dL) for all sampling times and groups. No statistical difference was present between results at T2, T3, T4, and T5 and at T1 in both groups for all analyses. In conclusion, five consecutive AO or C1–C2 CSF collections with at least a 7-d interval did not result in alterations in the CSF erythrocyte and nucleated cell counts and total protein concentrations and did not interfere with the CSF analysis results.

Lumbar cerebrospinal fluid-to-brain extracellular fluid surrogacy is context-specific: insights from LeiCNS-PK3.0 simulations

Predicting brain pharmacokinetics is critical for central nervous system (CNS) drug development yet difficult due to ethical restrictions of human brain sampling. CNS pharmacokinetic (PK) profiles are often altered in CNS diseases due to disease-specific pathophysiology. We previously published a comprehensive CNS physiologically-based PK (PBPK) model that predicted the PK profiles of small drugs at brain and cerebrospinal fluid compartments. Here, we improved this model with brain non-specific binding and pH effect on drug ionization and passive transport. We refer to this improved model as Leiden CNS PBPK predictor V3.0 (LeiCNS-PK3.0). LeiCNS-PK3.0 predicted the unbound drug concentrations of brain ECF and CSF compartments in rats and humans with less than two-fold error. We then applied LeiCNS-PK3.0 to study the effect of altered cerebrospinal fluid (CSF) dynamics, CSF volume and flow, on brain extracellular fluid (ECF) pharmacokinetics. The effect of altered CSF dynamics was simulated using LeiCNS-PK3.0 for six drugs and the resulting drug exposure at brain ECF and lumbar CSF were compared. Simulation results showed that altered CSF dynamics changed the CSF PK profiles, but not the brain ECF profiles, irrespective of the drug’s physicochemical properties. Our analysis supports the notion that lumbar CSF drug concentration is not an accurate surrogate of brain ECF, particularly in CNS diseases. Systems approaches account for multiple levels of CNS complexity and are better suited to predict brain PK.

Choroid Plexus and Drug Removal Mechanisms.

Timely and efficient removal of xenobiotics and metabolites from the brain is crucial in maintaining the homeostasis and normal function of the brain. The choroid plexus (CP) forms the blood-cerebrospinal fluid barrier and vitally removes drugs and wastes from the brain through several co-existing clearance mechanisms. The CP epithelial (CPE) cells synthesize and secrete the cerebrospinal fluid (CSF). As the CSF passes through the ventricular and subarachnoid spaces and eventually drains into the general circulation, it collects and removes drugs, toxins, and metabolic wastes from the brain. This bulk flow of the CSF serves as a default and non-selective pathway for the removal of solutes and macromolecules from the brain interstitium. Besides clearance by CSF bulk flow, the CPE cells express several multispecific membrane transporters to actively transport substrates from the CSF side into the blood side. In addition, several phase I and II drug-metabolizing enzymes are expressed in the CPE cells, which enzymatically inactivate a broad spectrum of reactive or toxic substances. This review summarizes our current knowledge of the functional characteristics and key contributors to the various clearance pathways in the CP-CSF system, overviewing recent developments in our understanding of CSF flow dynamics and the functional roles of CP uptake and efflux transporters in influencing CSF drug concentrations.

Impact of P-Glycoprotein-Mediated Active Efflux on Drug Distribution into Lumbar Cerebrospinal Fluid in Nonhuman Primates.

Estimation of unbound drug concentration in the brain (Cu,brain) is an essential part of central nervous system (CNS) drug development. As a surrogate for Cu,brain in humans and nonhuman primates, drug concentration in cerebrospinal fluid (CCSF) collected by lumbar puncture is often used; however, the predictability of Cu,brain by lumbar CCSF is unclear, particularly for substrates of the active efflux transporter P-glycoprotein (P-gp). Here, we measured lumbar CCSF in cynomolgus monkey after single intravenous administration of 10 test compounds with varying P-gp transport activities. The in vivo lumbar cerebrospinal fluid (CSF)-to-plasma unbound drug concentration ratios (Kp,uu,lumbar CSF) of nonsubstrates or weak substrates of P-gp were in the range 0.885-1.34, whereas those of good substrates of P-gp were in the range 0.195-0.458 and were strongly negatively correlated with in vitro P-gp transport activity. Moreover, concomitant treatment with a P-gp inhibitor, zosuquidar, increased the Kp,uu,lumbar CSF values of the good P-gp substrates, indicating that P-gp-mediated active efflux contributed to the low Kp,uu,lumbar CSF values of these compounds. Compared with the drug concentrations in the cisternal CSF and interstitial fluid (ISF) that we previously determined in cynomolgus monkeys, the lumbar CCSF were more than triple for two and all of the good P-gp substrates examined, respectively. Although lumbar CCSF may overestimate cisternal CSF and ISF concentrations of good P-gp substrates, lumbar CCSF allowed discrimination of good P-gp substrates from the weak and nonsubstrates and can be used to estimate the impact of P-gp-mediated active efflux on drug CNS penetration. SIGNIFICANCE STATEMENT: This is the first study to systematically evaluate the penetration of various P-glycoprotein (P-gp) substrates into lumbar cerebrospinal fluid (CSF) in nonhuman primates. Lumbar CSF may contain >3-fold higher concentrations of good P-gp substrates than interstitial fluid (ISF) and cisternal CSF but was able to discriminate the good substrates from the weak or nonsubstrates. Because lumbar CSF is more accessible than ISF and cisternal CSF in nonhuman primates, these findings will help increase our understanding of drug central nervous system penetration at the nonclinical stage.

Abstract 579: Ensartinib (X-396), a novel ALK TKI, in Chinese ALK-positive non-small cell lung cancer: A phase I, dose-escalation and expansion study

Abstract Background: Ensartinib (X-396) is a novel ALK inhibitor with high activity against a broad range of crizotinib-resistant ALK mutations (such as G1269A, F1174, C1156Y, and T1151) and CNS metastases. This Phase I study (NCT02959619) determined the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D), investigated the safety and PK, and explored the clinical efficiency for the compound as monotherapy in Chinese ALK+ NSCLC patients. Methods: Patients with advanced ALK+ NSCLC were treated with oral ensartinib (150, 200, 225, or 250 mg once daily) using a conventional 3+3 dose escalation design. The dose-escalation evaluated patients in 28-day cycles. In the dose-expansion phase, ensartinib was given at the recommended dose to further explore PK and clinical efficacy. Treatment was continued until disease progression, or unacceptable toxicity. Results: Between March, 2017 and August, 2018, 48 patients were enrolled. 43 patients were locally detected ALK positive by FISH or IHC (VANTANA), 5 patients harbored with ROS1 fusion. In 43 ALK positive patients, 32 patients were ALK TKI-naïve while 11 patients progressed on prior molecular targeted therapy (including 10 crizotinib-treatment and 2 ceritinib- or alectinib-treatment). Two DLTs were observed in the 250 mg dose cohort (grade 3 rash). All patients experienced at least one treatment-related adverse event, in which 19 (39.6%) had grade 3 or higher events with skin rash (16.7%) as the most common one. Ensartinib was moderately absorbed (median time to max concentration: 3.00-4.00 h) and slowly eliminated (mean half-life: 21.0-30.2 h). In multiple dose administration, a steady-state concentration of ensartinib was reached after 8-15 days. The geometric mean AUC0-tau and Cmax of ensartinib at 225 mg were 6950 h*ng/mL and 435 ng/mL, respectively. The ratio of drug concentration in cerebrospinal fluid (CSF) to that in plasma was 1.31-2.05% in 6 patients treated with ensartinib. Objective tumor responses were observed across all dose cohorts. In 46 evaluable patients, the objective response rates (ORR) and disease control rates (DCR) were 71.7% (1 CR and 32 PR) and 84.8% (6 SD), respectively. In ALK positive patients, the ORR and DCR were 80.5% (33/41) and 87.8% (36/41). The ORRs and DCRs at ≥225mg were 68.6% (24/35) and 85.7% (30/35), respectively. The confirmed ORR was 90.0% (27/30) in ALK TKI-naive patients compared to 54.5% (6/11) in ALK TKI-resistant patients. The ORR and DCR in 16 patients with baseline brain metastases were 75% and 75%, respectively. At data cut-off (07-Nov-2019), the median PFS for all 46 evaluable patients was 17.1 months (95% CI 6.3-27.9), and was 20.4 months (95% CI 13.2-27.6) for ALK positive patients, 8.6 months (95% CI 0-24.8) for ROS1 fusion patients. The median PFS was 24.5 months (95% CI 17.4-31.6) and 4.2 months (95% CI 0-8.9) for ALK TKI-naive and ALK TKI-resistant patients, respectively. Conclusions: Ensartinib was well tolerated in Chinese ALK-positive NSCLC patients with high antitumor activity. RP2D was established at 225 mg QD. Ensartinib could penetrate the blood-brain barrier with a CSF/plasma concentration ratio of 1.65%, supporting its remarkable intracranial efficacy. A global randomized phase 3 trial of ensartinib versus crizotinib in NSCLC patients who have not previously been treated with ALK TKIs is underway (NCT02767804). Citation Format: Hongyun Zhao, Yuxiang Ma, Yang Zhang, Shaodong Hong, Wenfeng Fang, Yunpeng Yang, Jianjin Huang, Jing Zhao, Yan Huang, Lieming Ding, Li Mao, Giovanni Selvaggi, Li Zhang. Ensartinib (X-396), a novel ALK TKI, in Chinese ALK-positive non-small cell lung cancer: A phase I, dose-escalation and expansion study [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 579.

Abstract 3026: Evaluation of brain pharmacokinetics (PK) and tumor growth inhibition of PARP inhibitors in mouse xenograft models using semi-mechanistic PK/pharmacodynamic (PD) modeling

Abstract OBJECTIVE: The PARP inhibitors rucaparib, niraparib, olaparib, and veliparib have shown remarkable antitumor activity against various cancer types. We evaluated the brain penetration of PARP inhibitors in mice and the anti-tumor effects of selected PARP inhibitors in orthotopic and intracranial BRCA1-mutant triple-negative breast cancer (TNBC) MDA-MB-436 mouse models. PK/PD models were used to characterize the systemic/brain PK and tumor growth inhibition. METHODS: In non-tumor-bearing NOD-SCID female mice, plasma concentrations were determined at selected time points following an oral dose of 2, 5, 15, 50, or 150 mg rucaparib. The antitumor efficacy of rucaparib (2, 5, 15, 50, or 150 mg BID for 28 days) was evaluated in the MDA-MB-436 orthotopic model. In addition, a single dose of rucaparib (150 mg), niraparib (50 mg), olaparib (150 mg), or veliparib (150 mg) was given to male CD-1 mice; plasma, brain, and cerebrospinal fluid (CSF) concentrations of these compounds were determined at various time points. Intracranial efficacy was evaluated in luciferase-expressing MDA-MB-436 tumors following treatment of rucaparib (150 mg BID) or niraparib (50 mg QD) for 57 days. Tumor burden was evaluated using bioluminescence measurements. Semi-mechanistic PK and tumor growth inhibition models were developed to evaluate systemic, brain, and CSF concentration-time profiles for all 4 PARP inhibitors, and to evaluate tumor inhibition for rucaparib and niraparib using NONMEM software. RESULTS: All of the PARP inhibitors showed limited brain penetration in mice with an intact blood-brain barrier. However, rucaparib and niraparib demonstrated antitumor efficacy in a BRCA1-mutant, intracranial, TNBC mouse model. Brain and CSF concentrations were modeled as separate physiologically relevant compartments with PARP inhibitors being able to distribute to both brain and CSF compartments from the systemic compartment following oral administration. The model characterized plasma, brain, and CSF drug concentrations simultaneously. A modified Simeoni model with a 1st-order tumor growth rate adequately described the dose-dependent tumor inhibition at different doses of rucaparib in the orthotopic tumor model. The effects of brain tumor inhibition by rucaparib and niraparib were sufficiently described by a simpler model with a 1st-order tumor growth rate and a 2nd-order tumor inhibition rate that was proportional to brain drug concentrations. CONCLUSIONS: Systemic and brain concentrations, as well as orthotopic and intracranial tumor inhibition data, following oral administration in mice, were adequately described using semi-mechanistic models. Further studies are warranted to understand the intracranial distribution and antitumor activity of PARP inhibitors. Citation Format: Michelle Liao, Feng Jin, Minh Nguyen, Liliane Robillard, Andrew D. Simmons, Thomas C. Harding, Jim J. Xiao. Evaluation of brain pharmacokinetics (PK) and tumor growth inhibition of PARP inhibitors in mouse xenograft models using semi-mechanistic PK/pharmacodynamic (PD) modeling [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3026.

Cerebrospinal fluid penetration of targeted therapeutics in pediatric brain tumor patients

Treatment with small-molecule inhibitors, guided by precision medicine has improved patient outcomes in multiple cancer types. However, these compounds are often not effective against central nervous system (CNS) tumors. The failure of precision medicine approaches for CNS tumors is frequently attributed to the inability of these compounds to cross the blood-brain barrier (BBB), which impedes intratumoral target engagement. This is complicated by the fact that information on CNS penetration in CNS-tumor patients is still very limited. Herein, we evaluated cerebrospinal fluid (CSF) drug penetration, a well-established surrogate for CNS-penetration, in pediatric brain tumor patients. We analyzed 7 different oral anti-cancer drugs and their metabolites by high performance liquid chromatography mass spectrometry (HPLC-MS) in 42 CSF samples obtained via Ommaya reservoirs of 9 different patients. Moreover, we related the resulting data to commonly applied predictors of BBB-penetration including ABCB1 substrate-character, physicochemical properties and in silico algorithms. First, the measured CSF drug concentrations depicted good intra- and interpatient precision. Interestingly, ribociclib, vorinostat and imatinib showed high (> 10 nM), regorafenib and dasatinib moderate (1–10 nM) penetrance. In contrast, panobinostat und nintedanib were not detected. In addition, we identified active metabolites of imatinib and ribociclib. Comparison to well-established BBB-penetrance predictors confirmed low molecular weight, high proportion of free-drug and low ABCB1-mediated efflux as central factors. However, evaluation of diverse in silico algorithms showed poor correlation within our dataset. In summary, our study proves the feasibility of measuring CSF concentration via Ommaya reservoirs thus setting the ground for utilization of this method in future clinical trials. Moreover, we demonstrate CNS presence of certain small-molecule inhibitors and even active metabolites in CSF of CNS-tumor patients and provide a potential guidance for physicochemical and biological factors favoring CNS-penetration.

Cerebrospinal Fluid Drug Concentrations and Clinical Outcome of Patients with Neoplastic Meningitis Treated with Liposomal Cytarabine.

Background and ObjectiveLiposomal cytarabine is a slow-release formulation for intrathecal application in patients with neoplastic meningitis. Although standard dosing intervals range from 2 to 4 weeks, it is unclear whether sustained cytotoxic cerebrospinal fluid (CSF) concentrations can be achieved beyond 14 days from drug injection. The objective of this study was to assess CSF and plasma concentrations of liposomal cytarabine more than 2 weeks after lumbar drug administration and to correlate those findings with clinical outcome.Methods66 matched CSF and plasma drug concentrations were analyzed by a validated liquid chromatography–tandem mass spectrometry method starting at day 13 from lumbar drug injection in 19 patients with neoplastic meningitis treated with liposomal cytarabine. CSF drug concentrations were correlated with clinical outcome.ResultsOverall response rate was 63.2% (12/19). 100% (9/9) of patients with positive CSF cytology at diagnosis achieved cytological complete remission, and none of the patients (0/19) experienced on-drug disease progression. In responding patients with controlled systemic disease, CNS-specific progression-free survival was 14 months (n = 4; range 5–25 months). The median CSF concentration of free cytarabine was 156 ng/ml (range 5–4581 ng/ml) and 146 ng/ml (range 5–353 ng/ml) in samples withdrawn at days 13–16 and at days 25–29 after intrathecal drug injection, respectively. Free cytarabine concentrations > 100 ng/ml were detected in 58.8% (20/34) and 53.3% (7/13) of the CSF samples obtained at days 13–16 and days 25–29, respectively. CSF drug concentrations did not differ significantly between responding and nonresponding patients.ConclusionLiposomal cytarabine permits prolonged CSF drug exposure, with cytotoxic cytarabine concentrations that are detectable for 4 weeks in the majority of patients. The preserved clinical activity seen in patients with inferior CSF drug concentrations (< 100 ng/ml) suggests that maintaining lower cytarabine concentrations for a longer period of time may be similarly effective as using short peak concentrations.

Development of a physiologically-based pharmacokinetic pediatric brain model for prediction of cerebrospinal fluid drug concentrations and the influence of meningitis.

Different pediatric physiologically-based pharmacokinetic (PBPK) models have been described incorporating developmental changes that influence plasma drug concentrations. Drug disposition into cerebrospinal fluid (CSF) is also subject to age-related variation and can be further influenced by brain diseases affecting blood-brain barrier integrity, like meningitis. Here, we developed a generic pediatric brain PBPK model to predict CSF concentrations of drugs that undergo passive transfer, including age-appropriate parameters. The model was validated for the analgesics paracetamol, ibuprofen, flurbiprofen and naproxen, and for a pediatric meningitis population by empirical optimization of the blood-brain barrier penetration of the antibiotic meropenem. Plasma and CSF drug concentrations derived from the literature were used to perform visual predictive checks and to calculate ratios between simulated and observed area under the concentration curves (AUCs) in order to evaluate model performance. Model-simulated concentrations were comparable to observed data over a broad age range (3 months–15 years postnatal age) for all drugs investigated. The ratios between observed and simulated AUCs (AUCo/AUCp) were within 2-fold difference both in plasma (range 0.92–1.09) and in CSF (range 0.64–1.23) indicating acceptable model performance. The model was also able to describe disease-mediated changes in neonates and young children (<3m postnatal age) related to meningitis and sepsis (range AUCo/AUCp plasma: 1.64–1.66, range AUCo/AUCp CSF: 1.43–1.73). Our model provides a new computational tool to predict CSF drug concentrations in children with and without meningitis and can be used as a template model for other compounds that passively enter the CNS.

A minimally-invasive serial cerebrospinal fluid sampling model in conscious Göttingen minipigs.

Drug concentrations in cerebrospinal fluid (CSF) are typically used as a as a surrogate measure of their availability in the CNS, and CSF penetration in animal studies are used for assessment of CNS drug delivery in early preclinical drug development. The minipig is a valid alternative to dogs and non-human primates as non-rodent species in preclinical research, but this species presents anatomical peculiarities that make the serial collection of CSF technically challenging. A minimally-invasive serial cerebrospinal fluid collection model via catheterization of the subarachnoid space in conscious minipigs was developed allowing assessment of longitudinal drug pharmacokinetics in the central nervous system in preclinical research. Shortly, the subarachnoid space was accessed in the anesthetized minipig by puncture with a Tuohy needle; when CSF was flowing through the needle a catheter was advanced and thereafter tunneled and fixed on the back. The PK of peptide A administered subcutaneously was performed and CSF could be sampled in the conscious animals for up to 48 h. When compared to the plasma kinetic data, there was a clear difference in the elimination phase of Pept. A from CSF, with an apparent longer average terminal half-life in CSF. The 3Rs are addressed by reducing the number of animals needed for a pharmacokinetic profile in central nervous system and by improving the validity of the model avoiding biases due to anesthesia, blood contamination, and inter-individual variability.

Phase I and Biomarker Study of Plerixafor and Bevacizumab in Recurrent High-Grade Glioma

Purpose: Although antiangiogenic therapy for high-grade glioma (HGG) is promising, responses are not durable. Correlative clinical studies suggest that the SDF-1α/CXCR4 axis may mediate resistance to VEGFR inhibition. Preclinical data have demonstrated that plerixafor (a reversible CXCR4 inhibitor) could inhibit glioma progression after anti-VEGF pathway inhibition. We conducted a phase I study to determine the safety of plerixafor and bevacizumab in recurrent HGG.Patients and Methods: Part 1 enrolled 23 patients with a 3 × 3 dose escalation design to a maximum planned dose of plerixafor 320 μg/kg subcutaneously on days 1 to 21 and bevacizumab 10 mg/kg intravenously on days 1 and 15 of each 28-day cycle. Cerebrospinal fluid (CSF) and plasma samples were obtained for pharmacokinetic analyses. Plasma and cellular biomarkers were evaluated before and after treatment. Part 2 enrolled 3 patients and was a surgical study to determine plerixafor's penetration in tumor tissue.Results: In Part 1, no dose-limiting toxicities were seen at the maximum planned dose of plerixafor + bevacizumab. Treatment was well tolerated. After plerixafor 320 μg/kg treatment, the average CSF drug concentration was 26.8 ± 19.6 ng/mL. Plerixafor concentration in resected tumor tissue from patients pretreated with plerixafor was 10 to 12 μg/g. Circulating biomarker data indicated that plerixafor + bevacizumab induces rapid and persistent increases in plasma SDF-1α and placental growth factor. Progression-free survival correlated with pretreatment plasma soluble mesenchymal-epithelial transition receptor and sVEGFR1, and overall survival with the change during treatment in CD34+ progenitor/stem cells and CD8 T cells.Conclusions: Plerixafor + bevacizumab was well tolerated in HGG patients. Plerixafor distributed to both the CSF and brain tumor tissue, and treatment was associated with biomarker changes consistent with VEGF and CXCR4 inhibition. Clin Cancer Res; 24(19); 4643-9. ©2018 AACR.

Monoclonal antibody exposure in rat and cynomolgus monkey cerebrospinal fluid following systemic administration

BackgroundMany studies have focused on the challenges of small molecule uptake across the blood–brain barrier, whereas few in-depth studies have assessed the challenges with the uptake of antibodies into the central nervous system (CNS). In drug development, cerebrospinal fluid (CSF) sampling is routinely used as a surrogate for assessing CNS drug exposure and biomarker levels. In this report, we have studied the kinetic correlation between CSF and serum drug concentration–time profiles for five humanized monoclonal antibodies in rats and cynomolgus monkeys and analyzed factors that affect their CSF exposure.ResultsUpon intravenous (IV) bolus injection, antibodies entered the CNS slowly and reached maximum CSF concentration (CSFTmax) in one to several days in both rats and monkeys. Antibody serum and CSF concentration–time curves converged until they became parallel after CSFTmax was reached. Antibody half-lives in CSF (CSFt½) approximated their serum half-lives (serumt½). Although the intended targets of these antibodies were different, the steady-state CSF to serum concentration ratios were similar at 0.1–0.2% in both species. Independent of antibody target and serum concentration, CSF-to-serum concentration ratios for individual monkeys ranged by up to tenfold from 0.03 to 0.3%.ConclusionUpon systemic administration, average antibodies CSF-to-serum concentration ratios in rats and monkeys were 0.1–0.2%. The CSFt½ of the antibodies was largely determined by their long systemic t½ (systemict½).

Cerebrospinal fluid drug concentrations and viral suppression in HIV-1-infected patients receiving ritonavir-boosted atazanavir plus lamivudine dual antiretroviral therapy (Spanish HIV/AIDS Research Network, PreEC/RIS 39).

This study aimed to assess cerebrospinal fluid (CSF) drug concentrations and viral suppression in HIV-1-infected patients on ritonavir-boosted atazanavir (ATV/r) plus lamivudine (3TC) dual therapy. HIV-1-infected adults with suppressed plasma HIV-1 RNA who switched to ATV/r plus 3TC were studied. Total ATV and 3TC concentrations at the end of the dosing interval (C24h), using a validated LC-MS/MS method, and HIV-1 RNA were measured in paired CSF and plasma samples 12weeks after switching. Ten individuals were included. Median (range) age was 42.5 (33-70) years, time on ART was 39.5 (11-197) months, and time with plasma HIV-1 RNA < 40 copies/mL was 15.5 (6-46) months. At baseline, CSF HIV-1 RNA was < 40 copies/mL in all patients. Twelve weeks after switching to ATV/r plus 3TC, HIV-1 RNA remained at < 40 copies/mL in both plasma and CSF in 9/10 patients. One patient with suboptimal adherence to ART had HIV-1 RNA rebound in both plasma and CSF. The median CSF-to-plasma concentration ratios of ATV and 3TC were 0.013 and 0.417, respectively. Median ATV C24h in CSF was 10.4 (3.7-33.4) ng/mL (in vitro ATV IC50 range, 1-11ng/mL). Median 3TC C24h in CSF was 43.4 (16.2-99.3) ng/mL (in vitro 3TC IC50 range, 0.68-20.6ng/mL). Most patients maintained HIV-1 RNA in CSF < 40 copies/mL despite CSF ATV C24h close to or within the IC50 range in the majority. ATV PK data in CSF should be considered and rigorous patient selection is advisable to assure effective CSF viral suppression with this two-drug simplification regimen.

Pharmacokinetics and pharmacodynamics of antibiotics in central nervous system infections.

The barriers surrounding the central nervous system (CNS) together with the emergence of multiresistant pathogens pose a therapeutic challenge for the effective treatment of CNS infections. In addition to vancomycin, colistin and aminoglycosides, classically used for intrathecal injection, drug concentrations in cerebrospinal fluid after intrathecal injection of daptomycin and tigecyclin were recently studied. The entry of antiinfectives into the CNS compartments is determined by the physicochemical properties of the drug and by conditions in the host. The most important drug properties are lipophilicity at a neutral pH, molecular mass and drug binding to serum proteins. In clinical practice, active transport is of importance only for some drugs. In recent years, intrathecal injection of antiinfectives in addition to systemic therapy has regained attention as a means to achieve high cerebrospinal fluid concentrations. The classification of antibacterials and antifungals into time-dependent and concentration-dependent compounds is also valid for the CNS compartments.

An Observation on Vancomycin Concentrations in Cerebrospinal Fluid and Serum of a Chinese Critically-Ill Patient with Intravenous Drug Injection

Background: The blood-brain-barrier (BBB), which is characterized with the selective permeability, has major impact on distribution, concentration and biological effects of most drugs in the central nervous system (CNS). Methods: In this study, we chose one critically-ill patient in year 2015 and monitored drug concentrations in the cerebrospinal fluid (CSF) and serum during vancomycin therapy, in order to observe vancomycin permeability of BBB or clinical application potential under CNS infection state. Results: During a period of 48h after intravenous drug injection, the peak level was 3.45 µg/ml, lowest level 0.13 µg/ml, and average level 1.46 µg/ml in the CSF. In the serum, the peak level was 64.23 µg/ml, lowest level 3.91 µg/ml and average level 21.56 µg/ml. In all nine time-points detected during 48h, CSF drug concentrations were lower than that in serum, but CSF drug levels in six of nine time-points showed above MIC (1.0 µg/ml) or effective for MRSA, indicating that BBB had larger influence on drug permeability or distribution of vancomycin in the CNS. However, intravenous injection could reach concentration effective for MASA of CNS infection. Conclusions: This was difficult to obtain case and it has provided new evidence on vancomycin usage in CNS for MASA infections in a Chinese critically-ill patient.