Concentrations In Central Nervous System Research Articles

Predictions of Bedaquiline Central Nervous System Exposure in Patients with Tuberculosis Meningitis Using Physiologically based Pharmacokinetic Modeling.

The use of bedaquiline as a treatment option for drug-resistant tuberculosis meningitis (TBM) is of interest to address the increased prevalence of resistance to first-line antibiotics. To this end, we describe a whole-body physiologically based pharmacokinetic (PBPK) model for bedaquiline to predict central nervous system (CNS) exposure. A whole-body PBPK model was developed for bedaquiline and its metabolite, M2. The model included compartments for brain and cerebrospinal fluid (CSF). Model predictions were evaluated by comparison to plasma PK time profiles following different dosing regimens and sparse CSF concentrations data from patients. Simulations were then conducted to compare CNS and lung exposures to plasma exposure at clinically relevant dosing schedules. The model appropriately described the observed plasma and CSF bedaquiline and M2 concentrations from patients with pulmonary tuberculosis (TB). The model predicted a high impact of tissue binding on target site drug concentrations in CNS. Predicted unbound exposures within brain interstitial exposures were comparable with unbound vascular plasma and unbound lung exposures. However, unbound brain intracellular exposures were predicted to be 7% of unbound vascular plasma and unbound lung intracellular exposures. The whole-body PBPK model for bedaquiline and M2 predicted unbound concentrations in brain to be significantly lower than the unbound concentrations in the lung at clinically relevant doses. Our findings suggest that bedaquiline may result in relatively inferior efficacy against drug-resistant TBM when compared with efficacy against drug-resistant pulmonary TB.

Interspecies Brain PBPK Modeling Platform to Predict Passive Transport through the Blood-Brain Barrier and Assess Target Site Disposition.

The high failure rate of central nervous system (CNS) drugs is partly associated with an insufficient understanding of target site exposure. Blood-brain barrier (BBB) permeability evaluation tools are needed to explore drugs' ability to access the CNS. An outstanding aspect of physiologically based pharmacokinetic (PBPK) models is the integration of knowledge on drug-specific and system-specific characteristics, allowing the identification of the relevant factors involved in target site distribution. We aimed to qualify a PBPK platform model to be used as a tool to predict CNS concentrations when significant transporter activity is absent and human data are sparse or unavailable. Data from the literature on the plasma and CNS of rats and humans regarding acetaminophen, oxycodone, lacosamide, ibuprofen, and levetiracetam were collected. Human BBB permeability values were extrapolated from rats using inter-species differences in BBB surface area. The percentage of predicted AUC and Cmax within the 1.25-fold criterion was 85% and 100% for rats and humans, respectively, with an overall GMFE of <1.25 in all cases. This work demonstrated the successful application of the PBPK platform for predicting human CNS concentrations of drugs passively crossing the BBB. Future applications include the selection of promising CNS drug candidates and the evaluation of new posologies for existing drugs.

PRX005, a novel anti‐MTBR tau monoclonal antibody: results from a first‐in‐human double‐blind, placebo‐controlled, single ascending dose phase 1 study

AbstractBackgroundMultiple lines of evidence indicate that tau protein spreads throughout the brain via synaptically connected pathways and that this propagation could be mediated by tau “seeds” containing the microtubule binding region (MTBR) of tau. In addition, cerebrospinal fluid (CSF) MTBR‐tau levels correlate with tau tangles and clinical stages of Alzheimer’s disease. To block the spread of tau pathology, we developed PRX005, a humanized monoclonal tri‐epitopic antibody that binds with high affinity to the R1, R2, and R3 repeats in the MTBR region of tau, and targets both 3R and 4R tau isoforms.MethodHealthy volunteers were randomly assigned to three dose cohorts and randomized in a 3:1 manner to receive either PRX005 or placebo. Primary endpoint was safety and tolerability with up to 2 months of follow‐up. Secondary endpoints included PRX005 pharmacokinetic parameters in plasma and CSF penetrance.ResultA total of 19 healthy volunteer participants received study drug or placebo. PRX005 was well tolerated and had a pharmacokinetic profile typical of IgG1 antibodies, with dose‐proportional increase in plasma concentration and central nervous system (CNS) penetrance. No persistent drug‐induced anti‐drug antibodies were observed following treatment with PRX005. Additional results from this Phase 1 will be presented.ConclusionIn this first‐in‐human, single ascending dose study, PRX005 was well tolerated and achieved CNS concentrations for pharmacological targeting of MTBR‐tau. Our results support the progression of the clinical development of PRX005 in an ongoing, multiple ascending dose study in patients with Alzheimer’s disease.

Dry Powder Inhaler with the technical and practical obstacles, and forthcoming platform strategies.

A Dry Powder Inhaler (DPI) is a technique as well as a device used to inhale formulation which is in the form of dry powder, and is inhaled through the nose or mouth. It was developed for the purpose of treating conditions like chronic obstructive pulmonary disease (COPD), Asthma, and even cystic fibrosis etc. The aim of the review is to discuss the different methods of preparation of dry powders along with the characterization of DPI. Here we present the outline of different methods like supercritical fluid extraction (SCF), spray drying, and milling. The review focussed on various devices including single and multi-dose devices used in the DPI. It also highlights on recent advances in the DPI including nano particulate system, siRNA-based medication, liposomes, and pro-liposomes based delivery. In COVID-19 silver nanoparticles-based DPIs provide very prominent results in the infected lungs. Moreover, this review states that the AI-based DPI development provides and improvement in the bioavailability and effectiveness of the drug along with the role of artificial neural networks (ANN). The study also showed that nasally administered drugs (nose to brain) can easily cross the blood-brain barrier (BBB) and enter the central nervous system (CNS) through the olfactory and trigeminal pathway which provides effective CNS concentrations at lower dosage. It is suggested that DPIs not only target respiratory complications but also treat CNS complications too. This review provides support and guides the researcher in the recent development and evaluation of DPI.

Evaluation of Lorlatinib Cerebrospinal Fluid Concentrations in Relation to Target Concentrations for Anaplastic Lymphoma Kinase (ALK) Inhibition.

Lorlatinib is a third‐generation, brain‐penetrant anaplastic lymphoma kinase (ALK) and c‐ros oncogene 1 (ROS1) tyrosine kinase inhibitor (TKI) with robust intracranial activity in patients with ALK‐ or ROS1‐positive non‐small cell lung cancer (NSCLC). Data from the ongoing open‐label, single‐arm, multicenter, phase‐1/2 study of lorlatinib in patients with metastatic ALK‐ or ROS1‐positive NSCLC were used to further investigate the potential brain penetration of lorlatinib. Patients received escalating lorlatinib doses (10–200 mg once daily or 35–100 mg twice daily) or the approved dosing (100 mg daily). Plasma was collected from all patients, and cerebrospinal fluid (CSF) was collected at baseline and during the study from 5 patients with suspected or confirmed leptomeningeal carcinomatosis or carcinomatous meningitis. For those 5 patients, lorlatinib concentrations ranged from 2.64 to 125 ng/mL in the CSF and from 12.7 to 457 ng/mL in the plasma; free plasma concentrations ranged from 4.318 to 155.385 ng/mL. The CSF/free plasma ratio was 0.77 (R2 = 0.96 and P < .001). Using a post‐hoc population pharmacokinetic model, the average steady‐state unbound plasma concentration of lorlatinib was derived and the CSF concentration was estimated for all patients. Known minimum efficacy concentrations (Ceff) for wild‐type and mutated (L1196M and G1202R) ALK were used to derive central nervous system (CNS) Ceff. Estimated CNS concentrations exceeded the derived CNS Ceff values in all patients for wild‐type ALK and the ALK L1196M mutation, and in 35.8% of patients for the ALK G1202R mutation. Projected lorlatinib CNS concentrations were consistent with the high intracranial response rates reported in clinical trials and provide further evidence of the potent CNS penetration of lorlatinib.

Small phenolic and indolic gut-dependent molecules in the primate central nervous system: levels vs. bioactivity.

A rapidly growing body of data documents associations between disease of the brain and small molecules generated by gut-microbiota (GMB). While such metabolites can affect brain function through a variety of mechanisms, the most direct action would be on the central nervous system (CNS) itself. Identify indolic and phenolic GMB-dependent small molecules that reach bioactive concentrations in primate CNS. We conducted a PubMed search for metabolomic studies of the primate CNS [brain tissue or cerebrospinal fluid (CSF)] and then selected for phenolic or indolic metabolites that (i) had been quantified, (ii) were GMB-dependent. For each chemical we then conducted a search for studies of bioactivity conducted in vitro in human cells of any kind or in CNS cells from the mouse or rat. 36 metabolites of interests were identified in primate CNS through targeted metabolomics. Quantification was available for 31/36 and in vitro bioactivity for 23/36. The reported CNS range for 8 metabolites 2-(3-hydroxyphenyl)acetic acid, 2-(4-hydroxyphenyl)acetic acid, 3-(3-hydroxyphenyl)propanoic acid, (E)-3-(3,4-dihydroxyphenyl)prop-2-enoic acid [caffeic acid], 3-hydroxybenzoic acid, 4-hydroxybenzoic acid, 2-acetamido-3-(1H-indol-3-yl)propanoic acid [N-acetyltryptophan], 1H-indol-3-yl hydrogen sulfate [indoxyl-3-sulfate] overlapped with a bioactive concentration. However, the number and quality of relevant studies of CNS neurochemistry as well as of bioactivity were highly limited. Structural isomers, multiple metabolites and potential confounders were inadequately considered. The potential direct bioactivity of GMB-derived indolic and phenolic molecules on primate CNS remains largely unknown. The field requires additional strategies to identify and prioritize screening of the most promising small molecules that enter the CNS.

A Phase 2a study evaluating the safety, tolerability, pharmacokinetics, and central nervous system activity of CY6463 when administered to participants with Alzheimer’s disease with vascular pathology

AbstractBackgroundThe soluble guanylate cyclase (sGC) stimulator, CY6463, is being developed as a symptomatic and potentially disease‐modifying therapy for serious central nervous system (CNS) diseases, including Alzheimer’s disease (AD). Nitric oxide (NO)‐sGC‐cyclic guanosine monophosphate (cGMP) is a fundamental neurotransmitter system critical to neuronal function. Impaired signaling of this pathway is known to play a role in the pathogenesis of many neurodegenerative diseases. CY6463, a positive allosteric modulator of sGC, amplifies endogenous NO signaling to increase cGMP production. In preclinical models, CY6463 improved neuronal function, cerebral blood flow, neuroinflammation, and cellular bioenergetics.CY6463 has been evaluated in two Phase 1 studies (110 healthy younger adult volunteers and 24 healthy elderly volunteers &gt;65 years of age) assessing the safety, tolerability, pharmacokinetics (PK), and CNS activity of CY6463. Once‐daily CY6463 administration was well tolerated across dose levels, led to target CNS concentrations, achieved predictable/linear food‐independent PK, and had positive impacts on saccadic eye movements as well as brain neurophysiology as measured by electroencephalography (EEG).MethodThis 12‐week, randomized, placebo‐controlled study will evaluate safety, tolerability, PK, and CNS activity of CY6463 in approximately 40 patients with a combination of AD pathology, sub‐cortical vascular disease, and cardiovascular risk factors. This defined subset of the larger AD population, referred to as AD with vascular pathology (ADv), is hypothesized to be more likely to respond to CY6463 treatment due to CY6463’s expected impact on vascular and CNS biology. This study is funded in part by a Translational Research Award from the Alzheimer’s Association Part the Cloud‐Gates Partnership Grant Program.ResultThe primary objective, safety and tolerability, will be evaluated based on adverse event reporting. Exploratory evaluations assessed variously at baseline and weeks 2, 4, 8, and 12, will include plasma and CSF biomarkers of disease; PK; quantitative EEG and event related potentials as biomarkers of neurophysiology; functional magnetic resonance imaging measures of cerebral perfusion and brain connectivity; and cognitive performance tests of attention, executive function, and memory.ConclusionResults from this study in patients with ADv will inform the design of larger, longer studies evaluating the potential for CY6463 to improve cognition in this patient population.

Dasatinib and dexamethasone followed by hematopoietic cell transplantation for adults with Ph-positive ALL

AbstractPost-remission strategies after dasatinib-corticosteroid induction in adult Philadelphia chromosome (Ph)–positive acute lymphoblastic leukemia (ALL) are not well studied. We evaluated dasatinib and dexamethasone induction then protocol-defined post-remission therapies, including hematopoietic cell transplantation (HCT). Adults (N = 65) with Ph-positive ALL received dasatinib-dexamethasone induction, methotrexate-based central nervous system (CNS) prophylaxis, reduced-intensity conditioning (RIC) allogeneic HCT, autologous HCT, or chemotherapy alone, and dasatinib-based maintenance. Key end points were disease-free survival (DFS) and overall survival (OS). The median age was 60 years (range, 22-87 years). The complete remission rate was 98.5%. With a median follow-up of 59 months, 5-year DFS and OS were 37% (median, 30 months) and 48% (median, 56 months), respectively. For patients receiving RIC allogeneic HCT, autologous HCT, or chemotherapy, 5-year DFS were 49%, 29%, and 34%, and 5-year OS were 62%, 57%, and 46%, respectively. Complete molecular response rate after CNS prophylaxis was 40%. Relative to the p190 isoform, p210 had shorter DFS (median 10 vs 34 months, P = .002) and OS (median 16 months vs not reached, P = .05). Relapse occurred in 25% of allogeneic HCT, 57% of autologous HCT, and 36% of chemotherapy patients. T315I mutation was detected in 6 of 8 marrow relapses. Dasatinib CNS concentrations were low. Dasatinib-dexamethasone followed by RIC allogeneic HCT, autologous HCT, or chemotherapy was feasible and efficacious, especially with RIC allogeneic HCT. Future studies should address the major causes of failure: T315I mutation, the p210 BCR-ABL1 isoform, and CNS relapse. This study was registered at www.clinicaltrials.gov as #NCT01256398.

ACT-1004-1239, a first-in-class CXCR7 antagonist with both immunomodulatory and promyelinating effects for the treatment of inflammatory demyelinating diseases.

Current strategies for the treatment of demyelinating diseases such as multiple sclerosis (MS) are based on anti-inflammatory or immunomodulatory drugs. Those drugs have the potential to reduce the frequency of new lesions but do not directly promote remyelination in the damaged central nervous system (CNS). Targeting CXCR7 (ACKR3) has been postulated as a potential therapeutic approach in demyelinating diseases, leading to both immunomodulation by reducing leukocyte infiltrates and promyelination by enhancing myelin repair. ACT-1004-1239 is a potent, selective, insurmountable, and orally available first-in-class CXCR7 receptor antagonist. The effect of ACT-1004-1239 was evaluated in the myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) and the cuprizone-induced demyelination mouse models. In addition, ACT-1004-1239 was assessed in a rat oligodendrocyte precursor cell (OPC) differentiation assay in vitro. In the MOG-induced EAE model, ACT-1004-1239 treatment (10-100mg/kg, twice daily, orally) showed a significant dose-dependent reduction in disease clinical scores, resulting in increased survival. At the highest dose tested (100mg/kg, twice daily), ACT-1004-1239 delayed disease onset and significantly reduced immune cell infiltrates into the CNS and plasma neurofilament light chain concentration. Treatment with ACT-1004-1239 dose-dependently increased plasma CXCL12 concentration, which correlated with a reduction of the cumulative disease score. Furthermore, in the cuprizone model, ACT-1004-1239 treatment significantly increased the number of mature myelinating oligodendrocytes and enhanced myelination in vivo. In vitro, ACT-1004-1239 promoted the maturation of OPCs into myelinating oligodendrocytes. These results provide evidence that ACT-1004-1239 both reduces neuroinflammation and enhances myelin repair substantiating the rationale to explore its therapeutic potential in a clinical setting.

Organic Cation Transporter (OCT/OCTN) Expression at Brain Barrier Sites: Focus on CNS Drug Delivery.

Therapeutic delivery to the central nervous system (CNS) continues to be a considerable challenge in the pharmacological treatment and management of neurological disorders. This is primarily due to the physiological and biochemical characteristics of brain barrier sites (i.e., blood-brain barrier (BBB), blood-cerebrospinal fluid barrier (BCSFB)). Drug uptake into brain tissue is highly restricted by expression of tight junction protein complexes and adherens junctions between brain microvascular endothelial cells and choroid plexus epithelial cells. Additionally, efflux transport proteins expressed at the plasma membrane of these same endothelial and epithelial cells act to limit CNS concentrations of centrally acting drugs. In contrast, facilitated diffusion via transporter proteins allows for substrate-specific flux of molecules across the plasma membrane, directing drug uptake into the CNS. Organic Cation Transporters (OCTs) and Novel Organic Cation Transporters (OCTNs) are two subfamilies of the solute carrier 22 (SLC22) family of proteins that have significant potential to mediate delivery of positively charged, zwitterionic, and uncharged therapeutics. While expression of these transporters has been well characterized in peripheral tissues, the functional expression of OCT and OCTN transporters at CNS barrier sites and their role in delivery of therapeutic drugs to molecular targets in the brain require more detailed analysis. In this chapter, we will review current knowledge on localization, function, and regulation of OCT and OCTN isoforms at the BBB and BCSFB with a particular emphasis on how these transporters can be utilized for CNS delivery of therapeutic agents.

Umbilical Blood Levels of IL-6 and TNF-α as Predictors of the Central Nervous System Damage and Retinopathy in Preterm Infants.

The aim was to identify the critical levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and vascular endothelial growth factor-A in umbilical cord blood that could be used as markers for predicting the central nervous system (CNS) damage and retinopathy of prematurity (ROP) in preterm infants. A total of 158 preterm infants, born at 22 to 34 weeks of gestation, were evaluated in the first week after birth and at 36 to 37 weeks of postconceptual age. A significant relationship between CNS changes and concentrations of IL-6 (p < 0.001) and TNF-α (p < 0.001) in umbilical cord blood at 22 to 34 weeks of gestation was determined. The concentration of IL-6 >13.0 pg/mL predicts significant CNS damages in 36 to 37-week infants (p = 0.013). ROP was diagnosed in 24.8% infants (n = 149). It was detected that the levels of TNF-α >116.4 pg/mL (p < 0.001) and IL-6 >13.0 pg/mL (p < 0.05) in umbilical cord blood could predict 2 to 3/3 to 4 stages of ROP. Critical values of IL-6 and TNF-α in predicting ≥grade III intraventricular hemorrhage in the early adaptation and in predicting marked CNS damages and severe ROP stages in the later adaptation of preterm infants were determined.

Quantification of Hydrochlorothiazide and Ramipril/Ramiprilate in Blood Serum and Cerebrospinal Fluid: A Pharmacokinetic Assessment of Central Nervous System Adverse Effects

Background: A drug must reach the central nervous system (CNS) in order to directly cause CNS adverse effects (AEs). Our current study addressed the pharmacokinetic (PK) background of the assumption that CNS concentrations of hydrochlorothiazide (HCT) and ramiprilate may directly cause CNS AEs such as headache and drowsiness. Methods: In neurological patients, paired serum and cerebrospinal fluid (CSF) samples were withdrawn simultaneously. Some of them were treated with HCT (n = 15, daily chronic doses 7.5–25 mg) or ramipril (n = 9, 2.5–10 mg). Total concentrations of HCT and ramiprilate were quantified in these samples. To this end, sensitive liquid chromatography/tandem mass spectrometry methods were developed. Results: CSF reached 4.1% (interquartile ranges 2.5–5%) of total serum concentrations for HCT and 2.3% (1.7–5.7%) for ramiprilate, corresponding to about 11.3% and 5.5% of respective unbound serum concentrations. Conclusion: The PK/Pharmacodynamic characteristics of HCT and ramiprilate in the CNS are unknown. However, since the CSF levels of these agents, both free and bound, were much lower than the corresponding concentrations in serum, it is unlikely that the observed CNS AEs are mediated primarily via direct effects in the brain.

The Effect of Aminophylline on Quinidine Passage into the Central Nervous System of Rats

Abstract: Background and Objective: There is significant interest in mutual influence of substances during their passage into the central nervous system (CNS). Quinidine is a drug which can achieve significant concentration in CNS and cause side effects and aminophylline is a drug with possibility to change distribution of drugs in CNS. Thus the aim of this work was to study the effect of aminophylline on the transition of quinidine through the bloodbrain barrier into the central nervous system. Material and Methods: The experiments were carried out on Wistar rats, which received quinidine in the form of the retrograde intra-arterial bolus injection into the right axillary vein. The control group of animals received subcutaneously physiological solution 30 min before the intra-arterial quinidine application, whereas the test group animals also received subcutaneously aminophylline 30 min before quinidine application. The rats were sacrificed by decapitation in specified time intervals in order to determine quinidine concentration in different parts of CNS. Results: There were no significant changes in serum quinidine levels by comparing the results of experimental group with those of the control group of animals. In all parts of CNS aminophylline pre-treatment caused significant decrease in CNS quinidine concentration. Conclusion: The results suggest that co-administration of aminophylline and quinidine, decreases quinidine concentrations in the CNS of rats. Key words: Aminophylline, Quinidine, Blood-brain barrier, Drug interactions.

First plasma and tissue pharmacokinetic study of the YSNSG cyclopeptide, a new integrin antagonist, using microdialysis

The YSNSG peptide is a synthetic peptide targeting αvβ3 integrin. This peptide exhibits promising activity in vitro and in vivo against melanoma. To determine pharmacokinetic parameters and predictive active doses in the central nervous system (CNS) and subcutaneous tissue (SC), we conducted microdialysis coupled with pharmacokinetic modeling and Monte Carlo simulation. After a recovery period of surgical procedures, a microdialysis probe was inserted in the caudate and in subcutaneous tissue. Plasma samples and dialysates collected 5h after YSNSG intravenous administration (10mg/kg) were analyzed by UPLC-MS/MS. A nonlinear mixed-effect modeling approach implemented in Monolix® 2016R1 was performed. Model selection and evaluation were based on the usual diagnostic plot, precision and information criteria. The primary plasma and tissue pharmacokinetic parameters were comparable with those of other integrin antagonists, such as cilengitide or ATN-161. Tissue/plasma and brain/plasma area under the curve (AUC) ratio were 66.2±21.6% and 3.6±4.7%, respectively. Two models of 2-compartments with an additional microdialysis compartment, parameterized as rate constants (k for elimination, k12/k21 and k13/k31 for distribution) and volumes (central V1 and peripheral microdialysis compartment V3) with zero-order input were selected to describe the dialysate concentrations in CNS and SC. The inter-individual variability (IIV) was described by exponential terms, and residual variability was described by a combined additive and proportional error model. Individual AUC (plasma and tissues) values were derived for each animal using the Empirical-Bayes-Estimates of the individual parameters. The regimens needed to achieve an in vitro predetermined target concentration in tissues were studied by Monte Carlo simulations using Monolix® 2016R1. YSNSG pharmacokinetic parameters show promising results in terms of subcutaneous disposition. Further investigations into such processes as encapsulation and intratumoral disposition are currently being conducted.

Microdialysis: the Key to Physiologically Based Model Prediction of Human CNS Target Site Concentrations

Despite the enormous research efforts that have been put into the development of central nervous system (CNS) drugs, the success rate in this area is still disappointing. To increase the successful rate in the clinical trials, first the problem of predicting human CNS drug distribution should be solved. As it is the unbound drug that equilibrates over membranes and is able to interact with targets, especially knowledge on unbound extracellular drug concentration-time profiles in different CNS compartments is important. The only technique able to provide such information in vivo is microdialysis. Also, obtaining CNS drug distribution data from human subjects is highly limited, and therefore, we have to rely on preclinical approaches combined with physiologically based pharmacokinetic (PBPK) modeling, taking unbound drug CNS concentrations into account. The next step is then to link local CNS pharmacokinetics to target interaction kinetics and CNS drug effects. In this review, system properties and small-molecule drug properties that together govern CNS drug distribution are summarized. Furthermore, the currently available approaches on prediction of CNS pharmacokinetics are discussed, including in vitro, in vivo, ex vivo, and in silico approaches, with special focus on the powerful combination of in vivo microdialysis and PBPK modeling. Also, sources of variability on drug kinetics in the CNS are discussed. Finally, remaining gaps and challenges are highlighted and future directions are suggested.

Intranasal administration of elastin-like polypeptide for therapeutic delivery to the central nervous system.

Bypassing the blood–brain barrier is one of the primary considerations when designing compounds intended to function in the central nervous system (CNS). Intranasal (IN) administration of otherwise blood–brain barrier impermeable molecules can result in high CNS concentrations and low systemic accumulation, indicating that IN administration may be a useful method of delivering therapeutics to the CNS. Elastin-like polypeptide (ELP) is a large, non-immunogenic, highly manipulable biopolymer with extensive evidence supporting its use as a carrier with the ability to improve drug pharmacokinetics and drug targeting. The ability of ELP to reach the CNS via IN administration has been shown previously. Previous studies have also identified the ability of cell penetrating peptides (CPPs) to increase the uptake of molecules in some instances, including via the IN route. Here, we compared and contrasted the biodistribution of ELPs with or without addition of the CPPs Tat or SynB1 via both the IN and intravenous routes. Administration of ELP via the IN route led to significant accumulation in the brain, especially in the olfactory bulbs. When injected intravenously, <3% of the ELP signal was present outside the vascular compartment. This contrasted with IN administration, which resulted in 79% of the fluorescence signal localized outside the vascular space. The fusion of Tat or SynB1 significantly altered the biodistribution of ELP, decreasing the total CNS accumulation following IN administration. The addition of CPPs to ELP increased their retention in the nasal epithelium. These results suggest ELP may represent an effective CNS delivery vector without further modification and that the addition of a CPP significantly influences biodistribution.

Comparison of Pantoprazole Concentrations in Simultaneous Cerebrospinal Fluid and Serum Samples

Background: Pantoprazole is a proton pump inhibitor drug mainly used for treating peptic diseases. Adverse effects of pantoprazole in the occasional central nervous system (CNS) include headache, vertigo and sleep disturbances. Data in rats suggest that proton pumps are expressed in the inner ear and in the epithelium of the choroid plexus, which would be a potential target to mediate such proton pump inhibitor effects. Methods: To assess the distribution of pantoprazole into the human CNS despite its low lipophilicity (log p = 0.5), we quantified pantoprazole concentrations by liquid chromatography/tandem mass spectrometry in serum and cerebrospinal fluid retain samples withdrawn simultaneously. Twenty-six sample pairs were obtained from 23 neurological patients with therapeutic administration of pantoprazole prior to sampling. Results: Median (interquartile range) serum concentration of total pantoprazole was 142 ng/ml (30.8-622). Cerebrospinal fluid concentration of total pantoprazole was 2.79 ng/ml (1.59-7.3) and reached 2.0% (1.0-4.5%) of simultaneous serum concentrations. Conclusion: This value corresponds to the unbound fraction of pantoprazole in serum reported previously and indicates that pantoprazole CNS concentrations are high enough to exert some effects on possible CNS targets.

Central nervous system penetration of antiretroviral drugs: pharmacokinetic, pharmacodynamic and pharmacogenomic considerations.

The prevalence of HIV-associated neurocognitive disorder (HAND) is increasing despite the widespread use of combination antiretroviral therapy (ART). Initial reports suggest that the use of antiretrovirals with good central nervous system (CNS) penetration leads to better neurocognitive outcomes, but this has not yet been confirmed in a large cohort study or randomised controlled trial. There is emerging evidence that high CNS concentrations of some antiretrovirals are potentially neurotoxic and may be associated with the development of HAND. Antiretroviral CNS exposure is ideally determined by determining the ratio of cerebrospinal fluid (CSF):plasma area under the curve of unbound drug, but usually only total drug concentrations are measured and the ratio of CSF:plasma drug concentration is done at a single time point, which can result in misclassifying CNS penetration ability. Efavirenz was previously thought to have poor CNS penetration, measured by the CSF:plasma ratio (0.87%), but when unbound concentrations were measured it was found to have good CNS penetration (85%). Indinavir and efavirenz are the only antiretroviral drugs for which CNS area under the concentration-time curves using unbound plasma and CSF concentrations has been calculated. Patient data to support the contribution of blood-brain barrier transporter polymorphisms to CNS antiretroviral concentrations are currently limited and lack power to detect true associations. Correlations between CNS antiretroviral exposure and effect is multifaceted, and to accurately predict CNS effects there is a need to develop a sophisticated intra-brain pharmacokinetic-pharmacodynamic-pharmacogenetic model that includes transporters as well as the influence of HIV.

Are capecitabine and the active metabolite 5-Fu CNS penetrable to treat breast cancer brain metastasis?

Brain metastasis (BM) is increasingly diagnosed in Her2 positive breast cancer (BC) patients. Lack of effective treatment to breast cancer brain metastases (BCBMs) is probably due to inability of the current therapeutic agents to cross the blood-brain barrier. The central nervous system (CNS) response rate in BCBM patients was reported to improve from 2.6%-6% (lapatinib) to 20%-65% (lapatinib in combination with capecitabine). Lapatinib is a poor brain penetrant. In this study, we evaluated the CNS penetration of capecitabine and hoped to interpret the mechanism of the improved CNS response from the pharmacokinetic (PK) perspective. Capecitabine does not have antiproliferative activity and 5-fluorouracil (5-FU) is the active metabolite. Capecitabine was orally administered to mouse returning an unbound brain-to-blood ratio (Kp,uu,brain) at 0.13 and cerebrospinal fluid (CSF)-to-unbound blood ratio (Kp,uu,CSF) at 0.29 for 5-FU. Neither free brain nor CSF concentration of 5-FU can achieve antiproliferative concentration for 50% of maximal inhibition of cell proliferation of 4.57 µM. BCBM mice were treated with capecitabine monotherapy or in combination with lapatinib. The Kp,uu,brain value of 5-FU increased to 0.17 in the brain tumor in the presence of lapatinib, which is still far below unity. The calculated free concentration of 5-FU and lapatinib in the brain tumor did not reach the antiproliferative potency and neither treatment showed antitumor activity in the BCBM mice. The CNS penetration of 5-FU in human was predicted based on the penetration in preclinical brain tumor, CSF, and human PK and the predicted free CNS concentration was below the antiproliferative potency. These results suggest that CNS penetration of 5-FU and lapatinib are not desirable and development of a true CNS penetrable therapeutic agent will further improve the response rate for BCBM.

Pharmacokinetics of Antibacterial Agents in the CSF of Children and Adolescents

The adequate management of central nervous system (CNS) infections requires that antimicrobial agents penetrate the blood-brain barrier (BBB) and achieve concentrations in the CNS adequate for eradication of the infecting pathogen. This review details the currently available literature on the pharmacokinetics (PK) of antibacterials in the CNS of children. Clinical trials affirm that the physicochemical properties of a drug remain one of the most important factors dictating penetration of antimicrobial agents into the CNS, irrespective of the population being treated (i.e. small, lipophilic drugs with low protein binding exhibit the best translocation across the BBB). These same physicochemical characteristics determine the primary disposition pathways of the drug, and by extension the magnitude and duration of circulating drug concentrations in the plasma, a second major driving force behind achievable CNS drug concentrations. Notably, these disposition pathways can be expected to change during the normal process of growth and development. Finally, CNS drug penetration is influenced by the nature and extent of the infection (i.e. the presence of meningeal inflammation). Aminoglycosides have poor CNS penetration when administered intravenously. Intrathecal gentamicin has been studied in children with more promising results, often exceeding the minimum inhibitory concentration. There are very limited data with intrathecal tobramycin in children. However, in the few patients that have been studied, the CSF concentrations were highly variable. Penicillins generally have good CNS penetration. Aqueous penicillin G reaches greater concentrations than procaine or benzathine penicillin. Concentrations remain detectable for ≥ 12 h. Of the aminopenicillins, both ampicillin and parenteral amoxicillin reach adequate CNS concentrations; however, orally administered amoxicillin resulted in much lower concentrations. Nafcillin and piperacillin are the final two penicillins with pediatric data: their penetration is erratic at best. Cephalosporins vary greatly in regard to their CSF penetration. Few first- and second-generation cephalosporins are able to reach higher CSF concentrations. Cefuroxime is the only exception and is usually avoided due to its adverse effects and slower sterilization of the CSF than third-generation agents. Ceftriaxone, cefotaxime, ceftazidime, cefixime and cefepime have been studied in children and are all able to adequately penetrate the CSF. As with penicillins, concentrations are greatest in the presence of meningeal inflammation. Meropenem and imipenem are the only carbapenems with pediatric data. Imipenem reaches higher CSF concentrations; however, meropenem is preferred due to its lower incidence of seizures. Aztreonam has also demonstrated favorable penetration but only one study has been completed in children. Both chloramphenicol and sulfamethoxazole/trimethoprim (cotrimoxazole) penetrate into the CNS well; however, significant toxicities limit their use. The small size and minimal protein binding of fosfomycin contribute to its favorable CNS PK. Although rarely used, it achieves higher concentrations in the presence of inflammation and accumulation is possible. Linezolid reaches high CSF concentrations; however, more frequent dosing might be required in infants due to their increased elimination. Metronidazole also has very limited information but it demonstrated favorable results similar to adult data; CSF concentrations even exceeded plasma concentrations at certain time points. Rifampin (rifampicin) demonstrated good CNS penetration after oral administration. Vancomycin demonstrates poor CNS penetration after intravenous administration. When combined with intraventricular therapy, CNS concentrations are much greater. Of the antituberculosis agents, isoniazid, pyrazinamide and streptomycin have been studied in children. Isoniazid and pyrazinamide have favorable CSF penetration. Streptomycin appears to produce unpredictable CSF levels. No pediatric-specific data are available for clindamycin, daptomycin, macrolides, tetracyclines, and fluoroquinolones. Daptomycin, fluoroquinolones, and tetracyclines have demonstrated favorable CNS penetration in adults; however, data are limited due to their potential pediatric-specific toxicities and newness within the marketplace. Macrolides and clindamycin have demonstrated poor CNS penetration in adults and thus have not been studied in pediatrics.