The childhood brain tumor, medulloblastoma, includes four subtypes with very different prognoses. Here, we show that paracrine signals driven by mutant β-catenin in WNT-medulloblastoma, an ...essentially curable form of the disease, induce an aberrant fenestrated vasculature that permits the accumulation of high levels of intra-tumoral chemotherapy and a robust therapeutic response. In contrast, SHH-medulloblastoma, a less curable disease subtype, contains an intact blood brain barrier, rendering this tumor impermeable and resistant to chemotherapy. The medulloblastoma-endothelial cell paracrine axis can be manipulated in vivo, altering chemotherapy permeability and clinical response. Thus, medulloblastoma genotype dictates tumor vessel phenotype, explaining in part the disparate prognoses among medulloblastoma subtypes and suggesting an approach to enhance the chemoresponsiveness of other brain tumors.
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•WNT-medulloblastoma but not other disease subtypes lack a blood brain barrier (BBB)•WNT-medulloblastoma secreted WNT antagonists block BBB formation•BBB function dictates chemotherapy exposure and response among medulloblastomas•The BBB can be manipulated in medulloblastoma by altering tumor vessel signaling
Phoenix et al. show that medulloblastoma genotype dictates tumor vessel phenotype, partially explaining disparate prognoses among subtypes. WNT-medulloblastoma paracrine signals block endothelial WNT signaling, and manipulation of the paracrine axis can alter chemotherapy permeability and response in vivo.
The aim of this study was to determine the prevalence and characteristics of postoperative pain after endodontic microsurgery and to identify potential predictors for severe pain.
One hundred ...seventy-three patients who underwent endodontic microsurgery at a private practice were included in the study. The patients were asked to fill out a questionnaire to assess their postoperative pain levels for 5 days after surgery. The questionnaires were analyzed to record the changes in pain levels over time. The presence and size of preoperative lesions and bone thickness were determined on preoperative cone-beam computed tomographic scans. Statistical analyses were performed to identify predictors for developing severe pain after surgery. A binary logistic regression model was established to predict the occurrence of severe pain.
Severe pain was most prevalent on day 1 (17.3%) and gradually decreased until a small increase on day 5. The average pain level also peaked on day 1 postoperatively and gradually decreased afterward. No significant difference was observed between patients who reported severe pain and those who did not report severe pain regarding tooth position (anterior vs posterior), lesion size, and presence of fenestration. However, sex, age, and bone thickness were all significant predictors of severe postoperative pain, with odds ratios of 2.8, 0.96, and 1.41, respectively.
Severe pain was reported only in a small number of patients after endodontic microsurgery. Younger patients, females, and patients with thicker bone covering the apex are significantly more likely to develop severe pain.
•Novel LC–MS/MS methods for the quantitation of ribociclib in mouse plasma and Ringer's solution were developed and validated.•Mouse plasma samples were extracted using solid phase extraction method, ...no extraction was required for the Ringer’s solution samples.•These methods were successfully applied for the determination of ribociclib concentration in preclinical samples obtained from cerebral microdialysis studies.
LC–MS/MS methods to measure ribociclib in mouse plasma and Ringer’s solution were successfully developed and validated. Reverse phase chromatography was performed with gradient elution using C18 (100A, 50×4.6mm, 3μ) and C8-A (50×2.0mm, 5μ) columns for plasma and Ringer’s samples, respectively. Mouse plasma samples were extracted using solid phase extraction method, whereas no extraction was required for the Ringer’s solution samples. Analytes were detected using positive ion MRM mode. The precursor to product ions (Q1→Q3) selected for ribociclib and d6-ribociclib were (m/z) 435.2→252.1 and 441.2→252.1, respectively. The linear range of quantification of ribociclib was 62.5–10,000ng/ml for plasma method and 0.1–100ng/ml for Ringer’s solution method. The results for the inter-day and intra-day accuracy and precision of quality control samples were within the acceptable range. The lower limit of quantitation (LLOQ) for plasma and Ringer’s samples were 62.5ng/ml (S/N>30) and 0.1ng/ml (S/N>13), respectively, whereas the limit of detection (LOD) was 6.9ng/ml (S/N>7) and 0.05ng/ml (S/N>3), respectively. The developed methods were successfully applied to the analysis of ribociclib in mouse plasma and dialysate samples collected during a cerebral microdialysis study of ribociclib in a non-tumor bearing mouse.
Despite significant improvement in outcomes for patients with hematologic malignancies and solid tumors over the past 10 years, patients with primary or metastatic brain tumors continue to have a ...poor prognosis. A primary reason for this is the inability of many chemotherapeutic drugs to penetrate into the brain and brain tumors at concentrations high enough to exert an antitumor effect because of unique barriers and efflux transporters. Several studies have been published recently examining the central nervous system pharmacokinetics of various anticancer drugs in patients with primary and metastatic brain tumors. To summarize recent advances in the field, this review critically presents studies published within the last 9 years examining brain and cerebrospinal fluid penetration of clinically available anticancer agents for patients with central nervous system tumors.
Ceftolozane-tazobactam, a combination of the novel antipseudomonal cephalosporin ceftolozane and the well-established extended-spectrum β-lactamase inhibitor tazobactam, is approved for treating ...complicated urinary tract infections (cUTI) and complicated intra-abdominal infections (cIAI) in adults. To determine doses likely to be safe and efficacious in phase 2 pediatric trials for the same indications, single-dose ceftolozane-tazobactam plasma pharmacokinetic data from a recently completed phase 1 trial in pediatric patients (birth to <18 years old) with proven/suspected Gram-negative bacterial infections, along with pharmacokinetic data from 12 adult studies, were integrated into a population pharmacokinetic (popPK) analysis. Two-compartment linear models with first-order elimination described the concentration-time profiles of ceftolozane and tazobactam in pediatric patients well. Renal function and body weight were identified to be significant predictors of ceftolozane-tazobactam pharmacokinetics. Renal function, as measured by the estimated glomerular filtration rate (eGFR), significantly affected the clearance of both ceftolozane and tazobactam. Body weight significantly affected clearance and the distribution volume, also of both ceftolozane and tazobactam. Patients with infections had a 32.3% lower tazobactam clearance than healthy volunteers. Using the final popPK models, simulations of various dosing regimens were conducted to assess each regimen's plasma exposure and the probability of pharmacokinetic/pharmacodynamic target attainment. Based on these simulations, the following doses are recommended for further clinical evaluation in phase 2 pediatric trials for cUTI and cIAI (in patients with an eGFR of ≥50 ml/min/1.73 m
only): for children ≥12 years old, 1.5 g ceftolozane-tazobactam (1 g ceftolozane with 0.5 g tazobactam), and for neonates/very young infants, infants, and children <12 years old, 20/10 mg/kg of body weight ceftolozane-tazobactam, both via a 1-h intravenous infusion every 8 h.
Purpose
Ribociclib, an orally bioavailable small-molecule CDK4/6 inhibitor is currently undergoing evaluation to treat pediatric central nervous system (CNS) tumors. However, it is crucial that it ...penetrates the brain and tumor. Thus, the objectives of the present study were to derive a clinically relevant mouse dosage for cerebral microdialysis studies, and to characterize ribociclib CNS penetration in non-tumor bearing mice and in mice bearing DIPGx7 (glioma) cortical allograft tumors.
Methods
A plasma pharmacokinetic study of ribociclib (100 mg/kg, orally) was performed in CD1 nude mice bearing glioma cortical allografts to obtain initial plasma pharmacokinetic parameters and to derive D-optimal plasma sampling time-points for microdialysis studies. Using a cerebral microdialysis technique, the extracellular fluid (ECF) disposition of ribociclib was evaluated after a single oral ribociclib dose (100 mg/kg) in non-tumor bearing mice and in mice bearing glioma cortical allografts. A one-compartment plasma model with absorption and ECF compartments were fit to plasma and ECF concentration–time data using a nonlinear mixed effects modeling approach (NONMEM 7.2).
Results
The mean unbound ribociclib plasma exposure (6812 ng/ml*h) was similar to that observed clinically at recommended dosages in adults. The median ribociclib ECF to plasma partition coefficient (
K
p,uu
) in non-tumor bearing and glioma mice was 0.10 and 0.07, respectively, and was not statistically different (
t
test,
p
= 0.19).
Conclusions
The CNS penetration observed was encouraging enough to move ribociclib forward with preclinical efficacy studies in models of pediatric brain tumors.
Ceftolozane/tazobactam (C/T) is a combination of a novel cephalosporin with tazobactam, recently approved for the treatment of hospital‐acquired and ventilator‐associated pneumonia. The plasma ...pharmacokinetics (PK) of a 3‐g dose of C/T (2 g ceftolozane and 1 g tazobactam) administered via a 1‐hour infusion every 8 hours in adult patients with nosocomial pneumonia (NP) were evaluated in a phase 3 study (ASPECT‐NP; NCT02070757). The present work describes the development of population PK models for ceftolozane and tazobactam in plasma and pulmonary epithelial lining fluid (ELF). The concentration‐time profiles of both agents were well characterized by 2‐compartment models with zero‐order input and first‐order elimination. Consistent with the elimination pathway, renal function estimated by creatinine clearance significantly affected the clearance of ceftolozane and tazobactam. The central volumes of distribution for both agents and the peripheral volume of distribution for tazobactam were approximately 2‐fold higher in patients with pneumonia compared with healthy participants. A hypothetical link model was developed to describe ceftolozane and tazobactam disposition in ELF in healthy participants and patients with pneumonia. Influx (from plasma to the ELF compartment) and elimination (from the ELF compartment) rate constants were approximately 97% lower for ceftolozane and 52% lower for tazobactam in patients with pneumonia versus healthy participants. These population PK models adequately described the plasma and ELF concentrations of ceftolozane and tazobactam, thus providing a foundation for further modeling and simulation, including the probability of target attainment assessments to support dose recommendations of C/T in adult patients with NP.
Cyclophosphamide is widely used to treat children with medulloblastoma; however, little is known about its brain penetration. We performed cerebral microdialysis to characterize the brain penetration ...of cyclophosphamide (130 mg/kg, IP) and its metabolites 4-hydroxy-cyclophosphamide (4OH-CTX) and carboxyethylphosphoramide mustard (CEPM) in non-tumor bearing mice and mice bearing orthotopic Group 3 medulloblastoma.
A plasma pharmacokinetic study was performed in non-tumor-bearing CD1- nude mice, and four cerebral microdialysis studies were performed in non-tumor-bearing (M1 and M3) and tumor- bearing mice (M2 and M4). Plasma samples were collected up to 6-hours post-dose, and extracellular fluid (ECF) samples were collected over 60-minute intervals for 24-hours post-dose. To stabilize and quantify 4OH-CTX, a derivatizing solution was added in blood after collection, and either directly in the microdialysis perfusate (M1 and M2) or in ECF collection tubes (M3 and M4). Plasma/ECF cyclophosphamide and CEPM, and 4OH-CTX concentrations were separately measured using different LC-MS/MS methods.
All plasma/ECF concentrations were described using a population-based pharmacokinetic model. Plasma exposures of cyclophosphamide, 4OH-CTX, and CEPM were similar across studies (mean AUC=112.6, 45.6, and 80.8 µmol∙hr/L). Hemorrhage was observed in brain tissue when the derivatizing solution was in perfusate compared with none when in collection tubes, which suggested potential sample contamination in studies M1 and M2. Model-derived unbound ECF to plasma partition coefficients (Kp,uu) were calculated to reflect CNS penetration of the compounds. Lower cyclophosphamide Kp,uu was obtained in tumor-bearing mice versus non-tumor bearing mice (mean 0.15 versus 0.22, p=0.019). No differences in Kp,uu were observed between these groups for 4OH- CTX and CEPM (overall mean 0.10 and 0.07).
Future studies will explore potential mechanisms at the brain-tumor barrier to explain lower cyclophosphamide brain penetration in tumor-bearing mice. These results will be used to further investigate exposure-response relationships in medulloblastoma xenograft models.
While a small number of plasma membrane ABC transporters can export chemotherapeutic drugs and confer drug resistance, it is unknown whether these transporters are expressed or functional in less ...therapeutically tractable cancers such as Group 3 (G3) medulloblastoma. Herein we show that among this class of drug transporters, only ABCG2 was expressed at highly increased levels in human G3 medulloblastoma and a mouse model of this disease. In the mouse model, Abcg2 protein was expressed at the plasma membrane where it functioned as expected on the basis of export of prototypical substrates. By screening ABC substrates against mouse G3 medulloblastoma tumorspheres in vitro, we found that Abcg2 inhibition could potentiate responses to the clinically used drug topotecan, producing a more than 9-fold suppression of cell proliferation. Extended studies in vivo in this model confirmed that Abcg2 inhibition was sufficient to enhance antiproliferative responses to topotecan, producing a significant survival advantage compared with subjects treated with topotecan alone. Our findings offer a preclinical proof of concept for blockade of ABCG2 transporter activity as a strategy to empower chemotherapeutic responses in G3 medulloblastoma.
An exposure-efficacy analysis of the phase 3 ASPECT-NP trial was performed to evaluate the relationship between plasma exposure of ceftolozane and tazobactam and efficacy endpoints (primary: 28-day ...all-cause mortality; key secondary: clinical cure at test-of-cure visit) in adult participants with hospital-acquired or ventilator-associated bacterial pneumonia (HABP/VABP). Participants (
=
231) from the ceftolozane/tazobactam treatment group in the intention-to-treat population who had pharmacokinetic data available and relevant baseline lower respiratory tract (LRT) pathogen(s) susceptibility data were included. Population pharmacokinetic models were used to predict individual ceftolozane and tazobactam plasma exposure measures (percentage of the interdose interval with free drug concentrations above the MIC %
T>MIC and %
T above a threshold %
T>C
= 1 μg/mL, respectively) associated with the last dose using the highest ceftolozane/tazobactam MIC for the relevant baseline LRT pathogens. Efficacy measures were comparable between the baseline LRT pathogens and across MIC cutoffs (1-8 μg/mL). Most participants (82%) had 99%
T>MIC for ceftolozane; 9% (
=
21/231) had 0% ƒT>MIC due to high MICs of the LRT pathogen (64-256 μg/mL). The %ƒT>MIC for ceftolozane exceeded 73% for all participants with baseline LRT pathogen(s) MIC ≤4 μg/mL. All 231 participants achieved the tazobactam pharmacokinetic/pharmacodynamic target of >20%
T>C
where C
= 1 μg/mL. For either efficacy endpoint, median ceftolozane %ƒT>MIC was 99% in participants achieving efficacy. No exposure-efficacy trend was observed for ceftolozane or tazobactam. These results further support the recommended ceftolozane/tazobactam dosing regimens evaluated in ASPECT-NP for patients with HABP/VABP.
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