Identification of small molecules that mitigate vincristine‐induced neurotoxicity while sensitizing leukemia cells to vincristine

Vincristine (VCR) is one of the most widely prescribed medications for treating solid tumors and acute lymphoblastic leukemia (ALL) in children and adults. However, its major dose‐limiting toxicity is peripheral neuropathy that can disrupt curative therapy. Peripheral neuropathy can also persist into adulthood, compromising quality of life of childhood cancer survivors. Reducing VCR‐induced neurotoxicity without compromising its anticancer effects would be ideal. Here, we show that low expression of NHP2L1 is associated with increased sensitivity of primary leukemia cells to VCR, and that concomitant administration of VCR with inhibitors of NHP2L1 increases VCR cytotoxicity in leukemia cells, prolongs survival of ALL xenograft mice, but decreases VCR effects on human‐induced pluripotent stem cell‐derived neurons and mitigates neurotoxicity in mice. These findings offer a strategy for increasing VCR’s antileukemic effects while reducing peripheral neuropathy in patients treated with this widely prescribed medication.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Vincristine (VCR) is a widely prescribed drug, but its use is limited by its main side effect, neurotoxicity. There are currently no strategies to mitigate VCR neurotoxicity without altering its antileukemic effects.

• WHAT QUESTION DID THIS STUDY ADDRESS?

How to improve VCR efficacy while reducing its main side effect, neurotoxicity?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

The present study shows for the first time the possibility of reduced VCR ‐induced neurotoxicity while improving VCR anti‐leukemia effect by using small molecules.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

The current translational study could permit a safer and more efficient use of VCR.     

An untargeted metabolomics analysis of exogenous chemicals in human milk and transfer to the infant

Human milk is the optimal infant nutrition. However, although human‐derived metabolites (such as lipids and oligosaccharides) in human milk are regularly reported, the presence of exogenous chemicals (such as drugs, food, and synthetic compounds) are often not addressed. To understand the types of exogenous compounds that might be present, human milk (n = 996) was analyzed by untargeted metabolomics. This analysis revealed that lifestyle molecules, such as medications and their metabolites, and industrial sources, such as plasticizers, cosmetics, and other personal care products, are found in human milk. We provide further evidence that some of these lifestyle molecules are also detectable in the newborn''s stool. Thus, this study gives important insight into the types of exposures infants receiving human milk might ingest due to the lifestyle choices, exposure, or medical status of the lactating parent.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Although our ability to measure metabolites in human milk has greatly increased in the last decades, the true breadth and diversity of the human milk metabolome is still unknown. Endogenous (or human‐derived) compounds in milk have been extensively studied, but exogenous compounds in human milk due to environmental factors and lifestyle choices are relatively unexplored.

• WHAT QUESTION DID THIS STUDY ADDRESS?

What exogenous metabolites exist in human milk and are they transferred to the infant?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

We provide an analysis of exogenous metabolites in human milk, including medications, food metabolites, and industrial/environmental compounds. We also demonstrate that many of these metabolites can be transferred to the infant in detectable levels.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Several of the drug metabolites identified in this study have not been previously annotated, and demonstrate new ways in which we can address the pharmacokinetics of drugs in human milk.     

Metabolomics analysis of the serum from children with urolithiasis using UPLC‐MS

Pediatric urolithiasis is a common urologic disease with high morbidity and recurrence rates. Recent studies have shown that metabolic dysfunction plays a vital role in the pathogenesis of urolithiasis, especially in children, but the specific mechanism is still unclear. Metabolomics is an ideal technology for exploring the mechanism of metabolic disorders in urolithiasis. In the present study, a serum metabolomics based on ultra‐performance liquid chromatography mass spectrometry was performed. A total of 50 children subjects were recruited for the study, including 30 patients with kidney stones and 20 normal controls (NCs). Principal component analysis and orthogonal partial least‐squares determinant analysis were carried, and 40 metabolites were found to be significantly altered in patients with kidney stones, mainly involving retinol metabolism, steroid hormone biosynthesis, and porphyrin and chlorophyll metabolism. The kidney stone group appeared to have a lower serum level of bilirubin, but a relative higher level of retinal, all‐transretinoic acid, progesterone, and prostaglandin E2 compared with those of the NC group. All the findings suggest that patients with urolithiasis have several metabolic characteristics, which are related to stone formation or compensation. These metabolites and pathways are very likely associated with development of kidney stones and should be considered as potential novel targets for treatment and prevention.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Metabolic disorders can be found in most children with kidney stones, suggesting that it plays a vital role in the pathogenesis of pediatric urolithiasis. Metabolomics is an ideal strategy to explore the mechanism of metabolic disorders in kidney stones.

• WHAT QUESTION DID THIS STUDY ADDRESS?

We aimed to identify the changes of serum metabolites in children with urolithiasis compared with normal controls by using ultra‐performance liquid chromatography mass spectrometry.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

We found the special metabolic characteristics in patients with pediatric urolithiasis, which are related to stone formation or compensation.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Our findings indicate that the metabolic phenotype of serum in pediatric patients with urolithiasis is significantly different from that in normal controls. These metabolites and metabolic pathways associated with stone formation will help to develop novel therapeutic strategies and preventive interventions.     

Vericiguat in combination with isosorbide mononitrate in patients with chronic coronary syndromes: The randomized,phase Ib,VISOR study

Vericiguat was developed for the treatment of symptomatic chronic heart failure (HF) in adult patients with reduced ejection fraction who are stabilized after a recent decompensation event. Guidelines recommend long‐acting nitrates, such as isosorbide mononitrate, for angina prophylaxis in chronic coronary syndromes (CCS), common comorbidities in HF. This study evaluated safety, tolerability, and the pharmacodynamic (PD) interaction between co‐administered vericiguat and isosorbide mononitrate in patients with CCS. In this phase Ib, double‐blind, multicenter study, patients were randomized 2:1 to receive vericiguat plus isosorbide mononitrate (n = 28) or placebo plus isosorbide mononitrate (n = 13). Isosorbide mononitrate was uptitrated to a stable dose of 60 mg once daily, followed by co‐administration with vericiguat (uptitrated every 2 weeks from 2.5 mg to 5 mg and 10 mg) or placebo. Thirty‐five patients completed treatment (vericiguat, n = 23; placebo, n = 12). Mean baseline‐ and placebo‐adjusted vital signs showed reductions of 1.4–5.1 mmHg (systolic blood pressure) and 0.4–2.9 mmHg (diastolic blood pressure) and increases of 0.0–1.8 beats per minute (heart rate) with vericiguat plus isosorbide mononitrate. No consistent vericiguat dose‐dependent PD effects were noted. The incidence of adverse events (AEs) was 92.3% and 66.7% in the vericiguat and placebo groups, respectively, and most were mild in intensity. Blood pressure and heart rate changes observed with vericiguat plus isosorbide mononitrate were not considered clinically relevant. This combination was generally well‐tolerated. Concomitant use of vericiguat with isosorbide mononitrate is unlikely to cause significant AEs beyond those known for isosorbide mononitrate.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Vericiguat is indicated to reduce the risk of cardiovascular death and heart failure (HF) hospitalization following a hospitalization for HF or need for outpatient intravenous diuretics, in adults with symptomatic chronic HF and ejection fraction less than 45%.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study evaluated the impact of co‐administration of vericiguat and long‐acting nitrates. The combination of vericiguat with isosorbide mononitrate was generally well‐tolerated, and the adverse event profile was in line with the mode of action of both drugs.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

There is limited experience with vericiguat in combination with long‐acting nitrates and these data provide information to guide prescribers.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

These data support that there is no clinically relevant pharmacodynamic interaction between vericiguat and the long‐acting nitrate isosorbide mononitrate in patients with chronic coronary syndromes.     

Influence of CYP2D6 metabolizer status on ondansetron efficacy in pediatric patients undergoing hematopoietic stem cell transplantation: A case series

Chemotherapy‐induced nausea and vomiting (CINV) is commonly experienced by patients receiving antineoplastic agents prior to hemopoietic stem cell transplant (HSCT). Ondansetron, a 5‐HT3 antagonist metabolized by CYP2D6, is an antiemetic prescribed to treat short‐term CINV, but some patients still experience uncontrolled nausea and vomiting while taking ondansetron. Adult CYP2D6 ultrarapid metabolizers (UMs) are at higher risk for CINV due to rapid ondansetron clearance, but similar studies have not been performed in pediatric patients. We performed a retrospective chart review of 128 pediatric HSCT recipients who received ondansetron for CINV prevention and had CYP2D6 genotyping for 20 alleles and duplication detection. The number of emetic episodes for each patient was collected from the start of chemotherapy through 7 days after HSCT. The average age of the cohort was 6.6 years (range: 0.2–16.7) and included three UMs, 72 normal metabolizers, 47 intermediate metabolizers, and six poor metabolizers. Because UMs are the population at risk for inefficacy, we describe the course of treatment for these three patients, as well as the factors influencing emesis: chemotherapy emetogenicity, diagnosis, and duration of ondansetron administration. The cases described support guidelines recommending non‐CYP2D6 metabolized antiemetics (e.g., granisetron) when a patient is a known CYP2D6 UM, but pediatric studies with a larger sample of CYP2D6 UMs are needed to validate our findings.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

In adults, ondansetron is not as effective for chemotherapy‐induced nausea and vomiting (CINV) in CYP2D6 ultrarapid metabolizers (UMs) compared to non‐UMs. Ondansetron is a medication commonly prescribed to pediatric patients, especially for CINV.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Our study describes the efficacy of ondansetron for CINV in three pediatric CYP2D6 UMs.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Pediatric CYP2D6 UMs experienced more emesis when taking ondansetron for CINV on days where they did not receive opioids than expected, similar to findings in adults.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Based on these findings, at our institution, any patient undergoing a bone marrow transplant that is a CYP2D6 UM will receive granisetron rather than ondansetron; this practice may be applicable to pediatric patients at other institutions.     

Accelerating vaccine trial conduct in a pandemic with a hot spot‐based inclusion strategy using trial and epidemic simulation

Clinical development of vaccines in a pandemic situation should be rigorous but expedited to tackle the pandemic threat as fast as possible. We explored the effects of a novel vaccine trial strategy that actively identifies and enrolls subjects in local areas with high infection rates. In addition, we assessed the practical requirements needed for such a strategy. Clinical trial simulations were used to assess the effects of utilizing these so‐called “hot spot strategy” compared to a traditional vaccine field trial. We used preset parameters of a pandemic outbreak and incorporated realistic aspects of conducting a trial in a pandemic setting. Our simulations demonstrated that incorporating a hot spot strategy shortened the duration of the vaccine trial considerably, even if only one hot spot was identified during the clinical trial. The active hot spot strategy described in this paper has clear advantages compared to a “wait‐and‐see” approach that is used in traditional vaccine efficacy trials. Completion of a clinical trial can be expedited by adapting to resurgences and outbreaks that will occur in a population during a pandemic. However, this approach requires a speed of response that is unusual for a traditional phase III clinical trial. Therefore, several recommendations are made to help accomplish rapid clinical trial setup in areas identified as local outbreaks. The described model and hot spot vaccination strategy can be adjusted to disease‐specific transmission characteristics and could therefore be applied to any future pandemic threat.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Clinical development of vaccines in a pandemic situation requires a different development paradigm. It should be rigorous but expedited to tackle the pandemic threat as fast as possible. Field trials are considered pivotal, but are also the most time‐consuming stage of clinical vaccine development.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Would a novel vaccine trial strategy that actively identifies and enrolls subjects in local areas with high infection rates shorten the duration of a vaccine field trial compared to the traditional wait‐and‐see approach?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

By using clinical trial simulations it was demonstrated that trial duration can be shortened considerably if local outbreaks are identified and subjects from these outbreaks are enrolled in the clinical trial. Recommendations are made to facilitate this novel approach.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

This study provides new insight in possible strategies to expedite clinical vaccine development and is in support of a more agile approach to conduct vaccine trials during a pandemic.     

Effects of sevelamer carbonate versus calcium acetate on vascular calcification,inflammation, and endothelial dysfunction in chronic kidney disease

Hyperphosphatemia is present in most patients with end‐stage renal disease (ESRD) and has been associated with increased cardiovascular mortality. Phosphate binders (calcium‐based and calcium free) are the mainstay pharmacologic treatment to lower phosphorus levels in patients with ESRD. We evaluated biochemical markers of vascular calcification, inflammation, and endothelial dysfunction in patients with chronic kidney disease (CKD) treated with sevelamer carbonate (SC) versus calcium acetate (CA). Fifty patients with CKD (stages 3 and 4) were enrolled and assigned to treatment with SC and CA for 12 weeks. At the end of the study the biomarkers of vascular calcification, inflammation, and endothelial dysfunction were analyzed. A significant increase in HDL‐cholesterol was observed with SC but not with CA in patients with CKD. Treatment with SC reduced serum phosphate, calcium phosphate, and FGF‐23 levels and there was no change with CA treatment. The inflammatory markers IL‐8, IFN‐γ, and TNFα decreased with response to both treatments. The levels of IL‐6 significantly increased with CA treatment and no change was observed in the SC treatment group. SC showed favorable effects on anti‐inflammatory and vascular calcification biomarkers compared to CA treatment in patients with CKD stages 3 and 4 with normal phosphorous values.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Non‐calcium‐based phosphate binders are effective in the patients with end stage kidney disease for lowering serum phosphorus and have demonstrated anti‐inflammatory effects.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study demonstrates a favorable reduction in systemic, vascular, and bone‐related inflammatory markers from treatment with sevelamer carbonate (SC) in the patients with chronic kidney disease (CKD) not on dialysis with normal serum phosphorus levels.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This study suggests that patients with CKD not on dialysis may benefit from SC phosphate binders despite having a normal serum phosphorus level.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

This study offers insight to the role phosphates binder may play in lowering inflammation and vascular calcification in patients with CKD not on dialysis.     

A retrospective analysis of actionable pharmacogenetic/genomic biomarker language in FDA labels

The primary goal of precision medicine is to maximize the benefit‐risk relationships for individual patients by delivering the right drug to the right patients at the right dose. To achieve this goal, it has become increasingly important to assess gene‐drug interactions (GDIs) in clinical settings. The US Food and Drug Administration (FDA) periodically updates the table of pharmacogenetic/genomic (PGx) biomarkers in drug labeling on their website. As described herein, an effort was made to categorize various PGx biomarkers covered by the FDA‐PGx table into certain groups. There were 2 major groups, oncology molecular targets (OMT) and drug‐metabolizing enzymes and transporters (DMETs), which constitute ~70% of all biomarkers (~33% and ~35%, respectively). These biomarkers were further classified whether their labeling languages could be actionable in clinical practice. For OMT biomarkers, ~70% of biomarkers are considered actionable in clinical practice as they are critical for the selection of appropriate drugs to individual patients. In contrast, ~30% of DMET biomarkers are considered actionable for the dose adjustments or alternative therapies in specific populations, such as CYP2C19 and CYP2D6 poor metabolizers. In addition, the GDI results related to some of the other OMT and DMET biomarkers are considered to provide valuable information to clinicians. However, clinical GDI results on the other DMET biomarkers can possibly be used more effectively for dose recommendation. As the labels of some drugs already recommend the precise doses in specific populations, it will be desirable to have clear language for dose recommendation of other (or new) drugs if appropriate.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

• WHAT QUESTION DID THIS STUDY ADDRESS?

Pharmacogenetic/genomic (PGx) biomarkers are increasingly being used for precision medicine to focus on maximizing therapeutic efficacy while minimizing adverse events. The US Food and Drug Administration (FDA) provides an updated summary table of PGx biomarkers in the labels of approved drugs (FDA‐PGx table).

• WHAT QUESTION DID THIS STUDY ADDRESS?

PGx biomarkers listed in the FDA‐PGx table were analyzed to categorize into certain groups (e.g., as oncology molecular targets [OMTs] and drug‐metabolizing enzymes and transporters [DMETs]), and then classify whether their labeling language could be actionable in clinical practice.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

There are 2 major groups in the FDA‐PGx table, OMT and DMET biomarkers, accounting of ~70% of all biomarkers. Among them, ~70% of OMT biomarkers and ~30% of DMET biomarkers are considered actionable in clinical practice.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

The gene‐drug interaction results related to some DMET biomarkers can be used more effectively and practically for dose recommendation in specific populations. It will be therefore desirable to have clear labeling language on dose recommendation for other (or new) drugs if appropriate.     

Metabolomic profiling of extraesophageal reflux disease in children

Although respiratory symptoms in children are often attributed to gastroesophageal reflux disease, establishing a clear diagnosis of extraesophageal reflux disease (EERD) can be challenging, as there are no sensitive or specific EERD biomarkers. The aim of this study was to evaluate the metabolite profile in bronchoalveolar (BAL) fluid from children with suspected EERD and assess the impact of reflux treatment on these metabolites. In this prospective pilot study, we performed nontargeted global metabolomic profiling on BAL fluid from 43 children undergoing testing with bronchoscopy, upper endoscopy, and multichannel intraluminal impedance with pH (pH‐MII) for evaluation of chronic respiratory symptoms. Twenty‐three (54%) patients had an abnormal pH‐MII study. Seventeen (40%) patients were on proton pump inhibitors (PPIs) for testing. Levels of histamine, malate, adenosine 5′‐monophosphate, and ascorbate were significantly lower in subjects with abnormal pH‐MII studies compared to those normal studies. Furthermore, in children off PPI therapy, those with abnormal pH‐MII studies had robust increases in a number of glycerophospholipids within phospholipid metabolic pathways, including derivatives of glycerophosphorylcholine, glycerophosphoglycerol, and glycerophosphoinositol, compared to those with normal pH‐MII studies. These findings offer insight into the impact of reflux and PPIs on the lungs and provide a foundation for future studies using targeted metabolomic analysis to identify potential biomarkers of EERD.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Establishing an association between gastroesophageal reflux disease and respiratory disease in children is challenging as there are no sensitive or specific biomarkers for extraesophageal reflux disease (EERD). Metabolomic analysis of bronchoalveolar lavage (BAL) fluid has offered promising insight into possible biomarkers for a variety of respiratory diseases but has never been studied in children with suspected EERD.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study addressed the questions of (1) whether there are differences in BAL metabolites in children with abnormal reflux testing with multichannel intraluminal impedance with pH and (2) whether reflux therapy with proton pump inhibitors was associated with different metabolite profiles.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

We found that there were significant increases in a number of glycerophospholipids within phospholipid metabolic pathways in the BAL of children with untreated reflux, suggesting that gastroesophageal reflux may impact the lung metabolome.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

These findings may provide mechanistic insight into reflux‐induced lung injury and the impact of acid suppression medications on the lungs, which may help guide future biomarker discovery.     

Albumin to globulin ratio was associated with in‐stent restenosis and revascularization events after percutaneous coronary intervention

In‐stent restenosis is a common complication after percutaneous coronary intervention (PCI) for coronary heart disease requiring revascularization. We performed a retrospective analysis to assess the value of inflammatory biomarker albumin to globulin ratio (AGR) in clinical prognosis of PCI. In total, 992 patients with coronary heart disease who underwent the first drug‐eluting stent implantation and re‐examination angiography in our hospital were enrolled in this study. The AGR was measured. At mean follow‐up of 11.2 ± 4 months, the in‐stent restenosis (ISR) and revascularization events (including target lesion revascularization, target vessel revascularization, and revascularization of de novo lesions) occurred in 127 and 284 patients, respectively. Compared with the non‐ISR or non‐event group, AGR was significantly lower in the ISR group and the events group. Beyond that, albumin was significantly lower, whereas urea nitrogen, glucose, and Gensini score, as well as the proportions of a history of diabetes and peripheral vascular diseases were significantly higher in the ISR group and the events group. Age, heart rate, white blood cell, neutrophils, lymphocyte, monocyte, and incidence of ischemic stroke were significantly higher in the events group. Multivariate Cox regression analysis showed that AGR was independently associated with ISR (p = 0.032) and events (p = 0.024). Besides, Kaplan‐Meier analysis indicated that the higher quartile of AGR had a lower rate of ISR (p = 0.038) and events (p ≤ 0.001). Finally, the receiver operating characteristic curve for AGR in diagnosing ISR and events indicated that the area under the curve were 0.56 and 0.57, respectively. Therefore, AGR is one of the most important factors that independently associate with the ISR and revascularization events after PCI.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Albumin to globulin ratio (AGR) is regarded as an inflammatory biomarker and demonstrates a promising clinical role in various diseases. However, there are limited data suggesting it may serve as a biomarker of clinical outcomes, including in‐stent restenosis (ISR) and revascularization events, in patients with coronary heart disease (CHD) after percutaneous coronary intervention (PCI).

• WHAT QUESTION DID THIS STUDY ADDRESS?

We sought to perform this analysis to assess the value of inflammatory biomarker AGR in the clinical prognosis of PCI.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Compared with the non‐ISR and non‐event groups, AGR was significantly lower both in the ISR and revascularization events groups. Further, AGR was independently associated with ISR and revascularization events after PCI in patients with CHD.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Measures should be taken based on the level of AGR in time. Besides, albumin supplementation or decreasing globulin levels may help to improve the occurrence of adverse events, including ISR.     

Quantitative protein expression of blood‐brain barrier transporters in the vasculature of brain metastases of patients with lung and breast cancer

This study determined absolute transporter protein abundances in isolated microvessels of human noncancerous cerebral cortex as well as brain metastases of patients with lung and breast cancer, using a validated targeted proteomics approach. As compared with those in microvessels of noncancerous cerebral cortex, the median protein abundances of glucose transporter 1 (a brain endothelial marker) and sodium‐potassium pump (Na/K ATPase, a plasma membrane marker) were decreased by ~ 80% in brain metastasis microvessels. The major efflux transporters (ABCB1 and ABCG2) fell to undetectable in microvessels of more than 80% of brain metastasis specimens. Monocarboxylate transporter 1 was undetectable in microvessels of more than 80% of brain metastases, whereas large neutral amino acid transporter 1 levels remained unchanged. In conclusion, the integrity of the physical and biochemical barrier with respect to transporter protein expression is largely disrupted in brain metastasis tumor vasculatures. Differential transporter protein abundances at the blood‐brain barrier and blood‐brain tumor barrier provided mechanistic and quantitative basis for prediction of heterogeneous drug penetration into human brain and brain tumors, which is critical not only to the understanding of the success or failure of systemic chemotherapy in the treatment of brain tumors but also to the development of more effective therapeutic strategies.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Systemic chemotherapy for brain metastases is controversial, at least partly due to the incomplete understanding of the blood‐brain barrier (BBB) and blood‐brain tumor barrier (BBTB) with respect to transporter protein expression and function.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study determined the absolute protein abundances of major BBB transporters in isolated microvessels of brain metastases from lung and breast cancer patients as well as non‐cancerous brain cortex from primary or metastatic brain cancer patients.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This study complemented our previous knowledge on transporter expression in microvessels of human normal brain cortex and glioblastoma, which collectively provided a comprehensive dataset on the quantitative protein expression of BBB transporters in the vasculatures of human normal brain, primary and metastatic brain tumors.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Differential transporter protein abundances at the BBB and BBTB provided mechanistic and quantitative basis for prediction of heterogeneous drug penetration into human brain and brain tumors, which is critical not only to the understanding of the success or failure of systemic chemotherapy in the treatment of brain tumors but also to the development of more effective therapeutic strategies.     

Propsective evaluation of high‐dose methotrexate pharmacokinetics in adult patients with lymphoma using novel determinants of kidney function

High‐dose methotrexate (HDMTX) pharmacokinetics (PKs), including the best estimated glomerular filtration rate (eGFR) equation that reflects methotrexate (MTX) clearance, requires investigation. This prospective, observational, single‐center study evaluated adult patients with lymphoma treated with HDMTX. Samples were collected at predefined time points up to 96 h postinfusion. MTX and 7‐hydroxy‐MTX PKs were estimated by standard noncompartmental analysis. Linear regression determined which serum creatinine‐ or cystatin C‐based eGFR equation best predicted MTX clearance. The 80 included patients had a median (interquartile range [IQR]) age of 68.6 years (IQR 59.2–75.6), 54 (67.5%) were men, and 74 (92.5%) were White. The median (IQR) dose of MTX was 7.6 (IQR 4.8–11.3) grams. Median clearance was similar across three dosing levels at 4.5–5.6 L/h and was consistent with linear PKs. Liver function, weight, age, sex, concomitant chemotherapy, and number of previous MTX doses did not impact clearance. MTX area under the curve (AUC) values varied over a fourfold range and appeared to increase in proportion to the dose. The eGFR_cys (ml/min) equation most closely correlated with MTX clearance in both the entire cohort and after excluding outlier MTX clearance values (r = 0.31 and 0.51, respectively). HDMTX as a 4‐h infusion displays high interpatient pharmacokinetic variability. Population PK modeling to optimize MTX AUC attainment requires further evaluation. The cystatin C‐based eGFR equation most closely estimated MTX clearance and should be investigated for dosing and monitoring in adults requiring MTX as part of lymphoma management.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Methotrexate (MTX) clearance has a relationship with glomerular filtration rate (GFR), which is often calculated using serum creatinine as a surrogate marker of renal clearance; however, kidney function estimation derived from serum creatinine‐based GFR formulas has several known limitations, particularly in patients with cancer.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study attempts to answer the question of which estimated GFR (eGFR) equation has the strongest correlation with MTX clearance.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Results of this study suggest that, when high‐dose MTX is administered, cystatin C based eGFR equations more strongly correlate with MTX clearance than eGFR equations based on serum creatinine alone.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Incorporating cystatin C into baseline evaluation when estimating kidney function has potential to improve MTX safety and optimize MTX exposure.     

An exploratory machine learning approach to identify placebo responders in pharmacological binge eating disorder trials

Randomized, placebo‐controlled trials for binge eating disorder (BED) have revealed highly variable, and often marked, rates of short‐term placebo response. Several quantitative based analyses in patients with BED have inconsistently demonstrated which patient factors attribute to an increase in placebo response. The objective of this study is to utilize machine learning (ML) algorithms to identify moderators of placebo response in patients with BED. Data were pooled from 12 randomized placebo‐controlled trials evaluating different treatment options for BED. The final dataset consisted of 189 adults receiving placebo with complete information of baseline variables. Placebo responders were defined as patients experiencing ≥75% reduction in binge eating frequency (BEF) at study end point. Nine patient prerandomization variables were included as predictors. Patients were divided into training and testing subsets according to an 75%:25% distribution while preserving the proportion of placebo responders. All analysis was performed in the software Pumas 2.0. Gaussian Naïve Bayes algorithm showed the best cross‐validation accuracy (~64%) and was chosen as the final algorithm. Shapley analysis suggested that patients with low baseline BEF and anxiety status were strong moderators of placebo response. Upon applying the final algorithm on the test dataset, the resulting sensitivity was 88% and prediction accuracy was 72%. This is the first application of ML to identify moderators of placebo response in BED. The results of this analysis confirm previous findings of lesser baseline disease severity and adds that patients with no anxiety are more susceptible to placebo response.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Randomized, placebo‐controlled binge eating disorder (BED) trials have revealed highly variable, and often marked, rates of placebo response. Approximately 50% of all investigator‐led trials previously demonstrated a lack of separation between active treatment and placebo.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study provides a machine learning‐based approach to enrich future BED trials by identifying potential moderators of placebo response.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

By leveraging data from twelve BED investigator‐led randomized clinical trials, this study identified that patients with less disease severity and patients who do not exhibit symptoms of general anxiety disorder are more susceptible to placebo response.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

A machine learning approach using pooled data from similar clinical trials can provide recommendations for increasing probability of trial success in BED.     

Endogenous metabolic markers for predicting the activity of dihydropyrimidine dehydrogenase

Five‐fluorouracil (5‐FU) is a chemotherapeutic agent that is mainly metabolized by the rate‐limiting enzyme dihydropyrimidine dehydrogenase (DPD). The DPD enzyme activity deficiency involves a wide range of severities. Previous studies have demonstrated the effect of a DPYD single nucleotide polymorphism on 5‐FU efficacy and highlighted the importance of studying such genes for cancer treatment. Common polymorphisms of DPYD in European ancestry populations are less frequently present in Koreans. DPD is also responsible for the conversion of endogenous uracil (U) into dihydrouracil (DHU). We quantified U and DHU in plasma samples of healthy male Korean subjects, and samples were classified into two groups based on DHU/U ratio. The calculated DHU/U ratios ranged from 0.52 to 7.12, and the two groups were classified into the 10th percentile and 90th percentile for untargeted metabolomics analysis using liquid chromatography‐quantitative time‐of‐flight‐mass spectrometry. A total of 4440 compounds were detected and filtered out based on a coefficient of variation below 30%. Our results revealed that six metabolites differed significantly between the high activity group and low activity group (false discovery rate q‐value < 0.05). Uridine was significantly higher in the low DPD activity group and is a precursor of U involved in pyrimidine metabolism; therefore, we speculated that DPD deficiency can influence uridine levels in plasma. Furthermore, the cutoff values for detecting DPD deficient patients from previous studies were unsuitable for Koreans. Our metabolomics approach is the first study that reported the DHU/U ratio distribution in healthy Korean subjects and identified a new biomarker of DPD deficiency.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Dihydropyrimidine dehydrogenase (DPD) deficiency can cause severe 5‐fluorouracil toxicity. To predict DPD activity, DPYD genotyping and DPD phenotyping using dihydrouracil and uracil ratio were used.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study aimed to identify the distribution of DPD activity in a Korean population and explore new biomarkers of DPD activity using untargeted metabolomics.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This study recognized different distributions of DPD activity between a Korean population and populations of other ethnicities. The cutoff values for activity deficiency based on other ethnic groups could not be considered for East Asian populations, including Korean populations.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

This study indicated that a new cutoff value should be further validated to overcome the variability in DPD phenotyping in East Asian populations. The new biomarker for DPD deficiency uridine has the potential for more feasible and convenient prediction analysis.