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.     

Safety,tolerability, and pharmacokinetics of single‐ and multiple‐dose administration of islatravir (MK‐8591) in adults without HIV

Islatravir (MK‐8591) is a nucleoside analogue in development for the treatment and prevention of HIV‐1. Two phase 1 trials were conducted during initial evaluation of islatravir: rising single doses (Study 1) and rising multiple doses (Study 2) of oral islatravir in male and female participants without HIV (aged 18–60 years). Safety, tolerability, and pharmacokinetics of islatravir (plasma) and islatravir‐triphosphate (peripheral blood mononuclear cells) were assessed. In Study 1, 24 participants, assigned to 1 of 3 panels, received alternating single doses of islatravir in a fasted state from 5 mg to 400 mg, or placebo, over 3 dosing periods; a 30 mg dose was additionally assessed following a high‐fat meal. In Study 2, 8 participants per dose received 3 once‐weekly doses of 10, 30, or 100 mg islatravir or placebo in a fasted state. For each panel in both trials, 6 participants received active drug and 2 received placebo. Islatravir was generally well‐tolerated, with no serious adverse events or discontinuations due to adverse events. Islatravir was rapidly absorbed (median time to maximum plasma concentration 0.5 hours); plasma half‐life was 49–61 h; intracellular islatravir‐triphosphate half‐life was 118–171 h. Plasma exposure increased in an approximately dose‐proportional manner; there was no meaningful food effect. There was a modest degree of intracellular islatravir‐triphosphate accumulation after multiple weekly dosing. After single oral doses of islatravir greater than or equal to 5 mg, intracellular islatravir‐triphosphate levels were comparable to levels associated with efficacy in preclinical studies. These results warrant continued clinical investigation of islatravir.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

​Current HIV treatment and prevention strategies have limitations, and novel agents that offer improved safety and tolerability, a high barrier to HIV resistance, and more convenient dosing regimens are required.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Two phase 1 studies in participants without HIV assessed safety and pharmacokinetics of rising single and multiple doses of oral islatravir, a nucleoside analogue, to support continued development for the treatment and prevention of HIV‐1 infection.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Islatravir was generally well‐tolerated at single doses up to 400 mg. Oral doses of islatravir greater than or equal to 10 mg resulted in intracellular peripheral blood mononuclear cell levels of the active form, islatravir‐triphosphate, comparable to those associated with antiviral efficacy in preclinical studies.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

These studies provide important safety and pharmacokinetic information about islatravir in adults without HIV, which will be used to support further clinical investigation of islatravir for the treatment and prevention of HIV‐1 infection.     

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.     

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.     

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.     

Novel Bruton’s Tyrosine Kinase inhibitor remibrutinib: Drug‐drug interaction potential as a victim of CYP3A4 inhibitors based on clinical data and PBPK modeling

Remibrutinib, a novel oral Bruton’s Tyrosine Kinase inhibitor (BTKi) is highly selective for BTK, potentially mitigating the side effects of other BTKis. Enzyme phenotyping identified CYP3A4 to be the predominant elimination pathway of remibrutinib. The impact of concomitant treatment with CYP3A4 inhibitors, grapefruit juice and ritonavir (RTV), was investigated in this study in combination with an intravenous microtracer approach. Pharmacokinetic (PK) parameters, including the fraction absorbed, the fractions escaping intestinal and hepatic first‐pass metabolism, the absolute bioavailability, systemic clearance, volume of distribution at steady‐state, and the fraction metabolized via CYP3A4 were evaluated. Oral remibrutinib exposure increased in the presence of RTV 4.27‐fold, suggesting that remibrutinib is not a sensitive CYP3A4 substrate. The rich PK dataset supported the building of a robust physiologically‐based pharmacokinetic (PBPK) model, which well‐described the therapeutic dose range of 25–100 mg. Simulations of untested scenarios revealed an absence of drug‐drug interaction (DDI) risk between remibrutinib and the weak CYP3A4 inhibitor fluvoxamine (area under the concentration‐time curve ratio [AUCR] <1.25), and a moderate effect with the CYP3A4 inhibitor erythromycin (AUCR: 2.71). Predictions with the moderate and strong CYP3A4 inducers efavirenz and rifampicin, suggested a distinct remibrutinib exposure decrease of 64% and 89%. Oral bioavailability of remibrutinib was 34%. The inclusion of an intravenous microtracer allowed the determination of all relevant remibrutinib PK parameters, which facilitated construction of the PBPK model. This will provide guidance on the selection or restriction of comedications and prediction of DDI risks.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Remibrutinib is an irreversible Bruton’s Tyrosine Kinase inhibitor and moderate CYP3A4 substrate to be administered with caution with strong inhibitors.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study explored the drug‐drug interaction (DDI) risk of remibrutinib as a victim with CYP3A4 inhibitors.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Using a specifically tailored study design, most model‐relevant pharmacokinetic (PK) parameters were determined, including fractions of the dose escaping intestinal and hepatic first‐pass metabolism, absolute bioavailability, systemic drug clearance, apparent volume of distribution at steady‐state, and fraction of the drug metabolized via CYP3A4.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

The clinical study design offers opportunities to obtain important PK parameters, which enabled physiologically‐based pharmacokinetic (PBPK) model building of complex PK compounds. Taken together, the PK parameters and the PBPK simulations allowed robust DDI predictions of untested scenarios.     

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.     

Model‐based approach to sampling optimization in studies of antibacterial drugs for infants and young children

Clinical trials for pediatric indications and new pediatric drugs face challenges, including the limited blood volume due to the patients’ small bodies. In Japan, the Evaluation Committee on Unapproved or Off‐labeled Drugs with High Medical Needs has discussed the necessity of pediatric indications against the background of a lack of Japanese pediatric data. The limited treatment options regarding antibiotics for pediatric patients are associated with the emergence of antibiotic‐resistant bacteria. Regulatory guidelines promote the use of model‐based drug development to reduce practical and ethical constraints for pediatric patients. Sampling optimization is one of the key study designs for pediatric drug development. In this simulation study, we evaluated the precision of the empirical Bayes estimates of pharmacokinetic (PK) parameters based on the sampling times optimized by published pediatric population PK models. We selected three previous PK studies of cefepime and ciprofloxacin in infants and young children as paradigms. The number of sampling times was reduced from original full sampling times to two to four sampling times based on the Fisher information matrix. We observed that the precision of empirical Bayes estimates of the key PK parameters and the predicted efficacy based on the reduced sampling times were generally comparable to those based on the original full sampling times. The model‐based approach to sampling optimization provided a maximization of PK information with a minimum burden on infants and young children for the future development of pediatric drugs.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

The clinical trials in vulnerable populations, such as infants, face challenges, including the limited blood volume due to the small bodies. In Japan, the necessity of pediatric indications has been discussed against the background of a lack of Japanese pediatric data.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This simulation study aimed to apply a model‐based approach to the development of antibiotics for pediatric patients to reduce practical and ethical constraints.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

The model‐based approach to sampling optimization provided a maximization of pharmacokinetic information with a minimum burden on infants and young children.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

The approach will support future pediatric clinical trials and investigator‐initiated trials, as well as provide the valuable information for therapeutic drug monitoring and the administration plans for antibiotics in clinical settings.     

Dose‐dependent inactivation of airway tryptase with a novel dissociating anti‐tryptase antibody (MTPS9579A) in healthy participants: A randomized trial

Tryptase is the most abundant secretory granule protein in human lung mast cells and plays an important role in asthma pathogenesis. MTPS9579A is a novel monoclonal antibody that selectively inhibits tryptase activity by dissociating active tetramers into inactive monomers. The safety, tolerability, pharmacokinetics (PKs), and systemic and airway pharmacodynamics (PDs) of MTPS9579A were assessed in healthy participants. In this phase I single‐center, randomized, observer‐blinded, and placebo‐controlled study, single and multiple ascending doses of MTPS9579A were administered subcutaneously (s.c.) or intravenously (i.v.) in healthy participants. In addition to monitoring safety and tolerability, the concentrations of MTPS9579A, total tryptase, and active tryptase were quantified. This study included 106 healthy participants (82 on active treatment). Overall, MTPS9579A was well‐tolerated with no serious or severe adverse events. Serum MTPS9579A showed a dose‐proportional increase in maximum serum concentration (C_max) values at high doses, and a nonlinear increase in area under the curve (AUC) values at low concentrations consistent with target‐mediated clearance were observed. Rapid and dose‐dependent reduction in nasosorption active tryptase was observed postdose, confirming activity and the PK/PD relationship of MTPS9579A in the airway. A novel biomarker assay was used to demonstrate for the first time that an investigative antibody therapeutic (MTPS9579A) can inhibit tryptase activity in the upper airway. A favorable safety and tolerability profile supports further assessment of MTPS9579A in asthma. Understanding the exposure‐response relationships using the novel PD biomarker will help inform clinical development, such as dose selection or defining patient subgroups.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

MTPS9579A is a novel monoclonal antibody that selectively inhibits tryptase activity by dissociating active tetramers into inactive monomers. In preclinical studies, MTPS9579A inhibited tryptase activity in the airway.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This phase I study reports the safety and tolerability, pharmacokinetics (PKs), pharmacodynamics, and dose response of MTPS9579A in healthy human participants.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

MTPS9579A was well‐tolerated at all tested dose levels and had linear PKs at high concentrations. MTPS9579A is pharmacologically active and inhibits the target (active tryptase) in the upper airway of healthy participants.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

These results allow further exploration into the clinical efficacy and optimization of doses for MTSP9579A in treating patients with asthma and other mast cell‐related diseases.     

Application of machine learning to predict reduction in total PANSS score and enrich enrollment in schizophrenia clinical trials

Clinical trial efficiency, defined as facilitating patient enrollment, and reducing the time to reach safety and efficacy decision points, is a critical driving factor for making improvements in therapeutic development. The present work evaluated a machine learning (ML) approach to improve phase II or proof‐of‐concept trials designed to address unmet medical needs in treating schizophrenia. Diagnostic data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) trial were used to develop a binary classification ML model predicting individual patient response as either “improvement,” defined as greater than 20% reduction in total Positive and Negative Syndrome Scale (PANSS) score, or “no improvement,” defined as an inadequate treatment response (<20% reduction in total PANSS). A random forest algorithm performed best relative to other tree‐based approaches in model ability to classify patients after 6 months of treatment. Although model ability to identify true positives, a measure of model sensitivity, was poor (<0.2), its specificity, true negative rate, was high (0.948). A second model, adapted from the first, was subsequently applied as a proof‐of‐concept for the ML approach to supplement trial enrollment by identifying patients not expected to improve based on their baseline diagnostic scores. In three virtual trials applying this screening approach, the percentage of patients predicted to improve ranged from 46% to 48%, consistently approximately double the CATIE response rate of 22%. These results show the promising application of ML to improve clinical trial efficiency and, as such, ML models merit further consideration and development.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

In silico approaches for a priori prediction of patient therapeutic response in a clinical trial could improve clinical trial efficiency by reducing patient enrollment requirements and potentially decision time.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Application of a machine learning (ML) approach was investigated to determine if previously collected, patient‐specific data could be used to predict and categorize individual patient treatment response during a clinical trial assessing treatment efficacy in schizophrenia.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Based on three virtual trials, model application resulted in “improvement” predictions ranging from 46% to 48% compared to actual improvement of 22% in the CATIE trial.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

ML shows promise as a useful tool to supplement patient enrollment to thereby improve clinical trial efficiency.     

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.     

Kinetics of myelin breakdown products: A labeling study in patients with progressive multiple sclerosis

The majority of disease modifying therapies for multiple sclerosis (MS) reduce inflammation, but do no’t target remyelination. Development of remyelinating therapies will benefit from a method to quantify myelin kinetics in patients with MS. We labeled myelin in vivo with deuterium, and modeled kinetics of myelin breakdown products β‐galactosylceramide (β‐GalC) and N‐Octadecanoyl‐sulfatide (NO‐Sulf). Five patients with MS received 120 ml 70% D₂O daily for 70 days and were compared with six healthy subjects who previously received the same procedure. Mass spectrometry and compartmental modeling were used to quantify the turnover rate of β‐GalC and NO‐Sulf in cerebrospinal fluid (CSF). Turnover rate constants of the fractions of β‐GalC and NO‐Sulf with non‐negligible turnover were 0.00186 and 0.00714, respectively, in both healthy subjects and patients with MS. The turnover half‐life of β‐GalC and NO‐Sulf was calculated as 373 days and 96.5 days, respectively. The effect of MS on the NO‐Sulf (49.4% lower fraction with non‐negligible turnover) was more pronounced compared to the effect on β‐GalC turnover (18.3% lower fraction with non‐negligible turnover). Kinetics of myelin breakdown products in the CSF are different in patients with MS compared with healthy subjects. This may be caused by slower myelin production in these patients, by a higher level of degradation of a more stable component of myelin, or, most likely, by a combination of these two processes. Labeling myelin breakdown products is a useful method that can be used to quantify myelin turnover in patients with progressive MS and can therefore be used in proof‐of‐concept studies with remyelination therapies.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Myelin components can be labeled in healthy subjects using deuterium, allowing us to model the kinetics of the myelin breakdown product β‐galactosylceramide and N‐Octadecanoyl‐sulfatide. This approach offered a method to quantify changes in myelin kinetics after treatment with a remyelinating compound.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Can we measure myelin kinetics in patients with multiple sclerosis (MS), and is there a difference in kinetics of myelin breakdown products between healthy volunteers and patients?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Kinetics of myelin breakdown products are different in patients with MS compared with healthy subjects. The pattern observed between the patients is similar.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Labeling myelin breakdown products can be used to quantify myelin turnover in patients with MS and this method can be used in proof‐of‐concept studies with remyelination therapies.     

Effects of sedative psychotropic drugs combined with oxycodone on respiratory depression in the rat

Following a decision to require label warnings for concurrent use of opioids and benzodiazepines and increased risk of respiratory depression and death, the US Food and Drug Administratioin (FDA) recognized that other sedative psychotropic drugs may be substituted for benzodiazepines and be used concurrently with opioids. In some cases, data on the ability of these alternatives to depress respiration alone or in conjunction with an opioid are lacking. A nonclinical in vivo model was developed that could detect worsening respiratory depression when a benzodiazepine (diazepam) was used in combination with an opioid (oxycodone) compared to the opioid alone based on an increased arterial partial pressure of carbon dioxide (pCO₂). The current study used that model to assess the impact on respiration of non‐benzodiazepine sedative psychotropic drugs representative of different drug classes (clozapine, quetiapine, risperidone, zolpidem, trazodone, carisoprodol, cyclobenzaprine, mirtazapine, topiramate, paroxetine, duloxetine, ramelteon, and suvorexant) administered alone and with oxycodone. At clinically relevant exposures, paroxetine, trazodone, and quetiapine given with oxycodone significantly increased pCO₂ above the oxycodone effect. Analyses indicated that most pCO₂ interaction effects were due to pharmacokinetic interactions resulting in increased oxycodone exposure. Increased pCO₂ recorded with oxycodone‐paroxetine co‐administration exceeded expected effects from only drug exposure suggesting another mechanism for the increased pharmacodynamic response. This study identified drug‐drug interaction effects depressing respiration in an animal model when quetiapine or paroxetine were co‐administered with oxycodone. Clinical pharmacodynamic drug interaction studies are being conducted with these drugs to assess translatability of these findings.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Benzodiazepines exacerbate opioid‐induced respiratory depression. The impact of other sedative psychotropic drugs on respiration alone or co‐administered with an opioid is often unknown.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study addressed whether a rat model could detect increased partial pressure of carbon dioxide, indicative of respiratory depression, for sedative psychotropic drugs with previously unknown influence on respiration, alone or in combination with an opioid.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This study suggests that drug‐drug interactions between designated sedative psychotropic drugs and opioids could exacerbate opioid‐induced respiratory depression and that additional clinical studies would be informative.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Dependent upon outcomes in clinical studies, this work could define a model for early screening of drug‐drug interactions and respiratory depression risk as well as inform the need for additional clinical interaction studies with respiration as the end point.     

Hydrogen sulfide donor protects against mechanical ventilation‐induced atrophy and contractile dysfunction in the rat diaphragm

AbstractMechanical ventilation (MV) is a clinical tool providing adequate alveolar ventilation in patients that require respiratory support. Although a life‐saving intervention for critically ill patients, prolonged MV results in the rapid development of inspiratory muscle weakness due to both diaphragmatic atrophy and contractile dysfunction; collectively known as “ventilator‐induced diaphragm dysfunction” (VIDD). VIDD is a severe clinical problem because diaphragmatic weakness is a risk factor for difficulties in weaning patients from MV. Currently, no standard treatment to prevent VIDD exists. Nonetheless, growing evidence reveals that hydrogen sulfide (H₂S) possesses cytoprotective properties capable of protecting skeletal muscles against several hallmarks of VIDD, including oxidative damage, accelerated proteolysis, and mitochondrial damage. Therefore, we used an established animal model of MV to test the hypothesis that treatment with sodium sulfide (H₂S donor) will defend against VIDD. Our results confirm that sodium sulfide was sufficient to protect the diaphragm against both MV‐induced fiber atrophy and contractile dysfunction. H₂S prevents MV‐induced damage to diaphragmatic mitochondria as evidenced by protection against mitochondrial uncoupling. Moreover, treatment with sodium sulfide prevented the MV‐induced activation of the proteases, calpain, and caspase‐3 in the diaphragm. Taken together, these results support the hypothesis that treatment with a H₂S donor protects the diaphragm against VIDD. These outcomes provide the first evidence that H₂S has therapeutic potential to protect against MV‐induced diaphragm weakness and to reduce difficulties in weaning patients from the ventilator. Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Mechanical ventilation (MV) results in diaphragm atrophy and contractile dysfunction, known as ventilator‐induced diaphragm dysfunction (VIDD). VIDD is important because diaphragm weakness is a risk factor for problems in weaning patients from MV. Currently, no accepted treatment exists to protect against VIDD. Growing evidence reveals that hydrogen sulfide (H₂S) donors protect skeletal muscle against ischemia‐reperfusion‐induced injury. Nonetheless, it is unknown if treatment with a H₂S donor can protect against VIDD.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Can treatment with an H₂S donor protect against VIDD?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This study provides the first evidence that treatment with a H₂S donor protects against VIDD.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

These new findings provide the basis for further exploration of H₂S donors as a therapy to prevent VIDD and reduce the risk of problems in weaning patients from MV.     

Pharmacokinetics of daridorexant,a dual orexin receptor antagonist,are not affected by renal impairment

The aim of this study was to evaluate the impact of renal impairment on the pharmacokinetics (PKs), safety, and tolerability of daridorexant, a dual orexin receptor antagonist intended for the treatment of insomnia. A single‐center, open‐label study evaluated the PKs of daridorexant in patients with severe renal function impairment (SRFI; determined by creatinine clearance using the Cockcroft‐Gault equation; N = 8) not on dialysis, and in matched control subjects (based on sex, age, and body weight; N = 7). A single oral dose of daridorexant 25 mg was orally administered in the morning. Blood samples were collected up to 72 h postdose for PK assessments of daridorexant. In patients with SRFI, maximum plasma concentrations (C_max; geometric mean ratio [GMR] and 90% confidence interval [CI]: 0.94 [0.60–1.46]), time to reach C_max (T _max; median difference [90% CI] of −0.25 h [−0.75 to 0.25]), and half‐life (GMR [90% CI] of 0.99 [0.66–1.48]), were virtually unchanged. Exposure (area under the plasma concentration‐time profile) to daridorexant was slightly higher in patients with SRFI than in control subjects with the GMR (90% CI) being 1.16 (0.63–2.12). No safety issue of concern was detected as all adverse events were transient and of mild or moderate intensity, and no treatment‐related effects on vital signs, clinical laboratory, or electrocardiogram variables were observed following daridorexant administration in patients with SRFI and control subjects. Based on these observations, PK alterations of daridorexant due to renal function impairment are not considered of clinical relevance and no dose adjustment is necessary in these patients.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Daridorexant, a potent and selective dual orexin receptor antagonist being developed to treat insomnia, has been shown to have significant effects on sleep onset and sleep maintenance, and improves the impaired daytime functioning of patients with insomnia. Daridorexant has recently been submitted for marketing authorization (in the United States and the European Union).

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study compared the pharmacokinetics (PKs), safety, and tolerability of daridorexant between patients with severe renal function impairment (SRFI) and control subjects.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Similar PK profiles and no tolerability issues were observed in patients with SRFI and control subjects following single‐dose administration of 25 mg daridorexant.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

In clinical practice, the same dose of daridorexant can be administered to patients with insomnia with or without any degree of renal function impairment.     

Safety,tolerability, pharmacokinetics,and pharmacodynamics of HBM9161, a novel FcRn inhibitor,in a phase I study for healthy Chinese volunteers

Blockade of the binding between neonatal Fc receptor and IgG‐Fc reduces circulating IgG, and thus emerges as a potential therapy for IgG‐mediated autoimmune conditions. This was a double blind, randomized, single ascending dose study to evaluate the safety, pharmacokinetics, and pharmacodynamics of HBM9161 (a fully humanized Fc receptor monoclonal antibody) in healthy Chinese volunteers. Subjects were randomized to receive a single s.c. dose of HBM9161 or placebo in a 3:1 ratio in 3 dosing cohorts (340 mg, 510 mg, or 680 mg, respectively), and then followed up for 85 days. Study end points included incidence of adverse event (AE), serum drug concentration, IgG and its subclasses, and anti‐drug antibodies (ADAs). Twenty‐four subjects were randomized. Dose‐dependent reduction of total IgG occurred rapidly from baseline to reach nadir at day 11, then recovered steadily from day 11 to day 85. The mean maximum percentage reductions from baseline total IgG were 21.0 ± 9.3%, 39.8 ± 5.13%, and 41.2 ± 10.4% for subjects receiving HBM9161 340 mg, 510 mg, and 680 mg, respectively. The exposure of HBM9161 (areas under the curve [AUCs] and peak plasma concentration [C_max]) increased in a more than dose‐proportional manner at the dose examined. All reported AEs were mild in severity. The most reported AEs in the HBM9161 groups were influenza‐like illness and rash. Two subjects developed ADA during the study period. A single s.c. dose of HBM9161 results in sustained and dose‐dependent IgG reduction, and was well‐tolerated at a dose up to 680 mg in Chinese subjects. The data warrant further investigation of its effects in IgG‐mediated autoimmune disorders.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Animal studies and recent human data from White populations showed that treatment with neonatal Fc receptor (FcRn) inhibitor reduces circulating IgG levels and is well‐tolerated. Data of FcRn inhibitors in Asians is relatively limited.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study investigated the pharmacokinetics (PKs), pharmacodynamics (PDs), and safety profile of HBM9161 (an FcRn inhibitor) in healthy Chinese volunteers.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Subcutaneous HBM9161 is safe and effective in IgG reduction in Chinese subjects. The PKs, PDs, and safety characteristics in Chinese are similar to the first‐in‐human study in the White population.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

HBM9161 can be a potential treatment for IgG‐mediated autoimmune disorders and organ transplant rejection.     

Safety and clinical efficacy of the double switch from originator infliximab to biosimilars CT‐P13 and SB2 in patients with inflammatory bowel diseases (SCESICS): A multicenter cohort study

Data regarding double switching from originator infliximab (IFX) to IFX biosimilars in inflammatory bowel diseases (IBDs) are lacking. The purpose of this study was to evaluate the safety and efficacy of switching from originator IFX to CT‐P13 and subsequently to SB2 (double switch) in patients with IBD. Patients undergoing IFX‐double switch in eight Centers in Lombardy (Italy) from November 2018 to May 2019 were retrospectively analyzed. The IFX discontinuation rate, incidence and type of adverse events (AEs), and clinical remission rate were recorded. A comparison with a control group of patients with IBD single‐switched from originator IFX to CT‐P13 was performed, before and after an inverse probability of treatment weighting (IPTW)‐based propensity score analysis. Fifty‐two double‐switched patients with IBD were enrolled. The 24‐ and 52‐week proportions of patients continuing on IFX therapy following the second switch (CTP13 → SB2) were 98% (95% confidence interval [CI] 94%–100%) and 90% (95% CI 81%–99%), respectively. Four patients experienced a total of five AEs, all graded 1–3 according to Common Terminology Criteria for Adverse Events (CTCAE). No infusion reactions were observed. The 24‐week and follow‐up end clinical remission rates following the second switch were 94% and 88%, respectively. No differences were observed in the safety and efficacy outcomes by comparing the double‐switch group with a single‐switch group of 66 patients with IBD; all these results were confirmed by IPTW‐adjusted analysis. The study suggests both the safety and efficacy of the double switch from originator IFX to CT‐P13 and SB2 in patients with IBD is maintained. This strategy may be associated with potential cost implications.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Biosimilars reduce the direct costs of therapy and facilitate access to high‐cost therapies to patients. Data show that switching from originator infliximab to infliximab biosimilars (CT‐P13 or SB2) is safe and effective. Few data are available on the outcomes of double switch (from biological originator to a first biosimilar and then to a second biosimilar), and caution has been expressed by the European Crohn’s and Colitis Organization (ECCO) and the Italian Group for the study of inflammatory bowel disease (IBD; IG‐IBD).

• WHAT QUESTION DID THIS STUDY ADDRESS?

The study was aimed to compare the effectiveness and safety of single and double switch of infliximab (IFX) in patients with IBDs.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

No differences were found in clinical response and remission as well as adverse events between either single or double IFX switch. Data were consistent with the safety profile of IFX.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Double switch strategy is safe and effective in IBD. These data assume high relevance in terms of cost‐savings strategies.     

Type‐2 airway inflammation in mild asthma patients with high blood eosinophils and high fractional exhaled nitric oxide

Type‐2 (T2) inflammation is a characteristic feature of asthma. Biological therapies have been developed to target T2‐inflammation in asthma. IL‐13 is a key component of T2‐inflammation in asthma, driving mucus hypersecretion, IgE‐induction, and smooth muscle contraction. Early phase clinical trials for treatments that target T2‐inflammation require biomarkers to assess pharmacological effects. The aim of this study was to examine levels of IL‐13 inducible biomarkers in the airway epithelium of patients with mild asthma compared to healthy controls. Ten patients with mild asthma with high blood eosinophil and high fractional exhaled nitric oxide (FeNO) were recruited, and six healthy subjects. Blood eosinophil and FeNO reproducibility was assessed prior to bronchoscopy. Epithelial brushings were collected and assessed for IL‐13 inducible gene expression. Blood eosinophil and FeNO levels remained consistent in both patients with asthma and healthy subjects. Of the 11 genes assessed, expression levels of 15LOX1, POSTN, CLCA1, SERPINB2, CCL26, and NOS2 were significantly higher in patients with asthma compared to healthy controls. These six genes, present in patients with mild asthma with T2 inflammation, have the potential to be used in translational early phase asthma clinical trials of novel therapies as bronchial epithelial biomarkers.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Type 2 (T2) inflammation is found in many patients with asthma and is not always controlled by inhaled corticosteroids. T2‐specific biomarkers may be useful for measuring the pharmacological effects of novel anti‐T2 treatments.

• WHAT QUESTION DID THIS STUDY ADDRESS?

We sought to identify IL‐13 associated biomarkers in the airways of patients with asthma with T2 inflammatory phenotype.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Six genes were identified in airway epithelium whose expressions were elevated in patients with T2‐high asthma compared to healthy subjects.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

The six genes identified have the potential to be used as target engagement biomarkers in early phase clinical development for novel asthma treatments targeting T2‐inflammation.