Pharmacokinetics and pharmacodynamics of itepekimab in healthy adults and patients with asthma: Phase I first‐in‐human and first‐in‐patient trials

Itepekimab is a monoclonal antibody that targets interleukin (IL‐33) and has been shown to reduce airway inflammation and associated tissue damage in preclinical studies. We assessed the safety, tolerability, pharmacokinetics (PKs), and pharmacodynamic profiles of single‐ascending and multiple‐ascending doses of itepekimab in two randomized, double‐blind, placebo‐controlled phase I studies. Healthy adults (N = 40) were randomized to the single‐dose study and patients with moderate asthma (N = 23) to the multiple‐dose study. Itepekimab was administered intravenously (0.3, 1, 3, or 10 mg/kg infusion) or subcutaneously (150 mg) in the single‐dose study and subcutaneously (75 or 150 mg weekly for 4 weeks) in the multiple‐dose study. Itepekimab exhibited linear PKs across studies and dose‐proportional increases in mean maximum concentration in serum and area under the concentration–time curve following single intravenous or multiple subcutaneous doses. Itepekimab demonstrated mean subcutaneous bioavailability of 59–73% and a long terminal half‐life (30.0–31.6 days). IL‐33 concentrations in most healthy participants and patients with asthma were undetectable at baseline. Following administration of itepekimab in both studies, total IL‐33 concentrations increased and blood eosinophils decreased, both with durable effect. Itepekimab was well‐tolerated in both studies with no detection of treatment‐emergent anti‐drug antibody responses.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Preclinical data suggest that itepekimab, a monoclonal antibody targeting IL‐33, may benefit patients with chronic inflammatory airway diseases by blocking IL‐33–mediated pathologic inflammation. Neither the pharmacokinetic (PK) profile of itepekimab nor its safety has been fully elucidated in first‐in‐human or first‐in‐patient studies.

• WHAT QUESTION DID THIS STUDY ADDRESS?

The study evaluated the initial safety of itepekimab, and its PK and pharmacodynamic activity in healthy adults and patients with asthma.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Itepekimab demonstrated linear and dose‐proportional PKs in our studies and was well‐tolerated, with no evidence of immunogenicity. These findings have facilitated dose and regimen selection for subsequent clinical studies in patients with asthma and chronic obstructive pulmonary disease.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Itepekimab is one of a few anti‐alarmin biologics under development; if successful, it may provide an alternative mechanism of action with which to target chronic inflammatory airway diseases, alone or in combination with other targeted therapies.     

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.     

Relationship of hemoglobin level and plasma coproporphyrin‐I concentrations as an endogenous probe for phenotyping OATP1B

Plasma coproporphyrin‐I (CP‐I) concentration is used as a sensitive and selective endogenous probe for phenotyping organic anion transporting polypeptides 1B (OATP1B) activity in many studies. CP‐I is produced in the process of heme synthesis, but the relationship between plasma CP‐I concentrations and heme synthesis activity is unknown. In this study, we evaluated the relationship between plasma CP‐I concentration and hemoglobin level as a biomarker of heme synthesis activity. The data of 391 subjects selected from the Japanese general population were analyzed. One hundred twenty‐six participants had OATP1B1*15 allele, 11 of whom were homozygous (OATP1B1*15/*15). Multiple regression analysis identified hemoglobin level as an independent variable associated with plasma CP‐I concentration (p < 0.0001). A significant positive correlation was observed between hemoglobin level and plasma CP‐I concentration in participants without OATP1B1*15 allele (n = 265; r _s = 0.35, p < 0.0001) and with OATP1B1*15 allele (n = 126; r _s =0.27, p = 0.0022). However, Kruskal–Wallis test showed no large difference in Kruskal–Wallis statistics between the distribution of plasma CP‐I concentrations and that of ratio of plasma CP‐I to hemoglobin among six OATP1B1 polymorphism groups. These findings suggest that the hemoglobin level seems to reflect biosynthesis of CP‐I. However, correction by hemoglobin level is not required when using basal plasma CP‐I concentration for phenotyping OATP1B activity.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Coproporphyrin‐I (CP‐I) in plasma is a sensitive and specific endogenous biomarker for phenotyping organic anion transporting polypeptides 1B (OATP1B), and has been used for phenotyping OATP1B activity, such as in clinical drug‐drug interaction studies. CP‐I is produced during the process of heme synthesis, indicating that correction of plasma CP‐I concentration by hemoglobin level as an indicator of heme synthesis activity may be needed.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Does correction by hemoglobin level improve the usefulness of CP‐I as a probe for OATP1B phenotyping?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Hemoglobin level was identified as an independent variable associated with plasma CP‐I concentrations. However, no large difference in Kruskal–Wallis statistics was observed between the distribution of plasma CP‐I concentrations and that of CP‐I/Hb ratio among six OATP1B1 polymorphism groups.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Hemoglobin level seems to reflect biosynthesis of CP‐I. However, correction by hemoglobin level is not needed when using plasma CP‐I concentration for phenotyping OATP1B activity.     

Association of CYP3A5 polymorphisms and parathyroid hormone with blood level of tacrolimus in patients with end‐stage renal disease

Because tacrolimus is predominantly metabolized by CYP3A, the blood concentration/dose (C/D) ratio is affected by CYP3A5 polymorphism. Parathyroid hormone (PTH) expression increases in secondary hyperparathyroidism, which is frequently associated with end‐stage renal disease. Recently, PTH has been shown to downregulate CYP3A expression at mRNA level. In this study, we examined the influence of CYP3A5 polymorphism on and association of serum intact‐PTH (iPTH) level with blood tacrolimus concentration in patients with end‐stage renal disease just before kidney transplantation. Forty‐eight patients who satisfied the selection criteria were analyzed. Subjects were classified into two phenotype subgroups: CYP3A5 expressor (CYP3A5*1/*1 and *1/*3; n = 15) and CYP3A5 nonexpressor (CYP3A5*3/*3; n = 33). The blood tacrolimus C/D (per body weight) ratio was significantly lower in CYP3A5 expressors than that in CYP3A5 nonexpressors. A significant positive correlation was found between tacrolimus C/D and iPTH concentrations (r = 0.305, p = 0.035), and the correlation coefficient was higher after excluding 20 patients co‐administered CYP3A inhibitor or inducer (r = 0.428, p = 0.023). A multiple logistic regression analysis by stepwise selection identified CYP3A5 polymorphism and serum iPTH level as significant factors associated with tacrolimus C/D. These results may suggest the importance of dose design considering not only the CYP3A5 phenotype but also serum iPTH level when using tacrolimus in patients who undergo renal transplantation.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Tacrolimus is primarily metabolized by cytochrome P450 (CYP) 3A4/5 and the pharmacokinetics is affected by CYP3A5 polymorphism. Recently, intact parathyroid hormone (PTH) has been shown to downregulate CYP3A expression at the mRNA level.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Do CYP3A5 polymorphism and serum intact PTH influence the tacrolimus concentration/dose per body weight before kidney transplantation in patients with end‐stage renal failure?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

When designing dose of tacrolimus for patients scheduled to undergo renal transplantation, it may be important to consider not only the CYP3A5 phenotype but also the serum intact PTH level.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Confirming the CYP3A5 phenotype and serum intact PTH level could allow physicians to control blood concentration of tacrolimus from an earlier stage before transplantation. This may contribute to prevent rejection and graft‐versus‐host disease in patients who undergo renal transplantation and to prolong the post‐transplant survival of the transplanted kidney.     

Intraperitoneal pharmacokinetics of vancomycin in patients on automated peritoneal dialysis

It is unclear if the pharmacokinetics of vancomycin are the same during automated peritoneal dialysis (APD), where cycler exchanges may affect the systemic, peritoneal, and urinary disposition of drug. We conducted a prospective pharmacokinetic study evaluating the pharmacokinetics of vancomycin in plasma, dialysis fluid, and urine in peritonitis‐negative patients on APD. Patients underwent four drug‐free exchanges with 1.5% or 2.5% dextrose following the initial dwell period. Plasma, dialysis fluid, and urine was collected over the course of 7 days for pharmacokinetic analysis. Four patients completed the study with no adverse events. Following a median (range) dwell of 14.6 (14.2–17.6 h), the mean (±SD) observed maximum plasma concentration was 28.7 ± 4.9 mg/L with a mean bioavailability of 98.5 ± 1.4% prior to starting the cycler. The overall mean total plasma clearance estimated from study start to completion was 7.6 ± 1.2 ml/min. Mean total clearance during the dialytic exchange was 13.6 ± 4.9 ml/min. In patients with residual renal function, the mean vancomycin renal clearance was 3.1 ± 1.5 ml/min, representing 21.4%–58.9% of the overall total plasma clearance during the study period. Despite the small sample size, this pilot study suggests that the dwell time has important implications for systemic vancomycin exposure, time to therapeutic plasma concentration, and dosing. Dose is driven by dwell time, whereas the cycler determines the dosing interval. Rapid exchanges from APD will determine the frequency of dosing rather than the adequacy of absorption when vancomycin is given in the peritoneum.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Vancomycin dosing in patients with peritonitis during automated peritoneal dialysis (APD) is empiric and extrapolated from studies in patients on continuous ambulatory peritoneal dialysis (CAPD). Extrapolation of pharmacokinetic data from CAPD to APD may result in substantial under‐ or overdosing due to rapid exchanges and longer dwell times. The impact of residual renal function on vancomycin pharmacokinetics is also unknown.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study assessed the absorption and disposition of vancomycin following an intraperitoneal dose. Disposition of vancomycin was assessed in plasma, dialysis fluid, and urine.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Drug‐dialysis fluid dwell times of up to 15 h achieves adequate therapeutic vancomycin concentrations in plasma. Rapid exchanges from APD increases vancomycin total systemic plasma clearance during the exchange period.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Drug‐dialysis fluid dwell time has direct influence on the systemic bioavailability and therapeutic concentration of vancomycin. Initial and maintenance vancomycin dosing regimens should account for the dwell time, dialytic and renal clearance, and microbial susceptibility.     

Increased serum amiodarone concentration in hypertriglyceridemic patients: Effects of drug distribution to serum lipoproteins

Amiodarone and its main metabolite, desethylamiodarone (DEA), are highly distributed to serum lipoproteins such as very‐low‐density lipoprotein (VLDL) and low‐density lipoprotein (LDL), which are the carriers of triglyceride and cholesterol. This study aimed to investigate the association of serum concentrations of amiodarone and DEA with the levels of serum lipids in terms of drug distribution to lipoprotein fractions in patients with hyperlipidemia. Total serum concentrations of amiodarone and DEA were examined in 116 patients receiving amiodarone for tachyarrhythmias. The concentration‐to‐dose (C/D) ratio of amiodarone positively correlated with the level of serum triglyceride (r_s  = 0.541, p < 0.001) and was higher in the hypertriglyceridemic state than in normotriglyceridemic state (479 ± 211 vs. 320 ± 161, p < 0.001). No correlation was found between the C/D ratio of DEA and serum triglyceride levels (r_s  = 0.272), although higher values were observed in the hypertriglyceridemic state (322 ± 125 vs. 285 ± 143, p < 0.001). In the hypertriglyceridemic state, the distribution of amiodarone increased in LDL/VLDL fraction and decreased in high‐density lipoprotein and albumin fractions. The ratio of serum amiodarone to serum DEA, a metabolic ratio of amiodarone, positively correlated with serum triglyceride levels (r_s  = 0.572, p < 0.001) and was higher in the hypertriglyceridemic state, suggesting that amiodarone metabolism decreased in hyperlipidemia. The results of this study reveal that serum concentrations of amiodarone increase in the hypertriglyceridemic state through the increased lipoprotein‐binding and decreased metabolism of amiodarone.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Lipoproteins can carry not only serum lipids but also certain lipophilic compounds such as amiodarone. Changes in the lipoprotein‐binding of amiodarone may lead to highly variable pharmacokinetics and poor concentration–effect relationships of the drug.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study addressed the association between serum amiodarone concentration and serum lipid levels in patients with arrhythmia, as well as the lipoprotein‐binding and metabolism of amiodarone in the hyperlipidemic state.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Serum amiodarone concentration is increased in patients with hypertriglyceridemia and it is positively correlated with serum triglyceride levels. These results are attributable to an increase in the circulating lipoprotein‐bound form of amiodarone and decreased metabolism of the drug in the hypertriglyceridemic state.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Changes in the lipoprotein‐binding of amiodarone can help explain differences in the pharmacokinetics and pharmacodynamics of amiodarone related to normotriglyceridemic and hypertriglyceridemic states.     

A metabolomic analysis of thiol response for standard and modified N‐acetyl cysteine treatment regimens in patients with acetaminophen overdose

N‐acetylcysteine (NAC) is an antidote to prevent acetaminophen (paracetamol‐APAP)‐induced acute liver injury (ALI). The 3‐bag licensed 20.25 h standard regimen, and a 12 h modified regimen, are used to treat APAP overdose. This study evaluated the redox thiol response and APAP metabolites, in patients with a single APAP overdose treated with either the 20.25 h standard or 12 h modified regimen. We used liquid chromatography tandem mass spectrometry to quantify clinically important oxidative stress biomarkers and APAP metabolites in plasma samples from 45 patients who participated in a randomized controlled trial (SNAP trial). We investigated the time course response of plasma metabolites at predose, 12 h, and 20.25 h post‐start of NAC infusion. The results showed that the 12 h modified regimen resulted in a significant elevation of plasma NAC and cysteine concentrations at 12 h post‐infusion. We found no significant alteration in the metabolism of APAP, mitochondrial, amino acids, and other thiol biomarkers with the two regimens. We examined APAP and purine metabolism in overdose patients who developed ALI. We showed the major APAP‐metabolites and xanthine were significantly higher in patients with ALI. These biomarkers correlated well with alanine aminotransferase activity at admission. Receiver operating characteristic analysis showed that at admission, plasma APAP‐metabolites and xanthine concentrations were predictive for ALI. In conclusion, a significantly higher redox thiol response with the modified NAC regimen at 12 h postdose suggests this regimen may produce greater antioxidant efficacy. At baseline, plasma APAP and purine metabolites may be useful biomarkers for early prediction of APAP‐induced ALI.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

N‐acetylcysteine (NAC) is an effective antidote used to prevent acetaminophen (APAP)‐induced acute liver injury (ALI). The 12 h modified NAC regimen has a lower rate of adverse effects than the 20.25 h standard NAC regimen. However, the effect of NAC regimen on redox thiol and APAP metabolism have not been studied.

• WHAT QUESTION DID THIS STUDY ADDRESS?

What are the effects of modified and standard NAC regimens on circulating thiol biomarkers and APAP metabolites?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Patients who received 12 h modified NAC treatment have significantly higher circulating cysteine concentration at 12 h postinfusion than those who received 20.25 h standard NAC regimen. At baseline, plasma APAP and purine metabolites were significantly higher in patients who developed ALI.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

This study suggests the 12 h modified NAC regimen provides greater antioxidant protection to APAP overdose patients in this time frame allowing further NAC therapy to be targeted earlier to patients at risk. At baseline, plasma APAP and purine metabolites are predictive biomarkers for APAP‐induced ALI.     

First‐in‐human study of milvexian,an oral,direct, small molecule factor XIa inhibitor

Milvexian (BMS‐986177/JNJ‐70033093) is a small molecule, active‐site inhibitor of factor XIa (FXIa) being developed to prevent and treat thrombotic events. The safety, tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of milvexian were assessed in a two‐part, double‐blind, placebo‐controlled, sequential single ascending dose (SAD) and multiple ascending dose (MAD) study in healthy adults. Participants in SAD panels (6 panels of 8 participants; n = 48) were randomized (3:1) to receive milvexian (4, 20, 60, 200, 300, or 500 mg) or placebo. The 200‐ and 500‐mg panels investigated the pharmacokinetic impact of a high‐fat meal. Participants in MAD panels (7 panels of 8 participants; n = 56) were randomized (3:1) to receive milvexian (once‐ or twice‐daily) or placebo for 14 days. All milvexian dosing regimens were safe and well‐tolerated, with only mild treatment‐emergent adverse events and no clinically significant bleeding events. In SAD panels, maximum milvexian plasma concentration occurred 3 h postdose in all fasted panels. The terminal half‐life (T_1/2) ranged from 8.3 to 13.8 h. In fasted panels from 20 to 200 mg, absorption was dose‐proportional; results at higher doses (300 and 500 mg) were consistent with saturable absorption. Food increased milvexian bioavailability in a dose‐dependent fashion. In MAD panels, steady‐state milvexian plasma concentration was reached within 3 and 6 dosing days with once‐ and twice‐daily dosing, respectively. Renal excretion was less than 20% in all panels. Prolongation of activated partial thromboplastin time was observed and was directly related to drug exposure. These results suggest that the safety, tolerability, PK, and PD properties of milvexian are suitable for further clinical development.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Factor XI (FXI) amplifies thrombin generation and has a limited role in hemostasis. Targeted FXI inhibition may reduce the burden of vascular and thromboembolic diseases while preserving hemostasis.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study evaluated the safety/tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of the selective, direct, small molecule FXIa inhibitor milvexian.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Single and multiple ascending doses of milvexian up to 500 mg were generally safe and well‐tolerated, with no clinically significant bleeding events. Milvexian plasma concentration was dose proportional at doses up to 200 mg q.d. The milvexian half‐life is suitable for q.d. or b.i.d. dosing. Milvexian exhibited low renal excretion and low overall variability in PK and PD parameters.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

These results can inform the future clinical development of milvexian.     

Rituximab exposure‐response in triweekly R‐CHOP treatment in DLBCL: A loading dose is recommended to improve clinical outcomes

Previous exposure‐response analyses for rituximab suggest that higher rituximab concentrations were associated with an improvement in efficacy, however, clinical studies investigating a higher rituximab dose had mixed results. To further explore the exposure‐response relationship of rituximab, a prospective observational analysis was performed involving 121 newly diagnosed patients with diffuse large B‐cell lymphoma treated with triweekly rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R‐CHOP). The trough concentration in the first cycle (C_1‐trough) was significantly higher in patients achieving complete response (CR) compared with patients that did not achieve CR (22.00 μg/ml vs. 16.62 μg/ml, p = 0.0016), however, this difference between the two groups disappeared in later cycles. The relationship between rituximab C_1‐trough and achieving a CR was confirmed by matched‐pair logistic regression analysis (odds ratio, 0.79; p = 0.0020). In addition, a higher C_1‐trough (≥18.40 μg/ml) was associated with longer progression‐free survival (p < 0.0001) and overall survival (p = 0.0038). The percentages of patients that did not achieve a CR and had recurrence after CR within 24 months were 35% and 22.50%, respectively, for patients with a C_1‐trough less than or equal to 18.40 μg/ml, compared with 12.35% and 6.17% for patients with C_1‐trough greater than 18.40 μg/ml. Disease stage was found to be the most significant influencing factor of C_1‐trough, with 51.02% of patients at stage IV with an observed C_1‐trough less than 18.40 μg/ml. For these advanced patients, population pharmacokinetic simulations using an established model suggest that a loading dose of 800 mg/m² may help to improve clinical outcomes.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Several studies reported a good clinical response was correlated with a high rituximab concentration, however, not all trials that increased the dosage of rituximab exhibited clinical benefits.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Systemic investigation is warranted to explore the pharmacokinetic mechanism underlying this confusing dose/concentration‐effect relationship.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Lower rituximab concentration in the first cycle rather than other cycles was significantly associated with lower complete response rate and early disease recurrence. The recommendatory minimum optimal trough concentration in the first cycle (C_1‐trough) was 18.40 μg/ml, and a loading dose was recommended for advanced patients to obtain optimal exposure. Moreover, correction of hypoproteinemia and liver dysfunction before treatment was recommended to improve clinical benefits.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

The ideal administration of rituximab may involve a high initial dose and then maintenance at modest levels for a sufficient time, and increasing the initial dose of rituximab may be a new direction for future studies.     

Diagnostic and prognostic capabilities of a biomarker and EMR‐based machine learning algorithm for sepsis

Sepsis is a major cause of mortality among hospitalized patients worldwide. Shorter time to administration of broad‐spectrum antibiotics is associated with improved outcomes, but early recognition of sepsis remains a major challenge. In a two‐center cohort study with prospective sample collection from 1400 adult patients in emergency departments suspected of sepsis, we sought to determine the diagnostic and prognostic capabilities of a machine‐learning algorithm based on clinical data and a set of uncommonly measured biomarkers. Specifically, we demonstrate that a machine‐learning model developed using this dataset outputs a score with not only diagnostic capability but also prognostic power with respect to hospital length of stay (LOS), 30‐day mortality, and 3‐day inpatient re‐admission both in our entire testing cohort and various subpopulations. The area under the receiver operating curve (AUROC) for diagnosis of sepsis was 0.83. Predicted risk scores for patients with septic shock were higher compared with patients with sepsis but without shock (p < 0.0001). Scores for patients with infection and organ dysfunction were higher compared with those without either condition (p < 0.0001). Stratification based on predicted scores of the patients into low, medium, and high‐risk groups showed significant differences in LOS (p < 0.0001), 30‐day mortality (p < 0.0001), and 30‐day inpatient readmission (p < 0.0001). In conclusion, a machine‐learning algorithm based on electronic medical record (EMR) data and three nonroutinely measured biomarkers demonstrated good diagnostic and prognostic capability at the time of initial blood culture.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Sepsis represents significant morbidity, mortality, and cost in modern health care. Timely treatment with antibiotics improves outcomes, but it can be difficult to identify patients with sepsis early on in the clinical course.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Can a machine‐learning algorithm incorporating basic clinical data and nonroutinely measured biomarkers accurately predict sepsis and other related secondary outcomes?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

A machine‐learning algorithm incorporating basic clinical data and nonroutinely measured biomarkers accurately identify sepsis. Meanwhile, a higher score outputted by the algorithm predicts less favorable outcomes with respect to discharge time, 30‐day mortality, and 30‐day inpatient re‐admission.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Earlier treatment of patients who are on a course for poor outcomes has the potential to significantly improve those outcomes. This study suggests that a machine‐learning‐based score may assist clinicians in identifying such patients.     

REGN1908‐1909 monoclonal antibodies block Fel d 1 in cat allergic subjects: Translational pharmacokinetics and pharmacodynamics

REGN1908‐1909, a 1:1 cocktail of two fully human IgG₄ monoclonal antibodies (mAbs), REGN1908 and REGN1909, is being evaluated for treatment of cat allergy. Both REGN1908 and REGN1909 bind to the dominant cat allergen, Fel d 1. Adults with cat allergy confirmed by skin prick test (SPT) were randomized to single subcutaneous administration of placebo (n = 6) or REGN1908‐1909 at doses of 150 (n = 6), 300 (n = 6), or 600 mg (n = 6). Blood samples were taken at prespecified time points for pharmacokinetic (PK) analysis and exploratory evaluation of biomarkers (IgE and SPT). Safety was assessed. Drug concentration‐time profiles in serum for ascending doses of REGN1908‐1909 were consistent with linear PKs. Noncompartmental analysis showed that maximum concentration (C_max) and exposure increased proportionately with dose, with similar time to maximum concentration (T_max) for REGN1908 and REGN1909 (6.2 to 8.2 days across doses), and a longer terminal half‐life for REGN1908 (~ 30 days) relative to REGN1909 (~ 21 days). Adverse events were not dose dependent; there were no dose‐limiting toxicities. REGN1908‐1909 is characterized by linear and dose‐proportional kinetics of the two individual mAb components. A single 600 mg dose maintains total mAb mean concentrations in serum above the target (mean of ~ 10 mg/L) for 8–12 weeks. Maintaining this mean target concentration resulted in translational pharmacodynamic effects: maximal mast cell degranulation in a passive cutaneous anaphylaxis mouse model, and maintenance of clinical efficacy measured by Total Nasal Symptom Score in a previous proof‐of‐mechanism study.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

REGN1908 and REGN1909 are fully human IgG₄ monoclonal antibodies that demonstrated high affinity, noncompetitive binding to distinct epitopes of Fel d 1 allergen. Whereas a cocktail of these monoclonal antibodies, REGN1908‐1909, is being evaluated as a passive immunization strategy for treatment of cat allergy, its pharmacokinetics (PKs) have not been fully characterized, especially with respect to potential pharmacodynamic (PD) effects.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This first‐in‐human study of REGN1908‐1909 evaluated the PKs and safety of REGN1908‐1909 in cat‐allergic individuals who were otherwise healthy. Translational context is provided by discussing the PK profile with regard to PD effects observed in mouse models and among patients in a proof‐of‐mechanism study.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

The PK profile of subcutaneous administration of REGN1908‐1909 in subjects with cat allergy appeared to be dose‐proportional, with half‐lives of the individual components within the expected range for a typical monoclonal antibody. The concentration‐time curve was consistent with previously reported peak PD effects, including clinical response that temporally coincides with the time of peak concentrations of the drugs in serum.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE

Pharmacokinetic results support REGN1908‐1909 600 mg as the dose that maintains drug concentrations in serum above a mean target concentration required for PD effects, and suggest a prophylactic dosing regimen of every 2–3 months.     

Peppermint oil effects on the gut microbiome in children with functional abdominal pain

Peppermint oil (PMO) is effective in the treatment of functional abdominal pain disorders, but its mechanism of action is unclear. Evidence suggests PMO has microbicidal activity. We investigated the effect of three different doses of PMO on gut microbiome composition. Thirty children (7–12 years of age) with functional abdominal pain provided a baseline stool sample prior to randomization to 180, 360, or 540 mg of enteric coated PMO (10 participants per dose). They took their respective dose of PMO (180 mg once, 180 mg twice, or 180 mg thrice daily) for 1 week, after which the stool collection was repeated. Baseline and post‐PMO stools were analyzed for microbiome composition. There was no difference in alpha diversity of the gut microbiome between the baseline and post‐PMO treatment. Principal coordinate analysis revealed no significant difference in overall bacterial composition between baseline and post‐PMO samples, as well as between the PMO dose groups. However, the very low abundant Collinsella genus and three operational taxonomic units (one belonging to Collinsella) were significantly different in samples before and after PMO treatment. The Firmicutes/Bacteroidetes ratio was lower in children who received 540 mg of PMO compared to the 180 mg and 360 mg dose groups (p = 0.04). Network analysis revealed separation between pre‐ and post‐PMO fecal samples with the genus Collinsella driving the post‐PMO clusters. PMO administration appeared to impact only low abundance bacteria. The 540 mg PMO dose differentially impacted the Firmicutes/Bacteroidetes ratio. A higher dose and/or longer duration of treatment might yield different results.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Peppermint oil (PMO) is used commonly to treat gut disorders. In vitro PMO can be bactericidal.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Does oral administration of PMO impact gut microbiome composition? Is there a dose‐response impact on gut microbiome composition?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

PMO at the doses tested can impact gut microbiome composition. The highest dose of PMO (540 mg) changed the Firmicutes/Bacteroidetes ratio.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Some of the clinical benefit of PMO may be mediated through a change in gut microbiome composition. Higher doses and/or longer treatment should be tested to evaluate the impact on gut microbiome composition.     

HLA variants associated with azathioprine‐induced pancreatitis in patients with Crohn’s disease

The immunosuppressant drug azathioprine is associated with a 4% risk of acute pancreatitis in patients with inflammatory bowel disease (IBD). Studies have demonstrated an increased risk in carriers of HLA‐DQA1*02:01 and HLA‐DRB1*07:01. We investigated whether these human leukocyte antigen (HLA) types were associated with azathioprine‐induced pancreatitis also in Swedish patients with IBD, and whether the type of disease affected the association. Nineteen individuals with IBD who developed acute pancreatitis after initiation of azathioprine were genotyped and compared with a population control cohort (n = 4891) and a control group matched for disease (n = 81). HLA‐DQA1*02:01 and HLA‐DRB1*07:01 were in full linkage disequilibrium, and were significantly associated with acute pancreatitis both when cases were compared with population controls (OR 3.97 [95% CI 1.57–9.97], p = 0.0035) and matched controls (OR 3.55 [95% CI 1.23–10.98], p = 0.0275). In a disease‐specific analysis, the correlation was positive in patients with Crohn''s disease versus matched controls (OR 9.27 [95% CI 1.86–46.19], p = 0.0066), but not in those with ulcerative colitis versus matched controls (OR 0.69 [95% CI 0.07–6.74], p = 0.749). In patients with Crohn''s disease, we estimated the conditional risk of carriers of HLA‐DQA1*02:01‐HLA‐DRB1*07:01 to 7.3%, and the conditional risk of a non‐carrier to 2.2%. We conclude that HLA‐DQA1*02:01‐HLA‐DRB1*07:01 is a marker for increased risk of acute pancreatitis in individuals of Swedish genetic origin, treated with azathioprine for Crohn''s disease.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

HLA‐DQA1*02:01 and HLA‐DRB1*07:01 have been shown to increase the risk of acute pancreatitis in individuals with inflammatory bowel disease (IBD) treated with azathioprine.

• WHAT QUESTION DID THIS STUDY ADDRESS?

It is unknown whether this risk also applies to patients of Swedish origin and if the risk differs depending on type of IBD.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

We show that HLA‐DQA1*02:01 and HLA‐DRB1*07:01 are risk markers for azathioprine‐induced acute pancreatitis in patients of Swedish origin. We propose that this risk could be restricted to those with Crohn''s disease, where the estimated risk equals 7.3% for carriers and 2.2% for non‐carriers.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

As the HLA‐DQA1*02:01‐HLA‐DRB1*07:01 haplotype has a frequency of ~7% in the Swedish population, preemptive HLA‐typing could be useful for the selection of patients with Crohn''s disease that need intensified monitoring or for choice of a different therapy.     

Polypharmacy influences the renal composite outcome in patients treated with sodium‐glucose cotransporter 2 inhibitors

Polypharmacy is a serious concern in general practice, especially among elder patients; however, the evidence showing significantly poor renal outcomes is not sufficient. This survey was performed to evaluate the effect of polypharmacy on the incidence of the renal composite outcome among a sample of patients with sodium‐glucose cotransporter 2 inhibitor (SGLT2i) treatment. We assessed 624 Japanese patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease who received SGLT2i treatment for greater than 1 year. The patients were classified as those with concomitant treatment, that was limited to the medications for hypertension, T2DM, and dyslipidemia, with greater than or equal to seven medications (n = 110) and those with less than seven medications (n = 514). Evaluation of the renal composite outcome was performed by propensity score matching and stratification into quintiles. A subgroup analysis of patients of greater than or equal to 62 years of age and less than 62 years of age was also performed. The incidence of the renal composite outcome was larger in patients with greater than or equal to seven medications than in those with less than seven medications in the propensity score‐matched cohort model (6% vs. 17%, respectively, p = 0.007) and also in the quintile‐stratified analysis (odds ratio [OR], 2.23, 95% confidence interval [CI, 1.21–4.12, p = 0.01). The quintile‐stratified analysis of patients of less than 62 years of age—but not those of greater than or equal to 62 years of age—also showed a significant difference (OR, 3.29, 95% CI, 1.41–7.69, p = 0.006). Polypharmacy appears to be associated to the incidence of the renal composite outcome, especially in young patients.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Polypharmacy is an unaddressed concern and may worsen prognosis in clinical practice, especially in elderly patients.

• WHAT QUESTION DID THIS STUDY ADDRESS?

The evidence that polypharmacy correlates with poor cardiovascular or renal outcomes is insufficient in clinical practice.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This study clarified the relationship between polypharmacy and a renal composite outcome in patients with type 2 diabetes mellitus and chronic kidney disease receiving sodium‐glucose cotransporter 2 inhibitor treatment, especially in young patients.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Both specialists and general practitioners should pay attention to polypharmacy to improve renal outcomes in clinical practice.     

Large variability in plasma efavirenz concentration in Papua New Guinea HIV/AIDS patients associated with high frequency of CYP2B6 516T allele

Papua New Guinea (PNG) has a high HIV/AIDS prevalence and very high frequency of the CYP2B6 c.516G>T (rs3745274) variant. We have conducted the first investigation of the impact of c.516G>T and patient demographics on plasma efavirenz (EFV) and 8‐hydroxyefavirenz (8OH‐EFV) concentrations, metabolic ratio (8OH‐EFV/EFV) (MR), and their association with adverse effects, in PNG patients with HIV/AIDS. For 156 PNG patients with HIV/AIDS taking EFV 600 mg/day (for 3–156 months), plasma EFV and 8OH‐EFV concentrations were quantified, CYP2B6 c.516G>T genotyped, and demographic and self‐reported adverse effects data recorded. Genotype differences in EFV and 8OH‐EFV concentrations, MR, and percent within therapeutic range (1000–4000 ng/ml) were examined, in addition to EFV and 8OH‐EFV concentration differences between patients experiencing adverse effects. CYP2B6 c.516T allele frequency was 53%. Plasma EFV (p < 0.0001), 8OH‐EFV (p < 0.01), and MR (p < 0.0001) differed significantly between genotypes, with genotype explaining 38%, 10%, and 50% of variability, respectively. Plasma EFV concentrations were significantly higher in T/T (median = 5168 ng/ml) than G/G (1036 ng/ml, post hoc p < 0.0001) and G/T (1502 ng/ml, p < 0.0001) genotypes, with all patients above therapeutic range (n = 23) being T/T genotype (p < 0.0001). EFV and 8OH‐EFV concentrations were not significantly higher in patients experiencing adverse effects. In PNG HIV/AIDS population where the 516T frequency is very high, it explains a substantial portion of variability (38%) in EFV disposition; however, at least for the patients receiving EFV long term, this does not translate into significant side effects.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

High efavirenz (EFV) concentrations are strongly associated with the development of adverse effects, particularly central nervous system (CNS) and psychiatric toxicities. Papua New Guinea (PNG) has a high HIV/AIDS prevalence and the highest frequency of the CYP2B6 c.516G>T decreased function variant allele of any population assessed to date.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Whether there is a gene‐dose association among the c.516G>T genotype, EFV and metabolite concentrations, and adverse events.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

In PNG, the CYP2B6 c.516T/T genotype was strongly associated with substantially higher plasma EFV concentrations and lower metabolic ratio (8‐hydroxy‐efvairenz/efavirenz) in a gene‐dose manner. In PNG, plasma efavirenz and 8‐hydroxy‐efavirenz concentrations were not significantly higher in patients experiencing adverse effects after the first 3 months of treatment.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

For PNG people taking EFV, early (<3 months) pharmacokinetic, and nonpharmacokinetic, mechanisms of CNS toxicity need investigation.     

Pharmacokinetics and tolerability of apremilast in healthy Korean adult men

We performed a two‐part study to evaluate the pharmacokinetics, safety, and tolerability of oral apremilast, a phosphodiesterase 4 inhibitor indicated for the treatment of psoriasis, in healthy Korean adult men. In part 1, there were 12 subjects who randomly received a single oral dose of apremilast at 20, 30, or 40 mg in each of 3 periods in a crossover fashion. In part 2, there were 16 subjects who randomly received 30 mg of apremilast or its matching placebo in a ratio of 3:1 twice daily for 14 days. Apremilast was rapidly absorbed (maximum concentration: ~2–3 h postdose), and eliminated according to a monoexponential pattern with a terminal‐phase elimination half‐life of 8–9 h. The exposure to apremilast increased in a dose‐proportional manner and accumulation was 1.6‐fold at steady‐state. Apremilast was well‐tolerated after a single oral administration and multiple oral administrations in Korean adult men; all of the treatment‐emergent adverse events were mild and recovered without sequelae. In conclusion, apremilast was safe and well‐tolerated in healthy Korean adult men when administered single oral doses of 20, 30, or 40 mg or when administered multiple oral doses of 30 mg b.i.d. for 14 days. Overall exposures increased in an approximate dose proportional manner in healthy Korean adult men.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Apremilast, a phosphodiesterase 4 inhibitor, has been approved to treat patients with psoriasis in many countries, including the United States, Canada, and Japan. Although apremilast has shown a linear pharmacokinetic (PK) profile and little ethnic sensitivity, apremilast has never been studied specifically in Koreans.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This two‐part study evaluated differences in PKs and tolerability of apremilast between healthy Korean adult men and previously studied ethnic populations.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Our results clearly showed that apremilast was safe and well‐tolerated after single and multiple oral administrations in healthy Korean adult men. Linear PK profiles of apremilast were consistently observed in healthy Korean adult men.

• HOW MIGHT THIS CHANGE DRUG DISCOVERY, DEVELOPMENT, AND/OR THERAPEUTICS?

Our results support the notion that recommended apremilast dose of 30 mg b.i.d., after a first week of titration, would be also appropriate in Koreans.     

Population pharmacokinetics and exposure‐response analyses of teduglutide in adult and pediatric patients with short bowel syndrome

Teduglutide is a recombinant analog of human glucagon‐like peptide‐2 that regulates the functional and structural integrity of the cells lining the gastrointestinal tract. Teduglutide is approved for the treatment of patients with short bowel syndrome (SBS) who are dependent on parenteral support (PS). Population pharmacokinetic (PK) and exposure‐response analyses were performed to support teduglutide dosing in patients with SBS. The analysis included 219 patients with SBS (aged <1 year, 5 patients; 1–11 years, 86 patients; 12–17 years, 8 patients; 18–79 years, 120 patients), and 259 non‐SBS subjects (including healthy volunteers and subjects with renal or liver impairment). A one‐compartment model with first‐order absorption and linear elimination adequately characterized the PKs of teduglutide. In patients with SBS, the apparent clearance (CL/F), volume of distribution (V/F), and elimination half‐life of teduglutide were 16.0 L/h, 33.9 L, and 1.47 h, respectively. CL/F depended on body weight and renal function, and V/F depended on body weight and age. Maximum concentration (C _max) of teduglutide was similar in adult and pediatric patients, and in Japanese and non‐Japanese patients. A time‐ and exposure‐response model dependent on the C _max of teduglutide adequately characterized the reduction in PS over more than 2 years of treatment. Daily dosing of 0.05 mg/kg teduglutide resulted in a maximum reduction in PS of 5.76 L/week. Higher C _max values were associated with a more important reduction in PS over time. Adult and pediatric patients with SBS presented similar PKs and response to teduglutide.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Short bowel syndrome (SBS) is a malabsorption disorder that usually results from surgical resection of bowel but can also occur as a congenital condition. It manifests as a collection of signs and symptoms, such as malabsorption, diarrhea, fluid and electrolyte disturbances, and malnutrition, and patients with SBS may require long‐term parenteral support (PS). Teduglutide is a recombinant analog of naturally occurring human glucagon‐like peptide‐2, approved for the treatment of PS‐dependent patients with SBS in the United States, Canada, and Europe.

• WHAT QUESTION DID THIS STUDY ADDRESS?

What the population pharmacokinetic (PK) properties are of teduglutide and exposure‐response relationship in Japanese and non‐Japanese adult (18–79 years) and pediatric (4 months–17 years) patients with SBS, and how teduglutide exposure is related to the treatment response.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

PK properties and exposure parameters of teduglutide in Japanese adult and pediatric patients with SBS are similar to those observed in non‐Japanese adult and pediatric patients with SBS. Teduglutide clearance is dependent on body weight and renal function, and volume of distribution is dependent on body weight and age. The exposure‐response model shows that higher maximum concentrations of teduglutide are associated with a greater reduction in PS volume over time.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

The population PK properties and exposure‐response relationship of teduglutide support the selection of 0.05 mg/kg daily treatment as the effective dose regimen in adult and pediatric patients with SBS.     

Evaluation of moxifloxacin in canine and non‐human primate telemetry assays: Comparison of QTc interval prolongation by timepoint and concentration‐QTc analysis

The in vivo correct QT (QTc) assay is used by the pharmaceutical industry to characterize the potential for delayed ventricular repolarization and is a core safety assay mentioned in International Conference on Harmonization (ICH) S7B guideline. The typical telemetry study involves a dose‐response analysis of QTc intervals over time using a crossover (CO) design. This method has proven utility but does not include direct integration of pharmacokinetic (PK) data. An alternative approach has been validated and is used routinely in the clinical setting that pairs pharmacodynamic (PD) responses with PK exposure (e.g., concentration‐QTc (C‐QTc) analysis. The goal of our paper was to compare the QTc sensitivity of two experimental approaches in the conscious dog and non‐human primate (NHP) QTc assays. For timepoint analysis, a conventional design using eight animals (8 × 4 CO) to detect moxifloxacin‐induced QTc prolongation was compared to a PK/PD design in a subset (N = 4) of the same animals. The findings demonstrate that both approaches are equally sensitive in detecting threshold QTc prolongation on the order of 10 ms. Both QTc models demonstrated linearity in the QTc prolongation response to moxifloxacin dose escalation (6 to 46 ms). Further, comparison with human QTc findings with moxifloxacin showed agreement and consistent translation across the three species: C‐QTc slope values were 0.7‐ (dog) and 1.2‐ (NHP) fold of the composite human value. In conclusion, our data show that dog and NHP QTc telemetry with an integrated PK arm (C‐QTc) has the potential to supplement clinical evaluation and improve integrated QTc risk assessment.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Typical cardiovascular studies usually employ timepoint analysis. Published in vivo corrected QT (QTc) assay data has exhibited variability in QTc sensitivity that results in challenges in nonclinical‐clinical assessment of translation.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Comparison of nonclinical timepoint and concentration QTc (C‐QTc) analyses and how it relates to clinical moxifloxacin data.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Dog and non‐human primate (NHP) QTc timepoint and C‐QTc analyses detect QTc internal prolongation, have equivalent sensitivity, and improve confidence in these models for proarrhythmic risk mitigation.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Risk assessment in nonclinical models translates well to human thorough QT (TQT) data for moxifloxacin. The new data highlights the value of a high‐quality dog or NHP QTc assay to support clinical risk assessment and regulatory decision making.     

Phase I and scintigraphy studies to evaluate safety,tolerability, pharmacokinetics,and lung deposition of inhaled GDC‐0214 in healthy volunteers

Several inflammatory cytokines that promote inflammation and pathogenesis in asthma signal through the Janus kinase 1 (JAK1) pathway. This phase I, randomized, placebo‐controlled trial assessed the pharmacokinetics and safety of single and multiple ascending doses up to 15 mg twice daily for 14 days of a JAK1 inhibitor, GDC‐0214, in healthy volunteers (HVs; n = 66). Doses were administered with a dry powder, capsule‐based inhaler. An accompanying open‐label gamma scintigraphy study in HVs examined the lung deposition of a single dose of inhaled Technetium‐99m (^99mTc)‐radiolabeled GDC‐0214. GDC‐0214 plasma concentrations were linear and approximately dose‐proportional after both single and multiple doses. Peak plasma concentrations occurred at 15–30 min after dosing. The mean apparent elimination half‐life ranged from 32 to 56 h across all single and multiple dose cohorts. After single and multiple doses, all adverse events were mild or moderate, and none led to treatment withdrawal. There was no clear evidence of systemic toxicity due to JAK1 inhibition, and systemic exposure was low, with plasma concentrations at least 15‐fold less than the plasma protein binding‐corrected IC50 of JAK1 at the highest dose. Scintigraphy showed that approximately 50% of the emitted dose of radiolabeled GDC‐0214 was deposited in the lungs and was distributed well to the peripheral airways. ^99mTc‐radiolabeled GDC‐0214 (1 mg) exhibited a mean plasma C_max similar to that observed in phase I at the same dose level. Overall, inhaled GDC‐0214 exhibited pharmacokinetic properties favorable for inhaled administration.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Many factors drive asthma pathogenesis, including several cytokines that signal through the Janus kinase 1 (JAK1) pathway. Inhibition of JAK1 is a possible target for asthma treatments, but previous studies show oral JAK1 inhibitors lead to increased risk of severe infections, malignancy and cardiovascular events.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study investigated the safety, pharmacokinetics, and lung deposition of GDC‐0214, an inhaled JAK1 inhibitor designed to target the lungs.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Inhaled delivery of a JAK inhibitor for 14 days exhibited low systemic exposure, leading to few adverse events and limited systemic toxicity, while demonstrating high deposition in the lungs.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Local pulmonary application of JAK inhibitors may be an effective treatment for asthma with limited systemic risks.