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.     

Evaluation of drug‐drug interaction potential between omecamtiv mecarbil and rosuvastatin,a BCRP substrate,with a clinical study in healthy subjects and using a physiologically‐based pharmacokinetic model

Omecamtiv mecarbil (OM) is a novel cardiac myosin activator in development for the treatment of heart failure. In vitro, OM is an inhibitor of BCRP. Rosuvastatin, a BCRP substrate, is one of the most commonly prescribed medications in patients with heart failure. The potential for a pharmacokinetic (PK) drug‐drug interaction (DDI) was investigated, specifically to determine whether a single 50 mg dose of OM would impact the PKs of a single 10 mg dose of rosuvastatin in an open‐label study in 14 healthy subjects. The ratios of the geometric least‐square means (90% confidence intervals [CIs]) of rosuvastatin co‐administered with OM compared to rosuvastatin alone were 127.1% (90% CI 113.8–141.9), 132.8% (90% CI 120.7–146.1), and 154.2% (90% CI 132.8–179.1) for area under the plasma‐concentration time curve from time zero to infinity (AUC_inf), area under the plasma‐concentration time curve from time zero to time of last quantifiable concentration (AUC_last), and maximum observed plasma concentration (C_max), respectively. Whereas the DDI study with rosuvastatin was conducted with the co‐administration of a single dose of OM, in the clinical setting, patients receive OM at doses of 25, 37.5, or 50 mg twice daily (b.i.d.). Hence, to extrapolate the results of the DDI study to a clinically relevant scenario of continuous b.i.d. dosing with OM, physiologically‐based pharmacokinetic (PBPK) modeling was performed to explore the potential of BCRP inhibition following continuous b.i.d. dosing of OM at the highest 50 mg dose. Modeling results indicated that following 50 mg b.i.d. dosing of OM, the predicted ratios of the geometric means (90% CIs) for rosuvastatin AUC_inf and C_max were 1.18 (90% CI 1.16–1.20) and 2.04 (90% CI 1.99–2.10), respectively. Therefore, these results suggest that OM, following multiple dose administration, is a weak inhibitor of BCRP substrates and is in accordance with that observed in the single dose OM DDI clinical study.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Omecamtiv mecarbil (OM) is a cardiac myosin activator and is currently under investigation for the treatment of heart failure with reduced ejection fraction.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study investigated the drug‐drug interaction (DDI) potential of OM on the pharmacokinetics of rosuvastatin, a BCRP substrate, using a clinical study and a physiologically‐based pharmacokinetic (PBPK) modeling approach.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

The clinical study and PBPK modeling analyses confirm that OM is expected to be a weak inhibitor of BCRP in the clinical setting.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

This study highlights the DDI potential of single doses of OM for BCRP substrates from a clinical study and demonstrates the importance of the PBPK modeling approach to investigate DDI effects following multiple doses of OM at therapeutic concentrations.     

Model‐based assessments of CYP3A‐mediated drug‐drug interaction risk of milademetan

Milademetan is a small‐molecule inhibitor of murine double minute 2 (MDM2) that is in clinical development for advanced solid tumors and hematological cancers, including liposarcoma and acute myeloid leukemia. Milademetan is a CYP3A and P‐glycoprotein substrate and moderate CYP3A inhibitor. The current study aims to understand the drug‐drug interaction (DDI) risk of milademetan as a CYP3A substrate during its early clinical development. A clinical DDI study of milademetan ({"type":"clinical-trial","attrs":{"text":"NCT03614455","term_id":"NCT03614455"}}NCT03614455) showed that concomitant administration of single‐dose milademetan with the strong CYP3A inhibitor itraconazole or posaconazole increased milademetan mean area under the curve from zero to infinity (AUC_inf) by 2.15‐fold (90% confidence interval [CI], 1.98–2.34) and 2.49‐fold (90% CI, 2.26–2.74), respectively, supporting that the milademetan dose should be reduced by 50% when concomitantly administered with strong CYP3A inhibitors. A physiologically‐based pharmacokinetic (PBPK) model of milademetan was subsequently developed to predict the magnitude of CYP3A‐mediated DDI potential of milademetan with moderate CYP3A inhibitors. The PBPK model predicted an increase in milademetan exposure of 1.72‐fold (90% CI, 1.69–1.76) with fluconazole, 1.91‐fold (90% CI, 1.83–1.99) with erythromycin, and 2.02‐fold (90% CI, 1.93–2.11) with verapamil. In addition, it estimated that milademetan’s original dose (160 mg once daily) could be resumed from its half‐reduced dose 3 days after discontinuation of concomitant strong CYP3A inhibitors. The established PBPK model of milademetan was qualified and considered to be robust enough to support continued development of milademetan.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Milademetan is a CYP3A and P‐gp substrate and moderate CYP3A inhibitor. Evaluation of drug‐drug interaction (DDI) risk of milademetan by combining clinical studies and physiologically‐based pharmacokinetic (PBPK) modeling has not previously been described.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Will milademetan PK be affected by the concomitant administration of strong or moderate CYP3A inhibitors? When can the original dose of milademetan be resumed after the discontinuation of strong CYP3A inhibitors?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This study illustrates the use of a clinical DDI study and PBPK modeling in the early clinical development of milademetan to assess DDI risks in scenarios that have not yet been tested clinically at the time.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

PBPK modeling integrates in vitro and clinical data to facilitate the mechanistic understanding of PKs. Recommendations from PBPK modeling can support the design of clinical studies for the investigation of DDIs.     

Safety,tolerability, and pharmacokinetics of oral baicalein tablets in healthy Chinese subjects: A single‐center,randomized, double‐blind,placebo‐controlled multiple‐ascending‐dose study

Baicalein is a biologically important flavonoid in extracted from the Scutellaria baicalensis Georgi, which can effectively inhibit the influenza virus. This study aimed to analyze the safety and pharmacokinetic (PK) characteristics of baicalein tablets in healthy Chinese subjects and provide more information for phase II clinical trials. In this multiple‐ascending‐dose placebo‐controlled trial, 36 healthy subjects were randomized to receive 200, 400, and 600 mg of baicalein tablet or placebo once daily on day 1 and day 10, 3 times daily on days 4–9. All groups were intended to produce safety and tolerability outcomes (lowest dose first). Blood and urine samples were collected from subjects in the 600 mg group for baicalein PK analysis. Our study had shown that Baicalein tablet was generally safe and well‐tolerated. All adverse events were mild and resolved without any intervention except one case of fever reported in the 600 mg group, which was considered as moderate but not related with baicalein as judged by the investigator. Oral baicalein tablets were rapidly absorbed with peak plasma levels being reached within 2 h after multiple administration. The highest urinary excretion of baicalein and its metabolites peaked in 2 h, followed by 12 h, with a double peak trend.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Many studies have shown that baicalin has an anti‐influenza effect in cell and animal experiments. The primary mechanism of action is that baicalein has a strong inhibitory effect on the sialidase of the influenza virus.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study aimed to analyze the safety and pharmacokinetic (PK) characteristics of baicalein tablets in healthy Chinese subjects and provide more information for phase II clinical trials.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Our study results have shown that baicalein tablets were administered multiple times within the studied dose range were safe and well‐tolerated in healthy Chinese subjects with no serious or severe adverse effects. The highest urinary excretion of baicalein and its metabolites peaked in 2 h, followed by 12 h, with a double peak trend. Oral baicalein tablets were rapidly absorbed with peak plasma levels reached within 2 h after multiple administration.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Our study addresses the safety outcomes of baicalein tablets and emphasizes the PKs of baicalein, which provides a better understanding and a scientific basis of the clinical application of baicalein for further evaluation.     

Exploration for the effect of renal function and renal replacement therapy on pharmacokinetics of remdesivir and GS‐441524 in patients with COVID‐19: A limited case series

Remdesivir, an antiviral agent for the treatment of coronavirus disease 2019 (COVID‐19), is metabolized intracellularly, with these metabolites eliminated predominantly in urine. Because of a lack of safety and pharmacokinetic (PK) data, remdesivir is not currently recommended for patients with estimated glomerular filtration rate less than 30 ml/min/1.73 m² and those on hemodialysis. This study evaluated the PKs of remdesivir and its metabolite, GS‐441524, in patients with COVID‐19 who were and were not receiving renal replacement therapy (RRT). This study enrolled two patients with normal renal function, two with impaired renal function not receiving RRT, two receiving continuous RRT (CRRT), and three undergoing intermittent hemodialysis (IHD). Patients were administered 200 mg remdesivir on the first day, followed by 100 mg/day for 5–10 days. Serial blood samples were collected for PK analysis, and PK parameters were assessed by a noncompartmental method. Systemic exposure to remdesivir was higher in patients with impaired renal function and those receiving CRRT than in patients with normal renal function, but was similar in patients undergoing IHD and those with normal renal function. By contrast, systemic exposure to GS‐441524 was highest in patients undergoing IHD, followed by patients with impaired renal function and those receiving CRRT, and lowest in patients with normal renal function. The PK profiles of remdesivir and GS‐441524 varied according to renal function and RRT. The impact of PK changes of remdesivir and its metabolite on safety and efficacy should be considered when administering remdesivir to patients with COVID‐19 with renal impairment.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Renal impairment can alter systemic exposure to remdesivir and its metabolites. Although the pharmacokinetics (PKs) of remdesivir and its metabolite have been assessed in patients with coronarvirus disease 2019 (COVID‐19) with reduced renal function, the use of remdesivir in patients with an estimated glomerular filtration rate less than 30 ml/min/1.73 m² and those on hemodialysis is still limited due to a lack of information.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study evaluated the effect of renal function and renal replacement therapy on the PKs of remdesivir and its metabolite, GS‐441524, in patients with COVID‐19.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Systemic exposure to remdesivir was higher in patients with impaired renal function and those receiving continuous renal replacement therapy (CRRT) than in patients with normal renal function, whereas exposure was similar in patients undergoing intermittent hemodialysis (IHD) and those with normal renal function. By contrast, systemic exposure to GS‐441524 was highest in patients undergoing IHD, followed by patients with impaired renal function and those receiving CRRT, and lowest in patients with normal renal function.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

The results of this study may enable remdesivir dosage selection for patients with COVID‐19 with renal impairment who have great demand for remdesivir use. Despite this study including a small number of patients, small‐sized studies have advantages, as their results can be generated and shared rapidly, especially during the COVID‐19 pandemic.     

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.     

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.     

Translational and pharmacokinetic‐pharmacodynamic application for the clinical development of GDC‐0334, a novel TRPA1 inhibitor

GDC‐0334 is a novel small molecule inhibitor of transient receptor potential cation channel member A1 (TRPA1), a promising therapeutic target for many nervous system and respiratory diseases. The pharmacokinetic (PK) profile and pharmacodynamic (PD) effects of GDC‐0334 were evaluated in this first‐in‐human (FIH) study. A starting single dose of 25 mg was selected based on integrated preclinical PK, PD, and toxicology data following oral administration of GDC‐0334 in guinea pigs, rats, dogs, and monkeys. Human PK and PK‐PD of GDC‐0334 were characterized after single and multiple oral dosing using a population modeling approach. The ability of GDC‐0334 to inhibit dermal blood flow (DBF) induced by topical administration of allyl isothiocyanate (AITC) was evaluated as a target‐engagement biomarker. Quantitative models were developed iteratively to refine the parameter estimates of the dose‐concentration‐effect relationships through stepwise estimation and extrapolation. Human PK analyses revealed that bioavailability, absorption rate constant, and lag time increase when GDC‐0334 was administered with food. The inhibitory effect of GDC‐0334 on the AITC‐induced DBF biomarker exhibited a clear sigmoid‐Emax relationship with GDC‐0334 plasma concentrations in humans. This study leveraged emerging preclinical and clinical data to enable iterative refinement of GDC‐0334 mathematical models throughout the FIH study for dose selection in subsequent cohorts throughout the study. Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

GDC‐0334 is a novel, small molecule TRPA1 inhibitor and a pharmacokinetic‐pharmacodynamic (PK‐PD) modeling strategy could be implemented in a systematic and step‐wise manner to build and learn from emerging data for early clinical development.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Can noncompartmental and population‐based analyses be used to describe the PK and PD characteristics of GDC‐0334 in preclinical and clinical studies?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

GDC‐0334 exposure generally increased with dose in rats, dogs, and monkeys. The starting dose (25 mg) in the clinical study was determined based on the preclinical data. GDC‐0334 exhibited linear PK in humans and the bioavailability was increased with food. The inhibitory effect of GDC‐0334 on dermal blood flow induced by the TRPA1 agonist allyl isothiocyanate in humans indicates a clear PK‐PD relationship.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

The models developed based on TRPA1 agonist‐induced dermal blood flow inhibition data can be used to predict PK‐PD relationships in future preclinical and clinical studies evaluating new drug entities that target TRPA1.     

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.     

Pharmacokinetic/pharmacodynamic modeling for dose selection for the first‐in‐human trial of the activated Factor XII inhibitor garadacimab (CSL312)

Factor XII (FXII) is a serine protease involved in multiple cascades, including the kallikrein–kinin system. It may play a role in diseases in which the downstream cascades are dysregulated, such as hereditary angioedema. Garadacimab (CSL312) is a first‐in‐class, fully human, monoclonal antibody targeting activated FXII (FXIIa). We describe how translational pharmacokinetic (PK) and pharmacodynamic (PD) modeling enabled dose selection for the phase I, first‐in‐human trial of garadacimab. The PK/PD data used for modeling were derived from preclinical PK/PD and safety studies. Garadacimab plasma concentrations rose with increasing dose, and clear dose‐related PD effects were observed (e.g., a mechanism‐based prolongation of activated partial thromboplastin time). The PK/PD profile from cynomolgus monkeys was used to generate minimal physiologically‐based pharmacokinetic (mPBPK) models with target‐mediated drug disposition (TMDD) for data prediction in cynomolgus monkeys. These models were later adapted for prediction of human data to establish dose selection. Based on the final mPBPK model with TMDD and assuming a weight of 70 kg for an adult human, a minimal inhibition (<10%) of FXIIa with a starting dose of 0.1 mg/kg garadacimab and a near maximal inhibition (>95%) at 10 mg/kg garadacimab were predicted. The phase I study is complete, and data on exposure profiles and inhibition of FXIIa‐mediated kallikrein activity observed in the trial support and validate these simulations. This emphasizes the utility and relevance of translational modeling and simulation in drug development.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Models based on physiology and mechanisms of action can be highly useful in translating pharmacokinetic/pharmacodynamic (PK/PD) data from animal studies to expectations in humans.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This analysis sought to select doses for investigation in a phase I, first‐in‐human trial of garadacimab (CSL312), a first‐in‐class, fully human, immunoglobulin G4 monoclonal antibody that targets FXIIa.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This analysis demonstrated how a mechanism‐based PK/PD model describing the relationship between drug administration and pharmacologic response observed in cynomolgus monkeys was generated and extrapolated to select doses for investigation in a phase I, first‐in‐human trial of garadacimab. The detailed explanation of the modeling and extrapolation methodology used in this study provides guidance to future researchers selecting doses for phase I, first‐in‐human trials of monoclonal antibodies.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

This study highlights the importance and utility of insightful, physiologic, and mechanistic mathematical modeling in conjunction with robust animal data for translation of PK/PD and accurate prediction of first‐in‐human dosing for clinical trials.     

First‐in‐human study of the safety,tolerability, pharmacokinetics,and pharmacodynamics of ALPN‐101, a dual CD28/ICOS antagonist,in healthy adult subjects

ALPN‐101 (ICOSL vIgD‐Fc) is an Fc fusion protein of a human inducible T cell costimulatory ligand (ICOSL) variant immunoglobulin domain (vIgD) designed to inhibit the cluster of differentiation 28 (CD28) and inducible T cell costimulator (ICOS) pathways simultaneously. A first‐in‐human study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of ALPN‐101 in healthy adult subjects. ALPN‐101 was generally well‐tolerated with no evidence of cytokine release, clinically significant immunogenicity, or severe adverse events following single subcutaneous (SC) doses up to 3 mg/kg or single intravenous (IV) doses up to 10 mg/kg or up to 4 weekly IV doses of up to 1 mg/kg. ALPN‐101 exhibited a dose‐dependent increase in exposure with an estimated terminal half‐life of 4.3–8.6 days and SC bioavailability of 60.6% at 3 mg/kg. Minimal to modest accumulation in exposure was observed with repeated IV dosing. ALPN‐101 resulted in a dose‐dependent increase in maximum target saturation and duration of high‐level target saturation. Consistent with its mechanism of action, ALPN‐101 inhibited cytokine production in whole blood stimulated by Staphylococcus aureus enterotoxin B ex vivo, as well as antibody responses to keyhole limpet hemocyanin immunization, reflecting immunomodulatory effects upon T cell and T‐dependent B cell responses, respectively. In conclusion, ALPN‐101 was well‐tolerated in healthy subjects with dose‐dependent PK and PD consistent with the known biology of the CD28 and ICOS costimulatory pathways. Further clinical development of ALPN‐101 in inflammatory and/or autoimmune diseases is therefore warranted.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

ALPN‐101 is an Fc fusion protein of a human inducible T cell costimulatory ligand variant immunoglobulin domain designed to block the cluster of differentiation 28 CD28) and inducible T cell costimulator (ICOS) simultaneously, thereby inhibiting two key costimulatory pathways in T lymphocytes. Although inhibitors of each pathway alone have been studied in humans, this is the first assessment of a dual antagonist in humans.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This first‐in‐human study assessed the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of ALPN‐101 in healthy subjects. The PK‐PD relationship was evaluated.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

ALPN‐101 demonstrated favorable safety and tolerability profiles and dose‐dependent PK and PD in healthy subjects. The dose‐PK‐PD analysis showed that the target saturation of ALPN‐101 can be well‐predicted based on PK data and the observed PD effects are consistent with the known biology of the CD28 and ICOS pathways.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

The results support further clinical development of ALPN‐101 and the PK‐PD relationship will guide dosing regimens in autoimmune and inflammatory diseases.     

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.     

First‐in‐human trial assessing the pharmacokinetic‐pharmacodynamic profile of a novel recombinant human chorionic gonadotropin in healthy women and men of reproductive age

The purpose of this first‐in‐human trial was to examine the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of a novel recombinant human chorionic gonadotropin (rhCG; FE 999302, choriogonadotropin beta) to support its clinical development for various therapeutic indications. The single and multiple dose PK of choriogonadotropin beta (CG beta) were evaluated in women and the single dose PK and PD of CG beta were compared to those of CG alfa in men. CG beta was safe and well‐tolerated in all 84 healthy subjects. In women, the area under the curve (AUC) and the peak serum concentration (C_max) increased approximately dose proportionally following single and multiple doses of CG beta. The apparent clearance (CL/F) was ~ 0.5 L/h, the mean terminal half‐life (t_½) ~ 45 h and the apparent distribution volume (V_z/F) ~ 30 L. After single administration in men, the mean AUC was 1.5‐fold greater for CG beta than for CG alfa. Mean C_max and V_z/F were comparable for the 2 preparations. In accordance with the differences in AUC, the CL/F was lower for CG beta (CL/F 0.5 vs. 0.8 L/h), explained by a longer t_½ (47 vs. 32 h). Serum testosterone levels induced by a single dose rhCG reflected the PK profiles with a slight delay, resulting in 59% higher AUC for CG beta. The PK parameters for CG beta were comparable in men and in women. In conclusion, the PK differs between the two rhCG preparations, causing higher exposure and a higher PD response for CG beta, which may require relatively lower therapeutic doses.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Recombinant human chorionic gonadotropin (hCG) is indicated for the treatment of male or female infertility and administered by single or multiple subcutaneous injections.

• WHAT QUESTION DID THIS STUDY ADDRESS?

A new recombinant hCG (rhCG; choriogonadotropin [CG] beta) produced by a human‐derived cell line (PER.C6) is currently in clinical development. The amino acid sequence of the α‐ and β‐chains are identical to the natural sequences and also to that of rhCG expressed by Chinese Hamster Ovary (CHO) cell line (CG alfa), but the glycosylation provided by the PER.C6 and CHO cells is different. In this trial, the pharmacokinetics (PK) of choriogonadotropin beta were assessed in women and men and the PKs and pharmacodynamics (PDs) were compared in men to those of CG alfa.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

It is concluded that the PK of the two rhCG preparations are different, due to a slower clearance of CG beta resulting in a higher PD response.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Further development of CG beta may require lower doses of this potent hCG compared to current therapeutic hCG preparations.     

Effects of elagolix on the pharmacokinetics of omeprazole and its metabolites in healthy premenopausal women

This study evaluated the effect of repeated doses of elagolix on the pharmacokinetics (PK) of omeprazole and its metabolites in healthy premenopausal female subjects. Adult premenopausal female subjects (N = 20) received a single oral dose of omeprazole (40 mg) on day 1 and day 11 and oral doses of elagolix (300 mg) twice‐daily on days 3–11. Serial blood samples for assay of omeprazole and its metabolites were collected for 24 h after dosing on days 1 and 11. PK parameters were calculated for omeprazole, 5‐hydroxyomeprazole and omeprazole sulfone; and were compared between day 1 and day 11. Pharmacogenetic testing was performed for CYP2C19 variant alleles and the results were used to compare the magnitude of elagolix–omeprazole drug–drug interaction (DDI) between the different genotype subgroups. Administration of elagolix 300 mg twice‐daily for 9 days increased omeprazole exposure by 1.8‐fold and decreased the metabolite‐to‐parent ratio for 5‐hydroxyomeprazole by ~60%. Conversely, there was an increase in the metabolite‐to‐parent ratio for omeprazole sulfone by 25%. Elagolix increased omeprazole exposures by 2‐ to 2.5‐fold in CYP2C19 extensive (EM) and intermediate (IM) metabolizer subjects, but decreased omeprazole exposures by 40% in poor metabolizer subjects. Exposures of 5‐hydroxyomeprazole decreased by 20%–30% in all genotype subgroups, and omeprazole sulfone exposures increased by ~3‐fold in EM and IM subjects. Elagolix is a weak inhibitor of CYP2C19 and exposure of CYP2C19 substrates may be increased upon coadministration with elagolix. Omeprazole may exhibit drug interactions due to multiple mechanisms other than CYP2C19‐mediated metabolism; complicating the interpretation of results from omeprazole DDI studies.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Elagolix is an inhibitor of P‐glycoprotein (P‐gp) and a weak‐to‐moderate inducer of cytochrome P450 3A (CYP3A4). In vitro, elagolix was identified as a possible inhibitor of CYP2C19 with potential to increase plasma concentrations of drugs that are substrates of CYP2C19 if they are coadministered with elagolix.

• WHAT QUESTION DID THIS STUDY ADDRESS?

What are the effects of elagolix on the pharmacokinetics of omeprazole and its metabolites in healthy subjects with different CYP2C19 genotypes and are P‐gp and/or CYP3A4 potentially involved in the interaction between elagolix and omeprazole?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This study suggests that elagolix is a weak inhibitor of CYP2C19 and exposure of other CYP2C19 substrates may be increased upon coadministration with elagolix. These results also suggest P‐gp, CYP3A4, and/or another unknown mechanism may also be potential mechanisms for drug interactions with omeprazole.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Future DDI studies with omeprazole as a CYP2C19 substrate should consider that omeprazole may exhibit complex drug interactions due to multiple mechanisms mediating metabolism and transport, which may confound the interpretation of study results.     

Immune‐viral dynamics modeling for SARS‐CoV‐2 drug development

Coronavirus disease 2019 (COVID‐19) global pandemic is caused by severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2) viral infection, which can lead to pneumonia, lung injury, and death in susceptible populations. Understanding viral dynamics of SARS‐CoV‐2 is critical for development of effective treatments. An Immune‐Viral Dynamics Model (IVDM) is developed to describe SARS‐CoV‐2 viral dynamics and COVID‐19 disease progression. A dataset of 60 individual patients with COVID‐19 with clinical viral load (VL) and reported disease severity were assembled from literature. Viral infection and replication mechanisms of SARS‐CoV‐2, viral‐induced cell death, and time‐dependent immune response are incorporated in the model to describe the dynamics of viruses and immune response. Disease severity are tested as a covariate to model parameters. The IVDM was fitted to the data and parameters were estimated using the nonlinear mixed‐effect model. The model can adequately describe individual viral dynamics profiles, with disease severity identified as a covariate on infected cell death rate. The modeling suggested that it takes about 32.6 days to reach 50% of maximum cell‐based immunity. Simulations based on virtual populations suggested a typical mild case reaches VL limit of detection (LOD) by 13 days with no treatment, a moderate case by 17 days, and a severe case by 41 days. Simulations were used to explore hypothetical treatments with different initiation time, disease severity, and drug effects to demonstrate the usefulness of such modeling in informing decisions. Overall, the IVDM modeling and simulation platform enables simulations for viral dynamics and treatment efficacy and can be used to aid in clinical pharmacokinetic/pharmacodynamic (PK/PD) and dose‐efficacy response analysis for COVID‐19 drug development.

Study Highlight

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Several viral dynamics models have been developed to describe severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2) viral infection. However, the connections among SARS‐CoV‐2 viral dynamics, immune response, and coronavirus disease 2019 (COVID‐19) disease severity are still not established, and a model that incorporate these mechanisms and can be readily applied to inform drug development is not available.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study successfully developed the Immune‐Viral Dynamics Model (IVDM) for SARS‐CoV‐2 viral infection and COVID‐19 disease progression based on current biological mechanisms of SARS‐CoV‐2 viral infection. The model parameters are informed with a large public clinical dataset from literature. Viral infection and replication mechanisms of SARS‐CoV‐2, viral‐induced cell death, and time‐dependent immune response are incorporated in the model to describe the dynamics of viruses and immune response. Simulations are performed to explore possible clinical outcomes in response to different treatment options.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

The IVDM parameters are adequately informed and can well describe the individual viral load profiles from the dataset. Estimated time‐dependent immune response parameters suggests a potentially important role of adaptive immunity in controlling SARS‐CoV‐2 viral infection by actively killing infected cells. Disease severities are identified as a strong covariate for infected cell death rate, suggesting that slow immune killing of infected cell might prolong viral shedding and increase the risk of progression into severe disease.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

The study also shows that the IVDM‐based modeling and simulations can be used to optimize treatment options to achieve clinical end points by simulating treatment effects and exploring optimal treatment options of SARS‐CoV‐2 antivirals. The IVDM can be readily integrated with population pharmacokinetic (PK) model of COVID‐19 study drugs to drive clinical trial simulations. It might serve as a useful tool to help develop treatment and prophylactic drugs for COVID‐19.     

Model‐based dose selection to inform translational clinical oncology development of WNT974, a first‐in‐class Porcupine inhibitor

WNT974 is a potent, selective, and orally bioavailable first‐in‐class inhibitor of Porcupine, a membrane‐bound O‐acyltransferase required for Wnt secretion, currently under clinical development in oncology. A phase I clinical trial is being conducted in patients with advanced solid tumors. During the dose‐escalation part, various dosing regimens, including once or twice daily continuous and intermittent dosing at a dose range of 5–45 mg WNT974 were studied, however, the protocol‐defined maximum tolerated dose (MTD) was not established based on dose‐limiting toxicity. To assist in the selection of the recommended dose for expansion (RDE), a model‐based approach was utilized. It integrated population pharmacokinetic (PK) modeling and exposure–response analyses of a target‐inhibition biomarker, skin AXIN2 mRNA expression, and the occurrence of the adverse event, dysgeusia. The target exposure range of WNT974 that would provide a balance between target inhibition and tolerability was estimated based on exposure–response analyses. The dose that was predicted to yield an exposure within the target exposure range was selected as RDE. This model‐based approach integrated PK, biomarker, and safety data to determine the RDE and represented an alternative as opposed to the conventional MTD approach for selecting an optimal biological dose. The strategy can be broadly applied to select doses in early oncology trials and inform translational clinical oncology drug development.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

WNT974 is a potent, selective, and orally bioavailable first‐in‐class inhibitor of Porcupine, a membrane‐bound O‐acyltransferase required for Wnt secretion, currently under clinical development in oncology. The conventional approach for dose selection in small‐molecule oncology trials is based on the maximum tolerated dose (MTD).

• WHAT QUESTION DID THIS STUDY ADDRESS?

How to inform the clinical development path and selection of the recommended dose for expansion (RDE) for a first‐in‐class oncology molecule.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

A model‐based approach can be effectively used to integrate pharmacokinetic (PK), pharmacodynamic and safety data and inform RDE selection in oncology drug development.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

This model‐based approach integrated population PK and exposure–response analyses of biomarker and safety to determine the RDE, rather than the conventional MTD approach. The strategy can be applied to support translational clinical oncology development, and dose selection in early oncology trials to inform later phase clinical development and study design.     

Erythropoiesis‐stimulating agents and incident malignancy in chronic kidney and end‐stage renal disease: A population‐based study

Research investigating incident malignancy risk in erythropoiesis‐stimulating agent (ESA) users with chronic kidney disease (CKD) is lacking. We aimed to compare the incident cancer risk between ESA and non‐ESA users with CKD or end‐stage renal disease (ESRD). In this retrospective cohort study, all adults newly diagnosed with CKD or ESRD between 2000 and 2012 were enrolled. The study population included 98,748 patients. After case–control matching, 7115 patients were included. The defined daily dose (DDD) of ESA was used as the unit for measuring the amount of ESA prescribed. The primary outcome was the risk of incident malignancy. The secondary outcomes were incident malignancy risk in different tertiles of cumulative ESA doses and the risk of different types of cancers. The risk of incident malignancy was 1.84 times higher with ESA treatment than without ESA treatment (hazard ratio, 1.84; 95% confidence interval, 1.43–2.36; p < 0.001). The malignancy risk was positively correlated with the cumulative dose of ESA (p‐for‐trend = 0.001) and a significant difference in the high annual cumulative DDD cohort (hazard ratio [HR], 2.39; 95% confidence interval [CI], 1.76–3.25; p < 0.001). The risk of genitourinary malignancy was 12.55 times higher with ESA treatment than without ESA treatment (HR, 12.55; 95% CI, 5.78–27.24; p < 0.001). ESA usage is associated with an increased risk of malignancy, particularly genitourinary cancers, in patients with CKD or ESRD. Clinicians should be aware of the occurrence of malignancy, and keep ESA dosage as low as possible.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Erythropoiesis‐stimulating agents (ESAs) are known to impact the outcomes of pre‐existing cancer.

• WHAT QUESTION DID THIS STUDY ADDRESS?

The de novo cancer risk for users of ESAs has not been fully examined. We aimed to compare the incident cancer risk between ESA and non‐ESA users with chronic kidney disease (CKD) or end‐stage renal disease (ESRD).

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Users of erythropoiesis‐stimulating agents had 1.84 times increasing risk of overall de novo cancer, and a 12‐fold risk of genitourinary tract cancer. The risk of overall de novo cancer increased proportionally with the dosage of ESAs.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Clinicians should more aggressively taper the dosage of ESAs while achieving the target hemoglobin level. Patients with CKD or ESRD treated with ESAs should be more alert to occurrence of malignancies, particularly genitourinary tract cancers.     

A randomized,placebo‐controlled study to evaluate safety and pharmacokinetics of inhaled ribavirin

Ribavirin is an inosine monophosphate dehydrogenase inhibitor. Studies suggest ribavirin aerosol could be a safe and efficacious treatment option in the fight against coronaviruses. However, current treatment is long (12–18 h per day, 3–7 days), limiting clinical utility. A reduction in treatment time would reduce treatment burden. We aimed to evaluate safety and pharmacokinetics (PK) of four, single‐dose regimens of ribavirin aerosol in healthy volunteers. Thirty‐two subjects were randomized, to four cohorts of aerosolized ribavirin (active) or placebo. Cohort 1 received 50 mg/ml ribavirin/placebo (10 ml total volume); cohort 2, 50 mg/ml ribavirin/placebo (20 ml total volume); cohort 3, 100 mg/ml ribavirin/placebo (10 ml total volume); and cohort 4, 100 mg/ml ribavirin/placebo (20 ml total volume). Intense safety monitoring and PK sampling took place on days 1, 2, 3, and 40. Subjects were (mean ± SD, active vs. placebo) aged 57 ± 4.5 vs. 60 ± 2.5 years; 83% vs. 88% were female; and 75% vs. 50% were Caucasian. Some 12.5% (3/24) and 25% (2/8) experienced at least one treatment‐emergent adverse event (TEAE) (two moderate; five mild) in the active and placebo groups, respectively. No clinically significant safety concerns were reported. Mean maximum observed concentration (C _max) and area under the curve (AUC) values were higher in cohort 4, whereas cohorts 2 and 3 showed similar PK values. Ribavirin absorption reached C _max within 2 h across cohorts. Four single‐dose regimens of ribavirin aerosol demonstrated systemic exposure with minimal systemic effects. Results support continued clinical development of ribavirin aerosol as a treatment option in patients with coronaviruses.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Ribavirin is an inosine monophosphate dehydrogenase inhibitor, an enzyme in the synthesis of purine nucleotides, and a broad‐spectrum antiviral agent. It is approved in the USA and Canada for the treatment of lower respiratory tract infections in hospitalized infants and children due to the respiratory syncytial virus (RSV). Early data suggest that ribavirin is safe and effective in the treatment of COVID‐19. However, RSV treatment procedures are lengthy (12–18 h per day for 3−7 days), limiting wider clinical utility. A shorter treatment time, while maintaining safety and efficacy, is required for ribavirin to become a practical treatment option for coronaviruses.

• WHAT QUESTION DID THIS STUDY ADDRESS?

We performed this study to evaluate the safety and pharmacokinetics (PK) of four, single‐dose, clinically relevant regimens of ribavirin aerosol in healthy volunteers. Doses ranged from 50 to 100 mg/ml, delivered in a single inhalation of either 20 or 40 min duration.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Our results showed that four single‐dose regimens of ribavirin aerosol were safe and well‐tolerated, without dose‐limiting toxicities, and a comparable safety profile to placebo. The PK were linear and well‐tolerated across the four single‐dose regimens, demonstrating systemic exposure with minimal systemic effects.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

In the context of coronaviruses, delivery of drug directly to the site of infection (the respiratory tract) is key. As such, these results support the continued clinical development of ribavirin aerosol as a new treatment option in patients with coronaviruses.     

Hepatoprotective effects of semaglutide,lanifibranor and dietary intervention in the GAN diet‐induced obese and biopsy‐confirmed mouse model of NASH

Non‐alcoholic steatohepatitis (NASH) has emerged as a major challenge for public health because of high global prevalence and lack of evidence‐based therapies. Most animal models of NASH lack sufficient validation regarding disease progression and pharmacological treatment. The Gubra‐Amylin NASH (GAN) diet‐induced obese (DIO) mouse demonstrate clinical translatability with respect to disease etiology and hallmarks of NASH. This study aimed to evaluate disease progression and responsiveness to clinically effective interventions in GAN DIO‐NASH mice. Disease phenotyping was performed in male C57BL/6J mice fed the GAN diet high in fat, fructose, and cholesterol for 28–88 weeks. GAN DIO‐NASH mice with biopsy‐confirmed NASH and fibrosis received low‐caloric dietary intervention, semaglutide (30 nmol/kg/day, s.c.) or lanifibranor (30 mg/kg/day, p.o.) for 8 and 12 weeks, respectively. Within‐subject change in nonalcoholic fatty liver disease (NAFLD) Activity Score (NAS) and fibrosis stage was evaluated using automated deep learning‐based image analysis. GAN DIO‐NASH mice showed clear and reproducible progression in NASH, fibrosis stage, and tumor burden with high incidence of hepatocellular carcinoma. Consistent with clinical trial outcomes, semaglutide and lanifibranor improved NAS, whereas only lanifibranor induced regression in the fibrosis stage. Dietary intervention also demonstrated substantial benefits on metabolic outcomes and liver histology. Differential therapeutic efficacy of semaglutide, lanifibranor, and dietary intervention was supported by quantitative histology, RNA sequencing, and blood/liver biochemistry. In conclusion, the GAN DIO‐NASH mouse model recapitulates various histological stages of NASH and faithfully reproduces histological efficacy profiles of compounds in advanced clinical development for NASH. Collectively, these features highlight the utility of GAN DIO‐NASH mice in preclinical drug development.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Given the lack of effective therapies for non‐alcoholic steatohepatitis (NASH), there is a need to establish animal models that better predict clinical outcomes. A clear limitation in preclinical drug discovery is the lack of translational animal models, which recapitulate the various stages of NASH, and faithfully reproduce the individual efficacy profile of current clinical interventions.

• WHAT QUESTION DID THIS STUDY ADDRESS?

The study addressed disease progression and validated treatment outcomes of dietary intervention and compounds in advanced clinical development in the GAN diet‐induced obese (DIO) and biopsy‐confirmed mouse model of NASH.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

The GAN DIO‐NASH mouse model presents with metabolic, biochemical, and histological hallmarks of progressive NASH, characterized by deteriorating liver fibrosis and increasing hepatocellular carcinoma burden. The differential clinical histological efficacy profiles of low‐caloric dietary intervention, semaglutide, and lanifibranor were closely reproduced in the model.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

This preclinical model will be instrumental for probing efficacy of novel drugs targeting NASH and advancing novel drug therapies from preclinical to clinical development.