Physiologically‐based pharmacokinetic model‐based translation of OATP1B‐mediated drug–drug interactions from coproporphyrin I to probe drugs

The accurate prediction of OATP1B‐mediated drug–drug interactions (DDIs) is challenging for drug development. Here, we report a physiologically‐based pharmacokinetic (PBPK) model analysis for clinical DDI data generated in heathy subjects who received oral doses of cyclosporin A (CysA; 20 and 75 mg) as an OATP1B inhibitor, and the probe drugs (pitavastatin, rosuvastatin, and valsartan). PBPK models of CysA and probe compounds were combined assuming inhibition of hepatic uptake of endogenous coproporphyrin I (CP‐I) by CysA. In vivo K_i of unbound CysA for OATP1B (K_i,OATP1B), and the overall intrinsic hepatic clearance per body weight of CP‐I (CL_int,all,unit) were optimized to account for the CP‐I data (K_i,OATP1B, 0.536 ± 0.041 nM; CL_int,all,unit, 41.9 ± 4.3 L/h/kg). DDI simulation using K_i,OATP1B reproduced the dose‐dependent effect of CysA (20 and 75 mg) and the dosing interval (1 and 3 h) on the time profiles of blood concentrations of pitavastatin and rosuvastatin, but DDI simulation using in vitro K_i,OATP1B failed. The Cluster Gauss–Newton method was used to conduct parameter optimization using 1000 initial parameter sets for the seven pharmacokinetic parameters of CP‐I (β, CL_{int, all}, F_aF_g, R_dif, f_bile, f_syn, and v _syn), and K_i,OATP1B and K_i,MRP2 of CysA. Based on the accepted 546 parameter sets, the range of CL_{int, all} and K_i,OATP1B was narrowed, with coefficients of variation of 12.4% and 11.5%, respectively, indicating that these parameters were practically identifiable. These results suggest that PBPK model analysis of CP‐I is a promising translational approach to predict OATP1B‐mediated DDIs in drug development.

Abbreviations

AUC

area under the concentration time curve

AUCR

area under the concentration time curve ratio (rifampicin/control)

BCRP

breast cancer resistance protein

CGNM

Cluster Gauss–Newton method

C_max

maximum concentration

CV

coefficient of variation

CysA

cyclosporin A

DDI

drug–drug interaction

K_i

inhibition constant

MRP2

multidrug resistance protein 2

OATP1B1

organic anion transporting polypeptide 1B1

OATP1B3

organic anion transporting polypeptide 1B3

PBPK

physiologically‐based pharmacokinetic

T_max

time to maximum concentration

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Physiologically‐based pharmacokinetic (PBPK) models are used to predict transporter‐mediated drug–drug interactions (DDIs). Endogenous OATP1B biomarkers, such as coproporphyrin I (CP‐I), are strongly predicted to improve DDI prediction in drug development.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Can PBPK model analysis of the clinical CP‐I data successfully predict OATP1B‐mediated DDIs using probe drugs?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

The value of the most important DDI parameter, K_i,OATP1B, estimated by PBPK model‐based analysis of clinical CP‐I data, was able to overcome the discrepancy between the in vitro and in vivo effects of CysA on OATP1B, and could be applied to predict the change in the blood concentration time profiles of OATP1B probe drugs.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

The collection of endogenous OATP1B biomarker data is a feasible strategy to capture DDI potential. PBPK models aids in the prediction of its clinical impact more precisely, help to reduce risk in drug development, and impact the regulatory decision tree for DDI risk assessment.     

High intrapatient variability of tacrolimus exposure associated with poorer outcomes in liver transplantation

Tacrolimus (TAC) is a dose‐dependent immunosuppressor with considerable intrapatient variability (IPV) in its pharmacokinetics. The aim of this work is to ascertain the association between TAC IPV at 6 months after liver transplantation (LT) and patient outcome. This single‐center cohort study retrospectively analyzed adult patients who underwent transplantation from 2015 to 2019 who survived the first 6 months with a functioning graft. The primary end point was the patient’s probability of death and the secondary outcome was the loss of renal function between month 6 and the last follow‐up. TAC IPV was estimated by calculating the coefficient of variation (CV) of the dose‐corrected concentration (C₀/D) between the third and sixth months post‐LT. Of the 140 patients who underwent LT included in the study, the low‐variability group (C₀/D CV < 27%) comprised 105 patients and the high‐variability group (C₀/D CV ≥ 27%) 35 patients. One‐, 3‐, and 5‐year patient survival rates were 100%, 82%, and 72% in the high‐variability group versus 100%, 97%, and 93% in the low‐variability group, respectively (p = 0.005). Moreover, significant impaired renal function was observed in the high‐variability group at 1 year (69 ± 16 ml/min/1.73 m² vs. 78 ± 16 ml/min/1.73 m², p = 0.004) and at 2 years post‐LT (69 ± 17 ml/min/1.73 m² vs. 77 ± 15 ml/min/1.73 m², p = 0.03). High C₀/D CV 3–6 months remained independently associated with worse survival (hazard ratio = 3.57, 95% CI = 1.32–9.67, p = 0.012) and loss of renal function (odds ratio = 3.47, 95% CI = 1.30–9.20, p = 0.01). Therefore, high IPV between the third and sixth months appears to be an early and independent predictor of patients with poorer liver transplant outcomes.

Abbreviations

BPAR

Biopsy proven acute rejection

BMI

Body mass index

CKD‐EPI

chronic kidney disease epidemiology collaboration

CV

coefficient of variation

C₀/D

dose‐corrected concentration

CMV

cytomegalovirus

eGFR

estimated glomerular filtration rate

HR

hazard ratio

HCC

hepatocellular carcinoma

ICU

intensive care unit

IPV

intrapatient variability

i.v.

intravenously

LC–MS/MS

liquid chromatography‐ tandem mass spectrometry

LT

liver transplantation

MELD

model for end‐stage liver disease

MMF

mycophenolate mofetil

NASH

Non‐Alcoholic Steatohepatitis

OR

odds ratio

PCR

polymerase chain reaction

SD

Standard Deviation

TAC

tacrolimus

3–6 M

three–six months

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

There is high intrapatient variability of tacrolimus and its correlation with liver transplantation (LT) outcomes.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Could the intrapatient variability of tacrolimus between months 3 and 6 post‐LT be a potential prognostic tool for poor outcomes?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Those patients with dose‐corrected concentration coefficient of variation greater than or equal to 27% between months 3 and 6 post‐LT have worst overall survival and impaired renal function.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

If we promptly identify those patients, a closer therapeutic drug monitoring program should be imperative with the possibility to make therapeutic interventions to improve outcomes.     

Dexamethasone exposure in normal‐weight and obese hospitalized COVID‐19 patients: An observational exploratory trial

During the latest pandemic, the RECOVERY study showed the benefits of dexamethasone (DEX) use in COVID‐19 patients. Obesity has been proven to be an independent risk factor for severe forms of infection, but little information is available in the literature regarding DEX dose adjustment according to body weight. We conducted a prospective, observational, exploratory study at Geneva University Hospitals to assess the impact of weight on DEX pharmacokinetics (PK) in normal‐weight versus obese COVID‐19 hospitalized patients. Two groups of patients were enrolled: normal‐weight and obese (body mass index [BMI] 18.5–25 and >30 kg/m², respectively). All patients received the standard of care therapy of 6 mg DEX orally. Blood samples were collected, and DEX concentrations were measured. The mean DEX AUC_0–8 and C_max were lower in the obese compared to the normal‐weight group (572.02 ± 258.96 vs. 926.92 ± 552.12 ng h/ml and 138.67 ± 68.03 vs. 203.44 ± 126.30 ng/ml, respectively). A decrease in DEX AUC_0–8 of 4% per additional BMI unit was observed, defining a significant relationship between weight and DEX AUC_0–8 (p = 0.004, 95% CI 2–7%). In women, irrespective of the BMI, DEX AUC_0–8 increased by 214% in comparison to men (p < 0.001, 95% CI 154–298%). Similarly, the mean C_max increased by 205% in women (p < 0.001, 95% CI 141–297%). Conversely, no significant difference between the obese and normal‐weight groups was observed for exploratory treatment outcomes, such as the length of hospitalization. BMI, weight, and gender significantly affected DEX AUC. We conclude that dose adjustment would be needed if the aim is to achieve the same exposures in normal‐weight and obese patients.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

COVID‐19 is a disease caused by SARS‐CoV‐2 virus capable of causing mild to severe infections in humans up to pneumonia and acute respiratory distress complications. On the sudden emergence of the SARS‐Cov‐2 virus, analyses of people affected by the disease have suggested that obesity might be associated with worse COVID‐19 outcomes compared with the rest of COVID‐19 patients. Dexamethasone (DEX) is included in the guidelines by the World Health Organization but the impact of obesity on DEX pharmacokinetics (PK) and pharmacodynamics (PD) remains poorly explored.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Our prospective, observational, exploratory study assessed the impact of BMI on systemic DEX exposure in normal‐weight versus obese COVID‐19 hospitalized patients to investigate the need for DEX dose adjustment.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Our study demonstrated that body mass index (BMI) modulated DEX area under the curve (AUC). Obese patients had a lower systemic concentration (160%) than normal‐weight patients. We also observed a gender effect. Irrespective of the BMI, women had a statistically significant increase of 214% in DEX AUC compared to men.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

We demonstrated a statistically significant difference in mean DEX AUC_0–8 and C_max between the normal and obese patient groups. Our results suggest that different dosing would be needed if the aim is to achieve the same exposures in both groups.     

Safety,tolerability, pharmacokinetic,and pharmacodynamic characteristics of vutiglabridin: A first‐in‐class,first‐in‐human study

This study aimed to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of vutiglabridin, a potential anti‐obesity treatment under development, for the first time in humans. A randomized, placebo‐controlled, single‐ and multiple‐ascending dose study (SAD and MAD, respectively) was performed in healthy Koreans and Whites. Subjects randomly received a single oral dose of 30–720 mg vutiglabridin or placebo at a ratio of 8:2 in the SAD study or 240–480 mg vutiglabridin or placebo once daily for 14 days in the MAD study. Food effect was also evaluated in 240 mg single dose group. Pharmacokinetics were evaluated through plasma concentrations, and pharmacodynamic biomarkers related to obesity or inflammation were analyzed. Safety and tolerability were assessed throughout the study. Single and multiple doses of vutiglabridin were generally well‐tolerated. The pharmacokinetic parameters show less than dose‐proportionality increase, and plasma concentrations increased more than two‐fold after multiple administrations. The mean half‐life of Koreans and Whites in the MAD study was 110 and 73 h, respectively. The systemic exposure of vutiglabridin was significantly increased when taken with a high‐fat meal, and the systemic exposure was lower in Whites than in Koreans. Vutiglabridin was well‐tolerated in healthy Koreans and Whites. The plasma concentration increased less than the dose‐proportionality manner. These results justify further investigation of vutiglabridin in patients with obesity.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

A treatment with multifunctional effects is needed for obesity. Because the chronic inflammation caused by obesity plays an essential role in the progression of metabolic disorders, suppressing inflammatory pathways may be another important treatment goal.

• WHAT QUESTION DID THIS STUDY ADDRESS?

What is the safety, tolerability, pharmacokinetic, and pharmacodynamic characteristics of vutiglabridin, a novel anti‐obesity agent, in healthy Korean and White individuals?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Vutiglabridin was well‐tolerated in both Korean and White individuals. The pharmacokinetic parameters of vutiglabridin did not show dose‐proportionality, and after multiple administrations, vutiglabridin showed accumulation.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

This study provides safety, pharmacokinetic, and pharmacodynamic information about vutiglabridin, which will be used for further trials for the treatment of obesity.     

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.     

Pharmacogenetic variants and risk of remdesivir‐associated liver enzyme elevations in Million Veteran Program participants hospitalized with COVID‐19

Remdesivir is the first US Food and Drug Administration (FDA)‐approved drug for the treatment of coronavirus disease 2019 (COVID‐19). We conducted a retrospective pharmacogenetic study to examine remdesivir‐associated liver enzyme elevation among Million Veteran Program participants hospitalized with COVID‐19 between March 15, 2020, and June 30, 2021. Pharmacogene phenotypes were assigned using Stargazer. Linear regression was performed on peak log‐transformed enzyme values, stratified by population, adjusted for age, sex, baseline liver enzymes, comorbidities, and 10 population‐specific principal components. Patients on remdesivir had higher peak alanine aminotransferase (ALT) values following treatment initiation compared with patients not receiving remdesivir. Remdesivir administration was associated with a 33% and 24% higher peak ALT in non‐Hispanic White (NHW) and non‐Hispanic Black (NHB) participants (p < 0.001), respectively. In a multivariable model, NHW CYP2C19 intermediate/poor metabolizers had a 9% increased peak ALT compared with NHW normal/rapid/ultrarapid metabolizers (p = 0.015); this association was not observed in NHB participants. In summary, remdesivir‐associated ALT elevations appear to be multifactorial, and further studies are needed.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Remdesivir is associated with liver injury in patients with coronavirus disease 2019 (COVID‐19), yet the mechanism of this injury is unknown.

• WHAT QUESTION DID THIS STUDY ADDRESS?

We utilized a genetically guided approach to investigate whether polymorphisms in drug metabolizing genes or transporters were associated with alanine aminotransferase (ALT) elevations following remdesivir treatment.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE

Remdesivir was associated with a 30% increase in peak ALT in patients hospitalized with COVID‐19 which differs by population. Non‐Hispanic White (NHW) individuals with the CYP2C19 intermediate or poor metabolizer phenotype experienced a higher peak ALT than NHW individuals with normal, rapid, or ultrarapid metabolizer phenotype.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Pharmacogenetic approaches to investigation of severe adverse events may be useful in elucidating the mechanisms of drug metabolism and toxicity.     

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.     

The safety and tolerability of levodopa eye drops for the treatment of ocular disorders: A randomized first‐in‐human study

Myopia is the leading cause of low vision worldwide and can lead to significant pathological complications. Therefore, to improve patient outcomes, the field continues to develop novel interventions for this visual disorder. Accordingly, this first‐in‐human study reports on the safety profile of a novel dopamine‐based ophthalmic treatment for myopia, levodopa/carbidopa eye drops. This phase I, first‐in‐human, monocenter, placebo‐controlled, double‐blind, paired‐eye, multidose, randomized clinical trial was undertaken in healthy adult males aged 18–30 years (mean age 24.9 ± 2.7) at the University of Canberra Eye Clinic, Australia. Participants were randomly assigned to receive either a low (1.4 levodopa:0.34 carbidopa [μmoles/day], n = 14) or standard dose (2.7 levodopa:0.68 carbidopa [μmoles/day], n = 15) of levodopa/carbidopa eye drops in one eye and placebo in the fellow eye once daily for 4 weeks (28 days). Over this 4‐week trial, and after a 4‐month follow‐up visit, levodopa/carbidopa treatment had no significant effect on ocular tolerability and anterior surface integrity, visual function, ocular health, refraction/ocular biometry, and did not induce any non‐ocular adverse events. These results indicate that topical levodopa/carbidopa is safe and tolerable to the eye, paving the way for future studies on the efficacy of this novel ophthalmic formulation in the treatment of human myopia. The findings of this study have implications not only for the treatment of myopia, but in a number of other visual disorders (i.e., amblyopia, diabetic retinopathy, and age‐related macular degeneration) in which levodopa has been identified as a potential clinical intervention.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Preclinical data indicate that levodopa/carbidopa eye drops can safely inhibit the development of experimental myopia in animal models.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study investigated whether levodopa/carbidopa eye drops are safe and tolerable to the human eye.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

In this phase I, first‐in‐human, monocenter, randomized, double‐blind, placebo‐controlled, multidose trial, levodopa/carbidopa eye drops were found to be safe and well tolerated in healthy adult males over a 4‐week period. Furthermore, no non‐ocular adverse events were reported.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

As topical administration of levodopa/carbidopa eye drops is well tolerated in humans, the efficacy of this novel ophthalmic treatment at inhibiting the development of myopia in patient populations can now be assessed. If found to be effective, this will provide a powerful new method for inhibiting the onset and development of the leading cause of low vision worldwide. This topical formulation may also provide a valuable tool in the treatment of other visual disorders shown to be responsive to levodopa therapy (i.e., amblyopia, diabetic retinopathy, and age‐related macular degeneration).     

Reduced tear thrombospondin‐1/matrix metalloproteinase‐9 ratio can aid in detecting Sjögren's syndrome etiology in patients with dry eye

Differentiating patients with Sjögren''s syndrome (SS)‐associated dry eye from non‐SS dry eye is critical for monitoring and appropriate management of possible sight‐ or life‐threatening extraglandular complications associated with SS. We tested whether reduced tear levels of immunoregulatory thrombospondin (TSP)‐1, which also inhibits matrix metalloproteinase (MMP)‐9, would reflect SS pathogenesis aiding the identification of patients with SS‐dry eye. Total of 61 participants, including healthy controls (n = 20), patients with non‐SS dry eye (n = 20) and SS‐dry eye (n = 21) were enrolled prospectively. Tear TSP‐1 and MMP‐9 levels were measured using a custom magnetic bead‐based multi‐plex assay in a masked manner. Analyte concentrations were assessed further according to ocular surface and tear film parameters. Relative to median tear TSP‐1 (308 ng/ml) and MMP‐9 (1.9 ng/ml) levels in the control group, significantly higher proportion of patients with SS‐dry eye than non‐SS had lower tear TSP‐1 levels (55% vs. 29%, odds ratio [OR] = 3, 95% confidence interval [CI] = 1.64 to 5.35, p < 0.05) and higher tear MMP‐9 levels (65% vs. 24%, OR = 5.8, 95% CI = 4.46 to 19.81, p < 0.05), respectively. The tear TSP‐1/MMP‐9 ratio was significantly reduced in patients with SS‐dry eye compared to non‐SS (B = −2.36, 95% CI = −3.94 to −0.0.79, p < 0.05), regardless of tear MMP‐9 levels. Patients with a lower ratio were 2.3 times more likely to have SS (OR = 0.28, 95% CI = 0.1 to 0.75, p < 0.05). This ratio showed significant inverse correlations with clinical parameters (conjunctival and corneal staining scores). Our results denote that tear TSP‐1/MMP‐9 ratio can be useful in identifying patients with dry eye with underlying SS and used as a screening test.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Differentiating patients with Sjögren''s syndrome (SS)‐associated dry eye from non‐SS dry eye is critical for monitoring and appropriate management of possible sight‐ or life‐threatening extraglandular complications associated with SS. The high prevalence and multiple phenotypes and etiologies of dry eye in general make screening patients with underlying SS challenging.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Whether reduced tear levels of immunoregulatory thrombospondin (TSP)‐1/matrix metalloproteinase (MMP)‐9 would reflect SS pathogenesis and aid in the identification of patients with SS‐related dry eye.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This study demonstrates for the first time the feasibility of quantifying tear TSP‐1 levels. These results also indicate that determining tear TSP‐1/MMP‐9 ratio can be a better diagnostic tool in identifying patients with dry eye with underlying SS than tear MMP‐9 or TSP‐1 levels alone.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

The tear TSP‐1/MMP‐9 ratio can be used to screen patients with dry eye for the presence of underlying SS. Such an option can help guide clinical decisions regarding use of appropriate therapeutics to relieve clinical symptoms and prevent detrimental disease progression toward systemic complications. Additionally, a screening test can be a useful tool to stratify patients in clinical trials designed to develop new therapeutics for SS.     

Tissue‐ and cell‐expression of druggable host proteins provide insights into repurposing drugs for COVID‐19

Several human host proteins play important roles in the lifecycle of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). Many drugs targeting these host proteins have been investigated as potential therapeutics for coronavirus disease 2019 (COVID‐19). The tissue‐specific expressions of selected host proteins were summarized using proteomics data retrieved from the Human Protein Atlas, ProteomicsDB, Human Proteome Map databases, and a clinical COVID‐19 study. Protein expression features in different cell lines were summarized based on recent proteomics studies. The half‐maximal effective concentration or half‐maximal inhibitory concentration values were collected from in vitro studies. The pharmacokinetic data were mainly from studies in healthy subjects or non‐COVID‐19 patients. Considerable tissue‐specific expression patterns were observed for several host proteins. ACE2 expression in the lungs was significantly lower than in many other tissues (e.g., the kidneys and intestines); TMPRSS2 expression in the lungs was significantly lower than in other tissues (e.g., the prostate and intestines). The expression levels of endocytosis‐associated proteins CTSL, CLTC, NPC1, and PIKfyve in the lungs were comparable to or higher than most other tissues. TMPRSS2 expression was markedly different between cell lines, which could be associated with the cell‐dependent antiviral activities of several drugs. Drug delivery receptor ICAM1 and CTSB were expressed at a higher level in the lungs than in other tissues. In conclusion, the cell‐ and tissue‐specific proteomics data could help interpret the in vitro antiviral activities of host‐directed drugs in various cells and aid the transition of the in vitro findings to clinical research to develop safe and effective therapeutics for COVID‐19.

Abbreviations

ACE2

angiotensin‐converting enzyme 2

ASGPR

asialoglycoprotein receptor

CI‐M6PR

cation‐independent 6‐phosphate receptor

CLTC

clathrin heavy chain 1

COVID‐19

coronavirus disease 2019

CTSB

cathepsin B

CTSL

cathepsin L

EC50

half maximal effective concentration

EEF1A1

elongation factor 1‐alpha 1

EEF1A2

elongation factor 1‐alpha 2

EGFR

epidermal growth factor receptor

FIP

feline infectious peritonitis

HBV

hepatitis B virus

HCQ

hydroxychloroquine

HCV

hepatitis C virus

HIV

human immunodeficiency virus

HPA

Human Protein Atlas

HPM

Human Proteome Map

IC50

half maximal inhibitory concentration

ICAM‐1

intercellular adhesion molecule 1

IGF2R

insulin‐like growth factor 2 receptor

iPSC

induced pluripotent stem cell

M6P

mannose‐6‐phosphate

MOI

multiplicity of infection

MS

mass spectrometry

NPC1

Niemann‐Pick type C1

PBMC

peripheral blood mononuclear cell

PFU

plaque‐forming units

PIKfyve

1‐phosphatidylinositol 3‐phosphate 5‐kinase

PPIA

peptidyl‐prolyl cis‐trans isomerase A

S100A8

protein S100‐A8

SARS‐CoV‐2

severe acute respiratory syndrome coronavirus 2

SLE

systemic lupus erythematosus

TBEC

tracheal bronchial epithelial cells

TMPRSS2

transmembrane protease serine 2

TPD

targeted protein degradation

     

Lipidomics of cyclophosphamide 4‐hydroxylation in patients receiving post‐transplant cyclophosphamide

Biomarker‐guided dosing may improve the efficacy and toxicity of cyclophosphamide (CY); however, clinical studies evaluating their association with the area under the plasma concentration–time curve (AUC) of CY and its metabolites are time‐ and resource‐intensive. Therefore, we sought to identify lipidomic biomarkers associated with the time‐varying differences in CY formation clearance to 4‐hydroxycyclophosphamide (4HCY), the principal precursor to CY''s cytotoxic metabolite. Hematopoietic cell transplant (HCT) patients receiving post‐transplant CY (PT‐CY) were enrolled, cohort 1 (n = 25) and cohort 2 (n = 26) donating longitudinal blood samples before they started HCT (pre‐HCT), before infusion of the donor allograft (pre‐graft), before the first dose of PT‐CY (pre‐CY) and 24 h after the first dose of PT‐CY (24‐h post‐CY) which is also immediately before the second dose of CY. A total of 409 and 387 lipids were quantitated in the two cohorts, respectively. Associations between lipids, individually and at a class level, and the ratio of 4HCY/CY AUC (i.e., 4HCY formation clearance) were evaluated using linear regression with a false discovery rate <0.05. There were no individual lipids that passed control for false discovery at any time point. These results demonstrate the feasibility of lipidomics, but future studies in larger samples with multiple omic tools are warranted to optimize CY dosing in HCT.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

The old yet commonly used drug cyclophosphamide (CY) has a complex pharmacokinetic disposition. There is a paucity of information regarding the formation clearance of 4‐hydroxycyclophosphamide (4HCY), the precursor to CY’s primary cytotoxic metabolite phosphoramide mustard. To date, scientists have not been able to create a more effective or safer analog to CY or to identify a precision medicine tool consistently associated with the efficacy, toxicity, or pharmacokinetics of CY.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study addresses the question if the plasma lipidome before post‐transplant cyclophosphamide (PT‐CY) administration in hematopoietic cell transplant (HCT) patients is associated with the ratio of 4HCY/CY area under the plasma concentration–time curve (AUC).

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This study shows that longitudinal collection of plasma lipidomic samples is feasible in HCT patients receiving PT‐CY. However, in this small patient population, we could not find an association of the plasma lipidome with the ratio of 4HCY/CY AUC. Furthermore, this study shows that the plasma lipidome changes over the ~21‐day period that starts before HCT to 24‐h after the first PT‐CY dose. This study is also among the first to evaluate the plasma lipidome in HCT patients.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

This study shows how interrogating the plasma lipidome may provide insight into the pharmacokinetics of CY and how interrogating the plasma lipidome is feasible for biomarker studies.     

A phase I,randomized, placebo‐controlled study of molnupiravir in healthy Japanese to support special approval in Japan to treat COVID‐19

Molnupiravir (MK‐4482) is an oral prodrug of the antiviral ribonucleoside analog, N‐hydroxycytidine (NHC), which has activity against RNA viruses, including severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2). We conducted a phase I safety and pharmacokinetic study of molnupiravir in healthy Japanese adult participants. A sample size larger than typically used in pharmacokinetic studies was implemented to collect additional safety data in the Japanese population to support special approval for emergency use in Japan. Single doses of molnupiravir up to 1600 mg and multiple doses of 400 and 800 mg administered every 12 h (q12h) for 5.5 days were generally well‐tolerated. NHC appeared rapidly in plasma and reached maximum concentration (C _max), with a median time to C _max (T _max) between 1.00 and 2.00 h. Area under the concentration versus time curve from zero to infinity (AUC_0–inf), area under the concentration versus time curve from zero to 12 h (AUC_0–12), and C _max of plasma NHC increased approximately dose proportionally. With q12h dosing, the geometric mean (GM) accumulation ratios for NHC AUC_0–12 and C _max were ~1 for 400 and 800 mg. Pharmacokinetics of NHC triphosphate (NHC‐TP), the active metabolite of NHC was assessed in peripheral blood mononuclear cells and also demonstrated roughly dose proportional pharmacokinetics. The GM accumulation ratios for NHC‐TP AUC_0–12 and C _max were ~2.5 for 400 and 800 mg. Following administration with food, only a modest reduction (24%) in plasma NHC C _max with comparable AUC_0–inf was seen, supporting administration without regard to food.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Molnupiravir (MK‐4482) is a prodrug of the antiviral ribonucleoside analog, which has activity against severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2). Molnupiravir is an oral drug being developed for treating patients with coronavirus disease 2019 (COVID‐19). Rapid approval in Japan was desired for molnupiravir.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study evaluated the safety, tolerability, and pharmacokinetics of molnupiravir, including food effect in healthy Japanese participants. The study was conducted with a relatively larger sample size than a typical pharmacokinetic study to collect expanded Japanese safety data to support a “special approval for emergency” process in Japan.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Molnupiravir was generally well‐tolerated in healthy Japanese. Area under the concentration versus time curve (AUC) and maximum concentration (C _max) of plasma N‐hydroxycytidine increased approximately in a dose proportional manner. Only a modest reduction in C _max without a clinically meaningful change in AUC following administration with food was observed. Based on the data from this study, in conjunction with the global phase II and phase III studies, molnupiravir was approved in Japan through a “special approval for emergency” process. The therapeutic dose is 800 mg q12h and is the same as that used globally. Molnupiravir may be taken regardless of food.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

The results of this study supported the “special approval for emergency” process for molnupiravir in Japan by obtaining extra safety data from healthy Japanese participants. “Special approval for emergency” process is a viable regulatory path in Japan that should be considered for new drugs to treat diseases in pandemic situations.     

Investigation of CYP3A induction by PF‐05251749 in early clinical development: comparison of linear slope physiologically based pharmacokinetic prediction and biomarker response

PF‐05251749 is a dual inhibitor of casein kinase 1 δ/ε under clinical development to treat disruption of circadian rhythm in Alzheimer''s and Parkinson''s diseases. In vitro, PF‐05251749 (0.3–100 μM) induced CYP3A in cryopreserved human hepatocytes, demonstrating non‐saturable, dose–dependent CYP3A mRNA increases, with induction slopes in the range 0.036–0.39 μM⁻¹. In a multiple‐dose study (B8001002) in healthy participants, CYP3A activity was explored by measuring changes in 4β‐hydroxycholesterol/cholesterol ratio. Following repeated oral administration of PF‐05251749, up to 400 mg q.d., no significant changes were observed in 4β‐hydroxycholesterol/cholesterol ratio; this ratio increased significantly (~1.5‐fold) following administration of PF‐05251749 at 750 mg q.d., suggesting potential CYP3A induction at this dose. Physiologically based pharmacokinetic (PBPK) models were developed to characterize the observed clinical pharmacokinetics (PK) of PF‐05251749 at 400 and 750 mg q.d.; the PBPK induction model was calibrated using the in vitro linear fit induction slope, with rifampin as reference compound (Ind_max = 8, EC₅₀ = 0.32 μM). Clinical trial simulation following co‐administration of PF‐05251749, 400 mg q.d. with oral midazolam 2 mg, predicted no significant drug interaction risk. PBPK model predicted weak drug interaction following co‐administration of PF‐05251749, 750 mg q.d. with midazolam 2 mg. In conclusion, good agreement was obtained between CYP3A drug interaction risk predicted using linear‐slope PBPK model and exploratory biomarker trends. This agreement between two orthogonal approaches enabled assessment of drug interaction risks of PF‐05251749 in early clinical development, in the absence of a clinical drug–drug interaction study.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Physiologically based pharmacokinetic (PBPK) predictions are commonly applied in clinical development to predict drug interaction risks associated with CYP3A inducers. Changes in 4β‐hydroxycholesterol levels are explored to assess the clinical relevance of CYP3A induction in humans.

• WHAT QUESTION DID THIS STUDY ADDRESS?

PF‐05251749 was identified as a potential CYP3A inducer in vitro. The objective of this analysis was to investigate clinical drug–drug interaction (DDI) risk associated with PF‐05251749 during early clinical development, using PBPK and biomarker outcomes.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This study exemplifies the assessment of drug interaction risks in early clinical development, using changes in 4β‐hydroxycholesterol/cholesterol ratio as preliminary evidence of CYP3A activity, leading to investigation using a PBPK model‐informed approach. This PBPK model was developed using in vitro CYP3A mRNA induction linear‐fit‐slope. This investigation shows good concordance of linear‐fit‐slope‐calibrated PBPK predictions with observed trends in hepatic CYP3A biomarker changes.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Measuring changes in 4β‐hydroxycholesterol/cholesterol ratio should be considered for potential CYP3A inducers during phase I multiple‐dose studies. Assessment of DDI risks during early development should consider totality of data including in vitro, in vivo/biomarker, and PBPK approaches.     

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.     

Platelet thromboxane inhibition by low‐dose aspirin in polycythemia vera: Ex vivo and in vivo measurements and in silico simulation

Low‐dose aspirin is currently recommended for patients with polycythemia vera (PV), a myeloproliferative neoplasm with increased risk of arterial and venous thromboses. Based on aspirin pharmacodynamics in essential thrombocythemia, a twice‐daily regimen is recommended for patients with PV deemed at particularly high thrombotic risk. We investigated the effects of low‐dose aspirin on platelet cyclooxygenase activity and in vivo platelet activation in 49 patients with PV, as assessed by serum thromboxane (TX) B₂ and urinary TXA₂/TXB₂ metabolite (TXM) measurements, respectively. A previously described pharmacokinetic‐pharmacodynamic in silico model was used to simulate the degree of platelet TXA₂ inhibition by once‐daily (q.d.) and twice‐daily (b.i.d.) aspirin, and to predict the effect of missing an aspirin dose during q.d. and b.i.d. regimens. Serum TXB₂ averaged 8.2 (1.6–54.7) ng/ml and significantly correlated with the platelet count (γ = 0.39) and urinary TXM (γ = 0.52) in multivariable analysis. One‐third of aspirin‐treated patients with PV displayed less‐than‐maximal platelet TXB₂ inhibition, and were characterized by significantly higher platelet counts and platelet‐count corrected serum TXB₂ than those with adequate inhibition. Eight patients with PV were sampled again after 12 ± 4 months, and had reproducible serum TXB₂ and urinary TXM values. The in silico model predicted complete inhibition of platelet‐derived TXB₂ by b.i.d. aspirin, a prediction verified in a patient with PV with the highest TXB₂ value while on aspirin q.d. and treated short‐term with a b.i.d. regimen. In conclusion, one in three patients with PV on low‐dose aspirin display less‐than‐maximal inhibition of platelet TXA₂ production. Serum TXB₂ measurement can be a valuable option to guide precision dosing of antiplatelet therapy in patients with PV.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Polycythemia vera (PV) is a myeloproliferative neoplasm (MPN) characterized by clonal erythrocytosis and increased thrombotic complications. Once‐daily, low‐dose aspirin is currently recommended in patients with PV.

• WHAT QUESTION DID THIS STUDY ADDRESS?

The aim of the present study was to characterize the antiplatelet pharmacodynamics (PDs) of low‐dose aspirin, its determinants, and the level of in vivo platelet activation in a contemporary PV cohort. We also used in silico modeling of aspirin pharmacokinetics/PDs to simulate the platelet response to a once‐daily regimen, and to predict the effects of a twice‐daily regimen on thromboxane (TX) production in PV.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

One in three patients with PV display inadequate inhibition of platelet TXA₂ production and TXA₂‐dependent platelet activation, despite standard aspirin therapy. In silico modeling may help design future studies in this setting.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Impaired aspirin PDs can be diagnosed with a serum TXB₂ determination 24 h after dosing, and can be rescued by a b.i.d. dosing regimen. This relatively simple approach may be applied to other non‐MPN clinical settings.     

Pharmacokinetic evaluation of radiolabeled intraocular anti‐CLEC14a antibody in preclinical animal species and application in humans

Anti‐angiogenic antibodies are widely used in the treatment of neovascular macular degeneration. Human antibody targeting C‐type lectin domain family 14 member A (CLEC14a) is potential therapeutic agents owing to its antiangiogenic activity. In the present study, we aimed to predict the human intraocular pharmacokinetic (PK) properties of an anti‐CLEC14a antibody. I‐125 labeled aflibercept and anti‐CLEC14a antibody were intravitreally injected into mice, rats, and rabbits. Single photon emission computed tomography/computed tomography imaging was performed, and the intraocular radioactivity concentration (%ID/ml) was obtained. The PK parameters in those three animal species were obtained by compartmental analysis. The PK parameters in humans were estimated by allometric scaling of the animal PK parameters with consideration of the hydrodynamic radius of the antibody. The mean half‐life values of intraocular I‐125‐labeled aflibercept in mice, rats, and rabbits were 1.13 days, 1.25 days, and 4.91 days, respectively, by analysis with a one‐compartment model. The predicted human half‐life of intraocular aflibercept was 5.75 days based on vitreal volume by allometric scaling. The half‐life values of intraocular I‐125‐labeled anti‐CLEC14a in mice, rats and rabbits were 1.05 days, 1.84 days, and 6.37 days, respectively, by analysis with a one‐compartment model. The predicted human half‐life of intraocular anti‐CLEC14a was 10.29 days based on vitreal volume. According to the hydrodynamic volume of the anti‐CLEC14a, the predicted human half‐life of intraocular anti‐CLEC14a was 9.81 days. The PK characteristics of the intraocular anti‐CLEC14a antibody were evaluated noninvasively in animals using I‐125 labeling, and the intraocular PK characteristics in humans were predicted using these animal data. This methodology can be applied for the development of new antiangiogenic antibodies to treat macular degeneration.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Allometric scaling based on multiple species of animals could be used in first‐in‐human studies.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Could molecular imaging using radiolabeled antibodies be used in the pharmacokinetic (PK) analysis of intravitreally injected antibodies and precise prediction of human PK parameters?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Molecular imaging using radiolabeled antibodies can be used in PK analysis.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Methodologies using molecular imaging can be applied for the development of new antibodies to treat macular degeneration by intravitreal injection.     

MicroRNA sequencing in patients with coronary artery disease – considerations for use as biomarker for thrombotic risk

MicroRNAs (miRNAs) are small RNAs integral in the regulation of gene expression. Analysis of circulating miRNA levels may identify patients with coronary artery disease (CAD) at risk for recurrent myocardial infarction (MI) after percutaneous coronary interventions (PCIs). Subjects with CAD were selected from the GENCATH cardiac catheterization biobank. Subjects with recurrent MI after PCI were compared with those without recurrent MI during follow‐up in the initial (n = 48) and replication cohort (n = 67). Next generation MiRNA sequencing was performed on plasma samples and whole blood samples fixed with PAXGENE tubes upon collection. Overall, 164 miRNAs derived from whole blood were differentially expressed in the replication cohort between subjects with and without recurrent MI events (p < 0.05), with 69 remaining significant after false‐discovery rate (FDR) correction. None of the miRNAs in plasma was significantly different by FDR among subjects with and without MI. Overall, correlation between direction of effects between plasma and whole blood assays was variable, and only two miRNAs were concordant and significant in both. Associations of miRNA with vascular disease, MI, and thrombosis were further explored. MiRNA profiling has potential as the future biomarker for disease prognosis and treatment response marker in secondary treatment of patients with CAD after PCI. Whole blood may be the preferred sample source as compared to plasma.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Micro RNAs (miRNAs) are promising biomarkers associated with various disease states, including coronary artery disease (CAD). Most studies evaluating miRNA as biomarkers in CAD have previously utilized miRNA extracted from plasma sources, mainly due to widely available sample sources. Few studies have specifically compared overlap between whole blood and plasma sources of miRNA in CAD, or relative contribution of cellular components to miRNA levels in whole blood.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study examined next‐generation sequencing miRNA profiles in patients with established CAD comparing patients with recurrent myocardial infarction (MI) during follow‐up versus those without recurrent events. We analyzed overlap of miRNA identified with differential expression in plasma versus whole blood.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Our study expands on prior work using miRNA to establish a high‐risk biometric profile of patients with recurrent MI events. We identified a series of miRNAs in whole blood potentially associated with increased risk of recurrent MI after coronary intervention. No significant difference was found in samples derived from plasma. Several of these miRNAs have been previously linked to thrombosis, vascular inflammation, and coronary disease.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Knowledge about the significant impact of sample source on miRNA profiling should influence future investigations on use of miRNA in determining vascular thrombotic risk profiles, with larger variability and differential expression found in miRNA sequenced from whole blood sources. Specific miRNA associated with recurrent thrombotic events may be suitable for risk assessment or may be involved in gene regulation of potentially novel disease modifying pathways.     

A proof of concept using the Ussing chamber methodology to study pediatric intestinal drug transport and age‐dependent differences in absorption

Little is known about the impact of age on the processes governing human intestinal drug absorption. The Ussing chamber is a system to study drug transport across tissue barriers, but it has not been used to study drug absorption processes in children. This study aimed to explore the feasibility of the Ussing chamber methodology to assess pediatric intestinal drug absorption. Furthermore, differences between intestinal drug transport processes of children and adults were explored as well as the possible impact of age. Fresh terminal ileal leftover tissues from both children and adults were collected during surgery and prepared for Ussing chamber experiments. Paracellular (enalaprilat), transcellular (propranolol), and carrier‐mediated drug transport by MDR1 (talinolol) and BCRP (rosuvastatin) were determined with the Ussing chamber methodology. We calculated apparent permeability coefficients and efflux ratios and explored their relationship with postnatal age. The success rate for the Ussing chamber experiments, as determined by electrophysiological measurements, was similar between children (58%, N = 15, median age: 44 weeks; range 8 weeks to 17 years) and adults (67%, N = 13). Mean serosal to mucosal transport of talinolol by MDR1 and rosuvastatin by BCRP was higher in adult than in pediatric tissues (p = 0.0005 and p = 0.0091). In contrast, within our pediatric cohort, there was no clear correlation for efflux transport across different ages. In conclusion, the Ussing chamber is a suitable model to explore pediatric intestinal drug absorption and can be used to further elucidate ontogeny of individual intestinal pharmacokinetic processes like drug metabolism and transport.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

The intestine plays an important role in oral drug absorption. However, an information gap exists on age‐related differences in intestinal drug transport.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Can we study the ontogeny of intestinal drug transport with the Ussing chamber methodology?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

The Ussing chamber methodology is a feasible model to study pediatric intestinal drug transport of orally dosed drugs. Passive permeability as well as efflux transport can be studied with the use of this technique. Our exploratory data suggest lower intestinal MDR1 and BCRP transport in children, but sample size was too small to make definitive conclusions.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Characterization of age‐related absorption differences in the intestine could support pediatric intestinal physiologically‐based pharmacokinetic models that will help to develop advanced drug dosing guidelines and improve therapeutic efficacy and safety.     

A permeability‐ and perfusion‐based PBPK model for improved prediction of concentration‐time profiles

To improve predictions of concentration‐time (C‐t) profiles of drugs, a new physiologically based pharmacokinetic modeling framework (termed ‘PermQ’) has been developed. This model includes permeability into and out of capillaries, cell membranes, and intracellular lipids. New modeling components include (i) lumping of tissues into compartments based on both blood flow and capillary permeability, and (ii) parameterizing clearances in and out of membranes with apparent permeability and membrane partitioning values. Novel observations include the need for a shallow distribution compartment particularly for bases. C‐t profiles were modeled for 24 drugs (7 acidic, 5 neutral, and 12 basic) using the same experimental inputs for three different models: Rodgers and Rowland (RR), a perfusion‐limited membrane‐based model (K_p,mem), and PermQ. K_p,mem and PermQ can be directly compared since both models have identical tissue partition coefficient parameters. For the 24 molecules used for model development, errors in V_ss and t _1/2 were reduced by 37% and 43%, respectively, with the PermQ model. Errors in C‐t profiles were reduced (increased EOC) by 43%. The improvement was generally greater for bases than for acids and neutrals. Predictions were improved for all 3 models with the use of parameters optimized for the PermQ model. For five drugs in a test set, similar results were observed. These results suggest that prediction of C‐t profiles can be improved by including capillary and cellular permeability components for all tissues.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Compared to compartmental models, concentration‐time profiles of drugs are often not well‐predicted by perfusion‐limited PBPK models.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Can C‐t profiles be better predicted by including capillary, cellular and membrane permeability in a new PBPK framework?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This study suggests that variable capillary permeability for different tissues is an important anatomical component for drug distribution. Apparent permeability and membrane partitioning can be used to model clearances in and out of membranes. Early distribution kinetics observed in the C‐t profile of basic drugs indicates that an additional shallow distribution compartment is necessary. Parameters optimized for input into the new PermQ framework also decrease the prediction errors in perfusion‐limited PBPK models.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Improved prediction of drug concentration‐time profiles with new modeling frameworks such as the PermQ model can result in improved therapeutic outcomes for healthy and special populations.     

Population pharmacokinetic/pharmacodynamic modeling of the psychedelic experience induced by N,N‐dimethyltryptamine – Implications for dose considerations

N,N‐dimethyltryptamine (DMT) is a psychedelic compound that is believed to have potential as a therapeutic option in several psychiatric disorders. The number of clinical investigations with DMT is increasing. However, very little is known about the pharmacokinetic properties of DMT as well as any relationship between its exposure and effects. This study aimed to characterize population pharmacokinetics of DMT as well as the relationship between DMT plasma concentrations and its psychedelic effects as measured through subjective intensity ratings. Data were obtained from 13 healthy subjects after intravenous administration of DMT. The data were analyzed using nonlinear mixed‐effects modeling in NONMEM. DMT plasma concentrations were described by a two‐compartment model with first‐order elimination leading to formation of the major metabolite indole 3‐acetic acid. The relationship between plasma concentrations and psychedelic intensity was described by an effect site compartment model with a sigmoid maximum effect (E _max) response. DMT clearance was estimated at 26 L/min, a high value indicating elimination of DMT to be independent of blood flow. Higher concentrations of DMT were associated with a more intense experience with the concentration of DMT at the effect site required to produce half of the maximum response estimated at 95 nM. The maximum achievable intensity rating was 10 and the simulated median maximum rating was zero, 2, 4, 8, and 9 after doses of 1, 4, 7, 14, and 20 mg, respectively. The model can be useful in predicting suitable doses for clinical investigations of DMT based on the desired intensity of the subjective experience.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

N,N‐dimethyltryptamine (DMT) is a psychedelic compound being investigated as a therapeutic option in psychiatric disorders. Very little is known about its pharmacokinetic/pharmacodynamic properties.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study aimed to investigate the pharmacokinetics of DMT and to quantify the relationship between DMT concentrations and intensity of the psychedelic experience after intravenous administration of DMT to 13 healthy subjects.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

DMT pharmacokinetics were characterized, showing a large DMT clearance of 26 L/min. The relationship between DMT concentrations and psychedelic intensity was also described. The applicability of the model was demonstrated through simulations of obtained intensity at different dose levels, illustrating what doses may be required for suboptimal and maximal responses, respectively.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

This is the first time the pharmacokinetics/pharmacodynamics of DMT has been modeled. We believe this model can be useful in guiding DMT dosing in future clinical research. Further, the work demonstrates the benefits of using a quantitative pharmacokinetic/pharmacodynamic approach in future clinical development of psychedelics in general.