Preoperative medication use and development of postoperative delirium and cognitive dysfunction

Postoperative delirium (POD) and postoperative (neuro‐)cognitive disorder (POCD) are frequent and serious complications after operations. We aim to investigate the association between pre‐operative polypharmacy and potentially inappropriate medications and the development of POD/POCD in elderly patients. This investigation is part of the European BioCog project (www.biocog.eu), a prospective multicenter observational study with elderly surgical patients. Patients with a Mini‐Mental State Examination score less than or equal to 23 points were excluded. POD was assessed up to 7 days after surgery using the Nursing Delirium Screening Scale, Confusion Assessment Method (for the intensive care unit [ICU]), and a patient chart review. POCD was assessed 3 months after surgery with a neuropsychological test battery. Pre‐operative long‐term medication was evaluated in terms of polypharmacy (≥5 agents) and potentially inappropriate medication (defined by the PRISCUS and European list of potentially inappropriate medications [EU(7)‐PIM] lists), and associations with POD and POCD were analyzed using logistic regression analysis. Eight hundred thirty‐seven participants were included for analysis of POD and 562 participants for POCD. Of these, 165 patients (19.7%) fulfilled the criteria of POD and 60 (10.7%) for POCD. After adjusting for confounders, pre‐operative polypharmacy and intake of potentially inappropriate medications could not be shown to be associated with the development of POD nor POCD. We found no associations between pre‐operative polypharmacy and potentially inappropriate medications and development of POD and POCD. Future studies should focus on the evaluation of drug interactions to determine whether patients benefit from a pre‐operative adjustment.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Polypharmacy and drugs listed on PRISCUS or European list of potentially inappropriate medications (EU(7)‐PIM) lists are associated with higher hospitalization rates, increased morbidity, and poorer outcome regarding quality of life. Studies examining such medication in addition to polypharmacy and the occurrence of postoperative delirium/postoperative (neuro‐)cognitive disorder (POD/POCD) are lacking.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Is there an association between preoperative polypharmacy and potentially inappropriate medications (defined by PRISCUS and EU(7)‐PIM lists) and the development of POD and POCD in elderly patients?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Pre‐operative polypharmacy and intake of potentially inappropriate medications were not associated with the development of POD or POCD. It may be reasonable to focus on the evaluation of drug interactions rather than sole avoidance of listed medications.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Based on these results, simply considering the number of drugs or screening for potentially inadequate medication is insufficient as a preventive strategy regarding POD and POCD. Future studies should consider drug interactions and use randomized controlled approaches to determine the interaction of predisposing and precipitating factors.     

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

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

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

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

• WHAT QUESTION DID THIS STUDY ADDRESS?

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

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

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

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

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

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

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

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

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

• WHAT QUESTION DID THIS STUDY ADDRESS?

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

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

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

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

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

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.     

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

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

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

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

• WHAT QUESTION DID THIS STUDY ADDRESS?

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

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

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

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

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

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

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

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

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

• WHAT QUESTION DID THIS STUDY ADDRESS?

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

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

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

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

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

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

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

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

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

• WHAT QUESTION DID THIS STUDY ADDRESS?

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

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

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

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

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

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

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

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

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

• WHAT QUESTION DID THIS STUDY ADDRESS?

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

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

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

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

These results can inform the future clinical development of milvexian.     

COVID‐19 vaccine hesitancy: Race/ethnicity,trust, and fear

Understanding and minimizing coronavirus disease 2019 (COVID‐19) vaccine hesitancy is critical to population health and minimizing health inequities, which continue to be brought into stark relief by the pandemic. We investigate questions regarding vaccine hesitancy in a sample (n = 1205) of Arkansas adults surveyed online in July/August of 2020. We examine relationships among sociodemographics, COVID‐19 health literacy, fear of COVID‐19 infection, general trust in vaccines, and COVID‐19 vaccine hesitancy using bivariate analysis and a full information maximum likelihood (FIML) logistic regression model. One in five people (21,21.86%) reported hesitancy to take a COVID‐19 vaccine. Prevalence of COVID‐19 vaccine hesitancy was highest among Black/African Americans (50.00%), respondents with household income less than $25K (30.68%), some college (32.17%), little to no fear of infection from COVID‐19 (62.50%), and low trust in vaccines in general (55.84%). Odds of COVID‐19 vaccine hesitancy were 2.42 greater for Black/African American respondents compared to White respondents (p < 0.001), 1.67 greater for respondents with some college/technical degree compared to respondents with a 4‐year degree (p < 0.05), 5.48 greater for respondents with no fear of COVID‐19 infection compared to those who fear infection to a great extent (p < 0.001), and 11.32 greater for respondents with low trust in vaccines (p < 0.001). Sociodemographic differences in COVID‐19 vaccine hesitancy raise concerns about the potential of vaccine implementation to widen existing health disparities in COVID‐19 related infections, particularly among Black/African Americans. Fear of infection and general mistrust in vaccines are significantly associated with vaccine hesitancy.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Prior research has documented that coronavirus disease 2019 (COVID‐19) vaccine hesitancy varies greatly by race and ethnicity. However, many questions remain regarding patterns of vaccine hesitancy across sociodemographics and attitudes.

• WHAT QUESTION DID THIS STUDY ADDRESS?

What proportion of Arkansans are hesitant to get the COVID‐19 vaccine? How does COVID‐19 vaccine hesitancy differ across sociodemographic groups in Arkansas? How does knowledge of how to protect one’s self against the virus, fear of the virus, and general trust for vaccines relate to COVID‐19 vaccine hesitancy?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This study is the first to look at sociodemographic differences in COVID‐19 vaccine hesitancy in a highly vulnerable rural state that ranks third for prevalence of individuals at high risk for serious illness from COVID‐19. The COVID‐19 vaccine hesitancy was highest among respondents with lower household income, some college, and little to no fear of infection from COVID‐19.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

This study can inform public health interventions aiming to reduce the unequal burden of COVID‐19 morbidity and mortality through equitable vaccine distribution and health communication.     

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

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

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

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

• WHAT QUESTION DID THIS STUDY ADDRESS?

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

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

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

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

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

Impact of pretreatment dihydropyrimidine dehydrogenase genotype‐guided fluoropyrimidine dosing on chemotherapy associated adverse events

Consensus guidelines exist for genotype‐guided fluoropyrimidine dosing based on variation in the gene dihydropyrimidine dehydrogenase (DPYD). However, these guidelines have not been widely implemented in North America and most studies of pretreatment DPYD screening have been conducted in Europe. Given regional differences in treatment practices and rates of adverse events (AEs), we investigated the impact of pretreatment DPYD genotyping on AEs in a Canadian context. Patients referred for DPYD genotyping prior to fluoropyrimidine treatment were enrolled from December 2013 through November 2019 and followed until completion of fluoropyrimidine treatment. Patients were genotyped for DPYD c.1905+1G>A, c.2846A>T, c.1679T>G, and c.1236G>A. Genotype‐guided dosing recommendations were informed by Clinical Pharmacogenetics Implementation Consortium guidelines. The primary outcome was the proportion of patients who experienced a severe fluoropyrimidine‐related AE (grade ≥3, Common Terminology Criteria for Adverse Events version 5.0). Secondary outcomes included early severe AEs, severe AEs by toxicity category, discontinuation of fluoropyrimidine treatment due to AEs, and fluoropyrimidine‐related death. Among 1394 patients, mean (SD) age was 64 (12) years, 764 (54.8%) were men, and 47 (3.4%) were DPYD variant carriers treated with dose reduction. Eleven variant carriers (23%) and 418 (31.0%) noncarriers experienced a severe fluoropyrimidine‐related AE (p = 0.265). Six carriers (15%) and 284 noncarriers (21.1%) experienced early severe fluoropyrimidine‐related AEs (p = 0.167). DPYD variant carriers treated with genotype‐guided dosing did not experience an increased risk for severe AEs. Our data support a role for DPYD genotyping in the use of fluoropyrimidines in North America.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Dihydropyrimidine dehydrogenase (DPD) deficiency is associated with fluoropyrimidine‐related adverse events (AEs), and screening for DPD deficiency can be carried out using DPYD genotype testing of clinically relevant variants, as noted in the Clinical Pharmacogenetics Implementation Consortium guidelines.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Given the paucity of data relating to pretreatment use of DPYD genotyping in North America, this Canadian study adds new insights to the clinical impact of DPYD testing.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

DPYD genotype‐guided dosing can ameliorate fluoropyrimidine‐related AE risk for patients treated with fluoropyrimidine dose and regimens prescribed in North America.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Although the European Medicines Agency supports DPD deficiency screening, this study suggests that similar efforts should be undertaken in North America.     

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.     

Weight reduction added to CPAP decreases blood pressure and triglyceride level in OSA: Systematic review and meta‐analysis

Obstructive sleep apnea (OSA) is associated with treatment‐resistant hypertension and high cardiovascular risk. Continuous positive airway pressure (CPAP) fails to reduce cardiovascular risks consistently. Obesity and OSA show reciprocal association and they synergistically increase hypertension via different pathways. Our meta‐analysis aimed to assess the cardiovascular benefits of combining weight loss (WL) with CPAP (vs. WL or CPAP alone) in OSA. Outcomes included systolic and diastolic blood pressure (BP) and blood lipid parameters. We explored Medline, Embase, Cochrane, and Scopus. Eight randomized controlled studies (2627 patients) were included. The combined therapy decreased systolic BP more than CPAP alone. Weighted mean difference (WMD) for CPAP + WL versus CPAP was −8.89 mmHg, 95% confidence interval (95% CI; −13.67 to −4.10, p < 0.001) for systolic BP. For diastolic BP, this decrease was not significant. In case of blood lipids, the combined treatment decreased triglyceride levels more than CPAP alone (WMD = −0.31, 95% CI −0.58 to −0.04, p = 0.027). On the other hand, addition of CPAP to WL failed to suppress BP further. The certainty of evidence according to GRADE was very low to moderate. In conclusion, our results showed that the addition of WL to CPAP significantly improved BP and blood lipid values in OSA. On the other hand, the addition of CPAP to WL could not significantly improve BP or blood lipid values. Review protocol: PROSPERO CRD42019138998.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Moderate to severe obstructive sleep apnea (OSA) is associated with obesity and increased cardiovascular risks. Positive pressure ventilation (CPAP) alone does not address these risks. The CPAP‐induced reduction of blood pressure (BP) was shown to be around 2–3 mmHg, whereas no CPAP‐induced weight loss (WL) was confirmed.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Our meta‐analysis aimed to assess the evidence with regard to the cardiovascular benefits (change in BP and blood lipids) of combining weight reduction intervention with CPAP in OSA.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Addition of efficient WL intervention to CPAP induces significant further reduction in systolic BP of ~ 8–9 mmHg. BP reduction elicited by the combination therapy could contribute to the suppression of cardiovascular risks. Additionally, WL improves the suppression of blood triglyceride levels as well.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

It is strongly recommended that patients with OSA characterized by overweight and hypertension should be treated by a combination of efficient weight loss intervention and CPAP. It could prevent the weight gain induced by CPAP therapy and efficiently decrease the cardiovascular risks of these high‐risk patients.     

Population pharmacokinetic/pharmacodynamic assessment of imipenem/cilastatin/relebactam in patients with hospital‐acquired/ventilator‐associated bacterial pneumonia

In the phase III RESTORE‐IMI 2 study (ClinicalTrials.gov: {"type":"clinical-trial","attrs":{"text":"NCT02493764","term_id":"NCT02493764"}}NCT02493764), the combination antibacterial agent imipenem/cilastatin/relebactam (IMI/REL) demonstrated noninferiority to piperacillin/tazobactam for the end points of all‐cause mortality at day 28 and favorable clinical response at the early follow‐up visit in adult participants with gram‐negative hospital‐acquired bacterial pneumonia/ventilator‐associated bacterial pneumonia (HABP/VABP). Existing population pharmacokinetic models for imipenem (IPM) and REL were updated using data from patients with HABP/VABP from RESTORE‐IMI 2. Creatinine clearance (CrCl), body weight, infection type, and ventilation status were significant covariates in the updated model. The following simulations were performed to calculate the pharmacokinetic/pharmacodynamic joint probability of target attainment among patients with HABP/VABP and varying degrees of renal function: augmented renal clearance (CrCl ≥150 ml/min), normal renal function (CrCl ≥90 to <150 ml/min), renal impairment (mild, CrCl ≥60 to <90 ml/min; moderate, CrCl ≥30 to <60 ml/min; or severe, CrCl ≥15 to <30 ml/min), and end‐stage renal disease (CrCl <15 ml/min). At the recommended IMI/REL dosing regimens across renal categories, greater than 90% of patients in all renal function groups were predicted to achieve joint pharmacokinetic/pharmacodynamic targets at a minimum inhibitory concentration breakpoint of ≤2 μg/ml, regardless of ventilation status. This modeling and simulation analysis supports use of the recommended IMI/REL dosing regimens, adjusted based on renal function, in patients with HABP/VABP.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Imipenem (IPM)/cilastatin/relebactam (REL) is approved for the treatment of patients with hospital‐acquired bacterial pneumonia/ventilator‐associated bacterial pneumonia (HABP/VABP), a critically ill population likely to present with pathophysiological changes that can affect pharmacokinetic parameters of antibacterials. Existing population pharmacokinetic models for IPM and REL were developed with limited data from participants with HABP/VABP.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This analysis integrated data from the phase III RESTORE‐IMI 2 study into an existing population pharmacokinetic model to evaluate the effects of covariates on IPM and REL exposures and to analyze pharmacokinetic/pharmacodynamic probability of target attainment (PTA) in patients with HABP/VABP.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Patients with HABP/VABP had slightly higher exposures than healthy participants and patients with complicated urinary tract or intra‐abdominal infection. High, adequate joint PTA was attained regardless of ventilation status. These findings were consistent among patients with impaired renal function.

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

These findings confirm that the 500/500/250‐mg IPM/cilastatin/REL dose, adjusted for renal function, is appropriate for patients with HABP/VABP.     

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

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

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

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

• WHAT QUESTION DID THIS STUDY ADDRESS?

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

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

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

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

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

Required dose of sugammadex or neostigmine for reversal of vecuronium‐induced shallow residual neuromuscular block at a train‐of‐four ratio of 0.3

Residual shallow neuromuscular block (NMB) is potentially harmful and contributes to critical respiratory events. Evidence for the optimal dose of sugammadex required to reverse vecuronium‐induced shallow NMB is scarce. The aims of the present study were to find suitable doses of sugammadex and neostigmine to reverse a residual vecuronium‐induced NMB from a time of flight (TOF) ratio of 0.3–0.9 and evaluate their safety and efficacy. In total, 121 patients aged 18–65 years were randomly assigned to 11 groups to receive placebo, sugammadex (doses of 0.125, 0.25, 0.5, 1.0, or 2.0 mg/kg), or neostigmine (doses of 10, 25, 40, 55, or 70 μg/kg). The reversal time of sugammadex and neostigmine to antagonize a vecuronium‐induced shallow residual NMB (i.e., TOF ratio of 0.3) and related adverse reactions were recorded. Several statistical models were tested to find an appropriate statistical model to explore the suitable doses of sugammadex and neostigmine required to reverse a residual vecuronium‐induced NMB. Based on a monoexponential model with the response variable on a logarithmic scale, sugammadex 0.56 mg/kg may be sufficient to reverse vecuronium‐induced shallow residual NMB at a TOF ratio of 0.3 under anesthesia maintained with propofol. Neostigmine may not provide prompt and satisfactory antagonism as sugammadex, even in shallow NMB.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Sugammadex 4 and 2 mg/kg can effectively reverse deep and moderate neuromuscular blockade (NMB) induced by aminosteroidal NMB agents, respectively. The optimal dose of sugammadex required to reverse vecuronium on shallow NMB has not yet been evaluated, and whether neostigmine can provide the same satisfactory antagonism as sugammadex in vecuronium‐induced shallow NMB remains unknown.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This analysis of a single‐center, randomized, double‐blind trial evaluated biological models to find an appropriate model to explore suitable doses of sugammadex and neostigmine to reverse residual vecuronium‐induced NMB from a time of flight (TOF) ratio of 0.3 to 0.9.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Sugammadex 0.56 mg/kg may be sufficient to reverse vecuronium‐induced shallow residual NMB at a TOF ratio of 0.3 under anesthesia maintained with propofol. Neostigmine may not provide antagonism as satisfactory as the sugammadex dose due to its less stable recovery time and higher incidence of recurarization even in shallow NMB.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

A small dose of sugammadex—0.56 mg/kg—can satisfactorily reverse vecuronium‐induced shallow NMB at a TOF ratio of 0.3. If doctors use the required dose of sugammadex, it will promote rational drug use and avoid some side effects of excessive medication.     

Upadacitinib pharmacokinetics and exposure‐response analyses of efficacy and safety in psoriatic arthritis patients – Analyses of phase III clinical trials

Upadacitinib is an oral Janus kinase inhibitor approved for the treatment of rheumatoid arthritis (RA) and recently approved by the European Medicines Agency for the treatment of psoriatic arthritis (PsA). The efficacy and safety profile of upadacitinib in PsA have been established in the SELECT‐PsA program in two global phase III studies, which evaluated upadacitinib 15 and 30 mg q.d. The analyses described here characterized upadacitinib pharmacokinetics and exposure‐response relationships for efficacy and safety endpoints using data from the SELECT‐PsA studies. Upadacitinib pharmacokinetics in patients with PsA were characterized through a Bayesian population analysis approach and were comparable to pharmacokinetics in patients with RA. Exposure‐response relationships for key efficacy and safety endpoints were characterized using data from 1916 patients with PsA. The percentage of patients achieving efficacy endpoints at week 12 (American College of Rheumatology [ACR]50 and ACR70), 16 and 24 (sIGA0/1) increased with increasing upadacitinib average plasma concentration over a dosing interval, whereas no clear exposure‐response trend was observed for ACR20 at week 12 or ACR20/50/70 at week 24 within the range of plasma exposures evaluated in the phase III PsA studies. No clear trends for exposure‐response relationships were identified for experiencing pneumonia, herpes zoster infection, hemoglobin less than 8 g/dl, lymphopenia (grade ≥ 3), or neutropenia (grade ≥ 3) after 24 weeks of treatment. Shallow relationships with plasma exposures were observed for serious infections and hemoglobin decrease greater than 2 g/dl from baseline at week 24. Based on exposure‐response analyses, the upadacitinib 15 mg q.d. regimen is predicted to achieve robust efficacy in patients with PsA and to be associated with limited incidences of reductions in hemoglobin or occurrence of serious infections.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Upadacitinib is a selective JAK1 inhibitor approved for the treatment of rheumatoid arthritis and approved in Europe for the treatment of psoriatic arthritis (PsA). The pharmacokinetics, efficacy, and safety of upadacitinib in patients with PsA were evaluated in two global phase III trials as monotherapy or in combination with non‐biologic disease‐modifying antirheumatic drugs.

• WHAT QUESTION DID THIS STUDY ADDRESS?

These analyses characterized the relationships between upadacitinib plasma exposures and key efficacy and safety endpoints in patients with moderate to severe PsA.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

The presented exposure‐response analyses demonstrated that the plasma exposures associated with upadacitinib 15 mg q.d. regimen achieves robust efficacy in patients with PsA with limited decreases in hemoglobin or occurrence of serious infections, even under scenarios of increased exposures due to intrinsic or extrinsic factors.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Using model‐based approaches, characterization of the relationships between upadacitinib plasma exposures and efficacy/safety supported optimal dose selection for upadacitinib use in patients with PsA, benefit‐risk evaluation, and regulatory filings for upadacitinib.     

A longitudinal study of cytochrome P450 2D6 (CYP2D6) activity during adolescence

CYP2D6 substrates are among the most highly prescribed medications in teenagers and also commonly associated with serious adverse events. To investigate the relative contributions of genetic variation, growth, and development on CYP2D6 activity during puberty, healthy children and adolescents 7–15 years of age at enrollment participated in a longitudinal phenotyping study involving administration of 0.3 mg/kg dextromethorphan (DM) and 4‐h urine collection every 6 months for 3 years (7 total visits). At each visit, height, weight, and sexual maturity were recorded, and CYP2D6 activity was determined as the urinary molar ratio of DM to its metabolite dextrorphan (DX). A total of 188 participants completed at least one visit, and 102 completed all seven study visits. Following univariate analysis, only CYP2D6 activity score (p < 0.001), urinary pH (p < 0.001), weight (p = 0.018), and attention‐deficit/hyperactivity disorder (ADHD) diagnosis (p < 0.001) were significantly correlated with log(DM/DX). Results of linear mixed model analysis with random intercept, random slope covariance structure revealed that CYP2D6 activity score had the strongest effect on log(DM/DX), with model‐estimated average log(DM/DX) being 3.8 SDs higher for poor metabolizers than for patients with activity score 3. A moderate effect on log(DM/DX) was observed for sex, and smaller effects were observed for ADHD diagnosis and urinary pH. The log(DM/DX) did not change meaningfully with age or pubertal development. CYP2D6 genotype remains the single, largest determinant of variability in CYP2D6 activity during puberty. Incorporation of genotype‐based dosing guidelines should be considered for CYP2D6 substrates given the prevalent use of these agents in this pediatric age group.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Several CYP2D6 substrates are used in the management of neurodevelopmental, behavioral, and psychiatric disorders in children and adolescents, often off‐label, for indications that often differ from the adult conditions for which the medications originally were developed. Therefore, little information is available to guide dosing in pediatric patients, and even less regarding the influence of growth and development on the processes influencing drug disposition and response.

• WHAT QUESTION DID THIS STUDY ADDRESS?

What is the relative contribution of genetic variation and the processes of growth and development on variability in CYP2D6 activity during puberty?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

CYP2D6 genotype remains the single, largest biological determinant of variability of CYP2D6 activity during puberty. Effects of factors associated with growth and sexual maturation are small and have limited ability to explain variability in CYP2D6 activity.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Incorporation of genotype‐based dosing guidelines should be considered for CYP2D6 substrates, especially given the prevalent use of antipsychotic and antidepressant medications in children and adolescents. A challenge for the future remains to build on, and extend the accumulating database describing the relative contribution of ontogeny and genetic variation to observed variability in drug disposition and response across the continuum from birth to adulthood.     

Phase I studies of the safety,tolerability, pharmacokinetics,and pharmacodynamics of DS‐1211, a tissue‐nonspecific alkaline phosphatase inhibitor

Tissue‐nonspecific alkaline phosphatase (TNAP) hydrolyzes and inactivates inorganic pyrophosphate (PPi), a potent inhibitor of calcification; therefore, TNAP inhibition is a potential target to treat ectopic calcification. These two first‐in‐human studies evaluated safety, tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of single (SAD) and multiple‐ascending doses (MAD) of DS‐1211, a TNAP inhibitor. Healthy adults were randomized 6:2 to DS‐1211 or placebo, eight subjects per dose cohort. SAD study subjects received one dose of DS‐1211 (range, 3–3000 mg) or placebo, whereas MAD study subjects received DS‐1211 (range, 10–300 mg) once daily, 150 mg twice daily (b.i.d.), or placebo for 10 days. Primary end points were safety and tolerability. PK and PD assessments included plasma concentrations of DS‐1211, alkaline phosphatase (ALP) activity, and TNAP substrates (PPi, pyridoxal 5′‐phosphate [PLP], and phosphoethanolamine [PEA]). A total of 56 (DS‐1211: n = 42; placebo: n = 14) and 40 (DS‐1211: n = 30; placebo: n = 10) subjects enrolled in the SAD and MAD studies, respectively. In both studies, adverse events were mild or moderate and did not increase with dose. PKs of DS‐1211 were linear up to 100 mg administered as a single dose and 150 mg b.i.d. administered as a multiple‐dose regimen. In multiple dosing, there was minimal accumulation of DS‐1211. Increased DS‐1211 exposure correlated with dose‐dependent ALP inhibition and concomitant increases in PPi, PLP, and PEA. In two phase I studies, DS‐1211 appeared safe and well‐tolerated. Post‐treatment PD assessments were consistent with exposure‐dependent TNAP inhibition. These data support further evaluation of DS‐1211 for ectopic calcification diseases.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

In preclinical studies, successful inhibition of tissue‐nonspecific alkaline phosphatase (TNAP) decreased soft‐tissue calcification. However, TNAP inhibition is untested in humans, and the safety and pharmacological effects are unknown.

• WHAT QUESTION DID THIS STUDY ADDRESS?

What are the safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) effects of TNAP‐specific inhibitor DS‐1211?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

TNAP inhibition mediated by orally administered DS‐1211 appears to be safe and well‐tolerated in humans. The PD effects of DS‐1211 on alkaline phosphatase, inorganic pyrophosphate, pyridoxal 5′‐phosphate, and phosphoethanolamine suggest it can inhibit TNAP in humans. This is the first clinical trial with a TNAP‐specific inhibitor; its safety over 10 days and PK‐dependent profiles of TNAP inhibition were established.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Ectopic calcification lacks a direct and safe treatment. TNAP inhibition with DS‐1211 may provide a novel targeted therapy for excess soft‐tissue calcification.     

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.