Search

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by loss of tolerance to nuclear antigens. The formation of autoantibodies and the deposition of immune complexes trigger inflammatory tissue damage that can affect any part of the body. In most cases, SLE is a complex disease involving multiple genetic and environmental factors. Despite advances in the treatment of SLE, there is currently no cure for SLE and patients are treated with immunosuppressive drugs with significant side effects. The elucidation of rare monogenic forms of SLE has provided invaluable insights into the molecular mechanisms underlying systemic autoimmunity. Harnessing this knowledge will facilitate the development of more refined and reliable biomarker profiles for diagnosis, therapeutic monitoring, and outcome prediction, and guide the development of novel targeted therapies not only for monogenic lupus, but also for complex SLE., (© 2024. The Author(s).)

Introduction: Letermovir is a cytomegalovirus (CMV) terminase complex inhibitor approved for prophylaxis of CMV infection and disease in adult CMV-seropositive allogeneic hematopoietic cell transplantation (allo-HCT) recipients (R+). We report pharmacokinetics (PK), safety, and efficacy of letermovir in adolescent (12-18 years) allogeneic HCT recipients from an ongoing clinical study., Methods: In this phase 2b, multicenter, open-label study (NCT03940586), 28 adolescents received 480 mg letermovir [240 mg with cyclosporin A (CsA)] once daily orally or intravenously. Blood was collected for intensive (n = 14) plasma concentrations of letermovir. Intensive PK data were used for dose confirmation. Target exposure range 34,400-100,000 h × ng/mL for pediatric median exposures was based on model-predicted phase 3 population PK simulations in adult HCT recipients., Results: All participants were CMV-seropositive (body weight 28.7-95.0 kg). Of 12 PK-evaluable participants, 8 receiving 480 mg letermovir without CsA and 4 receiving 240 mg letermovir with CsA achieved exposures comparable to the adult exposure range. Exposure above the target but below the adult clinical program maximum was observed in 1 patient. Safety was consistent with previously described safety in adults. The proportion of participants with clinically significant CMV infection through week 24 post-HCT was comparable (24%) to that in the pivotal phase 3 study in adults (37.5%)., Conclusions: Administration of adult letermovir doses in this adolescent cohort resulted in exposures within adult clinical program margins and was associated with safety and efficacy similar to adults. Results support a letermovir dose of 480 mg (240 mg with CsA) in adolescent allo-HCT recipients., Competing Interests: A.H.G. has received research support from Gilead Sciences, Merck Sharp & Dohme and Pfizer; is a consultant for Amplyx, Astellas, Basilea, F2G, Gilead Sciences, Merck Sharp & Dohme and Pfizer and served on the speakers’ bureau of Astellas, Basilea, F2G, Gilead Sciences, Merck Sharp & Dohme and Pfizer. J.H.S. is supported by the German Cancer Consortium (DKTK). A.B.A. is a consultant for Novo Nordisk, Pfizer, Roche and Takeda. C.J.F. has no potential conflicts of interest to declare. B.H., J.B.M., M.P., K.M. and C.B. are current employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, and may own stock and/or stock options in Merck & Co., Inc., Rahway, NJ. V.L.T., C.F. and L.C. are former employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ and may own stock and/or stock options in Merck & Co., Inc., Rahway, NJ., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

UNC93B1 is critical for trafficking and function of nucleic acid-sensing Toll-like receptors (TLRs) TLR3, TLR7, TLR8, and TLR9, which are essential for antiviral immunity. Overactive TLR7 signaling induced by recognition of self-nucleic acids has been implicated in systemic lupus erythematosus (SLE). Here, we report UNC93B1 variants (E92G and R336L) in four patients with early-onset SLE. Patient cells or mouse macrophages carrying the UNC93B1 variants produced high amounts of TNF-α and IL-6 and upon stimulation with TLR7/TLR8 agonist, but not with TLR3 or TLR9 agonists. E92G causes UNC93B1 protein instability and reduced interaction with TLR7, leading to selective TLR7 hyperactivation with constitutive type I IFN signaling. Thus, UNC93B1 regulates TLR subtype-specific mechanisms of ligand recognition. Our findings establish a pivotal role for UNC93B1 in TLR7-dependent autoimmunity and highlight the therapeutic potential of targeting TLR7 in SLE.

Aims: The aims of this systematic review were to (1) identify assessment approaches of Indigenous food sovereignty using the core domains of community ownership, inclusion of traditional food knowledge, inclusion/promotion of cultural foods and environmental/intervention sustainability, (2) describe Indigenous research methodologies when assessing Indigenous food sovereignty., Methods: Guided by Indigenous members of the research team, a systematic review across four databases (Medline, Embase, CINAHL and PsycINFO) was performed. Studies in any language from 1996 to 2021, that used one or more of the core domains (identified from a recent scoping review) of community ownership, inclusion of traditional food knowledge, inclusion/promotion of cultural foods and environmental/intervention sustainability were included., Results: From 20 062 records, after exclusion criteria were applied, 34 studies were included. Indigenous food sovereignty assessment approaches were mostly qualitative (n = 17) or mixed methods (n = 16), with interviews the most utilised (n = 29), followed by focus groups and meetings (n = 23) and validated frameworks (n = 7) as assessment tools. Indigenous food sovereignty assessment approaches were mostly around inclusion of traditional food knowledge (n = 21), or environmental/intervention sustainability (n = 15). Community-Based Participatory Research approaches were utilised across many studies (n = 26), with one-third utilising Indigenous methods of inquiry. Acknowledgement of data sovereignty (n = 6) or collaboration with Indigenous researchers (n = 4) was limited., Conclusion: This review highlights Indigenous food sovereignty assessment approaches in the literature worldwide. It emphasises the importance of using Indigenous research methodologies in research conducted by or with Indigenous Peoples and acknowledges Indigenous communities should lead future research in this area., (© 2023 The Authors. Nutrition & Dietetics published by John Wiley & Sons Australia, Ltd on behalf of Dietitians Australia.)

Aims: Letermovir, a cytomegalovirus (CMV) DNA terminase complex inhibitor, is a substrate of ABCB1 (P-glycoprotein; P-gp), organic anion transporting polypeptide (OATP)1B1/3, UDP-glucuronosyltransferase (UGT)1A1, UGT1A3 and possibly ABCG2 (breast cancer resistance protein; BCRP). A study was conducted to evaluate the effects of itraconazole, a prototypic ABCB1/ABCG2 inhibitor, on letermovir pharmacokinetics (PK) and the effects of letermovir on itraconazole PK., Methods: In an open-label, fixed-sequence study in 14 healthy participants, 200 mg oral itraconazole was administered once daily for 4 days. Following a 10-day washout, 480 mg oral letermovir was administered once daily for 14 days (Days 1-14) and then coadministered with 200 mg itraconazole once daily for 4 days (Days 15-18). Intensive PK sampling was performed for letermovir and itraconazole. PK and safety were evaluated., Results: Letermovir geometric mean ratio (GMR; 90% confidence interval [CI]) for area under the concentration-time curve from time 0 to 24 h (AUC 0-24 ) was 1.33 (1.17, 1.51) and for maximum concentration (C max ) was 1.21 (1.05, 1.39) following administration with/without itraconazole. Itraconazole GMR (90% CI) for AUC 0-24 was 0.76 (0.71, 0.81) and for C max was 0.84 (0.76, 0.92) following administration with/without letermovir. Coadministration of letermovir with itraconazole was generally well tolerated., Conclusions: The increase in letermovir exposure with coadministration of itraconazole is likely predominantly due to inhibition of intestinal ABCB1 and potentially ABCG2 transport. The mechanism for the decrease in itraconazole exposure is unknown. The modest changes in letermovir and itraconazole PK are not considered clinically meaningful., (© 2023 British Pharmacological Society.)

Competing Interests: DMK reports travel support from the International Fund for Agricultural Development to attend as an observer to the UNPFII. GR reports travel support from the National Indian Health Board (NIHB) to attend meetings on the Indigenous determinants of health, an NIHB conference, and the World Health Assembly meeting in Geneva, and travel support from the UN Department of Economic and Social Affairs (secretariat to the UNPFII) to attend the UNPFII as an unpaid Expert Member and Vice Chair of the UNPFII. All other authors report no competing interests. NR, PR, DKW, AK, and GR were volunteer coauthors of the study Indigenous determinants of health in the 2030 Agenda for Sustainable Development(7) that is discussed in this Comment; PR, DMK, DKW, and AK were in attendance at the UNPFII meeting as observers.

Letermovir is approved for use in cytomegalovirus-seropositive hematopoietic stem cell transplant recipients and is investigated in other transplant settings. Nonlinear pharmacokinetics (PKs) were observed in clinical studies after intravenous and oral dosing across a wide dose range, including the efficacious doses of 240 and 480 mg. A physiologically-based PK (PBPK) model for letermovir was built to develop a plausible explanation for the nonlinear PKs observed in clinical studies. In vitro studies suggested that letermovir elimination and distribution are mediated by saturable uridine glucuronosyltransferases (UGT)-metabolism and by saturable hepatic uptake via organic anion-transporting polypeptides (OATP) 1B. A sensitivity analysis of parameters describing the metabolism and distribution mechanisms indicated that the greater than dose-proportional increase in letermovir exposure is best described by a saturable OATP1B-mediated transport. This PBPK model was further used to evaluate the drug interaction potential between letermovir and everolimus, an immunosuppressant that may be co-administered with letermovir depending on regions. Because letermovir inhibits cytochrome P450 (CYP) 3A and everolimus is a known CYP3A substrate, an interaction when concomitantly administered is anticipated. The drug-drug interaction simulation confirmed that letermovir will likely increase everolimus are under the curve by 2.5-fold, consistent with the moderate increase in exposure observed with midazolam in the clinic. The output highlights the importance of drug monitoring, which is common clinical practice for everolimus to maintain safe and efficacious drug concentrations in the targeted patient population when concomitantly administered with letermovir., (© 2023 Merck Sharp and Dohme LLC. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Letermovir inhibits renal tubular organic anion transporter 3 (OAT3) in vitro and is predicted to inhibit OAT3 in vivo. Acyclovir, a substrate for OAT3, is likely to be coadministered with letermovir; therefore, letermovir may increase acyclovir concentrations. A drug-drug interaction study was conducted in healthy participants (N = 16) to assess the effect of letermovir on acyclovir pharmacokinetics. On Day 1, participants received a single oral dose of 400 mg acyclovir; on Days 2-7, participants received oral doses of 480 mg letermovir once daily with a single oral dose of 400 mg acyclovir coadministered on Day 7. Coadministration with letermovir resulted in geometric mean ratios (90% confidence intervals) for acyclovir area under the concentration-time curve from administration to infinity and maximum plasma concentration of 1.02 (0.87-1.20) and 0.82 (0.71-0.93), respectively. No notable safety issues were reported. No clinically significant interaction was observed between letermovir and acyclovir in healthy participants and no dose adjustment is required for coadministration., (© 2022 British Pharmacological Society.)

Competing Interests: We declare no competing interests.

Introduction Accurately determining the supply and demand of hospital beds for new admissions can help prevent adverse patient outcomes. Quantitative analysis of modern electronic medical record data can help predict supply and demand for unoccupied staffed hospital beds (SEDs) and aid in eliminating human approximations, standardizing daily work through concrete and objective data. The purpose of this study was to reduce variability and human error in predicting the number of SEDs needed. Methods In this study,the authors analyzed bed calculator data from a medium-sized, suburban medical center to evaluate the efficacy of a unique bed calculator prediction tool to determine the need for SEDs. The calculator aggregates multiple key reference factors available through the bed calculator system into a cohesive linear regression model. Results Compared with human estimation, the authors found that the bed calculator is able to predict the number of SEDs needed more effectively. That being said, there was no significant difference in the average boarding times pre- and postintervention, indicating that the bed calculator did not result in decreased boarding times for patients. Discussion These findings establish the efficacy of the bed calculator and its ability to align bed supply and demand. Because patient boarding times depend on the system's patient flow management, future studies should focus on how to improve various streams of communication and coordination.

Objectives: The COVID-19 pandemic has highlighted the importance of access to telehealth as an alternative model of service during social restrictions and for urban and remote communities alike. This study aimed to elucidate whether First Nations and culturally and linguistically diverse (CALD) patients also benefited from the resource before or during the pandemic., Study Design: This study was a scoping review., Methods: A scoping review of MEDLINE, CINAHL and PsycINFO databases from 2000 to 2021 was performed. Paired authors independently screened titles, abstracts and full texts. A narrative synthesis was undertaken after data extraction using a standard template by a team including First Nations and CALD researchers., Results: Seventeen studies (N = 4,960 participants) mostly qualitative, covering First Nations and CALD patient recipients of telehealth in the United States, Canada, Australia, and the Pacific Islands, met the inclusion criteria. Telehealth was perceived feasible, satisfactory, and acceptable for the delivery of health screening, education, and care in mental health, diabetes, cancer, and other chronic conditions for remote and linguistically isolated populations. The advantages of convenience, lower cost, and less travel promoted uptake and adherence to the service, but evidence was lacking on the wider availability of technology and engagement of target communities in informing priorities to address inequalities., Conclusions: Further studies with larger samples and higher level evidence methods involving First Nations and CALD people as co-designers will assist in filling the gap of safety and cultural competency., (Copyright © 2022 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.)

Letermovir (MK-8228/AIC246) is a cytomegalovirus (CMV) DNA terminase complex inhibitor for CMV prophylaxis in adult patients undergoing hematopoietic stem cell transplant. It is cytochrome P450 (CYP) 3A inhibitor and inhibits organic anion transporting polypeptide 1B1/3 and breast cancer resistance protein transporters. Atorvastatin (ATV), a commonly used treatment for hypercholesterolemia, is a substrate of organic anion transporting polypeptide 1B1, potentially breast cancer resistance protein, and CYP3A. As letermovir may be coadministered with ATV, the effect of multiple-dose letermovir 480 mg once daily on the pharmacokinetics of single-dose ATV 20 mg and its metabolites (ortho-hydroxyatorvastatin [o-OH-ATV] and para-hydroxyatorvastatin [p-OH-ATV]) was evaluated in an open-label trial in healthy female adults (N = 14). ATV area under the plasma concentration-time curve from time 0 to infinity and maximum plasma concentration (C max ) increased ≈3-fold with letermovir coadministration. The time to ATV C max also increased, while apparent clearance decreased. The exposures of o-OH-ATV and p-OH-ATV were comparable in the presence versus absence of letermovir; however, o-OH-ATV C max decreased by 60% with coadministration, while p-OH-ATV C max was similar. Due to the increase in ATV exposure with letermovir coadministration, statin-associated adverse events such as myopathy should be closely monitored following coadministration. The dose of ATV should not exceed 20 mg daily when coadministered with letermovir., (© 2022, The American College of Clinical Pharmacology.)

Rifampin has acute inhibitory and chronic inductive effects that can cause complex drug-drug interactions. Rifampin inhibits transporters including organic-anion-transporting polypeptide (OATP)1B and P-glycoprotein (P-gp), and induces enzymes and transporters including cytochrome P450 3A, UDP-glucuronosyltransferase (UGT)1A, and P-gp. This study aimed to separate inhibitory and inductive effects of rifampin on letermovir disposition and elimination (indicated for cytomegalovirus prophylaxis in hematopoietic stem cell transplant recipients). Letermovir is a substrate of UGT1A1/3, P-gp, and OATP1B, with its clearance primarily mediated by OATP1B. Letermovir (single-dose) administered with rifampin (single-dose) resulted in increased letermovir exposure through transporter inhibition. Chronic coadministration with rifampin (inhibition plus potential OATP1B induction) resulted in modestly decreased letermovir exposure vs. letermovir alone. Letermovir administered 24 hours after the last rifampin dose (potential OATP1B induction) resulted in markedly decreased letermovir exposure. These data suggest rifampin may induce transporters that clear letermovir; the modestly reduced letermovir exposure with chronic rifampin coadministration likely reflects the net effect of inhibition and induction. OATP1B endogenous biomarkers coproporphyrin (CP) I and glycochenodeoxycholic acid-sulfate (GCDCA-S) were also analyzed; their exposures increased after single-dose rifampin plus letermovir, consistent with OATP1B inhibition and prior reports of inhibition by rifampin alone. CP I and GCDCA-S exposures were substantially reduced with letermovir administered 24 hours after the last dose of rifampin vs. letermovir plus chronic rifampin coadministration. This study suggests that OATP1B induction may contribute to reduced letermovir exposure after chronic rifampin administration, although given the complexity of letermovir disposition alternative mechanisms are not fully excluded., (© 2021 Merck Sharp & Dohme Corp. Clinical Pharmacology & Therapeutics © 2021 American Society for Clinical Pharmacology and Therapeutics.)

Recognizing the challenges of determining the relative contribution of different drug metabolizing enzymes to the metabolism of slowly metabolized compounds, a cytochrome P450 reaction phenotyping (CRP) method using cocultured human hepatocytes (HEPATOPAC) has been established. In this study, the emphasis on the relative contribution of different cytochrome P450 (P450) isoforms was assessed by persistently inhibiting P450 isoforms over 7 days with human HEPATOPAC. P450 isoform-selective inhibition was achieved with the chemical inhibitors furafylline (CYP1A2), tienilic acid (CYP2C9), (+)- N -3-benzylnirvanol (CYP2C19), paroxetine (CYP2D6), azamulin (CYP3A), and a combination of 1-aminobenzotriazole and tienilic acid (broad spectrum inhibition of P450s). We executed this CRP method using HEPATOPAC by optimizing for the choice of P450 inhibitors, their selectivity, and the temporal effect of inhibitor concentrations on maintaining selectivity of inhibition. In general, the established CRP method using potent and selective chemical inhibitors allows to measure the relative contribution of P450s and to calculate the fraction of metabolism ( f m ) of low-turnover compounds. Several low-turnover compounds were used to validate this CRP method by determining their hepatic intrinsic clearance and f m , with comparison with literature values. We established the foundation of a robust CRP for low-turnover compound test system which can be expanded to include inhibition of other drug metabolizing enzymes. This generic CRP assay, using human long-term hepatocyte cultures, will be an essential tool in drug development for new chemical entities in the quantitative assessment of the risk as a victim of drug-drug interactions. SIGNIFICANCE STATEMENT: An ongoing trend is to develop drug candidates which have limited metabolic clearance. The current studies report a generic approach to conducting reaction phenotyping studies with human HEPATOPAC, focusing on P450 metabolism of low-turnover compounds. Potent and selective chemical inhibitors were used to assess the relative contribution of the major human P450s. Validation was achieved by confirming hepatic intrinsic clearance and fraction of metabolism for previously reported low-turnover compounds. This approach is adaptable for assessment of all drug metabolizing enzymes., (Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics.)

Background: Recurrent congestion in cardiac amyloidosis (CA) remains a management challenge, often requiring high dose diuretics and frequent hospitalizations. Innovative outpatient strategies are needed to effectively manage heart failure (HF) in patients with CA. Ambulatory diuresis has not been well studied in restrictive cardiomyopathy. Therefore, we aimed to examine the outcomes of an ambulatory diuresis clinic in the management of congestion related to CA., Methods and Results: We retrospectively studied patients with CA seen in an outpatient HF disease management clinic for (1) safety outcomes of ambulatory intravenous (IV) diuresis and (2) health care utilization. Forty-four patients with CA were seen in the clinic a total of 203 times over 6 months. Oral diuretics were titrated at 96 (47%) visits. IV diuretics were administered at 56 (28%) visits to 17 patients. There were no episodes of severe acute kidney injury or symptomatic hypotension. There was a significant decrease in emergency department and inpatient visits and associated charges after index visit to the clinic. The proportion of days hospitalized per 1000 patient days of follow-up decreased as early as 30 days (147.3 vs 18.1/1000 patient days of follow-up, P< .001) and persisted through 180 days (33.6 vs 22.9/1000 patient days of follow-up, P< .001) pre- vs post-index visit to the clinic., Conclusions: We demonstrate the feasibility of ambulatory IV diuresis in patients with CA. Our findings also suggest that use of a HF disease management clinic may reduce acute care utilization in patients with CA. Leveraging multidisciplinary outpatient HF clinics may be an effective alternative to hospitalization in patients with HF due to CA, a population who otherwise carries a poor prognosis and contributes to high health care burden., Competing Interests: Conflicts of Interest None., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Letermovir is a prophylactic agent for cytomegalovirus infection and disease in adult cytomegalovirus-seropositive recipients of allogeneic hematopoietic stem cell transplant. As the antifungal agent fluconazole is administered frequently in transplant recipients, a drug-drug interaction study was conducted between oral letermovir and oral fluconazole. A phase 1 open-label, fixed-sequence study was performed in healthy females (N = 14, 19-55 years). In Period 1, a single dose of fluconazole 400 mg was administered. Following a 14-day washout, a single dose of letermovir 480 mg was administered (Period 2), and after a 7-day washout, single doses of fluconazole 400 mg and letermovir 480 mg were coadministered in Period 3. Pharmacokinetics and safety were evaluated. The pharmacokinetics of fluconazole and letermovir were not meaningfully changed following coadministration. Fluconazole geometric mean ratio (GMR; 90% confidence interval [CI]) with letermovir for area under the concentration-versus-time curve from time 0 to infinity (AUC 0-∞ ) was 1.03 (0.99-1.08); maximum concentration (C max ) was 0.95 (0.92-0.99). Letermovir AUC 0-∞ GMR (90%CI) was 1.11 (1.01-1.23), and C max was 1.06 (0.93-1.21) following coadministration with fluconazole. Coadministration of fluconazole and letermovir was generally well tolerated., (© 2020, The American College of Clinical Pharmacology.)

Background: Letermovir is approved for prophylaxis of cytomegalovirus infection and disease in cytomegalovirus-seropositive hematopoietic stem-cell transplant (HSCT) recipients., Objective: HSCT recipients are required to take many drugs concomitantly. The pharmacokinetics, absorption, distribution, metabolism, and excretion of letermovir and its potential to inhibit metabolizing enzymes and transporters in vitro were investigated to inform on the potential for drug-drug interactions (DDIs)., Methods: A combination of in vitro and in vivo studies described the absorption, distribution, metabolism, and routes of elimination of letermovir, as well as the enzymes and transporters involved in these processes. The effect of letermovir to inhibit and induce metabolizing enzymes and transporters was evaluated in vitro and its victim and perpetrator DDI potentials were predicted by applying the regulatory guidance for DDI assessment., Results: Letermovir was a substrate of CYP3A4/5 and UGT1A1/3 in vitro. Letermovir showed concentration- dependent uptake into organic anionic transporting polypeptide (OATP)1B1/3-transfected cells and was a substrate of P-glycoprotein (P-gp). In a human ADME study, letermovir was primarily recovered as unchanged drug and minor amounts of a direct glucuronide in feces. Based on the metabolic pathway profiling of letermovir, there were few oxidative metabolites in human matrix. Letermovir inhibited CYP2B6, CYP2C8, CYP3A, and UGT1A1 in vitro, and induced CYP3A4 and CYP2B6 in hepatocytes. Letermovir also inhibited OATP1B1/3, OATP2B1, OAT3, OCT2, BCRP, BSEP, and P-gp., Conclusion: The body of work presented in this manuscript informed on the potential for DDIs when letermovir is administered both intravenously and orally in HSCT recipients., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

As rifampicin can cause the induction and inhibition of multiple metabolizing enzymes and transporters, it has been challenging to accurately predict the complex drug-drug interactions (DDIs). We previously constructed a physiologically-based pharmacokinetic (PBPK) model of rifampicin accounting for the components for the induction of cytochrome P450 (CYP) 3A/CYP2C9 and the inhibition of organic anion transporting polypeptide 1B (OATP1B). This study aimed to expand and verify the PBPK model for rifampicin by incorporating additional components for the induction of OATP1B and CYP2C8 and the inhibition of multidrug resistance protein 2. The established PBPK model was capable of accurately predicting complex rifampicin-induced alterations in the profiles of glibenclamide, repaglinide, and coproporphyrin I (an endogenous biomarker of OATP1B activities) with various dosing regimens. Our comprehensive rifampicin PBPK model may enable quantitative prediction of DDIs across diverse potential victim drugs and endogenous biomarkers handled by multiple metabolizing enzymes and transporters., (© 2019 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

Letermovir (AIC246, MK-8228) is a human cytomegalovirus terminase inhibitor indicated for the prophylaxis of cytomegalovirus infection and disease in allogeneic hematopoietic stem cell transplant recipients that is also being investigated for use in other transplant settings. Many transplant patients receive immunosuppressant drugs, of which several have narrow therapeutic ranges. There is a potential for the coadministration of letermovir with these agents, and any potential effect on their pharmacokinetics (PK) must be understood. Five phase 1 trials were conducted in 73 healthy female participants to evaluate the effect of letermovir on the PK of cyclosporine, tacrolimus, sirolimus, and mycophenolic acid (active metabolite of mycophenolate mofetil [MMF]), as well as the effect of cyclosporine and MMF on letermovir PK. Safety and tolerability were also assessed. Coadministration of letermovir with cyclosporine, tacrolimus, and sirolimus resulted in 1.7-, 2.4-, and 3.4-fold increases in area under the plasma concentration-time curve and 1.1-, 1.6-, and 2.8-fold increases in maximum plasma concentration, respectively, of the immunosuppressants. Coadministration of letermovir and MMF had no meaningful effect on the PK of mycophenolic acid. Coadministration with cyclosporine increased letermovir area under the plasma concentration-time curve by 2.1-fold and maximum plasma concentration by 1.5-fold, while coadministration with MMF did not meaningfully affect the PK of letermovir. Given the increased exposures of cyclosporine, tacrolimus, and sirolimus, frequent monitoring of concentrations should be performed during administration and at discontinuation of letermovir, with dose adjustment as needed. These data support the reduction in clinical dosage of letermovir (to 240 mg) upon coadministration with cyclosporine., (© 2019, The American College of Clinical Pharmacology.)

The fraction unbound in the incubation, f u,inc , is an important parameter to consider in the evaluation of intrinsic clearance measurements performed in vitro in hepatocytes or microsomes. Reliable estimates of f u,inc based on a compound's structure have the potential to positively impact the screening timelines in drug discovery. Previous works suggested that f u,inc is primarily driven by passive processes and can be described using physicochemical properties such as lipophilicity and the protonation state of the molecule. While models based on these principles proved predictive in relatively small datasets that included marketed drugs, their applicability domain has not been extensively explored. The work presented here from the in silico ADME discussion group (part of the International Consortium for Innovation through Quality in Pharmaceutical Development, the IQ consortium) describes the accuracy of these models in large proprietary datasets that include several thousand of compounds across chemical space. Overall, the models do well for compounds with low lipophilicity. In other words, the equations correctly predict that f u,inc is, in general, above 0.5 for compounds with a calculated logP of less than 3. When applied to lipophilic compounds, the models failed to produce quantitatively accurate predictions of f u,inc , with a high risk of underestimating binding properties. These models can, therefore, be used quantitatively for less lipophilic compounds. On the other hand, internal machine-learning models using a company's own proprietary dataset also predict compounds with higher lipophilicity reasonably well. Additionally, the data shown indicate that microsomal binding is, in general, a good proxy for hepatocyte binding.

The cytomegalovirus (CMV) viral terminase inhibitor letermovir is indicated for prevention of CMV infection in CMV-seropositive allogeneic hematopoietic stem cell transplant recipients. In this analysis, functional variants in solute carrier organic anion transporter family member 1B1 (SLCO1B1), uridine diphosphate-glucuronosyltransferase 1A1 (UGT1A1), and breast cancer resistance protein (BCRP) were assessed for effects on letermovir pharmacokinetics (PK) using pooled genetic information from 296 participants in 12 phase 1 studies. Letermovir area under the plasma concentration-time curve (AUC) was increased in carriers of the SLCO1B1 variant rs4149056 C allele relative to noncarriers with a geometric mean ratio (GMR) of 1.18 (95% confidence interval [CI], 1.06-1.30) for carriers of 1 copy and 1.42 (1.10-1.84) for carriers of 2 copies of the risk allele C compared with noncarriers. The SLCO1B1 variant rs4149032 T allele was associated with a decrease in letermovir AUC with GMR (95%CI) of 0.93 (0.85-1.02) and 0.82 (0.73-0.92) for carriers of 1 and 2 copies of the risk allele T, respectively, compared with noncarriers. The UGT1A1*6 variant rs4148323 A allele was present predominantly in Asian participants and was associated with an increase in letermovir AUC compared with noncarriers (GMR, 1.36; 95%CI, 1. 1.07-1.74). SLCO1B1 variant rs2306283, UGT1A1*28 TA promoter repeat, and BCRP variant rs2231142 had no effect on letermovir PK. Together, these data suggest that variants of enzymes and transporters that are involved in the disposition of letermovir in vitro may account for some variability in letermovir PK, but do not affect exposure to a clinically relevant extent., (© 2019, The American College of Clinical Pharmacology.)

Letermovir is a human cytomegalovirus (CMV) terminase inhibitor for the prophylaxis of CMV infection in allogeneic hematopoietic stem-cell transplant (HSCT) recipients. In vitro, letermovir is a time-dependent inhibitor and an inducer of cytochrome P450 (CYP)3A, and an inhibitor of CYP2C8 and organic anion transporting polypeptide (OATP)1B. A stepwise approach was taken to qualify the interaction model of an existing letermovir physiologically based pharmacokinetic model to predict letermovir interactions with CYP3A and OATP1B. The model was then used to prospectively predict the interaction between letermovir and CYP2C8 substrates such as repaglinide, a substrate of CYP2C8, CYP3A, and OATP1B. The results showed that letermovir modestly increased the exposure of CYP2C8 substrates. These results were used to inform the US prescribing information in the absence of clinical drug-drug interaction studies. In addition, midazolam interactions with letermovir at therapeutic doses were also simulated to confirm that letermovir is a moderate CYP3A inhibitor., (© 2018 American Society for Clinical Pharmacology and Therapeutics.)

Aims: E-health-based technologies also play an increasing role in the collection of patient- reported outcomes (ePRO). However, it remains unclear how feasible and powerful e-health applications are in the collection of PRO. Therefore, it should be examined to what extent the requirements for the use of technology-based PRO instruments has already been explored in order to allow its broad use in the "e-health world". Specifically, the research focus is on practicability, capability and technical implementation of ePRO. The design of the basic legal requirements for the conduct of PRO interviews and how the challenges of ePRO have already been harmonized here need to be examined.Methods Literature study: selective literature research in Pubmed as well as in the databases of DIMDI, G-BA, FDA and EMA., Results: Current scientific knowledge about hurdles, acceptance and usefulness in relation to sociodemografic factors, health status and technical skills as well as about technical implementation is low. The legal standards for ePRO are restricted only to the composition of the survey instrument and methodology quality criteria. There are no prerequisites for a broad use of ePRO, which is why therapeutic measures should not be based on them., Conclusion: The standards of the legislators must be specified and adapted to the requirements of ePRO. Because the design of the tool surface and the rate of usability can influence the response behavior of the patients, the focus should be on the reliability and validity of ePRO surveys in the context of their implementation in relation to the patients, disease, questionnaire and ePRO-specific variables, which determine the response behavior, in order not to endanger the meaningfulness of PRO surveys., Competing Interests: Die Autoren geben an, dass kein Interessenkonflikt besteht., (© Georg Thieme Verlag KG Stuttgart · New York.)

Letermovir is a human cytomegalovirus terminase inhibitor for cytomegalovirus infection prophylaxis in hematopoietic stem cell transplant recipients. Posaconazole (POS), a substrate of glucuronosyltransferase and P-glycoprotein, and voriconazole (VRC), a substrate of CYP2C9/19, are commonly administered to transplant recipients. Because coadministration of these azoles with letermovir is expected, the effect of letermovir on exposure to these antifungals was investigated. Two trials were conducted in healthy female subjects 18 to 55 years of age. In trial 1, single-dose POS 300 mg was administered alone, followed by a 7-day washout; then letermovir 480 mg once daily was given for 14 days with POS 300 mg coadministered on day 14. In trial 2, on day 1 VRC 400 mg was given every 12 hours; on days 2 and 3, VRC 200 mg was given every 12 hours, and on day 4 VRC 200 mg. On days 5 to 8, letermovir 480 mg was given once daily. Days 9 to 12 repeated days 1 to 4 coadministered with letermovir 480 mg once daily. In both trials, blood samples were collected for the assessment of the pharmacokinetic profiles of the antifungals, and safety was assessed. The geometric mean ratios (90%CIs) for POS+letermovir/POS area under the curve and peak concentration were 0.98 (0.83, 1.17) and 1.11 (0.95, 1.29), respectively. Voriconazole+letermovir/VRC area under the curve and peak concentration geometric mean ratios were 0.56 (0.51, 0.62) and 0.61 (0.53, 0.71), respectively. All treatments were generally well tolerated. Letermovir did not affect POS pharmacokinetics to a clinically meaningful extent but decreased VRC exposure. These results suggest that letermovir may be a perpetrator of CYP2C9/19-mediated drug-drug interactions., (© 2018, The American College of Clinical Pharmacology.)

Background: Communication skills are essential in a patient-centred health service and therefore in medical teaching. Although significant differences in communication behaviour of male and female students are known, gender differences in the performance of students are still under-reported. The aim of this study was to analyse gender differences in communication skills of medical students in the context of an OSCE exam (OSCE = Objective Structured Clinical Examination)., Methods: In a longitudinal trend study based on seven semester-cohorts, it was analysed if there are gender differences in medical students' communication skills. The students (self-perception) and standardized patients (SP) (external perception) were asked to rate the communication skills using uniform questionnaires. Statistical analysis was performed by using frequency analyses and t-tests in SPSS 21., Results: Across all ratings in the self- and the external perception, there was a significant gender difference in favour of female students performing better in the dimensions of empathy, structure, verbal expression and non-verbal expression. The results of male students deteriorated across all dimensions in the external perception between 2011 and 2014., Discussion & Conclusion: It is important to consider if gender-specific teaching should be developed, considering the reported differences between female and male students.

Purpose: Application of endosseous implants in prosthetic orbital reconstruction seems to be very successful, but few reports have evaluated cumulative survival rates of orbital implants over a long period. The aim of this study was to analyze long-term survival rates and potential influencing factors of orbital implants., Materials and Methods: A retrospective evaluation of patients treated with extraoral screw implants for retaining orbital prostheses from 1991 to 2014 was performed. Patient records were assessed for implant survival, demographic data, defect etiology, irradiation status, location of implant placement, implant systems, length, and retention type. Data were analyzed using the Kaplan-Meier method and log-rank test to compare survival curves., Results: A total of 282 orbital implants placed in 78 patients were evaluated during an observation period ranging from 2 to 268 months (mean: 94.97 months). The cumulative implant survival rate was 91.3% at 2 years, 80.5% at 5 years, 68.7% at 10 years, and 62.2% after 15 years. The survival rate was significantly higher in females (75.3%) vs males (47.3%), in supraorbital vs infraorbital implants (67.4% vs 51.5%), and in Brånemark implants (70.2%) vs Straumann implants (54.5%)., Conclusion: The presented data suggest that the long-term predictability of orbital implants revealed good to acceptable results. Factors such as female gender, localization in the supraorbital rim, a machined surface of the implant system, length, and magnetic retention seem to affect the implant survival rate positively, whereas irradiation status does not show any influence. These factors should be considered in planning future patient rehabilitation.

Background and Objectives: Prediction of metabolic clearance has been a challenge for compounds exhibiting minimal turnover in typical in vitro stability experiments. The aim of the current study is to evaluate the utilization of plated human hepatocytes to predict intrinsic clearance of low-turnover compounds., Methods: The disappearance of test compounds was determined for up to 48 h while enzyme activities in plated hepatocytes were monitored concurrently in a complimentary experiment., Results: Consistent with literature reports, marked time-dependent loss of cytochrome P450 (CYP) enzyme activities was observed during the 48-h incubation period. To account for the loss of enzyme activities, a term "fraction of activity remaining" was calculated based on area-under-the-curve derived from the average rate of activity loss (k avg ), and then applied as a correction factor for intrinsic clearance determination. Twelve compounds were selected in this study to cover phase I and phase II biotransformation pathways, with in vivo intrinsic clearance values, representing metabolic clearance only, ranging from 0.66 to 47 ml/min/kg. Determination of in vitro intrinsic clearance using three individual preparations of hepatocytes revealed a reasonably good agreement (generally within threefold) between the predicted and the observed metabolic clearance for all 12 compounds tested., Conclusions: The current results indicated that plated hepatocytes can be utilized to provide clearance predictions for compounds with low-turnover in humans when corrected for the loss in enzyme activities.

In our efforts to develop CGRP receptor antagonists as backups to MK-3207, 2, we employed a scaffold hopping approach to identify a series of novel oxazolidinone-based compounds. The development of a structurally diverse, potent (20, cAMP+HS IC50=0.67 nM), and selective compound (hERG IC50=19 μM) with favorable rodent pharmacokinetics (F=100%, t1/2=7h) is described. Key to this development was identification of a 3-substituted spirotetrahydropyran ring that afforded a substantial gain in potency (10 to 35-fold)., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Application of endosseous implants in prosthetic craniofacial reconstruction represents a secure and reliable method and is a well-established surgical procedure. In areas of low bone presentation, standardized plate-like titanium implants are available. For allowing a congruent fitting to the recipient site, these contemporary implants have to be manually adapted--implicating drawbacks in terms of time consumption, technical complexity, and insufficient functional outcome. Owing to these limitations, a custom-made patient-specific implant is introduced based on Digital Imaging and Communications in Medicine (DICOM) data and designed for optimal prosthetic reconstruction., Methods: For the first time, the application of a prefabricated patient-specific implant for retaining a craniofacial prosthesis is described. In a 64-year-old man with partial nasal defect standardized plate-like implants failed because of compromised bone quality due to Osler disease. To realize an implant-retained prosthetic reconstruction, a patient-specific implant was fabricated based on computer-aided design and computer-aided manufacturing (CAD/CAM) technology. This technique allows for considering the implant's ideal geometry as well as its correct placement of the required magnetic abutments. Furthermore, the surface of the implant can be designed for optimal hygienic conditions., Results: The patient-specific implant was successfully inserted in a time effective operating procedure. Follow-up at 6 months showed an excellent functional and aesthetic outcome., Conclusions: Application of prefabricated patient-specific implants offers prospectively an ideal tool for retaining craniofacial prostheses and should be considered a viable option in standard cases, but obligatory in anatomically demanding defects.

Optimum functional and aesthetic facial reconstruction is still a challenge in patients who suffer from inborn or acquired facial deformity. It is known that functional and aesthetic impairment can result in significant psychosocial strain, leading to the social isolation of patients who are affected by major facial deformities. Microvascular techniques and increasing experience in facial transplantation certainly contribute to better restorative outcomes. However, these technologies also have some drawbacks, limitations and unsolved problems. Extensive facial defects which include several aesthetic units and dentition can be restored by combining dental prostheses and anaplastology, thus providing an adequate functional and aesthetic outcome in selected patients without the drawbacks of major surgical procedures. Referring to some representative patient cases, it is shown how extreme facial disfigurement after oncological surgery can be palliated by combining intraoral dentures with extraoral facial prostheses using individualized treatment and without the need for major reconstructive surgery., (Copyright © 2015 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.)

Purpose: To develop a tool based on siRNA-mediated knockdown of hepatic P450 oxidoreductase (POR) to decrease the CYP-mediated metabolism of small molecule drugs that suffer from rapid metabolism in vivo, with the aim of improving plasma exposure of these drugs., Methods: siRNA against the POR gene was delivered using lipid nanoparticles (LNPs) into rats. The time course of POR mRNA knockdown, POR protein knockdown, and loss of POR enzyme activity was monitored. The rat livers were harvested to produce microsomes to determine the impact of POR knockdown on the metabolism of several probe substrates. Midazolam (a CYP3A substrate with high intrinsic clearance) was administered into LNP-treated rats to determine the impact of POR knockdown on midazolam pharmacokinetics., Results: Hepatic POR mRNA and protein levels were significantly reduced by administering siRNA and the maximum POR enzyme activity reduction (~85%) occurred 2 weeks post-dose. In vitro analysis showed significant reductions in metabolism of probe substrates due to POR knockdown in liver, and in vivo POR knockdown resulted in greater than 10-fold increases in midazolam plasma concentrations following oral dosing., Conclusions: Anti-POR siRNA can be used to significantly reduce hepatic metabolism by various CYPs as well as greatly increase the bioavailability of high clearance compounds following an oral dose, thus enabling it to be used as a tool to increase drug exposure in vivo.