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Introduction: Nirmatrelvir/ritonavir (NMV/r) is approved in the United States (US) and more than 70 other countries for the treatment of mild to moderate COVID-19 in nonhospitalized adults at high risk for severe disease. Because ritonavir inhibits several drug metabolizing enzymes, potential drug–drug interactions (DDIs) between ritonavir and concomitant medications are an important consideration for prescribers. Here, we conducted a real-world analysis of data from Pfizer's global safety database regarding adverse events (AEs) reported during use of NMV/r concomitantly with potentially interacting drugs. Methods: Data were extracted regarding DDI cases occurring from the start of NMV/r authorization through October 31, 2023. Results regarding concomitant treatment, specific AEs, and clinical outcomes are summarized. Overall NMV/r exposure was estimated based on packs of medication dispensed and was used to calculate reporting rates. Results: Among 19,617,670 patients exposed globally to NMV/r, 966 cases of potential DDIs were reported. Of these, 594 occurred in the US against an estimated US exposure of 14,646,990 patients, representing a reporting rate of 0.004%. Globally and in the United States, 66.8% and 77.3% of cases, respectively, were nonserious. Simvastatin and tacrolimus were the most frequently reported drugs associated with potential DDIs, and the most frequently reported AE regarding a specific event or symptom was dysgeusia (altered sense of taste), an AE known to be associated with NMV/r. Conclusions: Low reporting rates of DDIs support the potential for NMV/r treatment to be safely managed with careful use of available drug interaction resources to aid in risk mitigation. [ABSTRACT FROM AUTHOR]

Lipoprotein a (Lp(a)) is a lipid biomarker that binds cholesterol and bears independent cardiovascular risk. Strategies to lower the level of Lp(a) and mitigate such risk are important both for primary and secondary prevention. Currently there are no approved therapies targeting Lp(a) directly. Lipid lowering therapies prescribed routinely may have no effect on Lp(a) levels. Some agents such as niacin and estrogens can significantly decrease Lp(a), but their use is not recommended due to their adverse safety profile. Statins increase Lp(a) levels by 10-20%, questioning the benefit of such therapy when this biomarker is elevated. The Food and Drug Administration (FDA) endorses new agents to address dyslipidemia such as proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9-i) and Inclisiran, a small interfering RNA. These approaches have been shown to also significantly reduce Lp(a), but more clinical data is needed before implementing their use in clinical practice. Clinical trials are currently ongoing to test the efficacy of newly developed antisense oligonucleotides and small interfering RNAs targeting the gene encoding for Lp(a) in hepatocytes, while other investigations assess small molecules that inhibit Lp(a) assembly. This review summarizes the pathophysiology and clinical implications of Lp(a) elevation, and focuses on proposed Lp(a) therapies and the current state of the clinical trials of such novel agents. [ABSTRACT FROM AUTHOR]

Elevated plasma levels of lipoprotein(a) (Lp(a)) are a prevalent, independent, and causal risk factor for atherosclerotic cardiovascular disease and calcific aortic valve disease. Lp(a) consists of a lipoprotein particle resembling low density lipoprotein and the covalently-attached glycoprotein apolipoprotein(a) (apo(a)). Novel therapeutics that specifically and potently lower Lp(a) levels are currently in advanced stages of clinical development, including in large, phase 3 cardiovascular outcomes trials. However, fundamental unanswered questions remain concerning some key aspects of Lp(a) biosynthesis and catabolism as well as the true pathogenic mechanisms of the particle. In this review, we describe the salient biochemical features of Lp(a) and apo(a) and how they underlie the disease-causing potential of Lp(a), the factors that determine plasma Lp(a) concentrations, and the mechanism of action of Lp(a)-lowering drugs. [ABSTRACT FROM AUTHOR]

Fostemsavir is an approved gp120‐directed attachment inhibitor and prodrug for the treatment of human immunodeficiency virus type 1 infection in combination with other antiretrovirals (ARVs) in heavily treatment‐experienced adults with multi‐drug resistance, intolerance, or safety concerns with their current ARV regimen. Initial in vitro studies indicated that temsavir, the active moiety of fostemsavir, and its metabolites, inhibited organic cation transporter (OCT)1, OCT2, and multidrug and toxin extrusion transporters (MATEs) at tested concentration of 100 uM, although risk assessment based on the current Food and Drug Administration in vitro drug–drug interaction (DDI) guidance using the mechanistic static model did not reveal any clinically relevant inhibition on OCTs and MATEs. However, a DDI risk was flagged with EMA static model predictions. Hence, a physiologically based pharmacokinetic (PBPK) model of fostemsavir/temsavir was developed to further assess the DDI risk potential of OCT and MATEs inhibition by temsavir and predict changes in metformin (a sensitive OCT and MATEs substrate) exposure. No clinically relevant impact on metformin concentrations across a wide range of temsavir concentrations was predicted; therefore, no dose adjustment is recommended for metformin when co‐administered with fostemsavir. [ABSTRACT FROM AUTHOR]

Background: Levonorgestrel implant is a highly effective hormonal contraceptive, but its efficacy may be compromised when used with cytochrome enzyme inducers such as efavirenz. The primary aim of this study was to evaluate methods of mitigating the drug interaction. Methods: Using a physiologically-based pharmacokinetic (PBPK) model for levonorgestrel that we developed within the Simcyp® program, we evaluated a higher dose of levonorgestrel implant, a lower dose of efavirenz, and the combination of both, as possible methods to mitigate the interaction. In addition, we investigated the impact on levonorgestrel total and unbound concentrations of other events likely to be associated with efavirenz coadministration: changes in plasma protein binding of levonorgestrel (as with displacement) and high variability of efavirenz exposure (as with genetic polymorphism of its metabolism). The range of fraction unbound tested was 0.6% to 2.6%, and the range of efavirenz exposure ranged from the equivalent of 200 mg to 4800 mg doses. Results: Levonorgestrel plasma concentrations at any given time with a standard 150 mg implant dose are predicted to be approximately 68% of those of control when given with efavirenz 600 mg and 72% of control with efavirenz 400 mg. With double-dose levonorgestrel, the predictions are 136% and 145% of control, respectively. A decrease in levonorgestrel plasma protein binding is predicted to primarily decrease total levonorgestrel plasma concentrations, whereas higher efavirenz exposure is predicted to decrease total and unbound concentrations. Conclusions: Simulations suggest that doubling the dose of levonorgestrel, particularly in combination with 400 mg daily efavirenz, may mitigate the drug interaction. Changes in levonorgestrel plasma protein binding and efavirenz genetic polymorphism may help explain differences between model predictions and clinical data but need to be studied further. [ABSTRACT FROM AUTHOR]

Background: Rheumatoid arthritis (RA) is a chronic inflammatory disorder primarily targeting joints, significantly impacting patients' quality of life. The introduction of tumor necrosis factor-alpha (TNF-α) inhibitors has markedly improved RA management by reducing inflammation. However, these medications are associated with adverse skin reactions, which can vary greatly among patients due to genetic differences. Objectives: This study aimed to identify risk factors associated with skin adverse events by TNF-α in RA patients. Methods: A cohort study was conducted, encompassing patients with RA who were prescribed TNF-α inhibitors. This study utilized machine learning algorithms to analyze genetic data and identify markers associated with skin-related adverse events. Various machine learning algorithms were employed to predict skin and subcutaneous tissue-related outcomes, leading to the development of a risk-scoring system. Multivariable logistic regression analysis identified independent risk factors for skin and subcutaneous tissue-related complications. Results: After adjusting for covariates, individuals with the TT genotype of rs12551103, A allele carriers of rs13265933, and C allele carriers of rs73210737 exhibited approximately 20-, 14-, and 10-fold higher incidences of skin adverse events, respectively, compared to those with the C allele, GG genotype, and TT genotype. The machine learning algorithms used for risk prediction showed excellent performance. The risk of skin adverse events among patients receiving TNF-α inhibitors varied based on the risk score: 0 points, 0.6%; 2 points, 3.6%; 3 points, 8.5%; 4 points, 18.9%; 5 points, 36.7%; 6 points, 59.2%; 8 points, 90.0%; 9 points, 95.7%; and 10 points, 98.2%. Conclusions: These findings, emerging from this preliminary study, lay the groundwork for personalized intervention strategies to prevent TNF-α inhibitor-associated skin adverse events. This approach has the potential to improve patient outcomes by minimizing the risk of adverse effects while optimizing therapeutic efficacy. [ABSTRACT FROM AUTHOR]

Background/Objectives: The right-sided aortic arch (RAA) is an uncommon variation of the aortic arch (AA), characterized by the aorta crossing over the right main bronchus. In the RAA, the descending aorta can be found on either the right or left side of the spine. The current study comprises a comprehensive retrospective computed tomography angiography (CTA) investigation into the prevalence of the RAA within the Greek population. Additionally, we will conduct a systematic review and meta-analysis to elucidate both common and rare morphological variants of the RAA. This research is significant as it sheds light on the prevalence and characteristics of the RAA in a specific population, providing valuable insights for clinical practice. Methods: Two hundred CTAs were meticulously investigated for the presence of a RAA. In addition, the PubMed, Google Scholar, and Scopus online databases were thoroughly searched for studies referring to the AA morphology. The R programming language and RStudio were used for the pooled prevalence meta-analysis, while several subgroup analyses were conducted. Results: Original study: A unique case of 200 CTAs (0.5%) was identified with an uncommon morphology. The following branches emanated from the RAA under the sequence: the right subclavian artery (RSA), the right common carotid artery (RCCA), the left common carotid artery (LCCA), and the left vertebral artery (LVA) in common origin with the aberrant left subclavian artery (ALSA). The ALSA originated from a diverticulum (of Kommerell) and followed a retroesophageal course. Systematic Review and Meta-Analysis: Sixty-two studies (72,187 total cases) met the inclusion criteria. The pooled prevalence of the RAA with a mirror-image morphology was estimated at 0.07%, and the RAA with an ALSA was estimated at <0.01%. Conclusions: AA anomalies, specifically the RAA, raise clinical interest due to their coexistence with developmental heart anomalies and possible interventional complications. Congenital heart anomalies, such as the Tetralogy of Fallot and patent foramen ovale, coexisted with RAA mirror-image morphology. [ABSTRACT FROM AUTHOR]

Steel plate girders substitute conventional hot rolled I-shaped beams in case of high applied loads where it becomes uneconomic to use hot rolled beams. It is more economic to employ tapered sections following shape of bending moment distribution throughout the plate girder. Most of the bridges are designed as simple spans as it is cost-effective which results in pure shear stresses in the tapered end web panels. However, specific design guidelines for tapered plate girders under shear are not available. Initial geometrical imperfections (IGIs) are usually random and depend mainly on the fabrication, shipping and construction processes. As the amplitude of initial imperfection increases, through-thickness bending stresses are enlarged, resulting in a reduction in the ultimate shear strength of the plate girder. As such, this study aims at the investigation of the ultimate shear strength of tapered imperfect end web panels in steel plate girders. The effect of initial geometric imperfections (IGIs) on the ultimate and post-buckling shear strengths of these plate girders is studied using a validated numerical model. Around two hundred finite element models representing plate girders are constructed and analyzed to cover a wide range of geometric parameters including: aspect ratio of end web panel, depth–to-thickness ratio of end web plate, inertia of intermediate stiffeners, and angle of tapering. Moreover, effect of imperfection is considered. Results are used to conclude design guidelines for evaluating the ultimate shear strength of tapered imperfect end web panels. [ABSTRACT FROM AUTHOR]

Background and Objectives: Esmethadone (dextromethadone; d-methadone; S-methadone (+)-methadone; REL-1017) is a low potency N-methyl-D-aspartate (NMDA) receptor channel blocker that showed a rapid and sustained adjunctive antidepressant effects in patients with major depressive disorder with inadequate response to ongoing serotonergic antidepressant treatment. Previous studies indicated that esmethadone is partially excreted by the kidney (53.9% of the dose) and by the liver (39.1% of the dose). Methods: Here we studied the pharmacokinetics and safety of esmethadone after a single oral dose of 25 mg in subjects with different stages of kidney and liver impairment. Results: In subjects with a mild and moderate decrease in glomerular fraction rate (GFR), esmethadone Cmax and AUC0–inf values did not differ compared with healthy subjects. In patients with severe renal impairment, the ratios of Cmax and AUC0–inf values compared with healthy subjects were above 100% (138.22–176.85%) and, while modest, these increases reached statistical significance. In subjects with end stage renal disease (ESRD) undergoing intermittent hemodialysis (IHD), Cmax and AUC0–inf values were not statistically different compared with healthy subjects. IHD did not modified plasma total esmethadone concentrations in blood exiting versus entering the dialyzer. Dose adjustment is not warranted in subjects with mild-to-moderate impaired renal function. Dose reduction may be considered for select patients with severe renal disfunction. In subjects with mild-or-moderate hepatic impairment, Cmax and AUC0–inf were approximately 20–30% lower compared with healthy controls. The drug free fraction increased with the severity of hepatic impairment, from 5.4% in healthy controls to 8.3% in subjects with moderate hepatic impairment. Conclusion: Mild and moderate hepatic impairment has a minimal to modest impact on exposure to total or unbound esmethadone and dose adjustments are not warranted in subjects with mild and moderate hepatic impairment. Administration of esmethadone was well tolerated in healthy adult subjects, in subjects with mild or moderate hepatic impairment, and in subjects with mild moderate or severe renal impairment, including patients with ESRF undergoing dialysis. [ABSTRACT FROM AUTHOR]

Ritonavir is a potent inhibitor of the cytochrome P450 3A4 enzyme and is commonly used as a pharmacokinetic (PK) enhancer in antiviral therapies because it increases bioavailability of concomitantly administered antivirals. Decades of experience with ritonavir-enhanced HIV therapies and, more recently, COVID-19 therapies demonstrate that boosting doses of ritonavir are well tolerated, with an established safety profile. The mechanisms of PK enhancement by ritonavir result in the potential for drug–drug interactions (DDIs) with several classes of drugs, thus making co-medication management an important consideration with enhanced antiviral therapies. However, rates of DDIs with contraindicated medications are low, suggesting these risks are manageable by infectious disease specialists who have experience with the use of PK enhancers. In this review, we provide an overview of ritonavir's mechanisms of action and describe approaches and resources available to mitigate adverse events and manage concomitant medication in both chronic and short-term settings. [ABSTRACT FROM AUTHOR]

The advent of biologic drugs has revolutionized the treatment of Inflammatory Bowel Disease, increasing rates of response and mucosal healing in comparison to conventional therapies by allowing the treatment of corticosteroid-refractory cases and reducing corticosteroid-related side effects. However, biologic therapies (anti-TNFα inhibitors, anti-α4β7 integrin and anti-IL12/23) are still burdened by rates of response that hover around 40% (in biologic-naïve patients) or lower (for biologic-experienced patients). Moreover, knowledge of the mechanisms underlying drug resistance or loss of response is still scarce. Several cellular and molecular determinants are implied in therapeutic failure; genetic predispositions, in the form of single nucleotide polymorphisms in the sequence of cytokines or Human Leukocyte Antigen, or an altered expression of cytokines and other molecules involved in the inflammation cascade, play the most important role. Accessory mechanisms include gut microbiota dysregulation. In this narrative review of the current and most recent literature, we shed light on the mentioned determinants of therapeutic failure in order to pave the way for a more personalized approach that could help avoid unnecessary treatments and toxicities. [ABSTRACT FROM AUTHOR]

In persons with dyslipidemia, a high residual risk of cardiovascular disease remains despite lipid lowering therapy. Current cardiovascular risk prediction mainly focuses on low-density lipoprotein cholesterol (LDL-c) levels, neglecting other contributing risk factors. Moreover, the efficacy of LDL-c lowering by statins resulting in reduced cardiovascular risk is only partially effective. Secondly, from a metrological viewpoint LDL-c falls short as a reliable measurand. Both direct and calculated LDL-c tests produce inaccurate test results at the low end under aggressive lipid lowering therapy. As LDL-c tests underperform both clinically and metrologically, there is an urging need for molecularly defined biomarkers. Over the years, apolipoproteins have emerged as promising biomarkers in the context of cardiovascular disease as they are the functional workhorses in lipid metabolism. Among these, apolipoprotein B (ApoB), present on all atherogenic lipoprotein particles, has demonstrated to clinically outperform LDL-c. Other apolipoproteins, such as Apo(a) - the characteristic apolipoprotein of the emerging risk factor lipoprotein(a) -, and ApoC-III - an inhibitor of triglyceride-rich lipoprotein clearance -, have attracted attention as well. To support personalized medicine, we need to move to molecularly defined risk markers, like the apolipoproteins. Molecularly defined diagnosis and molecularly targeted therapy require molecularly measured biomarkers. This review provides a summary of the scientific validity and (patho)physiological role of nine serum apolipoproteins, Apo(a), ApoB, ApoC-I, ApoC-II, ApoC-III, ApoE and its phenotypes, ApoA-I, ApoA-II, and ApoA-IV, in lipid metabolism, their association with cardiovascular disease, and their potential as cardiovascular risk markers when measured in a multiplex apolipoprotein panel. [ABSTRACT FROM AUTHOR]

Background and Objective: Esmethadone (dextromethadone; d-methadone; S-methadone (+)-methadone; REL-1017) is the opioid inactive dextro-isomer of racemic methadone. Esmethadone is a low potency N-methyl-D-aspartate (NMDA) receptor channel blocker with higher affinity for GluN2D subtypes. Esmethadone showed robust, rapid, and sustained antidepressant effects in patients with major depressive disorder (MDD) with inadequate response to ongoing serotonergic antidepressant treatment. Methods: Here we described the results of in vitro and phase 1 clinical trials aimed at investigating the esmethadone metabolism and possible drug-drug interactions. Results: Esmethadone is primarily metabolized to EDDP (2-ethylene-1,5-dimethyl-3,3-diphenylpyrrolidine) by multiple enzymes, including CYP3A4/5 and CYP2B6. In vitro studies showed that esmethadone inhibits CYP2D6 with IC50 of 9.6 μM and is an inducer of CYP3A4/5. The clinical relevance of the inhibition of CYP2D6 and the induction of CYP3A4 were investigated by co-administering esmethadone and dextromethorphan (a substrate for CYP2D6) or midazolam (a substrate for CYP3A4) in healthy volunteers. The administration of esmethadone at the dosage of 75 mg (which is the loading dose administered to patients in MDD clinical trials) significantly increased the exposure (AUC) of both dextromethorphan and its metabolite dextrorphan by 2.71 and 3.11-fold, respectively. Esmethadone did not modify the pharmacokinetic profile of midazolam, while it increased Cmax and AUC of its metabolite 1′-hydroxymidazolam by 2.4- and 3.8-fold, respectively. A second study evaluated the effect of the CYP3A4 inhibitor cobicistat on the pharmacokinetics of esmethadone. Cobicistat slightly increase (+32%) the total exposure (AUC0–inf) of esmethadone. Conclusions: In summary, esmethadone demonstrated a negligible effect on CYP3A4 induction and its metabolism was not meaningfully affected by strong CYP3A4 inhibitors while it increased exposure of CYP2D6-metabolized drugs. [ABSTRACT FROM AUTHOR]

Introduction: Hypertriglyceridemia is the most prevalent dyslipidemia in patients with chronic kidney disease (CKD). However, research about fibrate treatment in CKD patients is limited, and assessing its benefits becomes challenging due to the frequent concurrent use of statins. Thus, this study is aimed to investigate the role of fibrate in CKD stage 3 patients with hypertriglyceridemia who did not receive other lipid-lowering agents. Methods: This study enrolled patients newly diagnosed CKD3 with LDLC< 100mg/dL and had never received statin or other lipid-lowering agents from Chang Gung Research Database. The participants were categorized into 2 groups based on the use of fibrate: fibrate group and non-fibrate group (triglyceride >200mg/dL but not receiving fibrate treatment). The inverse probability of treatment weighting was performed to balance baseline characteristics. Results: Compared with the non-fibrate group (n=2020), the fibrate group (n=705) exhibited significantly lower risks of major adverse cardiac and cerebrovascular events (MACCEs) (10.4% vs. 12.8%, hazard ratios [HRs]: 0.69, 95% confidence interval [CI]: 0.50 to 0.95), AMI (2.3% vs. 3.9%, HR: 0.52, 95% CI: 0.37 to 0.73), and ischemic stroke (6.3% vs. 8.0%, HR: 0.67, 95% CI: 0.52 to 0.85). The risk of all-cause mortality (5.1% vs. 4.5%, HR: 1.09, 95% CI: 0.67 to 1.79) and death from CV (2.8% vs. 2.3%, HR: 1.07, 95% CI: 0.29 to 2.33) did not significantly differ between the 2 groups. Conclusion: This study suggests that, in moderate CKD patients with hypertriglyceridemia but LDL-C < 100mg/dL who did not take other lipidlowering agents, fibrates may be beneficial in reducing cardiovascular events. [ABSTRACT FROM AUTHOR]

Intestinal P‐glycoprotein (P‐gp) activity plays a crucial role in modulating the oral bioavailability of its substrates. Fexofenadine has commonly been used as a P‐gp probe, although it is important to note the involvement of other drug transporters like, OATP1B1, OATP1B3, and OATP2B1. In vitro studies demonstrated an upregulation of P‐gp protein in response to exposure to pregnancy‐related hormones. The objective of this study was to investigate how intestinal P‐gp activity is impacted by menopausal status. This study sampled fexofenadine plasma concentrations over 0–12 h after probe drug administration from two groups of patients with breast cancer: premenopausal (n = 20) and postmenopausal (n = 20). Fexofenadine plasma concentrations were quantified using liquid‐chromatography tandem mass spectrometry. Area under the plasma concentration‐time curve from zero to infinity (AUCinf) was calculated through limited sampling strategies equation. Multiple linear regression was applied on AUCinf, maximum plasma concentration (Cmax), and time to Cmax. Postmenopausal patients showed a significant increase in Cmax (geometric mean and 95% confidence interval [CI] 143.54, 110.95–176.13 vs. 223.54 ng/mL, 161.02–286.06 and in AUCinf 685.55, 534.98–878.50 vs. 933.54 ng·h/mL 735.45–1184.99) compared to premenopausal patients. The carriers of the ABCB1 3435 allele T displayed higher Cmax values of 166.59 (95% CI: 129.44–214.39) compared to the wild type at 147.47 ng/mL (95% CI: 111.91–194.34, p = 0.02). In postmenopausal individuals, the decrease in P‐gp activity of ~40% may lead to an increased plasma exposure of orally administered P‐gp substrates. [ABSTRACT FROM AUTHOR]