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Background For decades, vitamin K antagonists and specifically warfarin, have been the sole agents used orally to manage thromboembolic conditions, including stroke and venous thromboembolism (VTE). Several factors lead to warfarin dose variability, including genetic and non-genetic factors which made warfarin management challenging especially at the initiation phase. To overcome the challenges with warfarin dosing at initiation, strategies other than conventional or fixed dosing were introduced and explored. Aim In this narrative review, we aim to discuss and critique the different dosing strategies for warfarin at initiation with more focus on genotype-guided warfarin dosing and the most recent supporting evidence for and against its use. Method Medline database was searched from 1965 to July 2021. Articles addressing different warfarin dosing methods were screened for inclusion. Results A number of methods exist for warfarin initiation. Studies comparing different dosing methods for initiation yielded conflicting outcomes due to differences in study design, population studied, comparator, and outcomes measured. Conclusions Looking at the big picture, the use of genetic dosing for warfarin initiation can lead to better outcomes. Whether these better outcomes are clinically or economically beneficial remains controversial.

BackgroundAdherence to a therapy, though a key factor for successful treatment, is low among patients with chronic conditions such as migraine. Dose frequency plays a major role in adherence. This study evaluated the impact of having flexible dosing options on acceptance of and adherence to a new migraine preventive therapy class among adults with migraine.MethodsIn this observational study, two 20-min online surveys were completed: one by physicians currently treating adult patients with migraine and the other by adults with migraine. Both surveys presented the participants with three scenarios: 1) only monthly, 2) only quarterly, and 3) both dosing options of the new medication are available. Physicians estimated the proportion of their migraine patients who would receive the new medication in each scenario. Patients were asked about their dosing preference when either or both options are available. Respondents were asked to rate the likelihood of their acceptance of and adherence to the therapy.Results400 physicians and 417 US adults with migraine completed the surveys. The availability of both dosing options yielded a significant increase in the proportion of patients expected to receive the new medication. The overall proportion of patients favoring monthly dosing (35%) was similar to the proportion favoring quarterly dosing (40%). Among those who preferred monthly dosing (n = 147), a greater proportion indicated they are more likely to fill the prescription (77% vs 56%, P < 0.05) and remain adherent (80% vs 57%, P < 0.05) when only monthly is available versus when only quarterly is available. Similarly, among those who preferred quarterly dosing (n = 166), a greater proportion indicated they are likely to fill (63% vs 55%, P < 0.05) and remain adherent (62% vs 54%, P < 0.05) when only quarterly is available compared with when only monthly is available.ConclusionsPhysicians anticipated that the proportion of patients to receive the new medication would increase when both dosing options are available. Patients stated that they are more likely to fill the prescription and adhere to the new therapy when their preferred dosing regimen is available.

The administered dose of a drug modulates whether patients will experience optimal effectiveness, toxicity including death, or no effect at all. Dosing is particularly important for diseases and/or drugs where the drug can decrease severe morbidity or prolong life. Likewise, dosing is important where the drug can cause death or severe morbidity. Since we believe there are many examples where more precise dosing could benefit patients, it is worthwhile to consider how to prioritize drug-disease targets. One key consideration is the quality of information available from which more precise dosing recommendations can be constructed. When a new more precise dosing scheme is created and differs significantly from the approved label, it is important to consider the level of proof necessary to either change the label and/or change clinical practice. The cost and effort needed to provide this proof should also be considered in prioritizing drug-disease precision dosing targets. Although precision dosing is being promoted and has great promise, it is underutilized in many drugs and disease states. Therefore, we believe it is important to consider how more precise dosing is going to be delivered to high priority patients in a timely manner. If better dosing schemes do not change clinical practice resulting in better patient outcomes, then what is the use? This review paper discusses variables to consider when prioritizing precision dosing candidates while highlighting key examples of precision dosing that have been successfully used to improve patient care.

Background Correct dosing and therapeutic drug monitoring (TDM) practices are essential when aiming for optimal vancomycin treatment. Objective To assess target attainment after initial dosing and dose adjustments, and to determine compliance to dosing and TDM guidelines. Setting Tertiary care university hospital in Belgium. Method A chart review was performed in 150 patients, ranging from preterm infants to adults, treated intravenously with vancomycin. Patient characteristics, dosing and TDM data were compared to evidence-based hospital guidelines. Main outcome measures Target attainment of vancomycin after initial dosing and dose adjustments. Results Subtherapeutic concentrations were measured in 68% of adults, in 76% of children and in 52% of neonates after treatment initiation. Multiple dose adaptations (median 2, Q1 1–Q3 2) were required for target attainment, whilst more than 20% of children and neonates never reached targeted concentrations. Regarding compliance to the hospital guideline, some points of improvement were identified: omitted dose adjustment in adults with decreased renal function (53%), delayed sampling (16% in adults, 31% in children) and redundant sampling (34% of all samples in adults, 12% in children, 13% in neonates). Conclusion Target attainment for vancomycin with current dosing regimens and TDM is poor in all age groups. Besides, human factors should not be ignored when aiming for optimal treatment. This study reflects an ongoing challenge in clinical practice and highlights the need for optimization of vancomycin dosing strategies and improvement of awareness of all health care professionals involved.

Recently, using artificial intelligence (AI) in drug discovery has received much attention since it significantly shortens the time and cost of developing new drugs. Deep learning (DL)-based approaches are increasingly being used in all stages of drug development as DL technology advances, and drug-related data grows. Therefore, this paper presents a systematic Literature review (SLR) that integrates the recent DL technologies and applications in drug discovery Including, drug–target interactions (DTIs), drug–drug similarity interactions (DDIs), drug sensitivity and responsiveness, and drug-side effect predictions. We present a review of more than 300 articles between 2000 and 2022. The benchmark data sets, the databases, and the evaluation measures are also presented. In addition, this paper provides an overview of how explainable AI (XAI) supports drug discovery problems. The drug dosing optimization and success stories are discussed as well. Finally, digital twining (DT) and open issues are suggested as future research challenges for drug discovery problems. Challenges to be addressed, future research directions are identified, and an extensive bibliography is also included.

In the COVID-19 pandemic era, safety concerns have been raised regarding the risk of severe infection following administration of ocrelizumab (OCR), a B-cell-depleting therapy. We enrolled all relapsing remitting multiple sclerosis (RRMS) patients who received maintenance doses of OCR from January 2020 to June 2021. Data were extracted in December 2021. Standard interval dosing (SID) was defined as a regular maintenance interval of OCR infusion every 6 months, whereas extended interval dosing (EID) was defined as an OCR infusion delay of at least 4 weeks. Three infusions were considered in defining SID vs. EID (infusions A, B, and C). Infusion A was the last infusion before January 2020. The primary study outcome was a comparison of disease activity during the A-C interval, which was defined as either clinical (new relapses) or radiological (new lesions on T1-gadolinium or T2-weighted magnetic resonance imaging (MRI) sequences). Second, we aimed to assess confirmed disability progression (CDP). A total cohort of 278 patients (174 on SID and 104 on EID) was enrolled. Patients who received OCR on EID had a longer disease duration and a higher rate of vaccination against severe acute respiratory syndrome-coronavirus 2 (p < 0.05). EID was associated with an increased risk of MRI activity during the A-C interval (OR 5.373, 95% CI 1.203–24.001, p = 0.028). Being on SID or EID did not influence CDP (V-Cramer 0.47, p = 0.342). EID seemed to be associated with a higher risk of MRI activity in our cohort. EID needs to be carefully considered for OCR-treated patients.

Precision dosing aims to optimize and customize pharmacological treatment at the individual level. The integration of pharmacometric models with Reinforcement Learning (RL) algorithms is currently under investigation to support the personalization of adaptive dosing therapies. In this study, this hybrid technique is applied to the real multiobjective precision dosing problem of givinostat treatment in polycythemia vera (PV) patients. PV is a chronic myeloproliferative disease with an overproduction of platelets (PLT), white blood cells (WBC), and hematocrit (HCT). The therapeutic goal is to simultaneously normalize the levels of these efficacy/safety biomarkers, thus inducing a complete hematological response (CHR). An RL algorithm, Q‐Learning (QL), was integrated with a PK‐PD model describing the givinostat effect on PLT, WBC, and HCT to derive both an adaptive dosing protocol (QLpop‐agent) for the whole population and personalized dosing strategies by coupling a specific QL‐agent to each patient (QLind‐agents). QLpop‐agent learned a general adaptive dosing protocol that achieved a similar CHR rate (77% vs. 83%) when compared to the actual givinostat clinical protocol on 10 simulated populations. Treatment efficacy and safety increased with a deeper dosing personalization by QLind‐agents. These QL‐based patient‐specific adaptive dosing rules outperformed both the clinical protocol and QLpop‐agent by reaching the CHR in 93% of the test patients and completely avoided severe toxicities during the whole treatment period. These results confirm that RL and PK‐PD models can be valid tools for supporting adaptive dosing strategies as interesting performances were achieved in both learning a general set of rules and in customizing treatment for each patient.

Emerging autologous cellular therapies that utilize platelet-rich plasma (PRP) applications have the potential to play adjunctive roles in a variety of regenerative medicine treatment plans. There is a global unmet need for tissue repair strategies to treat musculoskeletal (MSK) and spinal disorders, osteoarthritis (OA), and patients with chronic complex and recalcitrant wounds. PRP therapy is based on the fact that platelet growth factors (PGFs) support the three phases of wound healing and repair cascade (inflammation, proliferation, remodeling). Many different PRP formulations have been evaluated, originating from human, in vitro, and animal studies. However, recommendations from in vitro and animal research often lead to different clinical outcomes because it is difficult to translate non-clinical study outcomes and methodology recommendations to human clinical treatment protocols. In recent years, progress has been made in understanding PRP technology and the concepts for bioformulation, and new research directives and new indications have been suggested. In this review, we will discuss recent developments regarding PRP preparation and composition regarding platelet dosing, leukocyte activities concerning innate and adaptive immunomodulation, serotonin (5-HT) effects, and pain killing. Furthermore, we discuss PRP mechanisms related to inflammation and angiogenesis in tissue repair and regenerative processes. Lastly, we will review the effect of certain drugs on PRP activity, and the combination of PRP and rehabilitation protocols.

To compare medication adherence rates for once-weekly (QW) versus once-daily (QD) dosing regimens in patients with chronic disease. A systematic literature review was conducted to identify articles published in English-language journals examining the rate of adherence to medications in patients with chronic disease. Relevant studies were identified from January 2002 through August 2013 using PubMed, EMBASE, and the Cochrane Library databases. Twenty-two published observational studies reporting adherence were identified by 2 independent reviewers, and 7 articles reported relevant measures for analysis. All studies were conducted in patients with osteoporosis. Meta-analyses estimated (1) mean difference (MD) in adherence (defined using the mean medication possession ratio [MPR]) between QW and QD dosing groups and (2) odds ratio (OR) for adherence (defined using an MPR cutoff of ≥80%) for QW versus QD dosing. Heterogeneity was assessed using Cochran’s Q and I2 values, and meta-analyses used both fixed- and random-effects models. The random-effects meta-analysis revealed a significantly greater MPR with QW compared with QD dosing (pooled MD = 12.29%; 95% CI, 10.76%–13.82%; n = 9 [data reported in 7 publications]). Because of the high level of heterogeneity (I2 = 83.4%), the fixed-effects model results were not appropriate to report for the pooled MD. When examining the OR for adherence, both fixed- and random-effects models provided similar results due to the low level of heterogeneity (I2 = 7.9%; n = 5 [data reported in 3 publications]). Using either model, the pooled odds of being adherent (MPR ≥80%) in the QW dosing group was approximately 1.9 times the odds in the QD dosing group (random-effects OR = 1.90; 95% CI, 1.81–2.00; fixed-effects OR = 1.92; 95% CI, 1.84–1.99). In our meta-analysis, QW dosing was associated with better adherence levels and greater odds of being adherent compared with QD dosing in patients with osteoporosis.

[This corrects the article DOI: 10.3389/fphar.2024.1524272.].