Dose Adjustment Research Articles

Nedosiran population pharmacokinetic and pharmacodynamic modelling and simulation to guide clinical development and dose selection in patients with primary hyperoxaluria type 1.

To characterize pharmacokinetic and pharmacodynamic profiles of nedosiran in patients with primary hyperoxaluria type 1 (PH1), identify influential covariates and confirm therapeutic doses. A population pharmacokinetic (PK)/pharmacodynamic (PD) (POP-PKPD) model was developed to characterize the concentration-time course of nedosiran and the corresponding effect on 24-h urinary oxalate (Uox). Simulations of dosing to achieve clinically meaningful reduction in Uox in children, adolescents and adults with PH1 were performed. Analyses included PK data from 143 healthy participants and PH1/PH2 patients, and PD data from 46 PH1 patients. Nedosiran PK was described by a two-compartment model with dual n-transit absorption and parallel linear and nonlinear elimination. The relationship between nedosiran exposure and Uox was described by an indirect response model. Body weight, estimated glomerular filtration rate (eGFR) and disease status were identified as influential covariates for the POP-PK model. The simulation results supported a weight-banded dosing regimen of nedosiran sodium in adolescents and adults (≥12 years) with PH1 of 170 mg (weight ≥50 kg) and 136 mg (weight <50 kg), in children (6-11 years) with PH1 of 3.5mg/kg, and no dose adjustments for PH1 patients with relatively preserved kidney function (eGFR ≥ 30 mL/min/1.73m2). Following the proposed dosing regimens, the simulated median fold-changes in PK AUC0-τ,ss were acceptable (≤1.51 fold-change) and ~71% of PH1 patients across all age groups achieved near-normal Uox (<0.6mmol) by week 52. The final POP-PKPD model characterizes observed nedosiran PK and Uox data. Simulations support nedosiran dosing regimens in PH1 patients aged ≥6years with relatively preserved kidney function.

Model-Informed Dosing Optimization of Tacrolimus for Concomitant Administration with Itraconazole to Japanese Lung Transplant Recipients.

Tacrolimus is an immunosuppressant administered to patients undergoing lung transplantation. Itraconazole is often concomitantly used with tacrolimus to prevent fungal infections and increase tacrolimus concentration. However, the pharmacokinetics of tacrolimus in Japanese lung transplant recipients and the effect of itraconazole on its pharmacokinetics have not been adequately evaluated. Population pharmacokinetic analysis was conducted to develop an optimal dose adjustment method for use upon itraconazole initiation in Japanese lung transplant recipients. This study comprised Japanese lung transplant recipients whose blood tacrolimus and itraconazole concentrations were measured between January 2017 and December 2019. A nonlinear mixed-effects modeling program was used to explore the covariates of tacrolimus pharmacokinetics and effects of concomitant itraconazole use. Using the model, the optimal initial tacrolimus dose was calculated and a dose adjustment method comprising concomitant itraconazole use was developed. A total of 1693 tacrolimus trough blood concentrations and 85 itraconazole trough plasma concentrations were obtained from 43 patients. Postoperative day, albumin level, and administration route were extracted as covariates for tacrolimus pharmacokinetics. The drug-drug interaction between tacrolimus and itraconazole could be predicted more accurately by considering the concentration-dependent inhibition of itraconazole. The optimal initial tacrolimus dose was 2.0 mg twice daily for tube and 1.5 mg twice daily for oral administration. To maintain the target concentration, the tacrolimus dose was reduced by 60% upon itraconazole initiation. This study is the first to use population pharmacokinetic analysis to assess the interaction between tacrolimus and itraconazole in patients who underwent lung transplantation. These results provide useful insights for optimizing the initial tacrolimus dose for concomitant itraconazole use.

Clinical Trial Data-Driven Risk Assessment of Drug-Drug Interactions: A Rapid and Accurate Decision-Making Tool.

In clinical practice, the vast array of potential drug combinations necessitates swift and accurate assessments of pharmacokinetic drug-drug interactions (DDIs), along with recommendations for adjustments. Current methodologies for clinical DDI evaluations primarily rely on basic extrapolations from clinical trial data. However, these methods are limited in accuracy owing to their lack of a comprehensive consideration of various critical factors, including the inhibitory potency, dosage, and type of the inhibitor, as well as the metabolic fraction and intestinal availability of the substrate. This study aims to propose an efficient and accurate clinical pharmacokinetic-mediated DDI assessment tool, which comprehensively considers the effects of inhibitory potency and dosage of inhibitors, intestinal availability and fraction metabolized of substrates on DDI outcomes. This study focuses on DDIs caused by cytochrome P450 3A4 enzyme inhibition, utilizing extensive clinical trial data to establish a methodology to calculate the metabolic fraction and intestinal availability for substrates, as well as the concentration and inhibitory potency for inhibitors ( or ). These parameters were then used to predict the outcomes of DDIs involving 33 substrates and 20 inhibitors. We also defined the risk index for substrates and the potency index for inhibitors to establish a clinical DDI risk scale. The training set for parameter calculation consisted of 73 clinical trials. The validation set comprised 89 clinical DDI trials involving 53 drugs. which was used to evaluate the reliability of in vivo values of and , the accuracy of DDI predictions, and the false-negative rate of risk scale. First, the reliability of the in vivo and values calculated in this study was assessed using a basic static model. Compared with values obtained from other methods, this study values showed a lower geometric mean fold error and root mean square error. Additionally, incorporating these values into the physiologically based pharmacokinetic-DDI model facilitated a good fitting of the C-t curves when the substrate's metabolic enzymes are inhibited. Second, area under the curve ratio predictions of studied drugs were within a 1.5× margin of error in 81% of cases compared with clinical observations in the validation set. Last, the clinical DDI risk scale developed in this study predicted the actual risks in the validation set with only a 5.6% incidence of serious false negatives. This study offers a rapid and accurate approach for assessing the risk of pharmacokinetic-mediated DDIs in clinical practice, providing a foundation for rational combination drug use and dosage adjustments.

Deep Ensemble Learning-Based Sensor for Flotation Froth Image Recognition

Froth flotation is a widespread and important method for mineral separation, significantly influencing the purity and quality of extracted minerals. Traditionally, workers need to control chemical dosages by observing the visual characteristics of flotation froth, but this requires considerable experience and operational skills. This paper designs a deep ensemble learning-based sensor for flotation froth image recognition to monitor actual flotation froth working conditions, so as to assist operators in facilitating chemical dosage adjustments and achieve the industrial goals of promoting concentrate grade and mineral recovery. In our approach, training and validation data on flotation froth images are partitioned in K-fold cross validation, and deep neural network (DNN) based learners are generated through pre-trained DNN models in image-enhanced training data, in order to improve their generalization and robustness. Then, a membership function utilizing the performance information of the DNN-based learners during the validation is proposed to improve the recognition accuracy of the DNN-based learners. Subsequently, a technique for order preference by similarity to an ideal solution (TOPSIS) based on the F1 score is proposed to select the most probable working condition of flotation froth images through a decision matrix composed of the DNN-based learners’ predictions via a membership function, which is adopted to optimize the combination process of deep ensemble learning. The effectiveness and superiority of the designed sensor are verified in a real industrial gold–antimony froth flotation application.

Pharmacokinetics, Tolerability, and Safety of Esmethadone in Subjects with Chronic Kidney Disease or Hepatic Impairment.

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). 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. 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. 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.

Effect of chloroquine pre-treatment on the metoclopramide’s pharmacokinetics after their co-administration

ABSTRACT Background This study evaluated the pharmacokinetic interactions of orally administered chloroquine and metoclopramide. Methods The study employed a randomized and two-phase cross-over design with four weeks washout plan. Twelve healthy male volunteers were shortlisted according to the set criteria and were administered with metoclopramide 10 mg PO, and chloroquine (a total of 1500 mg) at different intervals which were (500 mg at 0, 6, and 24 h). The concentration of chloroquine and metoclopramide in the blood samples was estimated using a validated HPLC-UV technique to affirm the maximum concentration (Cmax), time to reach Cmax (Tmax), and area under the curve (AUC). Results Cmax, T1/2, and AUC of metoclopramide were increased up to 20, 10, and 47.8% respectively by the concomitantly administering Chloroquine. Chloroquine-treated phase showed increased values of Cmax (ng/ml), AUC (ng.h/ml), and T½ (h), i.e. 41.35 ± 1.61, 504.12 ± 66.25 and 5.72 ± 2.63, as compared to that Reference phase i.e. 34.52 ± 4.92, 341.14 ± 112.8, and 5.19 ± 1.14, respectively. Conclusions Chloroquine was found to attenuate CYP2D6 activity in healthy Pakistani male volunteers. Hence, patients that are prescribed with metoclopramide or other CYP2D6-substrate drugs require a dose adjustment when administered with chloroquine.

Effect of vascular senescence on the efficacy and safety of warfarin: insights from rat models and a prospective cohort study.

Warfarin, with its narrow therapeutic range, requires the understanding of various influencing factors for personalized medication. Vascular senescence, marked by vascular stiffening and endothelial dysfunction, has an unclear effect on the efficacy and safety of warfarin. Based on previous studies, we hypothesized that vascular senescence increases the risk of bleeding during warfarin therapy. This study aimed to explore these effects using animal models and clinical cohorts. We established rat models of vascular senescence and calcification using d-galactose (D-Gal), vitamin D and nicotine (VDN). After validating the models, we examined changes in the International Normalized Ratio (INR) at fixed warfarin doses (0.20 and 0.35 mg/kg). We found that vascular senescence caused significantly elevated INR values and increasd bleeding risk. In the prospective clinical cohort study(NCT06428110), hospitalized warfarin patients with standard dose adjustments were divided into vascular senescence and control groups based on ultrasound and Computed Tomography (CT) diagnosis. Using propensity score matching (PSM) to exclude the influence of confounding factors, we found that the vascular senescence group had lower steady-state warfarin doses and larger dose adjustments, with a higher probability of INR exceeding the therapeutic range. The vascular senescence group tended to experience more bleeding or thromboembolic/ischemic events during one year of follow-up, while there was no statistical difference. In conclusion, vascular senescence leads to unstable INR values and increases higher bleeding risk during warfarin therapy, highlighting the importance of considering vascular senescence in future precision warfarin therapies. Significance Statement Many factors influence warfarin efficacy, however, the effect of vascular senescence remains unclear. This study aimed to investigate the effects of vascular senescence on the efficacy and safety of warfarin. Through both rat models and clinical cohort studies, our findings indicated that vascular senescence may compromise the stability of warfarin, presenting challenges in maintaining its efficacy and safety.

Relevance of plasma lenvatinib concentrations and endogenous urinary cytochrome P450 3A activity biomarkers in clinical practice.

Lenvatinib (LEN), a multitarget tyrosine kinase inhibitor used in various cancer treatments, is mainly metabolized by cytochrome P450 3A (CYP3A) enzymes. The importance of therapeutic drug monitoring (TDM) in patients administered LEN has been proposed. Although some biomarkers of endogenous CYP3A activity have been reported, their utility in dosage adjustments has not been well evaluated. This study investigated the correlation between plasma LEN concentrations and endogenous urinary CYP3A biomarkers in clinical practice. Concentrations of plasma LEN (N = 225) and CYP3A biomarkers (cortisol, 6β-hydroxycortisol, deoxycholic acid, and 1β-hydroxydeoxycholic acid) in urine (N = 214) from 20 patients (hepatocellular carcinoma, N = 6; thyroid cancer, N = 3; endometrial cancer, N = 8; and renal cell carcinoma, N = 3) collected for consultation for up to 1 year were evaluated using liquid chromatography-tandem mass spectrometry. Moreover, plasma trough LEN concentrations were predicted using a three-compartment model with linear elimination for outpatients administered LEN before sample collection. Moderate correlations were observed between the quantified actual concentrations and the predicted trough concentrations of LEN, whereas there was no correlation with endogenous urinary CYP3A biomarkers. The utility of endogenous urinary CYP3A biomarkers could not be determined. However, TDM for outpatients administered orally available medicines may be predicted using a nonlinear mixed effect model (NONMEM). This study investigated the utility of endogenous urinary CYP3A biomarkers for personalized medicine and NONMEM for predicting plasma trough drug concentrations. These findings will provide important information for further clinical investigation and detailed TDM.

Isavuconazole as prophylaxis and therapy for invasive fungal diseases: a real-life observational study.

Isavuconazole is a relatively new antifungal agent indicated for the management of various invasive fungal diseases (IFDs), including invasive aspergillosis. Information on real-world experience with isavuconazole is scarce. This retrospective observational study aimed to describe the usage of isavuconazole in clinical practice with an in-depth evaluation of individual isavuconazole exposure. Patients treated with isavuconazole were evaluated based on retrospective data, including therapeutic drug monitoring (TDM) data and efficacy and safety data. Additionally, we calculated the individual isavuconazole exposure described by the average AUC24 over the first 7 days of treatment by means of non-linear mixed-effects modelling and compared this with the currently desired lower target AUC of 60 mg·h/L. Ninety-nine patients treated with isavuconazole were evaluated. In our real-life cohort, isavuconazole was often deployed off-label in patients with non-classical host factors and infections with non-Aspergillus and non-Mucorales species. Isavuconazole was most often chosen for its safety profile, even after prior triazole treatment with manifestations of toxicity. TDM and subsequent dosage adjustments were frequently performed. The individual average AUC24 over 7 days was above 60 mg·h/L in 29 out of 77 (37.7%) patients. This overview provides practical insights that can aid clinicians in the management of their patients with IFD. Our study shows that isavuconazole was used in a diverse patient population and was well tolerated overall. Individual isavuconazole exposure reflected by the average AUC24 over the first 7 days of treatment was generally low and variable. Dosage adjustments following TDM were frequently performed. Our experience shows that isavuconazole is a feasible alternative after prior azole treatment.

Synchronized Diabetes Monitoring System: Development of Smart Mobile Apparatus for Diabetes Using Insulin

Accurate and timely injection of insulin doses in accordance with the treatment protocol is very important in the follow-up of insulin-dependent diabetes patients. In this study, a new smart mobile apparatus (SMA) has been developed. The SMA can be attached to insulin pens and record and transfer data by detecting the patient's dose of insulin and the time at which it was provided. The SMA can detect the dose determined in the insulin pen through linear capacitive sensors. Electronic parts and sensor mechanism are located on the designed SMA body. The insulin pen's two-part mechanical construction of the body senses movement during dosage adjustment while also making sure the dose information is recorded in the control unit. The dose and time information recorded in the SMA internal memory are transmitted to the patient's smartphone via the developed mobile application. The developed SMA prototypes were evaluated by a team of doctors in a hospital setting for three months. As a result of the three-month study, it was observed that the insulin dose and administration times could be accurately sent to the smartphone application via SMA. The SMA was created in the laboratory environment and was prepared for pilot research with insulin-dependent diabetes patients in a hospital setting. It was observed that the SMA prototype successfully identified and recorded the dose and timing of the patient's self-administered insulin.

Fatalities associated with failure to adjust drug dose in patients with renal insufficiency: A retrospective study at the Institute of Forensic Medicine in Munich (2019-2023)

Comorbidities in the elderly not only make them more susceptible to kidney disease, but also increase the risk of drug interactions due to polypharmacy. Such patients require regular kidney function tests when treated with renally excreted drugs. We conducted a retrospective study of post-mortem cases over a five- year period. Of 3040 toxicologically investigated cases, 3.8% had a history of renal failure. Thirteen deaths were directly attributable to inadequate drug dosing, 46% of which were related to lactic acidosis due to metformin accumulation. Appropriate dose adjustment could prevent fatal drug toxicity in patients with renal insufficiency.

Belatacept Removal by Plasmapheresis: Dose Adjustments and Clinical Recommendations.

Belatacept Removal by Plasmapheresis: Dose Adjustments and Clinical Recommendations.

No dose adjustment of metformin or substrates of organic cation transporters (OCT)1 and OCT2 and multidrug and toxin extrusion protein (MATE)1/2K with fostemsavir coadministration based on modeling approaches.

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 invitro 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 invitro 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.

An Overview of Acupuncture Dosage in Veterinary Medicine

Acupuncture is subject to dosage considerations, similar to pharmaceuticals, that significantly influence therapeutic outcomes. In instances where the initial diagnosis is confirmed to be accurate, and results are suboptimal, consideration should be given to augmenting the acupuncture dosage and technique used. Veterinary acupuncture dosage includes size of acupuncture needles, depth of needle insertion, frequency/duration of the treatments, and type of acupuncture technique used. Larger needle size generates stronger stimulation and studies indicate that acupuncture points can have specific effects on the body based on depth of stimulation (i.e. length of needle). Optimal therapy also depends on the frequency of treatment and will vary dependent on the clinical condition and acupuncture technique. In cases where clinical improvements remain absent after 4-6 sessions of dry needle acupuncture therapy, it is prudent to reevaluate both conventional and TCVM diagnoses, as well as acupuncture dosage. Adjustments in acupuncture dosage can include the use of longer needles, the incorporation of additional acupoints or the addition of other needle stimulation techniques. The use of advanced acupuncture modalities, such as electro-acupuncture, aqua-acupuncture, acupoint embedding and scalp acupuncture, may significantly enhance therapeutic efficacy. This paper aims to explore and elucidate the various factors influencing the dosage of acupuncture in a variety of species across ten commonly used acupuncture techniques, thereby providing insights into how they can be optimized to enhance treatment efficacy.

Comparative pharmacokinetics of phenylbutazone in healthy young-adult and geriatric horses.

To evaluate the effects of aging on phenylbutazone (PBZ) disposition in older horses (≥ 25 years old) compared to young adults (4 to 10 years old) by characterizing the pharmacokinetic profile of PBZ and its active metabolite, oxyphenbutazone (OPBZ), following a 2.2-mg/kg dose, IV. We hypothesized that the disposition of PBZ will be affected by age. 16 healthy horses (8 young adults aged 4 to 10 years and 8 geriatric horses ≥ 25 years old). Horses were administered a single 2.2-mg/kg PBZ dose, IV. Plasma samples were collected at designated time points and frozen at -80 °C until assayed using liquid chromatography-tandem mass spectrometry. Pharmacokinetic analyses were performed using Phoenix WinNonlin, version 8.0 (Certara). Both clinical and pharmacokinetic data were compared between age groups using independent samples t tests, with P < .05 considered significant. Baseline characteristics did not differ between groups, with the exception of age, weight, and plasma total solids. Plasma concentrations of PBZ were best described by a two-compartment model. The maximum plasma concentration of OPBZ was reached at 5 hours for both age groups, and the metabolite-to-parent-drug area-under-the-curve ratios were approximately 20% for both groups. None of the pharmacokinetic parameters of PBZ or its metabolite, OPBZ, differed significantly between age groups. The hypothesis was rejected as there was no significant difference in PBZ disposition in young-adult horses compared to geriatric horses. Our data do not support the need for dose adjustments of PBZ in clinically healthy geriatric horses.

An Evidence-Based Rationale for Dose De-escalation of Subcutaneous Atezolizumab.

Atezolizumab is a programmed death-ligand 1 (PD-L1) checkpoint inhibitor for the treatment of different forms of cancer. The subcutaneous formulation of atezolizumab has recently received approval. However, treatment with atezolizumab continues to be expensive, and the number of patients needing treatment with this drug continues to increase. We propose two alternative dosing regimens for subcutaneous atezolizumab to reduce drug expenses while ensuring effective exposure; one may be directly implemented in the clinic. We developed two alternative dose interval prolongation strategies based on pharmacokinetic modeling and simulation. The first dosing regimen was based on patients' weight while maintaining equivalent systemic drug exposure by adhering to Food and Drug Administration (FDA) guidelines for in silico dose adjustments. The second dosing regimen aimed to have a minimum atezolizumab concentration above the 6 µg/mL threshold, associated with 95% intratumoral PD-L1 receptor saturation for at least 95% of all patients. We found that, for the weight-based dosing regimen, the approved 3-week dosing interval could be extended to 5 weeks for patients < 50 kg and 4 weeks for patients weighing 50-65 kg. Besides improving patient convenience, these alternative dosing intervals led to a predicted 7% and 12% cost reduction for either the USA or European population. For the second dosing regimen, we predicted that a 6-week dosing interval would result in 95% of the patients above the 6 µg/mL threshold while reducing costs by 50%. We have developed and evaluated two alternative dosing regimens that resulted in a cost reduction. Our weight-based dosing regimen can be directly implemented and complies with FDA guidelines for alternative dosing regimens of PD-L1 inhibitors. For the more progressive alternative dosing regimen aimed at the intratumoral PD-L1 receptor threshold, further evidence on efficacy and safety is needed before implementation.

Time series forecasting of weight for diuretic dose adjustment using bidirectional long short-term memory

Loop diuretics are prevailing drugs to manage fluid overload in heart failure. However, adjusting to loop diuretic doses is strenuous due to the lack of a diuretic guideline. Accordingly, we developed a novel clinician decision support system for adjusting loop diuretics dosage with a Long Short-Term Memory (LSTM) algorithm using time-series EMRs. Weight measurements were used as the target to estimate fluid loss during diuretic therapy. We designed the TSFD-LSTM, a bi-directional LSTM model with an attention mechanism, to forecast weight change 48 h after heart failure patients were injected with loop diuretics. The model utilized 65 variables, including disease conditions, concurrent medications, laboratory results, vital signs, and physical measurements from EMRs. The framework processed four sequences simultaneously as inputs. An ablation study on attention mechanisms and a comparison with the transformer model as a baseline were conducted. The TSFD-LSTM outperformed the other models, achieving 85% predictive accuracy with MAE and MSE values of 0.56 and 1.45, respectively. Thus, the TSFD-LSTM model can aid in personalized loop diuretic treatment and prevent adverse drug events, contributing to improved healthcare efficacy for heart failure patients.

Population pharmacokinetics of total and unbound valemetostat and platelet dynamics in healthy volunteers and patients with non-Hodgkin lymphoma.

Valemetostat is an EZH2/1 inhibitor that has been approved in Japan for the treatment of patients with relapsed/refractory adult T-cell leukemia/lymphoma, based mainly on results from a single-arm phase II trial. It is currently under investigation worldwide for the treatment of other non-Hodgkin lymphomas (NHLs), including peripheral T-cell lymphoma, and for solid tumors. Semi-mechanistic population pharmacokinetic modeling of total and unbound valemetostat and an analysis of the platelet time course during treatment with valemetostat were conducted using data from five clinical trials (two in patients with NHL and three in healthy volunteers). Pharmacokinetic data, including 3162 total/1871 unbound valemetostat observations from 102 patients and 72 healthy volunteers, were described by a three-compartment model with sequential zero-/first-order absorption and saturable binding in the central compartment. Alpha-1-acid glycoprotein (AAG) was the most influential covariate for total valemetostat exposure, yet had little impact on unbound exposure, meaning no dose adjustment was warranted based on AAG levels. The longitudinal platelet data from 101 patients (2313 observations) were adequately described by a modified Friberg model with two proliferation compartments, which characterized unique spontaneous recovery of platelet counts without dose modifications. A model-based simulation quantitatively assessed the proposed dose-adjustment guidance in case of platelet count decreased by comparing the probability of treatment discontinuation due to platelet count decreased with or without the dose adjustment. In summary, the models described observed total and unbound valemetostat concentrations and a unique time course of platelets during treatment, which can justify the clinical dose and provide dose-adjustment guidance.

Combination of anti-thymocyte globulin with post-transplant cyclophosphamide for GVHD prophylaxis in patients undergoing haploidentical hematopoietic stem cell transplantation: systematic review and meta-analysis

Haploidentical stem cell transplantation (haplo-HSCT) is associated with higher incidences of graft-versus-host disease (GVHD). A new strategy combining anti-thymocyte globulin with post-transplant cyclophosphamide (ATG/PTCy) for GVHD prevention has been developed, but its benefits and risks remain unclear. This study aims to performs a systematic review and meta-analysis of studies comparing ATG/PTCy with ATG or PTCy in patients with hematological malignancies undergoing haplo-HSCT. Literature search was performed in databases including Ovid Medline, Embase, Cochrane Library and China Biology Medicine (CBM). Two investigators independently screened eligible studies and extracted data. Meta-analysis was conducted with Review Manager version 5.4, pooled hazard ratios (HRs) for time-to-event outcomes were obtained using generic inverse-variance method, and pooled risk ratios (RRs) for dichotomous data were obtained using Mantel-Haenszel method. Fixed-effects model was adopted if there is no significant heterogeneity. The primary outcome is incidence of acute GVHD. Literature search and study selection identified 14 eligible studies, including both 1 randomized controlled trial and 13 retrospective comparative studies. Different dosage adjustment strategies were applied, the total dose is 2.5-10 mg/kg for ATG and 29-100 mg/kg for PTCy. Meta-analysis results suggest that ATG/PTCy is associated with significantly lower risk of grade II-IV acute GVHD compared with ATG (RR 0.52; 95% CI: 0.41-0.65; P < 0.00001) and PTCy (RR 0.53; 95% CI: 0.34-0.83; P = 0.005) without increasing risk of disease relapse. In addition, ATG/PTCy is associated with significantly lower risk of grade III-IV acute GVHD (RR 0.33; 95% CI: 0.23-0.49; P < 0.00001) and chronic GVHD (RR 0.65; 95% CI: 0.51-0.81; P = 0.0002) in comparison with ATG. Further analyses suggest that ATG/PTCy is associated with significantly better overall survival and GVHD-free/relapse-free survival than ATG and PTCy, but the risks of CMV (RR 1.42; 95% CI: 1.03-1.95; P = 0.03) and EBV (RR 3.17; 95% CI: 1.61-6.23; P = 0.0008) reactivation are higher when compared with PTCy. Our results suggest that combination of ATG with PTCy for GVHD prevention in haplo-HSCT is associated with improved efficacy but higher risk of infection. Future researches are required to further establish the benefits and risks of ATG/PTCy and determine the optimal dosage adjustment strategies.

Migraine Management in Medically Complex Patients: a Narrative Review.

The current review aims to provide an overview of migraine treatment strategies in medically complex patients, including those with renal, liver, and cardiovascular disease. In cardiovascular disease, gepants are likely safe for acute therapy; NSAIDs, ergotamines, and triptans are not recommended. Beta-blockers, ACEi/ARBs, and verapamil have potential cardiovascular benefits in addition to migraine preventive benefit. Frovatriptan requires no dose adjustments in kidney disease or in mild to moderate liver disease. Gepants are safe acute and preventive treatment options in mild and moderate renal and hepatic disease. TCAs and valproic acid require no dose adjustments in renal disease. OnabotulinumtoxinA is likely safe in cardiac, renal, and hepatic impairment. Although CGRP monoclonal antibodies are likely safe in renal and hepatic disease, further study is needed in these conditions as well as in cardiac disease, and no dosing recommendations are available. Effective options are available for those with complex medical comorbidities. Further research is required on the safety of newer migraine-specific therapies in these complex populations.