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Background: The smallest dolutegravir (DTG) dose approved is 5 mg once-daily in infants ≥4 weeks and weighing ≥3 to <6 kg using a dispersible tablet (DT). Neonates (<28 days of life) may require a lower dose due to immature organ development. We evaluated the aqueous dispersibility of the generic DTG-DT 10-mg scored tablets (Viatris Inc.) to determine the possibility of uniform concentrations that could allow for lower daily doses in neonates. Methods: Each 5-mL polypropylene tube had DTG-DT 5 mg dissolved in 5-mL ultrapure water. Tubes were labeled with 3 "zones" (bottom: 0–1 mL; middle: 1–3 mL; top: 3–5 mL). Suspensions were mixed by swirling or swirling with a syringe pump, vortexing, or sonication. DTG concentration in each zone was determined using high-performance liquid chromatography. Tubes were rinsed with 1-mL acetonitrile to determine the residual drug. Acceptable criterion for percentage difference was set at ≤20% according to the European Medicines Agency guidelines. Results: Dispersion of DTG-DT in water did not remain homogeneous, resulting in DTG concentrations that varied by over 50% across the 3 zones within the tubes. Rapid sedimentation was observed shortly after mixing. Furthermore, it was found that 24%–35% of the DTG residue remained adhered to the tube after the aqueous dispersion had been eluted, highlighting the importance of the rinse step. Conclusions: Aqueous dispersion of the DTG-DT is not uniform and displays a high degree of sedimentation. It is therefore not possible to administer a fraction of the dispersion (lower DTG dose) to neonates by using this formulation. [ABSTRACT FROM AUTHOR]

Futibatinib is an excellent fibroblast growth factor receptor 1–4 (FGFR 1–4) inhibitor that exhibits selective anti-tumor activeness against FGFR-deregulated tumors. A new high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) technique for the quantitative analysis of futibatinib in beagle dog plasma was developed, and the effect of Yinchenhao decoction (YCHD) on the pharmacokinetics of futibatinib was evaluated. After processing plasma samples with ethyl acetate extraction in the alkaline condition of sodium carbonate, a C18 column (4.6 mm × 150, 5 μm) was used to accomplish the separation of futibatinib and ripretinib (internal standard, ISTD), with the mobile phase consisting of methanol and 0.1% formic acid in water (60:40). The scanning method adopted a multiple reaction monitoring (MRM) mode with positive ion detection through the triple quadrupole mass spectrometer. The ion transitions for futibatinib and IS were m/z 419.20 → 296.15 and m/z 510.36 → 417.00, respectively. Futibatinib displayed excellent linearity in the range of 1–200 ng/mL. Neither inter-day nor intra-day precision exceeded 6.3%. The %RE values for accuracy ranged from −3.1% to 0.9%. The recovery, stability, and matrix effect of futibatinib also complied with the guidelines for the validation of quantitative analysis methods for biological samples in the 2020 edition of the Chinese Pharmacopoeia. In combination with YCHD, the Cmax of futibatinib increased by 40.84% compared to futibatinib dosage alone., and the AUC(0–t) and AUC(0–∞) of futibatinib increased by 78.06% and 82.71%, respectively. The Vd and CL of futibatinib were reduced by 20.05% and 40.85%, respectively. T1/2 was extended from 3.88 h to 5.26 h. The results indicated that YCHD could affect the pharmacokinetics of futibatinib and increase the plasma exposure of futibatinib. If YCHD is administered along with futibatinib, this study gives a first impression how pharmacokinetics and toxicokinetics would change. [ABSTRACT FROM AUTHOR]

Background and Objectives: Dasatinib is one of the tyrosine kinase inhibitors. The main use of these agents is inhibition of cancerous cell proliferation. The therapeutic importance of tyrosine kinase inhibitors raises the necessity of many types of investigations, especially the pharmacokinetic analysis of these drugs in humans. This analysis, along with other investigations and clinical research, will contribute to the overall knowledge of the drug. This study focused on the population pharmacokinetics of dasatinib. The objective of the study was to investigate the sources of the variability of dasatinib in a population pharmacokinetics study in healthy participants. Methods: We utilized 4180 plasma observations from 110 subjects who were administered SPRYCEL® on two separate occasions under fasting conditions; data from 20% of the subjects (22 subjects) were extracted for the purpose of internal model evaluation and data from 88 subjects were used in modeling. The model was evaluated by visual predictive check of three different datasets. A two-compartmental model with first order absorption and transit compartment was considered the simplest base model to describe the data based on the corrected Bayesian information criterion evaluation. Covariates were tested through conditional sampling for the stepwise approach-screening procedure in Monolix 2020R1 version. Conditional sampling for the stepwise approach was used to include the correlated covariates within the base model in the forward inclusion step and then to eliminate them backwardly to ensure that the key covariates were kept in the model at the final stage. Results: The effect of body mass index on the absorption rate constant was considered as significant covariate in the final established model. Visual predictive check for simulations, 20% of the original dataset (internal dataset) and an external dataset demonstrated the appropriateness of the final model. Conclusions: Population pharmacokinetic modeling was performed to describe dasatinib pharmacokinetics in healthy subjects. Body mass index was considered as a factor that might be used in the future along with studies on patients to adjust the dosing regimens. Key Points: Dasatinib is classified as a highly variable drug; this variability was demonstrated in the study by the effect of body mass index on the absorption rate constant. [ABSTRACT FROM AUTHOR]

Patients receiving interleukin (IL)‐inhibiting biologics for moderate‐to‐severe psoriasis (PsO) may be treated with escalated doses to optimize outcomes. This study evaluated escalation prevalence in a Japanese claims analysis of patients with PsO diagnosis preceding IL‐inhibiting biologic treatment and ≥1 post‐induction maintenance claim (index date) with sufficient data availability from January 2014 to May 2022. Patients with non‐persistence were excluded. Expected daily dose (EDD) was calculated as the recommended maintenance dose divided by the treatment interval. Dose escalation was defined as ≥2 claims showing a ≥20% increase in the observed average daily dose (ADD) over the EDD (with sensitivities requiring ≥1 claim and ≥30%). Significant differences were tested using multivariable regressions. The study included 982 unique patients treated with brodalumab (BRO; n = 104), guselkumab (GUS; n = 207), ixekizumab (IXE; n = 159), risankizumab (RIS; n = 135), secukinumab (SEC; n = 215) and ustekinumab (UST; n = 196). Within 12 months, dose escalation was observed for all IL‐inhibiting biologics other than GUS and RIS: 44.4% for UST, 37.2% for IXE, 3.4% for SEC and 1.4% for BRO. In multivariable‐adjusted analyses, odds of dose escalation were significantly lower for all products relative to UST. In sensitivities, escalation was observed for all products except RIS. [ABSTRACT FROM AUTHOR]

An orchard sprayer prototype running a variable-rate algorithm to adapt the spray volume to the canopy characteristics (dimensions, shape and leaf density) in real-time was designed and implemented. The developed machine was able to modify the application rate by using an algorithm based on the tree row volume, in combination with a newly coefficient defined as Density Factor (Df). Variations in the canopy characteristics along the row crop were electronically measured using six ultrasonic sensors (three per sprayer side). These differences in foliage structure were used to adjust the flow rate of the nozzles by merging the ultrasonic sensors data and the forward speed information received from the on-board GNSS. A set of motor-valves was used to regulate the final amount of sprayed liquid. Laboratory and field tests using artificial canopy were arranged to calibrate and select the optimal ultrasonic sensor configuration (width beam and signal pre-processing method) that best described the physical canopy properties. Results indicated that the sensor setup with a medium beam width offered the most appropriate characterization of trees in terms of width and Df. The experimental sprayer was also able to calculate the application rate automatically depending on changes on target trees. In general, the motor valves demonstrated adequate capability to supply and control the required liquid pressure at all times, mainly when spraying in a range between 4.0 and 14.0 MPa. Further work is required on the equipment, such as designing field efficiency tests for the sprayer or refining the accuracy of Df. [ABSTRACT FROM AUTHOR]

78-year-old patient, polymedicated and enrolled in the medication compliance aids service. When she went to pick up her medication, she informed us that for a few months she has been suffering from fatigue, weakness, dizziness and confusion. A medication review is performed, focused on the dosage of renal metabolism or elimination medications, based on the patient’s estimated Glomerular Filtration Rate (eGFR). A referral was made to the Primary Care Physician (PCP) through a report, in which the dose reduction of losartan and manidipine was recommended according to the patient’s eGFR. The PCP reduced the dose of antihypertensives. A follow-up of the case was carried out, which allowed to observe that the patient stopped presenting the symptoms initially described. [ABSTRACT FROM AUTHOR]

Extracorporeal membrane oxygenation (ECMO) increases circulating volume of distribution, leading to capillary leakage and temporarily altering renal function. Therefore, this may affect pharmacokinetics. In this review, factors affecting pharmacokinetics and pharmacodynamics in veno-arterial and venovenous ECMO, the causes of drug sequestration that may occur in the ECMO circuit, the effects of physicochemical parameters of drugs in the ECMO circuit, and ECMO variable dose optimization have been reviewed from the studies in the current literature. Data reported on the limitations, indications and complications of ECMO are also mentioned. The limited use of ECMO in the coronavirus disease-2019 pandemic, its use in reported cases, and which symptoms it is usually used to support the treatment of are described.

Background & aimsPatients with Crohn's disease (CD) treated with ustekinumab who experience inadequate response, or loss of response after standard induction and/or maintenance dosing may benefit from dose escalation. We conducted a systematic review and meta-analysis examining the effectiveness of reinduction and/or dose interval shortening of ustekinumab in patients with active CD despite standard induction and maintenance.MethodsThrough a systematic literature search through March 31, 2021, we identified 15 cohort studies in 925 adults with CD with inadequate response or loss of response to standard dose ustekinumab, underwent dose escalation (reinduction and/or dose interval shortening to

Extracorporeal membrane oxygenation (ECMO) increases circulating volume of distribution, leading to capillary leakage and temporarily altering renal function. Therefore, this may affect pharmacokinetics. In this review, factors affecting pharmacokinetics and pharmacodynamics in veno-arterial and venovenous ECMO, the causes of drug sequestration that may occur in the ECMO circuit, the effects of physicochemical parameters of drugs in the ECMO circuit, and ECMOvariable dose optimization have been reviewed from the studies in the current literature. Data reported on the limitations, indications and complications of ECMO are also mentioned. The limited use of ECMO in the coronavirus disease-2019 pandemic, its use in reported cases, and which symptoms it is usually used to support the treatment of are described. [ABSTRACT FROM AUTHOR]

Background: A considerable inter‐individual variability has been reported in the relationship between methadone doses applied and serum concentrations achieved in methadone maintenance treatment. However, the underlying causes for this variability are not fully understood. Objectives: We investigated the influence of genetic, pathophysiological and pharmacological factors on serum methadone concentration‐to‐dose ratio (CDR) and discussed the clinical implications of the findings. Methods: We used data from two retrospective laboratory databases and a prospective cohort study to investigate the impact on methadone CDR of hepatic cytochrome P450 enzyme system (CYP) genetic polymorphisms, age, sex, concomitant medication, liver fibrosis and body mass index through linear mixed model analyses. Findings: A positive association was found between CDR and the homozygous CYP2B6*6 genotype, concurrent treatment with CYP3A4 inhibitors and body mass index. CDR was lower among women and during concomitant use of CYP inducers. CDR was not associated with age or the degree of liver fibrosis in our investigations. Conclusions: This research work supports the need for individually tailored dosage considering the various factors that influence methadone CDR. The gained knowledge can contribute to reducing the risks associated with the treatment and optimizing the desired outcomes. [ABSTRACT FROM AUTHOR]

Summary: Background: Understanding the impact of CYP2D6 metabolism on paroxetine, a widely used antidepressant, is essential for precision dosing. Methods: We conducted an 8-week, multi-center, single-drug, 2-week wash period prospective cohort study in 921 Chinese Han patients with depressive or anxiety disorders (ChiCTR2000038462). We performed CYP2D6 genotyping (single nucleotide variant and copy number variant) to derive the CYP2D6 activity score and evaluated paroxetine treatment outcomes including steady-state concentration, treatment efficacy, and adverse reaction. CYP2D6 metabolizer status was categorized into poor metabolizers (PMs), intermediate metabolizers (IMs), extensive metabolizers (EMs), and ultrarapid metabolizers (UMs). The influence of CYP2D6 metabolic phenotype on paroxetine treatment outcomes was examined using multiple regression analysis and cross-ethnic meta-analysis. The therapeutic reference range of paroxetine was estimated by receiver operating characteristic (ROC) analyses. Findings: After adjusting for demographic factors, the steady-state concentrations of paroxetine in PMs, IMs, and UMs were 2.50, 1.12, and 0.39 times that of EMs, with PM and UM effects being statistically significant (multiple linear regression, P = 0.03 and P = 0.04). Sex and ethnicity influenced the comparison between IMs and EMs. Moreover, poor efficacy of paroxetine was associated with UM, and a higher risk of developing adverse reactions was associated with lower CYP2D6 activity score. Lastly, cross-ethnic meta-analysis suggested dose adjustments for PMs, IMs, EMs, and UMs in the East Asian population to be 35%, 40%, 143%, and 241% of the manufacturer's recommended dose, and 62%, 68%, 131%, and 159% in the non-East Asian population. Interpretation: Our findings advocate for precision dosing based on the CYP2D6 metabolic phenotype, with sex and ethnicity being crucial considerations in this approach. Funding: National Natural Science Foundation of China; Academy of Medical Sciences Research Unit.

AbstractContext Derazantinib—an orally bioavailable, ATP competitive, multikinase inhibitor—has strong activity against fibroblast growth factor receptors (FGFR)2, FGFR1, and FGFR3 kinases. It has preliminary antitumor activity in patients with unresectable or metastatic FGFR2 fusion-positive intrahepatic cholangiocarcinoma (iCCA).Objective This experiment validates a novel sensitive and rapid method for the determination of derazantinib concentration in rat plasma by ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS), and applies it to the study of drug-drug interaction between derazantinib and naringin in vivo.Materials and methods A Xevo TQ-S triple quadrupole tandem mass spectrometer was used for mass spectrometry monitoring in selective reaction monitoring (SRM) mode with transitions of m/z 468 96 → 382.00 for derazantinib and m/z 488.01 → 400.98 for pemigatinib, respectively. The pharmacokinetics of derazantinib (30 mg/kg) was investigated in Sprague-Dawley (SD) rats divided into two groups (with the oral pretreatment of 50 mg/kg naringin or not).Results The newly optimized UPLC-MS/MS method was suitable for the determination of derazantinib in rat plasma. It was also successfully employed to evaluate the effect of naringin on derazantinib metabolism in rats. After pretreatment with naringin, there was no significant difference in the pharmacokinetic parameters (AUC0→t, AUC0→∞, t1/2, CLz/F, and Cmax) of derazantinib when compared with derazantinib alone.Conclusion Co-administration of naringin with derazantinib was not associated with significant changes in pharmacokinetic parameters. Thus, this study suggests that the combination of derazantinib with naringin can safely be administered concomitantly without dose adjustment.

Futibatinib is an excellent fibroblast growth factor receptor 1–4 (FGFR 1–4) inhibitor that exhibits selective anti-tumor activeness against FGFR-deregulated tumors. A new high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) technique for the quantitative analysis of futibatinib in beagle dog plasma was developed, and the effect of Yinchenhao decoction (YCHD) on the pharmacokinetics of futibatinib was evaluated. After processing plasma samples with ethyl acetate extraction in the alkaline condition of sodium carbonate, a C18 column (4.6 mm × 150, 5 μm) was used to accomplish the separation of futibatinib and ripretinib (internal standard, ISTD), with the mobile phase consisting of methanol and 0.1% formic acid in water (60:40). The scanning method adopted a multiple reaction monitoring (MRM) mode with positive ion detection through the triple quadrupole mass spectrometer. The ion transitions for futibatinib and IS were m/z 419.20 → 296.15 and m/z 510.36 → 417.00, respectively. Futibatinib displayed excellent linearity in the range of 1–200 ng/mL. Neither inter-day nor intra-day precision exceeded 6.3%. The %RE values for accuracy ranged from −3.1% to 0.9%. The recovery, stability, and matrix effect of futibatinib also complied with the guidelines for the validation of quantitative analysis methods for biological samples in the 2020 edition of the Chinese Pharmacopoeia. In combination with YCHD, the Cmax of futibatinib increased by 40.84% compared to futibatinib dosage alone., and the AUC(0–t) and AUC(0–∞) of futibatinib increased by 78.06% and 82.71%, respectively. The Vd and CL of futibatinib were reduced by 20.05% and 40.85%, respectively. T1/2 was extended from 3.88 h to 5.26 h. The results indicated that YCHD could affect the pharmacokinetics of futibatinib and increase the plasma exposure of futibatinib. If YCHD is administered along with futibatinib, this study gives a first impression how pharmacokinetics and toxicokinetics would change.

Derazantinib—an orally bioavailable, ATP competitive, multikinase inhibitor—has strong activity against fibroblast growth factor receptors (FGFR)2, FGFR1, and FGFR3 kinases. It has preliminary antitumor activity in patients with unresectable or metastatic FGFR2 fusion-positive intrahepatic cholangiocarcinoma (iCCA). This experiment validates a novel sensitive and rapid method for the determination of derazantinib concentration in rat plasma by ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS), and applies it to the study of drug-drug interaction between derazantinib and naringin in vivo. A Xevo TQ-S triple quadrupole tandem mass spectrometer was used for mass spectrometry monitoring in selective reaction monitoring (SRM) mode with transitions of m/z 468 96 → 382.00 for derazantinib and m/z 488.01 → 400.98 for pemigatinib, respectively. The pharmacokinetics of derazantinib (30 mg/kg) was investigated in Sprague-Dawley (SD) rats divided into two groups (with the oral pretreatment of 50 mg/kg naringin or not). The newly optimized UPLC-MS/MS method was suitable for the determination of derazantinib in rat plasma. It was also successfully employed to evaluate the effect of naringin on derazantinib metabolism in rats. After pretreatment with naringin, there was no significant difference in the pharmacokinetic parameters (AUC0→t, AUC0→∞, t1/2, CLz/F, and Cmax) of derazantinib when compared with derazantinib alone. Co-administration of naringin with derazantinib was not associated with significant changes in pharmacokinetic parameters. Thus, this study suggests that the combination of derazantinib with naringin can safely be administered concomitantly without dose adjustment. [ABSTRACT FROM AUTHOR]

The purpose of the study is to examine the switching pattern and dose adjustment of antidepressants (ADs) prescribed to women from six months before to six months during pregnancy in the Netherlands. The recorded dispenses or refills were collected from the University of Groningen IADB.nl pregnancy subset for all singleton pregnancies in which the mother received ≥ 1 prescription of an AD dispensed before pregnancy and was present in the database at least six months after conception. The rates of continuation, discontinuation, and switching between 2001 and 2020 were assessed for the ADs studied. The mean number of Defined Daily Doses (DDDs) of the most frequently continued ADs used was calculated both before and during pregnancy, and a paired t-test was used to test for significant changes. The continuation rates for AD users, especially for SSRI and SNRI continued users, increased over time from 27% and 19% (2001–2005) to 65% and 65% (2016–2020). The switching rate between ADs remained consistently low from the start of the study (2001–2005) at 2.0% to the end of the study (2016–2020) at 2.3%. Most women who switched between antidepressants during pregnancy received a different SSRI monotherapy (85%), followed by an SNRI (6%), a TCA (4%), and an "other AD" (4%). In most cases observed, the dose adjustment for the mean DDDs during pregnancy compared to the mean DDDs before pregnancy only changed little (less than 10%). Continued use of SSRIs among singleton pregnancies doubled over the study period. The low rate of AD switching and little changes in the DDD adjustment for most AD continuers indicate that pregnant women prefer to continue their prepregnancy medication rather than switch it. Most observed findings cohere with the Dutch national guidelines for antidepressant use during pregnancy. [ABSTRACT FROM AUTHOR]

Chronic kidney disease is a prevalent problem without specific treatment. Early detection is important and estimated glomerular filtration rate (eGFR) is a very affordable test that can be performed in community pharmacies. If present, it is very important not to further damage the kidney by avoiding the use of nephrotoxic drugs and adjusting the doses of other renal elimination drugs and the community pharmacy is very well positioned to do this. Objective: To describe the methodology used to detect nephrotoxic drugs and adjust doses of other drugs in community pharmacies for subsequent referral to primary care. Method: Multicentre experimental multicentre uncontrolled follow-up study carried out in community pharmacies in 4 autonomous communities in Spain. Patients who met the inclusion criteria and signed the informed consent form were included. Those with eGFR <60 ml/min/1.73m2 were studied and their medication was analysed using the BOT Plus and 4 other sources of information. Result: 670 patients were included, 215 of them with eGFR<60ml/min/1.73m2. Of these 90 (41.9%) needed some type of adjustment in the pharmacist's judgement. Of these 90, 43.3% (39) had some kind of change after the pharmacist's intervention. Conclusion: In patients with low glomerular filtration rate, with the appropriate methodology, the community pharmacist is able to detect the use of nephrotoxic drugs or the use of drugs at doses higher than those recommended according to their renal status. [ABSTRACT FROM AUTHOR]

Objective·To evaluate the effects of levothyroxine (L-T4) dose adjustment according to the level of thyroid stimulating hormone (TSH) on maternal and infant outcomes in the pregnant women with hypothyroidism by meta-analysis.Methods·China National Knowledge Infrastructure (CNKI), China Science and Technology Journal Database (VIP), Wanfang Data Knowledge Service Platform, PubMed, Cochrane Library and Embase were retrieved to collect all the controlled studies on the treatment of pregnant women with hypothyroidism by adjusting the dose of L-T4 according to TSH level from the establishment of the databases to April 9, 2022. The references were also traced. Literature screening, data extraction, and quality evaluation were performed independently by two researchers. Cochrane evaluation was used to evaluate the quality of the included literature. Outcome indicators included gestational hypertension, gestational diabetes, postpartum hemorrhage, delivery mode, preterm birth, fetal death, neonatal asphyxia, and low birth weight infants. RevMan 5.3 was used for meta-analysis.Result·A total of 1 268 articles were retrieved from 6 databases, and 8 were included in the study, including 4 Chinese articles and 4 English articles. The overall risk of study bias was at a moderate level. Compared with the control group, the OR of gestational diabetes risk was 0.61 (95%CI 0.44‒0.86, P=0.004) and the OR of fetal death risk was 0.38 (95%CI 0.18‒0.81, P=0.010) in the experimental group with L-T4 dose adjusted according to the TSH level of the pregnant women with hypothyroidism, which were both statistically significant. However, the treatment method of adjusting L-T4 dose did not affect the risks of vaginal delivery [OR=1.82 (95%CI 0.75‒4.40, P=0.180)], gestational hypertension [OR=0.77 (95%CI 0.53‒1.12, P=0.170)], postpartum hemorrhage [OR=1.20 (95%CI 0.50‒2.92, P=0.680)], preterm birth [OR=0.72 (95%CI 0.48‒1.06, P=0.100)], low birth weight infants [OR=1.00 (95%CI 0.65‒1.54, P=0.999)], or neonatal asphyxia [OR=0.50 (95%CI 0.20‒1.27, P=0.150)] significantly.Conclusion·Adjusting the L-T4 therapeutic dose according to the TSH level may help reduce the risks of gestational diabetes and fetal death in the pregnant women with hypothyroidism.

IntroductionUstekinumab (UST), a human monoclonal antibody against interleukin-12 and 23, is approved to treat adult patients with psoriasis or Crohn disease (CD). Outcomes data for off-label use in pediatric patients with CD are limited.AimWe conducted a retrospective cohort study to analyze the long-term efficacy of UST, including dose adjustments, in the treatment of pediatric patients with medically refractory CD. Adverse events were documented.MethodsWe identified 40 pediatric patients with CD treated with UST between January 1, 2016 and December 31, 2019. Electronic medical records were reviewed for demographics, Paris Classification, significant comorbidities, previous CD therapy, adverse events after initiation, and surveillance markers at the time of their first dose and most recent clinic visit. A validated abbreviated pediatric CD activity index (aPCDAI) was used to assess response to therapy.ResultsThirty-eight pediatric patients with CD, including 34.2% with stricturing or penetrating disease, were analyzed after initiation of treatment with UST. Median age at diagnosis of CD was 12.5 years, and median age at UST induction was 17.2 years. No patients were anti-TNF-naive, and 34.2% were previously exposed to 2 or more anti-TNF agents. At time of last follow-up, 84.2% of patients remained on UST for a median duration on UST of 62.1 weeks, and 60.5% achieved clinical remission. Patients had significant improvement in aPCDAI scores, clinical remission rates, albumin, and hematocrit, and 89.5% of patients had no significant adverse events. Similar results were observed among those who required dose adjustment, including 61.1% achieving clinical remission, and among those with perianal disease, including 38.5% achieving clinical remission.ConclusionsOur data suggest that, within our cohort of pediatric patients with CD, UST has long-term efficacy with no observed safety concerns. Dose adjustment may be helpful in achieving clinical remission.

Dolutegravir (DTG) has been introduced into first line combination antiretroviral therapy (ART) for HIV/AIDS. Penetration of ART into HIV reservoirs is essential to prevent continuous replication of HIV. However, accumulation of DTG in HIV reservoirs could be contributing to the adverse effects reported. We have developed and applied liquid chromatography tandem mass spectrometry (LC-MS/MS) methods to quantify DTG in wistar rat biological matrices following chronic DTG administration. DTG was detected using a Shimadzu 8040 triple quadrupole-mass spectrometer. The methods developed were in the concentration ranges of 17.5–8000 ng/mL for plasma and 15.5–16 680 ng/g for tissue matrices. Mean plasma DTG concentrations in the current study closely corresponded to plasma DTG levels reported in humans after chronic treatment. Plasma and tissue DTG concentrations were generally higher in females compared to male wistar rats, but these differences were nullified after correcting for body and organ size. Plasma DTG levels correlated with tissue DTG concentrations in the liver and gastrocnemius muscle tissue. Data suggest that body size – rather than sex – may be a major risk factor determining adverse outcomes of patients on the current DTG dosing strategy which does not account for differences in body mass. Furthermore, plasma DTG was not correlated with adipose tissue DTG concentration. This suggests that adipose may be a primary site for longer term inflammatory dysregulation and adverse outcome following DTG treatment.

Background and objectivePublished works have discussed the pharmacokinetic interactions of drugs with pregnancy, but none comprehensively identify all the approved United States Food and Drug Administration (FDA) and European Medicines Administration (EMA) drugs that have a pregnancy-related intervention. The objective of this systematic review is to comprehensively identify medications that have clinically meaningful interventions due to pharmacokinetic reasons.MethodsAn in-depth search of clinical data using the PDR3D: Reed Tech Navigator™ for Drug Labels was conducted from 1 June to 12 August 2022. The PDR3D was analyzed using the search terms “pregnant” and “pregnancy” within the proper label section. Regarding the US labels, the terms were searched under the “dosage and administration” section, whereas with the EU labels, the terms were searched within the “posology and method of administration” section. If a finding was discovered within the search, the rest of the label was analyzed for further information. Clinical relevance was based on whether an intervention was needed.ResultsUsing the search strategy, 139 US and 20 EU medications were found to have clinically meaningful interventions in pregnancy. The most common explanations for clinical relevance included hepatic metabolism, protein binding, renal elimination, and P-gp influence. Of the US labels: 40 were found to undergo hepatic metabolism, 11 were found to be influenced by renal elimination, 12 were found to be influenced by protein binding, 7 were found to be influenced by P-gp, and the remaining drugs required further research. Of the EU labels: 11 were found to undergo hepatic metabolism, 3 were found to be influenced by renal elimination, 3 were found to be influenced by protein binding, 1 was found to be influenced by P-gp, and the remaining drugs required further research.ConclusionThis comprehensive review of clinically relevant interventions in pregnancy will potentially aid in the treatment of pregnant females when they are undergoing therapy, provide intervention and dosing guidance for physicians, and save time for prescribers and pharmacists. Advances in non-clinical predictions for pregnancy dosing may guide the need for a future clinical evaluation.

Voriconazole (VRZ) is a broad-spectrum antifungal medication widely used to treat invasive fungal infections (IFI). The administration dosage and blood concentration of VRZ are influenced by various factors, posing challenges for standardization and individualization of dose adjustments. On the one hand, VRZ is primarily metabolized by the liver, predominantly mediated by the cytochrome P450 (CYP) 2C19 enzyme. The genetic polymorphism of CYP2C19 significantly impacts the blood concentration of VRZ, particularly the trough concentration (Ctrough), thereby influencing the drug's efficacy and potentially causing adverse drug reactions (ADRs). Recent research has demonstrated that pharmacogenomics-based VRZ dose adjustments offer more accurate and individualized treatment strategies for individuals with hepatic insufficiency, with the possibility to enhance therapeutic outcomes and reduce ADRs. On the other hand, the security, pharmacokinetics, and dosing of VRZ in individuals with hepatic insufficiency remain unclear, making it challenging to attain optimal Ctrough in individuals with both hepatic insufficiency and IFI, resulting in suboptimal drug efficacy and severe ADRs. Therefore, when using VRZ to treat IFI, drug dosage adjustment based on individuals' genotypes and hepatic function is necessary. This review summarizes the research progress on the impact of genetic polymorphisms and hepatic insufficiency on VRZ dosage in IFI individuals, compares current international guidelines, elucidates the current application status of VRZ in individuals with hepatic insufficiency, and discusses the influence of CYP2C19, CYP3A4, CYP2C9, and ABCB1 genetic polymorphisms on VRZ dose adjustments and Ctrough at the pharmacogenomic level. Additionally, a comprehensive summary and analysis of existing studies' recommendations on VRZ dose adjustments based on CYP2C19 genetic polymorphisms and hepatic insufficiency are provided, offering a more comprehensive reference for dose selection and adjustments of VRZ in this patient population. [ABSTRACT FROM AUTHOR]

The aim of the study is to evaluate the effectiveness of the pediatric sofosbuvir weight-based dosing strategy in providing an equitable drug exposure compared to the marketed dose. The physiologically based pharmacokinetic (PBPK) modeling and simulation is a valuable tool in assessing drug dosing and toxicity in populations with physiological, pathological, and genetic pharmacokinetic (PK) variability. The PBPK model of the sofosbuvir compound was developed using Simcyp® V20. The model was developed and verified using the published sofosbuvir's physicochemical properties and clinical data from multiple studies on healthy adult volunteers, hepatitis C virus (HCV)-infected adults, and HCV-infected pediatrics. The AUC and Cmax fold ratio of (predicted/observed) fell within the acceptable range of 0.5–2 in all tested adults' data, confirming the successful development of the sofosbuvir Simcyp® compound model. Using this model, a weight-based dosing regimen of 6 mg/kg in pediatric patients was simulated and compared to the 150 mg and 200 mg approved dose for 3–6 and 6–12 y/o pediatric patients, respectively. No dose adjustment was recommended in patients ages 6–12 y/o. However, compared to the approved 150 mg for 3–6 y/o, the weight base dose provided an equitable drug exposure to adults. Further clinical studies are warranted to verify this finding. [ABSTRACT FROM AUTHOR]

Background: Obesity (body mass index [BMI] ≥30 kg/m2) is an important epidemiological risk factor for developing acute myeloid leukemia (AML). Therefore, the authors studied the association of obesity with clinical and genetic phenotype and its impact on outcome in adults with AML. Methods: The authors analyzed BMI in 1088 adults who were receiving intensive remission induction and consolidation therapy in two prospective, randomized therapeutic clinical trials of the Eastern Cooperative Oncology Group‐American College of Radiology Imaging Network: E1900 (ClinicalTrials.gov identifier NCT00049517; patients younger than 60 years) and E3999 (ClinicalTrials.gov identifier NCT00046930; patients aged 60 years or older). Results: Obesity was prevalent at diagnosis (33%) and, compared with nonobesity, was associated with intermediate‐risk cytogenetics group (p =.008), poorer performance status (p =.01), and a trend toward older age (p =.06). Obesity was not associated with somatic mutations among a selected 18‐gene panel that was tested in a subset of younger patients. Obesity was not associated with clinical outcome (including complete remission, early death, or overall survival), and the authors did not identify any patient subgroup that had inferior outcomes based on BMI. Obese patients were significantly more likely to receive <90% of the intended daunorubicin dose despite protocol specification, particularly in the E1900 high‐dose (90 mg/m2) daunorubicin arm (p =.002); however, this did not correlate with inferior overall survival on multivariate analysis (hazard ratio, 1.39; 95% confidence interval, 0.90–2.13; p =.14). Conclusions: Obesity is associated with unique clinical and disease‐related phenotypic features in AML and may influence physician treatment decisions regarding daunorubicin dosing. However, the current study demonstrates that obesity is not a factor in survival, and strict adherence to body surface area‐based dosing is not necessary because dose adjustments do not affect outcomes. Obesity is prevalent in adults with acute myeloid leukemia, and these patients are more likely to have intermediate‐risk cytogenetics and worse performance status; however, obesity does not affect clinical outcomes, including complete remission, early death, or overall survival. Dose modifications of daunorubicin (dose reductions and dose capping) in obese patients does not affect clinical outcomes; therefore, strict adherence to the full dose based on body surface area is not required for intensive therapy in adults with acute myeloid leukemia. [ABSTRACT FROM AUTHOR]

New spraying systems embedded with different technologies have been developed for pesticide application in 3D crops. However, while applied to specific tree crops, the potential spray drift mitigation for advanced spraying systems needs to be classified due to the great variability of spray equipment and canopy structure. Here a precision spraying system was developed and compared with two typical spraying systems (conventional system, optimized system following the best management practices) for the applied volume/pesticide and spray drift in an apple orchard at two growth stages following the ISO22866-2005 protocol. Compared to the conventional system, the other two advanced systems significantly reduced the amount of ground drift (> 60%) at most of the sampling distances at the growth stage BBCH 72, while the precision system demonstrated the best drift mitigation (57.3% reduction) at the stage BBCH 99. For the airborne drift, a remarkable drift reduction was also achieved with the two advanced systems. Specifically, the optimized spraying system exhibited a drift reduction by approximately 80% at the first growth stage, and the precision application demonstrated its considerable advantages in minimizing drift loss for the sparse canopy at the stage BBCH 99. Moreover, the saving of applied volume/pesticide was achieved by 12% with the optimized system and 43% with the precision system. This study revealed the necessity and prospect of the advanced spraying systems to reduce the environmental contamination and health risk from pesticide applications in fruit tree production. [ABSTRACT FROM AUTHOR]

Potential medication errors and related adverse drug events (ADE) pose major challenges in clinical medicine. Clinical decision support systems (CDSSs) help identify preventable prescription errors leading to ADEs but are typically characterized by high sensitivity and low specificity, resulting in poor acceptance and alert-overriding. With this cross-sectional study we aimed to analyze CDSS performance, and to identify factors that may increase CDSS specificity. Clinical pharmacology services evaluated current pharmacotherapy of 314 patients during hospitalization across three units of two Swiss tertiary care hospitals. We used two CDSSs (pharmaVISTA and MediQ), primarily for the evaluation of drug-drug interactions (DDI). Additionally, we evaluated potential drug-disease, drug-age, drug-food, and drug-gene interactions. Recommendations for change of therapy were forwarded without delay to treating physicians. Among 314 patients, automated analyses by both CDSSs produced an average of 15.5 alerts per patient. In contrast, additional expert evaluation resulted in only 0.8 recommendations per patient to change pharmacotherapy. For clinical pharmacology experts, co-factors such as comorbidities and laboratory results were decisive for the classification of CDSS alerts as clinically relevant in individual patients in about 70% of all decisions. Such co-factors should therefore be used for the development of multidimensional CDSS alert algorithms with improved specificity. In combination with local expert services, this poses a promising approach to improve drug safety in clinical practice. [ABSTRACT FROM AUTHOR]

Objective·To evaluate the effects of levothyroxine (L-T4) dose adjustment according to the level of thyroid stimulating hormone (TSH) on maternal and infant outcomes in the pregnant women with hypothyroidism by meta-analysis. Methods·China National Knowledge Infrastructure (CNKI), China Science and Technology Journal Database (VIP), Wanfang Data Knowledge Service Platform, PubMed, Cochrane Library and Embase were retrieved to collect all the controlled studies on the treatment of pregnant women with hypothyroidism by adjusting the dose of L-T4 according to TSH level from the establishment of the databases to April 9, 2022. The references were also traced. Literature screening, data extraction, and quality evaluation were performed independently by two researchers. Cochrane evaluation was used to evaluate the quality of the included literature. Outcome indicators included gestational hypertension, gestational diabetes, postpartum hemorrhage, delivery mode, preterm birth, fetal death, neonatal asphyxia, and low birth weight infants. RevMan 5.3 was used for meta-analysis. Result·A total of 1 268 articles were retrieved from 6 databases, and 8 were included in the study, including 4 Chinese articles and 4 English articles. The overall risk of study bias was at a moderate level. Compared with the control group, the OR of gestational diabetes risk was 0.61 (95%CI 0.44‒0.86, P=0.004) and the OR of fetal death risk was 0.38 (95%CI 0.18‒0.81, P=0.010) in the experimental group with L-T4 dose adjusted according to the TSH level of the pregnant women with hypothyroidism, which were both statistically significant. However, the treatment method of adjusting L-T4 dose did not affect the risks of vaginal delivery [OR=1.82 (95%CI 0.75 ‒4.40, P=0.180)], gestational hypertension [OR=0.77 (95%CI 0.53‒1.12, P=0.170)], postpartum hemorrhage [OR=1.20 (95%CI 0.50 ‒2.92, P=0.680)], preterm birth [OR=0.72 (95%CI 0.48‒1.06, P=0.100)], low birth weight infants [OR=1.00 (95%CI 0.65‒1.54, P=0.999)], or neonatal asphyxia [OR=0.50 (95%CI 0.20 ‒ 1.27, P=0.150)] significantly. Conclusion·Adjusting the L-T4 therapeutic dose according to the TSH level may help reduce the risks of gestational diabetes and fetal death in the pregnant women with hypothyroidism. [ABSTRACT FROM AUTHOR]

The Food and Drug Administration currently approves the combination of hypomethylating agents (HMA), azacytidine or decitabine with venetoclax (VEN) for acute myeloid leukemia (AML) patients aged more than 75 years and for patients unsuitable for intensive chemotherapy. The risk of fungal infection in the early phase of treatment is not negligible; therefore, posaconazole (PCZ) is commonly administered as primary prophylaxis. A drug–drug interaction between VEN and PCZ is well known, but the trend of serum levels of venetoclax when both drugs are overlapped is not clear. In total, 165 plasma samples from 11 elderly AML patients receiving combined treatment with HMA, VEN and PCZ were analyzed by a validated analytical method (high-pressure liquid chromatography–tandem mass spectrometry). Venetoclax trough plasma concentrations were detected during the 3 days of ramp-up as well as on day 7 and day 12 of treatment when the exposure as the area under the plasma concentration–time curve and the accumulation ratio were also calculated. The results were compared with the expected data for 400 mg/dose VEN administered alone—the confirmed high inter-individual variability in pharmacokinetics suggests the need for therapeutic drug monitoring. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: It is generally recommended to reduce basal insulin doses after exercise to reduce the risk of post-exercise nocturnal hypoglycaemia. Based on its long t½, it is unknown whether such adjustments are required or beneficial for insulin degludec. Methods: The ADREM study (Adjustment of insulin Degludec to Reduce post-Exercise (nocturnal) hypoglycaeMia in people with diabetes) was a randomised controlled, crossover study in which we compared 40% dose reduction (D40), or postponement and 20% dose reduction (D20-P), with no dose adjustment (CON) in adults with type 1 diabetes at elevated risk of hypoglycaemia, who performed a 45 min aerobic exercise test in the afternoon. All participants wore blinded continuous glucose monitors for 6 days, measuring the incidence of (nocturnal) hypoglycaemia and subsequent glucose profiles. Results: We recruited 18 participants (six women, age 38 ± 13 years, HbA1c 56 ± 8 mmol/mol [7.3 ± 0.8%], mean ± SD). Time below range (i.e. glucose <3.9 mmol/l) the night after the exercise test was generally low and occurrence did not differ between the treatment regimens. During the subsequent whole day, time below range was lower for D40 compared with CON (median [IQR], 0 [0–23] vs 18 [0–55] min, p=0.043), without differences in the number of hypoglycaemic events. Time above range (i.e. glucose >10 mmol/l) was greater for D20-P vs CON (mean ± SEM, 584 ± 81 vs 364 ± 66 min, p=0.001) and D40 (385 ± 72 min, p=0.003). Conclusions/interpretation: Post-exercise adjustment of degludec does not mitigate the risk of subsequent nocturnal hypoglycaemia in people with type 1 diabetes. Although reducing degludec reduced next-day time below range, this did not translate into fewer hypoglycaemic events, while postponing degludec should be avoided because of increased time above range. Altogether, these data do not support degludec dose adjustment after a single exercise bout. Trial registration: EudraCT number 2019-004222-22 Funding: The study was funded by an unrestricted grant from Novo Nordisk, Denmark. [ABSTRACT FROM AUTHOR]

Sertraline is one of the most prescribed antidepressants, but its pharmacokinetic (PK) properties are still not completely characterized. Using nonlinear mixed-effects modeling, we examined factors influencing sertraline PK variability in outpatients with major depressive disorder. Blood samples from 53 male and female adults treated with sertraline orally were collected at a steady state. Various demographic and clinical covariates were tested by stepwise regression procedure. We found that sertraline clearance is significantly influenced by serum concentrations of its main metabolite N-desmethylsertraline, whereas clearance of N-desmethylsertraline is affected by both creatinine clearance and drug daily dose. These results were confirmed by the reduction of points dispersion in goodness-of-fit plots for their predicted versus measured concentrations and with bootstrapping analyses. This finding can serve to inform sertraline dosing optimization, especially when changes in kidney function occur in treated individuals, to prevent adverse drug reactions and maximize therapeutic benefits. [ABSTRACT FROM AUTHOR]

Aims: This study aims to investigate prescribing and therapeutic drug monitoring (TDM) practices for vancomycin in paediatrics at the Jordan University Hospital and to determine the impact of inaccuracies in TDM data on dosing decisions. Methods: Patterns of vancomycin prescriptions, appropriateness of vancomycin dosing, duration, TDM, and the accuracy of the recorded dosing/sampling times were determined prospectively based on prespecified criteria. Finally, Monte Carlo simulations were undertaken using the mrgsolve‐package in R to assess the effect of inaccuracies in recording dosing/sampling times on subsequent dose adjustments. Results: Four hundred forty‐two vancomycin courses were analysed. Vancomycin prescriptions were mainly empirical (77.4%). Initial vancomycin doses were appropriate in 73.1% of vancomycin courses. Prolonged use (>5 days) was found in 45.7% of admissions with negative cultures; this was related to the diagnosis of suspected sepsis unadjusted‐OR: 1.8 (1.1–2.9). TDM was appropriately ordered in 90.7% of concentrations. Discrepancies between the recorded and actual times were noted in 83.9% and 82.7% of audited times of dose administration and sample collection, respectively. Based on simulations, these discrepancies were predicted to result in inappropriate dose adjustment in 37.9% of patients. Conclusions: Inappropriate empirical and prolonged vancomycin use and inaccuracies in recording dosing/sampling times are important areas of improvement in the current clinical practice. [ABSTRACT FROM AUTHOR]

The treatment process in acute myeloid leukemia (AML) often results in prolonged neutropenia, especially in the early period, and this requires antifungal prophylaxis. In the era of venetoclax (VEN), concomitant antifungal prophylaxis has been abandoned because azole antifungals inhibit cytochrome P450 3A4, the primary enzyme responsible for VEN metabolism. If azole antifungal prophylaxis is used with VEN, the dose of VEN needs to be reduced, but the clinical consequences in this situation are unknown. Limited clinical data exist on outcomes for patients treated with VEN, a hypomethylating agent (HMA), and posaconazole. We retrospectively evaluated our single-center experience on 46 patients, 20 treatment-naive and 26 relapsed/refractory (RR) AML patients. VEN was used after dose adjustment due to concomitant posaconazole use for antifungal prophylaxis. The median age was 65.5 years (range, 18-78). The median follow-up was 5.5 months (range, 1-25). The overall response rate (ORR) was 60.8%. The incidence of invasive fungal infection was 15.2%. The median OS from venetoclax initiation of all the patients and those with CR/CRi was 6 and 10 months, respectively. After VEN dose reduction due to concomitant posaconazole use, the observed ORR was comparable to the ORR previously reported in the literature without VEN dose reduction and antifungal prophylaxis. However, the OS obtained in our patients was shorter than previously reported in the literature. In addition, the incidence of invasive fungal infections in our patients was not less than that reported in the VEN and HMA studies without antifungal prophylaxis. [ABSTRACT FROM AUTHOR]

Antimicrobial consumption is increasing. In order to maximize the effectiveness of antimicrobial stewardship and provide safe and optimal use of restricted antimicrobial drugs, renal dosing should be evaluated. The aim of this study was to determine the prevalence of restricted antimicrobial drugs that required dose adjustment according to renal function. A retrospective, consecutive study was conducted at University Hospital Dubrava. This study analyzed requests for restricted antimicrobial drugs (n = 2890) during a 3-month period. Requests for antimicrobial agents were evaluated by the antimicrobial therapy management team (A-team). This study included 412 restricted antimicrobial drug requests requiring dose adjustment, of which 39.1% did not have an adjusted dose. Meropenem, Ciprofloxacin, Piperacillin/Tazobactam, Vancomycin, Colistin and the antimycotic Fluconazole were the most frequent restricted antimicrobial drugs that required dose adjustment according to impaired renal function. The results of this research highlight the importance of the A-team in the optimization of restricted antimicrobial therapy. Non-adjusted doses of restricted antimicrobial drugs increase the possibility of adverse drug reactions and therefore jeopardize pharmacotherapy outcomes and patient safety. [ABSTRACT FROM AUTHOR]

Objective: Contezolid is an oxazolidinone antimicrobial agent newly approved for treatment of Gram-positive bacterial infections. It is primarily metabolized by the liver. This study aimed to assess whether it is required to adjust the dose of contezolid in patients with moderate hepatic impairment for clinicians to use the drug more rationally. Methods: A single-center, open-label, parallel-group study was conducted to compare the pharmacokinetic (PK) parameters of contezolid and its metabolite M2 between the patients with moderate hepatic impairment and healthy controls with normal liver function after oral administration of 800 mg contezolid tablets. Monte Carlo simulation was performed to calculate the probability of target attainment (PTA) and cumulative fraction of response (CFR) of contezolid based on the PK and pharmacodynamic data. Results: Oral treatment with 800 mg contezolid tablets was safe and well tolerated in both the patients with moderate hepatic impairment and healthy controls. Moderate hepatic impairment did not result in substantial difference in the area under the concentration-time curve from 0 to 24 h (AUC0–24h, 106.79 vs. 97.07 h μg/mL) of contezolid even though lower maximum concentration (Cmax, 19.03 vs. 34.49 μg/mL) compared with healthy controls. The mean cumulative amount excreted in urine from 0 to 48 h (Ae0–48h) and renal clearance (CLR) of contezolid did not show significant difference between the two groups. Moderate hepatic impairment was associated with lower Cmax, slightly lower AUC and Ae0–48h of M2 compared to the healthy controls. fAUC/MIC was the best PK/PD index to predict the clinical efficacy of contezolid. Monte Carlo simulation results indicated that at the proposed fAUC/MIC target value of 2.3, the dosing regimen of oral contezolid 800 mg q12h could achieve satisfactory PTA and CFR (both >90%) for the target pathogen (methicillin-resistant S. aureus, MIC ≤4 mg/L) in patients with moderate hepatic impairment. Conclusion: Our preliminary data suggest that dose adjustment is not required for contezolid in patients with moderate hepatic impairment. [ABSTRACT FROM AUTHOR]

Diffuse large B-cell lymphoma (DLBCL) accounts for approximately 24% of new cases of B-cell non-Hodgkin lymphoma in the US each year. Up to 50% of patients relapse or are refractory (R/R) to the standard first-line treatment option, R-CHOP. The anti-CD19 monoclonal antibody tafasitamab, in combination with lenalidomide (LEN), is an NCCN preferred regimen for transplant-ineligible patients with R/R DLBCL and received accelerated approval in the US (July 2020) and conditional marketing authorization in Europe (August 2021) and other countries, based on data from the L-MIND study. The recommended dose of tafasitamab is 12 mg/kg by intravenous infusion, administered in combination with LEN 25 mg for 12 cycles, followed by tafasitamab monotherapy until disease progression or unacceptable toxicity. Tafasitamab + LEN is associated with durable responses in patients with R/R DLBCL. The majority of clinically significant treatment-associated adverse events are attributable to LEN and can be managed with dose modification and supportive therapy. We provide guidelines for the management of patients with R/R DLBCL treated with tafasitamab and LEN in routine clinical practice, including elderly patients and those with renal and hepatic impairment, and advice regarding patient education as part of a comprehensive patient engagement plan. Our recommendations include LEN administration at a reduced dose if required in patients unable to tolerate the recommended dose. No dose modification is required for tafasitamab in special patient populations. [ABSTRACT FROM AUTHOR]

Objective: Contezolid is an oxazolidinone antimicrobial agent newly approved for treatment of Gram-positive bacterial infections. It is primarily metabolized by the liver. This study aimed to assess whether it is required to adjust the dose of contezolid in patients with moderate hepatic impairment for clinicians to use the drug more rationally.Methods: A single-center, open-label, parallel-group study was conducted to compare the pharmacokinetic (PK) parameters of contezolid and its metabolite M2 between the patients with moderate hepatic impairment and healthy controls with normal liver function after oral administration of 800 mg contezolid tablets. Monte Carlo simulation was performed to calculate the probability of target attainment (PTA) and cumulative fraction of response (CFR) of contezolid based on the PK and pharmacodynamic data.Results: Oral treatment with 800 mg contezolid tablets was safe and well tolerated in both the patients with moderate hepatic impairment and healthy controls. Moderate hepatic impairment did not result in substantial difference in the area under the concentration-time curve from 0 to 24 h (AUC0–24h, 106.79 vs. 97.07 h μg/mL) of contezolid even though lower maximum concentration (Cmax, 19.03 vs. 34.49 μg/mL) compared with healthy controls. The mean cumulative amount excreted in urine from 0 to 48 h (Ae0–48h) and renal clearance (CLR) of contezolid did not show significant difference between the two groups. Moderate hepatic impairment was associated with lower Cmax, slightly lower AUC and Ae0–48h of M2 compared to the healthy controls. fAUC/MIC was the best PK/PD index to predict the clinical efficacy of contezolid. Monte Carlo simulation results indicated that at the proposed fAUC/MIC target value of 2.3, the dosing regimen of oral contezolid 800 mg q12h could achieve satisfactory PTA and CFR (both >90%) for the target pathogen (methicillin-resistant S. aureus, MIC ≤4 mg/L) in patients with moderate hepatic impairment.Conclusion: Our preliminary data suggest that dose adjustment is not required for contezolid in patients with moderate hepatic impairment.Clinical Trial Registration:https://chinadrugtrials.org.cn, identifier: CTR20171377.

Objective: The influence of continuous renal replacement therapy (CRRT) on the steady-state plasma concentration of high-dose tigecycline was investigated in septic shock patients to provide references for drug dosing.Methods: In this prospective observational study, 17 septic shock patients presenting with severe infections needing a broad-spectrum antibiotic therapy with high-dose tigecycline (100 mg per 12 h) in the intensive care unit were included and divided into CRRT group (n = 6) or non-CRRT group (n = 11). The blood samples were collected and plasma drug concentration was determined by SHIMADZU LC-20A and SHIMADZU LCMS 8040. The steady-state plasma concentration was compared between groups using unpaired t-test. Furthermore, between-groups comparisons adjusted for baseline value was also done using multivariate linear regression model.Results: Peak concentration (Cmax) of tigecycline was increased in CRRT group compared to non-CRRT group, but there were no statistical differences (505.11 ± 143.84 vs. 406.29 ± 108.00 ng/mL, p-value: 0.129). Trough concentration (Cmin) of tigecycline was significantly higher in CRRT group than in non-CRRT group, with statistical differences (287.92 ± 41.91 vs. 174.79 ± 33.15 ng/mL, p-value: 0.000, adjusted p-value: 0.000). In safety, Cmin was reported to be a useful predictor of hepatotoxicity with a cut-off of 474.8 ng/mL. In our studies, Cmin of all patients in CRRT group was lower than 474.8 ng/mL.Conclusion: The plasma concentration of tigecycline was increased in septic shock patients with CRRT treatment and only Cmin shown statistical differences. No dose adjustment seems needed in the view of hepatotoxicity.Clinical Trial Registration:https://www.chictr.org.cn/, identifier ChiCTR2000037475.

Pharmacogenetic variability in drug metabolism leads to patient vulnerability to side effects and to therapeutic failure. Our purpose was to introduce a systematic statistical methodology to estimate quantitative dose adjustments based on pharmacokinetic differences in pharmacogenetic subgroups, addressing the concerns of sparse data, incomplete information on phenotypic groups, and heterogeneity of study design. Data on psychotropic drugs metabolized by the cytochrome P450 enzyme CYP2C19 were used as a case study. CYP2C19 activity scores were estimated, while statistically assessing the influence of methodological differences between studies, and used to estimate dose adjustments in genotypic groups. Modeling effects of activity scores in each substance as a population led to prudential predictions of adjustments when few data were available ('shrinkage'). The best results were obtained with the regularized horseshoe, an innovative Bayesian approach to estimate coefficients viewed as a sample from two populations. This approach was compared to modeling the population of substance as normally distributed, to a more traditional "fixed effects" approach, and to dose adjustments based on weighted means, as in current practice. Modeling strategies were able to assess the influence of study parameters and deliver adjustment levels when necessary, extrapolated to all phenotype groups, as well as their level of uncertainty. In addition, the horseshoe reacted sensitively to small study sizes, and provided conservative estimates of required adjustments. [ABSTRACT FROM AUTHOR]

Purpose: To avoid adverse drug reactions, dose reductions are recommended when prescribing selective serotonin reuptake inhibitors (SSRIs) to patients with impaired kidney function. The extent of this practice in routine clinical care is however unknown. We aimed to evaluate the starting and maintenance SSRI doses prescribed to patients stratified by levels of kidney function in real‐world practice. Methods: Using data from the Stockholm CREAtinine Measurements (SCREAM) project, we identified 101 409 new users of antidepressants (including 52 286 SSRI users) in the region of Stockholm during 2006–2019, who were ≥50 years of age and had a recent creatinine test taken in order to estimate glomerular filtration rate (eGFR). SSRI dose reduction was defined as a prescribed SSRI dose of ≤0.5 defined daily doses, according to current recommendations. We examined the associations between eGFR and reductions in initial dose and maintenance dose of SSRIs using logistic regression models. Results: Overall, reductions in initial and maintenance dose were observed among 54.1% and 34.1% of new SSRI users. Nevertheless, about 40% of individuals with an eGFR <30 ml/min/1.73 m2 were prescribed an SSRI without dose reduction. After adjusting for age and other covariates, lower eGFR was associated with moderately higher odds of dose reduction, for both initial and maintenance dose. Compared to individuals with an eGFR of 90–104 ml/min/1.73 m2, the adjusted odds ratios for those with an eGFR <30 ml/min/1.73 m2 were 1.18 (95% CI: 1.03, 1.36) for initial dose reduction, and 1.49 (1.29, 1.72) for maintenance dose reduction. Stratified analyses showed stronger associations between lower eGFR and SSRI dose reduction among individuals aged 50–64 years and in those receiving prescriptions from psychiatric care. Conclusions: Lower kidney function was moderately associated with a reduced SSRI dose, independently of age. Prescribing SSRIs to middle‐aged and older patients should not only consider patients' age but also their kidney function. [ABSTRACT FROM AUTHOR]

• We report the development of the first adjustable-dose gene therapy system. • The vector is non-antigenic and produces durable and adjustable gene expression. • The system is localized to the subQ injection site and is specific for adipocytes. • Delivered DNA cassettes enable gene expression of secreted therapeutic proteins. • Exenatide, delivered in vivo , achieves clinically relevant levels in circulation. Despite significant potential, gene therapy has been relegated to the treatment of rare diseases, due in part to an inability to adjust dosage following initial administration. Other significant constraints include cost, specificity, antigenicity, and systemic toxicity of current generation technologies. To overcome these challenges, we developed a first-in-class adjustable-dose gene therapy system, with optimized biocompatibility, localization, durability, and cost. A lipid nanoparticle (LNP) delivery system was developed and characterized by dynamic light scattering for size, zeta potential, and polydispersity. Cytocompatibility and transfection efficiency were optimized in vitro using primary human adipocytes and preadipocytes. Durability, immunogenicity, and adjustment of expression were evaluated in C57BL/6 and B6 albino mice using in vivo bioluminescence imaging. Biodistribution was assessed by qPCR and immunohistochemistry; therapeutic protein expression was quantified by ELISA. Following LNP optimization, in vitro transfection efficiency of primary human adipocytes reached 81.3 % ± 8.3 % without compromising cytocompatibility. Critical physico-chemical properties of the system (size, zeta potential, polydispersity) remained stable over a broad range of genetic cassette sizes (1,871–6,203 bp). Durable expression was observed in vivo over 6 months, localizing to subcutaneous adipose tissues at the injection site with no detectable transgene in the liver, heart, spleen, or kidney. Gene expression was adjustable using several physical and pharmacological approaches, including cryolipolysis, focused ultrasound, and pharmacologically inducible apoptosis. The ability of transfected adipocytes to express therapeutic transgenes ranging from peptides to antibodies, at potentially clinically relevant levels, was confirmed in vitro and in vivo. We report the development of a novel, low-cost therapeutic platform, designed to enable the replacement of subcutaneously administered protein treatments with a single-injection, adjustable-dose gene therapy. [ABSTRACT FROM AUTHOR]

The aim of the study is to evaluate the effectiveness of the pediatric sofosbuvir weight-based dosing strategy in providing an equitable drug exposure compared to the marketed dose. The physiologically based pharmacokinetic (PBPK) modeling and simulation is a valuable tool in assessing drug dosing and toxicity in populations with physiological, pathological, and genetic pharmacokinetic (PK) variability. The PBPK model of the sofosbuvir compound was developed using Simcyp® V20. The model was developed and verified using the published sofosbuvir’s physicochemical properties and clinical data from multiple studies on healthy adult volunteers, hepatitis C virus (HCV)-infected adults, and HCV-infected pediatrics. The AUC and Cmax fold ratio of (predicted/observed) fell within the acceptable range of 0.5–2 in all tested adults’ data, confirming the successful development of the sofosbuvir Simcyp® compound model. Using this model, a weight-based dosing regimen of 6 mg/kg in pediatric patients was simulated and compared to the 150 mg and 200 mg approved dose for 3–6 and 6–12 y/o pediatric patients, respectively. No dose adjustment was recommended in patients ages 6–12 y/o. However, compared to the approved 150 mg for 3–6 y/o, the weight base dose provided an equitable drug exposure to adults. Further clinical studies are warranted to verify this finding.

For patients with end-stage renal disease (ESRD), peritoneal dialysis (PD) and hemodialysis (HD) are important renal replacement treatments. Patients on dialysis usually have a high incidence rate of malignant tumors. In 2020, breast cancer has become the malignant tumor with the highest incidence rate in the world. Human epidermal growth factor receptor-2-positive (HER-2+) breast cancer accounts for 20%-30% of the total breast cancer patients. It is highly invasive and has a poor prognosis. Anti-HER-2 treatment is an important therapy for this type of cancer. There are few case reports of anti-HER2-targeted therapy in dialysis patients. We report a 56-year-old Chinese woman with breast cancer (cT3N1MX, Her-2+/HR-). She underwent peritoneal dialysis for 11 years since she had suffered end-stage renal disease. The clinician prescribed the regimen (pyrotinib 320mg qd + capecitabine 1g bid D1-D14 Q3W). The tumor was significantly reduced after 1 month of single administration of pyrotinib, and partially relieved after 2 months of pyrotinib + capecitabine. The main side effects were grade II hand foot syndrome and grade II diarrhea. This case shows that the combination of pyrotinib and capecitabine has potential therapeutic benefits in HER-2+ breast cancer patients with end-stage renal disease.

Purpose: Venetoclax (VEN), an anti-tumor drug that is a substrate of cytochrome P450 3A enzyme (CYP3A4), is used to treat leukemia. Voriconazole (VCZ) is an antifungal medication that inhibits CYP3A4. The goal of this study is to predict the effect of VCZ on VEN exposure. Method: Two physiological based pharmacokinetics (PBPK) models were developed for VCZ and VEN using the bottom-up and top-down method. VCZ model was also developed to describe the effect of CYP2C19 polymorphism on its pharmacokinetics (PK). The reversible inhibition constant (Ki) of VCZ for CYP3A4 was calibrated using drug-drug interaction (DDI) data of midazolam and VCZ. The clinical verified VCZ and VEN model were used to predict the DDI of VCZ and VEN at clinical dosing scenario. Result: VCZ model predicted VCZ exposure in the subjects of different CYP2C19 genotype and DDI related fold changes of sensitive CYP3A substrate with acceptable prediction error. VEN model can capture PK of VEN with acceptable prediction error. The DDI PBPK model predicted that VCZ increased the exposure of VEN by 4.5–9.6 fold. The increase in VEN exposure by VCZ was influenced by subject's CYP2C19 genotype. According to the therapeutic window, VEN dose should be reduced to 100 mg when co-administered with VCZ. Conclusion: The PBPK model developed here could support individual dose adjustment of VEN and DDI risk assessment. Predictions using the robust PBPK model confirmed that the 100 mg dose adjustment is still applicable in the presence of VCZ with high inter-individual viability. [ABSTRACT FROM AUTHOR]

Introduction: Dose adjustments in patients with renal or hepatic dysfunction using anticancer drugs are indicated according to guidelines. However, implementation depends on awareness of prescribing physicians. We implemented a Clinical Decision Support System (CDSS), recommending dose adjustments upon electronic prescriptions based on renal and hepatic function. The alert provides a dose adjustment proposal and recent laboratory results. Our objective was to determine the frequency of dose adjustments before and after implementation of this CDSS. Methods: We included all first orders for patients ≥18 years treated with parenteral antineoplastic agents, for whom dosage adjustment is necessary based on renal or hepatic function between February 2018 and January 2019. This study was performed at the department of Clinical Oncology and Hematology of the Amsterdam University Medical Center. We implemented the CDSS August first. All prescriptions were prescribed according to common practice. We analyzed the orders where a dose reduction based on renal or hepatic function was indicated. Results: We included 73 orders before implementation and 99 orders after implementation. Before implementation 21% of doses were reduced in line with the guidelines versus 34% after implementation (p = 0.048). For hepatic dysfunction the proportion changed from 11% to 46% p = 0.011, while there was no effect for renal dysfunction (24% vs. 26% p = 0.75). Conclusion: Dosages are more frequently adjusted in concordance with guidelines in patients with hepatic dysfunction who are treated with parenteral antineoplastic agents after implementation of a CDSS. The change was not seen in patients with renal dysfunction. [ABSTRACT FROM AUTHOR]

Aim: To observe the difference in the risk of polymyxin B (PMB)-induced acute kidney injury (AKI) with or without dose adjustment based on the patients renal function. Materials & methods: This retrospective cohort analysis was carried out in 115 patients treated with PMB from November 2018 to October 2019. Results: No significant difference in the incidence of AKI as well as secondary outcomes was observed between these two groups (47.5 vs 37.14%; p = 0.304). Conclusion: Dosing adjustment based on renal function does not significantly lower the risk of PMB-induced AKI. A non adjusted dosing strategy for PMB is recommended in patients exhibiting various levels of renal impairment. [ABSTRACT FROM AUTHOR]

Aim: To assess the effectiveness and safety of a new protocol for adjusting doses during interrupted subcutaneous immunotherapy maintenance, exceeding an 8-week interval, with mite allergen injections in children with allergic rhinitis. Patients & methods: 194 children with allergic rhinitis who underwent subcutaneous immunotherapy and experienced interruptions lasting more than 8 weeks during maintenance were enrolled. Following the adoption of a novel dose-adjustment protocol, a real-world study was conducted. Results: After 3 years of subcutaneous immunotherapy, the novel group exhibited a significant reduction in allergy symptoms compared with baseline. Systemic reactions related to the novel protocol did not significantly increase. Conclusion: The novel protocol was deemed safe and effective, offering advantages of time savings and reduced burdens.

Sublingual allergen immunotherapy (SLIT) is a safe, effective, disease-modifying treatment for moderate-to-severe respiratory allergies. The function and responsiveness of the immune system components underlying the effects of allergen immunotherapy may vary from one patient to another. Furthermore, the severity of the symptoms of allergic disease can fluctuate over time, due to changes in environmental allergen exposure, effector cell responsiveness, and cell signaling. Hence, the allergen dose provided through SLIT can be fine-tuned to establish an optimal balance between effectiveness and tolerability. The objective of the MaDo study was to describe and understand dose adjustments of SLIT liquid formulations in France. We performed a retrospective, observational, cross-sectional, real-life study of allergists and other specialist physicians. Physicians described their patients via an anonymous case report form (CRF). The main patient inclusion criteria were age 5 years or over, at least one physician-confirmed IgE-driven respiratory allergy, and treatment for at least 2 years with one or more SLIT liquid preparations. A nationally representative sample of 33 specialist physicians participated in the study. The physicians' main stated reasons for dose adjustment were adverse events (according to 90.9% of the physicians), treatment effectiveness (60.6%), sensitivity to the allergen (42.4%) and other characteristics (30.3%: mainly symptom severity, type of allergen, and asthma). 392 CRFs (mean ± standard deviation patient age: 27.8 ± 17.5; under-18s: 42.1%; polyallergy: 30.9%) were analyzed. Respectively 53.6%, 25.8%, 15.3%, and 8.7% of the patients received house dust mite, grass pollen, birch pollen and cypress pollen SLIT. Dose adjustments were noted in 258 (65.8%) patients (at the start of the maintenance phase for 101 patients (39.2%) and later for 247 (95.7%)). Dose adjustment was not linked to sex, age, or the number of allergens administered. All measures of disease severity (including symptom severity noted on a 0-to-10 visual analogue scale by the physician) decreased significantly during SLIT. Notably, the mean AR symptom severity score decreased to a clinically relevant extent from 7.6 at SLIT initiation to 2.4 at last follow-up, and the mean asthma symptom severity score decreased from 5.0 to 1.3. The few differences in effectiveness between patients with vs. without dose adjustment were not major. For about one patient in five, a specialist physician decided to reduce or increase the SLIT liquid dose at the start of maintenance treatment and/or during maintenance treatment. This decision was influenced by a broad range of patient and treatment factors, mainly to improve tolerability to treatment and/or enhance effectiveness. In France, dose adjustment of SLIT liquid preparations as a function of the patient profile and/or treatment response is anchored in clinical practice. Precision dosing might optimize the overall benefit-risk profile of AIT for individual patients throughout their entire treatment course, enabling them to achieve both short- and long-term treatment goals, whilst maximizing the safety and tolerability.

The Food and Drug Administration currently approves the combination of hypomethylating agents (HMA), azacytidine or decitabine with venetoclax (VEN) for acute myeloid leukemia (AML) patients aged more than 75 years and for patients unsuitable for intensive chemotherapy. The risk of fungal infection in the early phase of treatment is not negligible; therefore, posaconazole (PCZ) is commonly administered as primary prophylaxis. A drug–drug interaction between VEN and PCZ is well known, but the trend of serum levels of venetoclax when both drugs are overlapped is not clear. In total, 165 plasma samples from 11 elderly AML patients receiving combined treatment with HMA, VEN and PCZ were analyzed by a validated analytical method (high-pressure liquid chromatography–tandem mass spectrometry). Venetoclax trough plasma concentrations were detected during the 3 days of ramp-up as well as on day 7 and day 12 of treatment when the exposure as the area under the plasma concentration–time curve and the accumulation ratio were also calculated. The results were compared with the expected data for 400 mg/dose VEN administered alone—the confirmed high inter-individual variability in pharmacokinetics suggests the need for therapeutic drug monitoring.