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Drugs exhibiting nonlinear pharmacokinetics hold significant importance in drug research and development. However, evaluating drug exposure accurately is challenging with the current formulae established for linear pharmacokinetics. This article aims to investigate the steady-state drug exposure for a one-compartment pharmacokinetic (PK) model with sigmoidal Hill elimination, focusing on three key topics: the comparison between steady-state drug exposure of repeated intravenous (IV) bolus ( AUC ss ) and total drug exposure after a single IV bolus ( AUC 0 - ∞ ); the evolution of steady-state drug concentration with varying dosing frequencies; and the control of drug pharmacokinetics in multiple-dose therapeutic scenarios. For the first topic, we established conditions for the existence of AUC ss , derived an explicit formula for its calculation, and compared it with AUC 0 - ∞ . For the second, we identified the trending properties of steady-state average and trough concentrations concerning dosing frequency. For the third, we developed formulae to compute dose and dosing time for both regular and irregular dosing scenarios. As an example, our findings were applied to a real drug model of progesterone used in lactating dairy cows. In conclusion, these results provide a theoretical foundation for designing rational dosage regimens and conducting therapeutic trials. [ABSTRACT FROM AUTHOR]

AbstractFor fixed-duration therapies against chronic lymphocytic leukemia (CLL), undetectable measurable residual disease (MRD) predicts overall and progression-free survival more accurately than complete remission. For indefinite therapies, MRD status can direct discontinuation of treatment. We systematically reviewed the relationship between antineoplastic drug exposures and undetectable MRD in CLL. Seventeen trials from MEDLINE and EMBASE met the inclusion criteria; four of which evaluated drug exposures in relation to MRD status. Undetectable MRD was associated with higher trough concentrations of ofatumumab and alemtuzumab, as well as increased maximum concentration and area under the plasma concentration curve (AUC) of ibrutinib. One study found an association between high rituximab AUC and undetectable MRD until adjusting for tumor burden. The limited studies, lack of exposure measurements of concomitant drugs, and high heterogeneity in designs limit the results’ generalizability. Further research is needed to explore the exposure–MRD relationship and the possibility for therapeutic drug monitoring in CLL. [ABSTRACT FROM AUTHOR]

Background: Linezolid is commonly used to treat severe and/or resistant Gram-positive infections. Few studies have assessed its pharmacokinetic (PK) target attainment in pediatrics. Objective: To evaluate the percentage of pediatrics achieving the PK targets of linezolid with standard dosing regimens and to assess the incidence and risk factors associated with its hematologic toxicity. Methods: This prospective observational study included pediatric patients aged 0–14 who received linezolid for suspected or proven Gram-positive infections. Linezolid trough concentrations and the 24-h area under the curve (AUC24) were estimated, and hematologic toxicity was assessed. Results: Seventeen pediatric patients (5 neonates and 12 older pediatrics) were included. A wide variability was observed in linezolid's trough and AUC24 (ranging from 0.5 to 14.4 mg/L and from 86 to 700 mg.h/L, respectively). The median AUC24 was significantly higher in neonates than older pediatrics (436 [350–574] vs. 200 [134–272] mg,h/L, P = 0.01). Out of all patients, only 41% achieved adequate drug exposure (AUC24 160–300 mg.h/L and trough 2–7 mg/L), with 24% having subtherapeutic, and 35% having higher-than-optimal exposures. Hematological toxicity was observed in 53% of cases. Identified risk factors include treatment duration over 7 days, baseline platelet counts below 150 × 109/L, sepsis/septic shock, and concomitant use of meropenem. Conclusions: Linezolid's standard dosing failed to achieve its PK targets in approximately half of our pediatric cohort. Our findings highlight the complex interplay between the risk factors of linezolid-associated hematological toxicity and underscore the importance of its vigilant use and monitoring, particularly in pediatrics with concomitant multiple risk factors. [ABSTRACT FROM AUTHOR]

Infantile occult exposure to cocaine in domestic environments represents a complex clinical and medico-legal problem, which can be associated with abuse and neglect and with potential short- and long-term health risks for children. The authors present a retrospective study on 764 children under 14 years old who accessed the Emergency Department of IRCCS Meyer from 2016 to 2023 and were included in the GAIA (Child and Adolescent Abuse Group) protocol for suspected maltreatment and abuse, and for which a urine toxicology analysis was performed. The aim is to discuss the medico-legal implications and highlight the need for a thorough evaluation and management of such situations. Urine screening tests for substances of abuse (e.g., cocaine, opiates, etc.) were performed with an EMIT® Siemens VIVA-E drug testing system (Siemens, Newark DE) in 124 cases for which the child's clinical condition raised suspicion of intoxication, or the family context indicated distress or substance abuse dependency. The screening results revealed the presence of cocaine and its main metabolite, benzoylecgonine, in the urine of 11 children. In one case, a single girl was brought to the Emergency Department by staff from the facility where she and her mother were staying. In most of the cases, children were brought to the Emergency Department by their parents who accessed the Emergency Department due to various clinical manifestations (drowsiness, agitation, seizures, hypotonia, diarrhea, vomiting, etc.), except for one case of eye trauma suspected to be caused by abuse or neglect by one of the parents. Three of the children did not have signs or symptoms attributable to substance exposure, whilst eight of the cases presented some of the symptoms associated with occult infant exposure to cocaine, such as neurological manifestations, seizures, gastrointestinal symptoms, and respiratory depression. The probable mode of intake was mostly through breastfeeding and continuous environmental exposure due to domestic contamination or inhalation of "crack". In the case of a 12-hour-old infant, there was probable prenatal in utero exposure. All the children were hospitalized, some for medical reasons and others solely as a precautionary measure for proper care. In all cases, a report was made to the Prosecutors as required by the Italian Penal Code, as well as to the Court of Minor. The study highlighted the importance of a multidisciplinary approach involving pediatricians, social workers, and forensics, as well as close collaboration with the relevant authorities, as the Gaia service at IRCCS Meyer offers. The occasional detection of cocaine in cases that showed no suspicion of intoxication led to a modification of the procedure and the development of a standardized protocol at IRCCS Meyer both in terms of prevention and in the detection and interception of hidden cases, in order to intervene early and initiate the necessary care pathways (secondary prevention). This protocol includes routine toxicological urine testing in all suspected or confirmed cases of child abuse, not just in those where symptoms might suggest a suspicion of intoxication. [ABSTRACT FROM AUTHOR]

Abstract Background Exposure to alcohol and/or other addictive drugs in pregnancy is a documented risk factor for neurological impairment. We aimed to assess neurodevelopmental outcome at two years of age in infants exposed to prenatal alcohol and/or other addictive drugs and to examine the predictive value of early motor assessment. Methods This was a follow-up at two years of age in the prospective cohort study Children Exposed to Alcohol and/or Drugs in Intrauterine Life (CEADIL). The exposed group comprised 73 infants recruited from primary health care and included in a hospital follow-up programme at St. Olavs Hospital, Trondheim University Hospital, Norway. The control group comprised 93 healthy, unexposed infants recruited from the maternity ward at the same hospital. All children had been assessed by physiotherapists using the General Movement Assessment (GMA) at three months of age. Presence of fidgety movements, movement character and the Motor Optimality Score – Revised (MOS-R) were used. At two years of age, the children were assessed by trained examiners using the Bayley Scales of Infant and Toddler Development – Third Edition (BSID-III), Ages & Stages Questionnaires: Social-Emotional (ASQ:SE) and the Hollingshead Two-Factor Index of Social Position (SES). Results The cognitive, language and motor composite scores of BSID-III were considerably lower in the exposed group than in the control group. Mean differences adjusted for age and parental SES ranged from − 13.3 (95% confidence interval, CI: -18.6 to -8.0) to -17.7 (95% CI: -23.3 to -12.2). Suboptimal fidgety movements and monotonous movement character had high sensitivity (0.94 to 0.74), but low specificity (0.10 to 0.32), while sensitivity and specificity of the MOS-R was around 50 and 60%, respectively. Conclusions Neurodevelopmental outcome at two years of age was poorer in a group of children exposed to alcohol and/or drugs in pregnancy compared with a control group of healthy, unexposed children. Sensitivity of suboptimal fidgety movements and monotonous movement character at three months of age for later neurodevelopmental outcome was high to acceptable, but the MOS-R had limited sensitivity.

Background: Exposure to alcohol and/or other addictive drugs in pregnancy is a documented risk factor for neurological impairment. We aimed to assess neurodevelopmental outcome at two years of age in infants exposed to prenatal alcohol and/or other addictive drugs and to examine the predictive value of early motor assessment. Methods: This was a follow-up at two years of age in the prospective cohort study Children Exposed to Alcohol and/or Drugs in Intrauterine Life (CEADIL). The exposed group comprised 73 infants recruited from primary health care and included in a hospital follow-up programme at St. Olavs Hospital, Trondheim University Hospital, Norway. The control group comprised 93 healthy, unexposed infants recruited from the maternity ward at the same hospital. All children had been assessed by physiotherapists using the General Movement Assessment (GMA) at three months of age. Presence of fidgety movements, movement character and the Motor Optimality Score – Revised (MOS-R) were used. At two years of age, the children were assessed by trained examiners using the Bayley Scales of Infant and Toddler Development – Third Edition (BSID-III), Ages & Stages Questionnaires: Social-Emotional (ASQ:SE) and the Hollingshead Two-Factor Index of Social Position (SES). Results: The cognitive, language and motor composite scores of BSID-III were considerably lower in the exposed group than in the control group. Mean differences adjusted for age and parental SES ranged from − 13.3 (95% confidence interval, CI: -18.6 to -8.0) to -17.7 (95% CI: -23.3 to -12.2). Suboptimal fidgety movements and monotonous movement character had high sensitivity (0.94 to 0.74), but low specificity (0.10 to 0.32), while sensitivity and specificity of the MOS-R was around 50 and 60%, respectively. Conclusions: Neurodevelopmental outcome at two years of age was poorer in a group of children exposed to alcohol and/or drugs in pregnancy compared with a control group of healthy, unexposed children. Sensitivity of suboptimal fidgety movements and monotonous movement character at three months of age for later neurodevelopmental outcome was high to acceptable, but the MOS-R had limited sensitivity. [ABSTRACT FROM AUTHOR]

Background The management of multidrug-resistant tuberculosis (MDR-TB) remains challenging. Treatment outcome is influenced by multiple factors; the specific roles of diabetes and glycemic control remain uncertain. This study aims to assess the impact of glycemic control on drug exposure, to investigate the association between drug exposure and treatment outcomes, and to identify clinically significant thresholds predictive of treatment outcome, among patients with diabetes. Methods This multicenter prospective cohort study involved patients with confirmed MDR-TB and diabetes. Drug exposure level was estimated by noncompartmental analysis. The minimum inhibitory concentrations (MICs) were determined for the individual Mycobacterium tuberculosis isolates. The influence of poor glycemic control (glycated hemoglobin ≥7%) on drug exposure and the associations between drug exposure and treatment outcome were evaluated by univariate and multivariate analysis. Classification and regression tree analysis was used to identify the drug exposure/susceptibility thresholds. Results Among the 131 diabetic participants, 43 (32.8%) exhibited poor glycemic control. Poor glycemic control was independently associated with decreased exposure to moxifloxacin, linezolid, bedaquiline, and cycloserine, but not clofazimine. Additionally, a higher ratio of drug exposure to susceptibility was found to be associated with a favorable MDR-TB treatment outcome. Thresholds predictive of 6-month culture conversion and favorable outcome were bedaquiline area under the concentration–time curve (AUC)/MIC ≥245 and moxifloxacin AUC/MIC ≥67, demonstrating predictive accuracy in patients, regardless of their glycemic control status. Conclusions Glycemic control and optimal TB drug exposure are associated with improved treatment outcomes. This dual management strategy should be further validated in randomized controlled trials of patients with MDR-TB and diabetes. [ABSTRACT FROM AUTHOR]

Aims/Background The relationship between drug exposure and pregnancy outcomes is still unclear. The study was designed to characterise the overall condition of drug exposure during pregnancy and uncover related pregnancy outcomes. Methods Pregnant women were enrolled in the study from 1 October 2019 to 31 April 2022, at a tertiary hospital in Jiangsu Province, China. Basic maternal information and data regarding drug exposure during different pregnancy trimesters were gathered using the 'Eugenic Baby' platform. Based on drug use data and the pregnancy and lactation labelling rule, pregnant women were divided into three groups to explore the relationship between drug exposure and pregnancy outcomes. Results Analysis revealed that fetal protection drugs were used in 43.99% of early pregnancy cases. Pregnant women utilised more unrecommended drugs (according to the pregnancy and lactation labelling rule) in the first trimester than in the following trimesters. Regarding pregnancy outcomes, 56 of the 837 live infants had a malformation, and congenital heart disease was the main type. Gestational age, mode of delivery, birth weight, height, and head circumference were significantly different (p < 0.05) among the three groups. According to multivariate logistic regression analysis, preterm birth (odds ratio=3.226, 95% confidence intervals: 1.447–7.194, p=0.004) and low birth weight (odds ratio=4.270, 95% confidence intervals: 1.299–14.034, p=0.017) predicted increased risk of maternal drug exposure after adjusting for covariates. Conclusion Drug exposure of various types is common during pregnancy. Compared to the second and third trimester, unrecommended drugs are used more frequently in the first trimester. Drug exposure is associated with adverse pregnancy outcomes and these associations need to be further confirmed. It is vital to fully consider treatment benefits and potential risks before medication initiation during pregnancy. [ABSTRACT FROM AUTHOR]

Renal impairment is a common complication in patients with short bowel syndrome with intestinal failure (SBS‐IF). Glucagon‐like peptide‐2 analogs, such as apraglutide, have been developed as a treatment option for SBS‐IF. This study assessed the potential for apraglutide overexposure in individuals with severely impaired renal function versus healthy volunteers with normal renal function. In this phase 1, open‐label, multicenter, nonrandomized, parallel‐group study, a single dose of apraglutide 5 mg was administered subcutaneously to individuals with severely impaired renal function (<30 mL/min/1.73 m2) and healthy volunteers with normal renal function (≥90 mL/min/1.73 m2). Primary pharmacokinetic endpoints were maximum observed concentration (Cmax) and exposure to apraglutide (area under the curve [AUC] from time 0 to infinity [AUCinf], and AUC from time 0 to the last quantifiable concentration [AUClast]). Each group comprised 8 individuals. Results show that patients with severe renal impairment do not have increased apraglutide exposure. Apraglutide achieved a lower Cmax and AUCinf in individuals with severe renal impairment versus those with normal renal function (Cmax = 36.9 vs 59.5 ng/L; AUCinf = 3100 vs 4470 h · ng/mL, respectively). The respective geometric mean ratios were 0.620 and 0.693 for Cmax and AUCinf, and the upper bound of their 90% confidence intervals were <2, indicating patients with severe renal impairment were not overexposed to apraglutide versus those with normal renal function. Adverse events were mild or moderate in severity. Apraglutide does not require dose reduction for any degree of renal impairment and could be used in a broader patient population of renally impaired patients without dose adjustment. [ABSTRACT FROM AUTHOR]

Subunit vaccines are an important platform for controlling current and emerging infectious diseases. The lymph nodes are the primary site generating the humoral response and delivery of antigens to these sites is critical to effective immunization. Indeed, the duration of antigen exposure within the lymph node is correlated with the antibody response. While current licensed vaccines are typically given through the intramuscular route, injecting vaccines subcutaneously allows for direct access to lymphatic vessels and therefore can enhance the transfer of antigen to the lymph nodes. However, protein subunit antigen uptake into the lymph nodes is inefficient, and subunit vaccines require adjuvants to stimulate the initial immune response. Therefore, formulation strategies have been developed to enhance the exposure of subunit proteins and adjuvants to the lymph nodes by increasing lymphatic uptake or prolonging the retention at the injection site. Given that lymph node exposure is a crucial consideration in vaccine design, in depth analyses of the pharmacokinetics of antigens and adjuvants should be the focus of future preclinical and clinical studies. This review will provide an overview of formulation strategies for targeting the lymphatics and prolonging antigen exposure and will discuss pharmacokinetic evaluations which can be applied toward vaccine development. [ABSTRACT FROM AUTHOR]

Pexidartinib is a systemic treatment for patients with tenosynovial giant cell tumor not amenable to surgery. Oral absorption of pexidartinib is affected by food; administration with a high‐fat meal (HFM) or low‐fat meal (LFM) increases absorption by approximately 100% and approximately 60%, respectively, compared with the fasted state. Pexidartinib is currently dosed 250 mg orally twice daily with an LFM (approximately 11‐14 g of total fat). We developed a physiologically based pharmacokinetic model to determine the impact on drug exposure of dose timing with respect to meals, meal type, and caloric content. A 15%‐16% increase in plasma exposure was predicted when consuming an HFM 1 hour after dosing with an LFM, but almost no effect on pharmacokinetics was predicted when an HFM was consumed 3 hours or more before or after pexidartinib dosing with an LFM. Exposure was not significantly affected when pexidartinib was taken with a 500‐kcal LFM over the range of fat (approximately 11‐14 g of total fat; 20%‐25% calories from fat) for an LFM. These findings on timing of pexidartinib dose with respect to meals should be considered by patients and physicians to reduce the potential for side effects. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to investigate the association between drug exposure and adverse events (AEs) during the standardized multidrug-resistant tuberculosis (MDR-TB) treatment, as well as to identify predictive drug exposure thresholds. Methods: We conducted a prospective, observational multicenter study among participants receiving standardized MDR-TB treatment between 2016 and 2019 in China. AEs were monitored throughout the treatment and their relationships to drug exposure (e.g., the area under the drug concentration-time curve from 0 to 24 h, AUC0-24 h) were analyzed. The thresholds of pharmacokinetic predictors of observed AEs were identified by boosted classification and regression tree (CART) and further evaluated by external validation. Results: Of 197 study participants, 124 (62.9%) had at least one AE, and 15 (7.6%) experienced serious AEs. The association between drug exposure and AEs was observed including bedaquiline, its metabolite M2, moxifloxacin and QTcF prolongation (QTcF >450 ms), linezolid and mitochondrial toxicity, cycloserine and psychiatric AEs. The CART-derived thresholds of AUC0-24 h predictive of the respective AEs were 3.2 mg·h/l (bedaquiline M2); 49.3 mg·h/l (moxifloxacin); 119.3 mg·h/l (linezolid); 718.7 mg·h/l (cycloserine). Conclusions: This study demonstrated the drug exposure thresholds predictive of AEs for key drugs against MDR-TB treatment. Using the derived thresholds will provide the knowledge base for further randomized clinical trials of dose adjustment to minimize the risk of AEs.

Abstract Background In pediatric rheumatic diseases (PRD), adalimumab is dosed using fixed weight-based bands irrespective of methotrexate co-treatment, disease activity (DA) or other factors that might influence adalimumab pharmacokinetics (PK). In rheumatoid arthritis (RA) adalimumab exposure between 2–8 mg/L is associated with clinical response. PRD data on adalimumab is scarce. Therefore, this study aimed to analyze adalimumab PK and its variability in PRD treated with/without methotrexate. Methods A two-center prospective study in PRD patients aged 2–18 years treated with adalimumab and methotrexate (GA-M) or adalimumab alone (GA) for ≥ 12 weeks was performed. Adalimumab concentrations were collected 1–9 (maximum concentration; Cmax), and 10–14 days (minimum concentration; Cmin) during ≥ 12 weeks following adalimumab start. Concentrations were analyzed with enzyme-linked immunosorbent assay (lower limit of quantification: 0.5 mg/L). Log-normalized Cmin were compared between GA-M and GA using a standard t-test. Results Twenty-eight patients (14 per group), diagnosed with juvenile idiopathic arthritis (71.4%), non-infectious uveitis (25%) or chronic recurrent multifocal osteomyelitis (3.6%) completed the study. GA-M included more females (71.4%; GA 35.7%, p = 0.13). At first study visit, children in GA-M had a slightly longer exposure to adalimumab (17.8 months [IQR 9.6, 21.6]) compared to GA (15.8 months [IQR 8.5, 30.8], p = 0.8). Adalimumab dosing was similar between both groups (median dose 40 mg every 14 days) and observed DA was low. Children in GA-M had a 27% higher median overall exposure compared to GA, although median Cmin adalimumab values were statistically not different (p = 0.3). Cmin values ≥ 8 mg/L (upper limit RA) were more frequently observed in GA-M versus GA (79% versus 64%). Overall, a wide range of Cmin values was observed in PRD (0.5 to 26 mg/L). Conclusion This study revealed a high heterogeneity in adalimumab exposure in PRD. Adalimumab exposure tended to be higher with methotrexate co-treatment compared to adalimumab monotherapy although differences were not statistically significant. Most children showed adalimumab exposure exceeding those reported for RA with clinical response, particularly with methotrexate co-treatment. This highlights the need of further investigations to establish model-based personalized treatment strategies in PRD to avoid under- and overexposure. Trial registration NCT04042792 , registered 02.08.2019.

Infantile occult exposure to cocaine in domestic environments represents a complex clinical and medico-legal problem, which can be associated with abuse and neglect and with potential short- and long-term health risks for children. The authors present a retrospective study on 764 children under 14 years old who accessed the Emergency Department of IRCCS Meyer from 2016 to 2023 and were included in the GAIA (Child and Adolescent Abuse Group) protocol for suspected maltreatment and abuse, and for which a urine toxicology analysis was performed. The aim is to discuss the medico-legal implications and highlight the need for a thorough evaluation and management of such situations. Urine screening tests for substances of abuse (e.g., cocaine, opiates, etc.) were performed with an EMIT® Siemens VIVA-E drug testing system (Siemens, Newark DE) in 124 cases for which the child’s clinical condition raised suspicion of intoxication, or the family context indicated distress or substance abuse dependency. The screening results revealed the presence of cocaine and its main metabolite, benzoylecgonine, in the urine of 11 children. In one case, a single girl was brought to the Emergency Department by staff from the facility where she and her mother were staying. In most of the cases, children were brought to the Emergency Department by their parents who accessed the Emergency Department due to various clinical manifestations (drowsiness, agitation, seizures, hypotonia, diarrhea, vomiting, etc.), except for one case of eye trauma suspected to be caused by abuse or neglect by one of the parents. Three of the children did not have signs or symptoms attributable to substance exposure, whilst eight of the cases presented some of the symptoms associated with occult infant exposure to cocaine, such as neurological manifestations, seizures, gastrointestinal symptoms, and respiratory depression. The probable mode of intake was mostly through breastfeeding and continuous environmental exposure due to domestic contamination or inhalation of “crack”. In the case of a 12-hour-old infant, there was probable prenatal in utero exposure. All the children were hospitalized, some for medical reasons and others solely as a precautionary measure for proper care. In all cases, a report was made to the Prosecutors as required by the Italian Penal Code, as well as to the Court of Minor. The study highlighted the importance of a multidisciplinary approach involving pediatricians, social workers, and forensics, as well as close collaboration with the relevant authorities, as the Gaia service at IRCCS Meyer offers. The occasional detection of cocaine in cases that showed no suspicion of intoxication led to a modification of the procedure and the development of a standardized protocol at IRCCS Meyer both in terms of prevention and in the detection and interception of hidden cases, in order to intervene early and initiate the necessary care pathways (secondary prevention). This protocol includes routine toxicological urine testing in all suspected or confirmed cases of child abuse, not just in those where symptoms might suggest a suspicion of intoxication.

• This prospective study identified drug thresholds predictive of adverse events. • An AUC 0-24 h of bedaquiline M2 (≥ 3.2 mg·h/l) was identified for QTcF prolongation. • A linezolid AUC 0-24 h ≥ 119.3 mg·h/l was identified for mitochondrial toxicity. • A cycloserine AUC 0-24 h ≥ 718.7 mg·h/l was identified for psychiatric disorders. • Therapeutic drug monitoring is suggested to minimize the risk of adverse events. This study aimed to investigate the association between drug exposure and adverse events (AEs) during the standardized multidrug-resistant tuberculosis (MDR-TB) treatment, as well as to identify predictive drug exposure thresholds. We conducted a prospective, observational multicenter study among participants receiving standardized MDR-TB treatment between 2016 and 2019 in China. AEs were monitored throughout the treatment and their relationships to drug exposure (e.g., the area under the drug concentration-time curve from 0 to 24 h, AUC 0-24 h) were analyzed. The thresholds of pharmacokinetic predictors of observed AEs were identified by boosted classification and regression tree (CART) and further evaluated by external validation. Of 197 study participants, 124 (62.9%) had at least one AE, and 15 (7.6%) experienced serious AEs. The association between drug exposure and AEs was observed including bedaquiline, its metabolite M2, moxifloxacin and QTcF prolongation (QTcF >450 ms), linezolid and mitochondrial toxicity, cycloserine and psychiatric AEs. The CART-derived thresholds of AUC 0-24 h predictive of the respective AEs were 3.2 mg·h/l (bedaquiline M2); 49.3 mg·h/l (moxifloxacin); 119.3 mg·h/l (linezolid); 718.7 mg·h/l (cycloserine). This study demonstrated the drug exposure thresholds predictive of AEs for key drugs against MDR-TB treatment. Using the derived thresholds will provide the knowledge base for further randomized clinical trials of dose adjustment to minimize the risk of AEs. [ABSTRACT FROM AUTHOR]

Objective Mitotane is the standard therapy of adrenocortical carcinoma (ACC) due to its relative selectivity of its cytotoxic effects toward adrenocortical cells. Therefore, it virtually always leads to adrenal insufficiency. Frequency and characteristics of hypothalamic–pituitary–adrenal axis recovery after discontinuation are ill-defined. Methods This was a retrospective study of patients with ACC adjuvantly treated with mitotane for ≥12 months who were disease-free at mitotane stop and had a minimum follow-up ≥1 year. Primary endpoint was adrenal recovery. Cox regression analyses were used to identify predictive factors. Moreover, mitotane plasma elimination rate and hormonal changes after mitotane stop were investigated. Results Fifty-six patients (36 women) treated with mitotane for a median time of 25 months and an average daily dose of 2.8 g were included. Median time after discontinuation until mitotane levels dropped below 5 and 2 mg/L, and the detection limit was 152 days (interquartile range: 114-202), 280 days (192-370), and 395 days (227-546), respectively. Full adrenal recovery was documented in 32 (57%) patients after a median time of 26 months (95% confidence interval [CI] = 19.6-32.4). In 4 patients (7.1%), adrenal insufficiency persisted >5 years after discontinuation. Mitotane peak ≥ 27 mg/L significantly correlated with longer time to adrenal recovery (hazard ratio [HR] = 0.2, 95% CI = 0.1-0.8, P =.03). Twenty-seven of 38 patients (71%) followed in reference centers achieved adrenal recovery compared with only 5/18 (28%) followed up in non-reference centers (HR = 4.51, 95% CI = 1.71-11.89, P =.002). Other investigated factors were not associated with adrenal function after discontinuation. Conclusions Our study demonstrates that adrenal recovery occurs in most patients after stopping mitotane, particularly when followed up in specialized centers, but not in all. Elimination time of mitotane after treatment discontinuation is very long but individually quite variable. [ABSTRACT FROM AUTHOR]

Purpose: Antipsychotic agents, which may increase the risk of infection through dopaminergic dysregulation, are prescribed to a fraction of patients following critical illness. We compared the rate of recurrent sepsis among patients who filled a prescription for antipsychotics with high‐ or low‐D2 affinity. Methods: Population‐based cohort with active comparator design. We included sepsis survivors older than 65 years with intensive care unit admission and new prescription of antipsychotics in Ontario 2008–2019. The primary outcome were recurrent sepsis episodes within 1 year of follow‐up. Patients who filled a prescription within 30 days of hospital discharge for high‐D2 affinity antipsychotics (e.g., haloperidol) were compared with patients who filled a prescription within 30 days of hospital discharge for low‐D2 affinity antipsychotics (e.g., quetiapine). Multivariable zero‐inflated Poisson regression models with robust standard errors adjusting for confounding at baseline were used to estimate incidence rate ratios (IRR) and 95% confidence intervals (CI). Results: Overall, 1879 patients filled a prescription for a high‐D2, and 1446 patients filled a prescription for a low‐D2 affinity antipsychotic. Patients who filled a prescription for a high‐D2 affinity antipsychotic did not present a higher rate of recurrent sepsis during 1 year of follow‐up, compared with patients who filled a prescription for a low‐D2 affinity antipsychotic (IRR: 1.12; 95% CI: 0.94, 1.35). Conclusions: We did not find conclusive evidence of a higher rate of recurrent sepsis associated with the prescription of high‐D2 affinity antipsychotics (compared with low‐D2 affinity antipsychotics) by 1 year of follow‐up in adult sepsis survivors with intensive care unit admission. [ABSTRACT FROM AUTHOR]

Background Obesity is increasingly prevalent among people with HIV (PWH) and can possibly result in suboptimal antiretroviral drug (ARV) exposure and response. However, this has not been thoroughly evaluated given that obese PWH are underrepresented in clinical trials. We performed virtual trials using physiologically based pharmacokinetic (PBPK) modelling combined with observed clinical data to provide ARV dosing guidance in obese individuals. Methods Each trial included a cohort of virtual adults with a body mass index (BMI) between 18.5 and 60 kg/m2. Therapeutic drug-monitoring data from the Swiss HIV Cohort Study (SHCS) were used to verify the predictive performance of the model. Subsequently, the model was applied to predict the pharmacokinetics of ARVs for different obesity classes. The association between ARV plasma concentrations and virological response was investigated in obese and nonobese individuals. Results The PBPK model predicted an average reduction in ARV exposure of ∼20% and trough concentrations of ∼6% in obese (BMI ≥30 kg/m2) compared with nonobese (BMI: 18.5–25 kg/m2) individuals, consistent with observed clinical data. Etravirine and rilpivirine were the most impacted, especially in individuals with BMI >40 kg/m2 whose trough concentrations were below the clinical target threshold. Obese PWH in the SHCS did not have a higher rate of unsuppressed viral load than nonobese PWH. Conclusions The concentrations of ARVs are modestly reduced in obese individuals, with no negative impact on the virological response. Our data provide reassurance that standard doses of ARVs are suitable in obese PWH, including those who gained substantial weight with some of the first-line ARVs. [ABSTRACT FROM AUTHOR]

Test methods in anti‐doping, most of which rely on the most modern mass spectrometric instrumentation, undergo continuous optimization in order to accommodate growing demands as to comprehensiveness, sensitivity, retrospectivity, cost‐effectiveness, turnaround times, etc. While developing and improving analytical approaches is vital for appropriate sports drug testing programs, the combination of today's excellent analytical potential and the inevitable exposure of humans to complex environmental factors, specifically chemicals and drugs at the lowest levels, has necessitated dedicated research, particularly into the elite athlete's exposome. Being subjected to routine doping controls, athletes frequently undergo blood and/or urine tests for a plethora of drugs, chemicals, corresponding metabolic products, and various biomarkers. Due to the applicable anti‐doping regulations, the presence of prohibited substances in an athlete's organism can constitute an anti‐doping rule violation with severe consequences for the individual's career (in contrast to the general population), and frequently the question of whether the analytical data can assist in differentiating scenarios of 'doping' from 'contamination through inadvertent exposure' is raised. Hence, investigations into the athlete's exposome and how to distinguish between deliberate drug use and potential exposure scenarios have become a central topic of anti‐doping research, aiming at supporting and consolidating the balance between essential analytical performance characteristics of doping control test methods and the mandate of protecting the clean athlete by exploiting new strategies in sampling and analyzing specimens for sports drug‐testing purposes. [ABSTRACT FROM AUTHOR]

Introduction: "Secondary exposure to anticancer drugs" refers to exposure to anticancer drugs after chemotherapy via the patient's urine and other excretions. The necessity of countermeasures against secondary exposure to anticancer drugs has been recently highlighted. Although anticancer drugs are also excreted through sweat, few studies have reported exposure to drug residues via this route. We investigated the amount of cyclophosphamide (CPA) excreted in the sweat of patients receiving CHOP therapy (cyclophosphamide, doxorubicin, vincristine, and prednisone). Methods: The study population included eight patients with malignant lymphoma who received CHOP therapy between May and December 2021. The amount of CPA in their underwear (namely, cotton short-sleeved shirts) worn from the start of the CHOP therapy until 24 h after the end of CPA administration was measured, using liquid chromatography-mass spectrometry (LC-MS/MS). Results: CPA was detected in the underwear of all the patients, with levels ranging between 7.38 and 160.77 ng/cm2. No subjective changes were observed in the sweating status of any patients during the study period. Conclusions: These results suggested that patients' sweat, as well as urine, is a potential route for exposure to anticancer drugs. Whether visibly contaminated or not, the clothing and linen worn directly by patients should be handled as a source of sweat-mediated exposure to anticancer drugs both in medical facilities and at home. [ABSTRACT FROM AUTHOR]

Background. Lapatinib is an oral small-molecule tyrosine kinase inhibitor indicated for advanced or metastatic HER2-positive breast cancer. In order to reduce the treatment cost, a high-fat enteral nutrition emulsion TPF-T was selected as a dose-sparing agent for lapatinib-based therapies. This study aimed to investigate the effect of TPF-T on lapatinib pharmacokinetics. Methods. First, a simple and rapid liquid chromatography tandem mass spectrometry (LC--MS/MS) method was developed to quantitatively evaluate lapatinib in rabbit plasma. The method was fully validated according to the China Pharmacopoeia 2020 guidance. Rabbits and rats were chosen as the animal models due to their low and high bile flows, respectively. The proposed LC--MS/MS method was applied to pharmacokinetic studies of lapatinib, with or without TPF-T, in rabbit and rat plasma. Results. The LC---MS/MS method revealed high sensitivity and excellent efficiency. In the rabbit model, co-administration with TPF-T resulted in a 32.2% increase in lapatinib exposure. In the rat model, TPF-T had minimal influence on the lapatinib exposure. In both models, TPF-T was observed to significantly elevate lapatinib concentration in the absorption phase. Conclusion. Co-administration with TPF-T had a moderate effect on increasing exposure to lapatinib. Dose sparing using a high-fat liquid diet is potentially feasible for lapatinib-based therapies. [ABSTRACT FROM AUTHOR]

Exposure to opioids can lead to the alteration of several neurotransmitters. Among these neurotransmitters, glutamate is thought to be involved in opioid dependence. Glutamate neurotransmission is mainly regulated by astrocytic glutamate transporters such as glutamate transporter 1 (GLT-1) and cystine/glutamate antiporter (xCT). Our laboratory has shown that exposure to lower doses of hydrocodone reduced the expression of xCT in the nucleus accumbens (NAc) and the hippocampus. In the present study, we investigated the effects of chronic exposure to hydrocodone, and tested ceftriaxone as a GLT-1 upregulator in mesocorticolimbic brain regions such as the NAc, the amygdala (AMY), and the dorsomedial prefrontal cortex (dmPFC). Eight-week-old male mice were divided into three groups: (1) the saline vehicle control group; (2) the hydrocodone group; and (3) the hydrocodone + ceftriaxone group. Mice were injected with hydrocodone (10 mg/kg, i.p.) or saline for 14 days. On day seven, the hydrocodone/ceftriaxone group was injected with ceftriaxone (200 mg/kg, i.p.) for last seven days. Chronic exposure to hydrocodone reduced the expression of GLT-1, xCT, protein kinase B (AKT), extracellular signal-regulated kinases (ERK), and c-Jun N-terminal Kinase (JNK) in NAc, AMY, and dmPFC. However, hydrocodone exposure increased the expression of G-protein-coupled metabotropic glutamate receptors (mGluR5) in the NAc, AMY, and dmPFC. Importantly, ceftriaxone treatment normalized the expression of mGluR5, GLT-1, and xCT in all these brain regions, except for xCT in the AMY. Importantly, ceftriaxone treatment attenuated hydrocodone-induced downregulation of signaling pathways such as AKT, ERK, and JNK expression in the NAc, AMY, and dmPFC. These findings demonstrate that ceftriaxone has potential therapeutic effects in reversing hydrocodone-induced downregulation of GLT-1 and xCT in selected reward brain regions, and this might be mediated through the downstream kinase signaling pathways such as AKT, ERK, and JNK. [ABSTRACT FROM AUTHOR]

Introduction: Drug testing typically follows a one-size-fits-all approach that is inadequate in some clinical scenarios, such as child maltreatment, neglect, and unintentional drug exposure. Results from immunoassay-based testing, which are non-specific, insensitive, and far from comprehensive, can lead to unintended consequences for children and their families. Objectives: The objective of this retrospective case series study is to evaluate the utility of real-time (0–1 day) comprehensive drug testing as an alternative to immunoassay-based testing in the pediatric acute care setting. Methods: Comprehensive drug testing results obtained by mass spectrometry testing and associated medical data for all pediatric cases (0–12 years) at one institution from 2019 to 2022 were included in the analysis. The final case series (n = 7) included all cases from patients

Characterization of infant drug exposure through human milk is important and underexplored. Because infant plasma concentrations are not frequently collected in clinical lactation studies, modeling and simulation approaches can integrate physiology, available milk concentrations, and pediatric data to inform exposure in breastfeeding infants. A physiologically based pharmacokinetic model was built for sotalol, a renally eliminated drug, to simulate infant drug exposure from human milk. Intravenous and oral adult models were built, optimized, and scaled to an oral pediatric model for a breastfeeding‐relevant age group (<2 years). Model simulations captured the data that were put aside for verification. The resulting pediatric model was applied to predict the impacts of sex, infant body size, breastfeeding frequency, age, and maternal dose (240 and 433 mg) on drug exposure during breastfeeding. Simulations suggest a minimal effect of sex or frequency on total sotalol exposure. Infants in the 90th percentile in height and weight have predicted exposures ≈20% higher than infants of the same age in the 10th percentile due to increased milk intake. The simulated infant exposures increase throughout the first 2 weeks of life and are maintained at the highest concentrations in weeks 2‐4, with a consistent decrease observed as infants age. Simulations suggest that breastfeeding infants will have plasma concentrations in the lower range observed in infants administered sotalol. With further validation on additional drugs, physiologically based pharmacokinetic modeling approaches could use lactation data to a greater extent and provide comprehensive information to support decisions regarding medication use during breastfeeding. [ABSTRACT FROM AUTHOR]

Background: Epirubicin is an anthracycline antineoplastic drug that is primarily used in combination therapies for the treatment of breast, gastric, lung and ovarian cancers and lymphomas. Epirubicin is administered intravenously (IV) over 3 to 5 min once every 21 days with dosing based on body surface area (BSA; mg/m2). Despite accounting for BSA, marked inter-subject variability in circulating epirubicin plasma concentration has been reported. Methods: In vitro experiments were conducted to determine the kinetics of epirubicin glucuronidation by human liver microsomes in the presence and absence of validated UGT2B7 inhibitors. A full physiologically based pharmacokinetic model was built and validated using Simcyp® (version 19.1, Certara, Princeton, NJ, USA). The model was used to simulate epirubicin exposure in 2000 Sim-Cancer subjects over 158 h following a single intravenous dose of epirubicin. A multivariable linear regression model was built using simulated demographic and enzyme abundance data to determine the key drivers of variability in systemic epirubicin exposure. Results: Multivariable linear regression modelling demonstrated that variability in simulated systemic epirubicin exposure following intravenous injection was primarily driven by differences in hepatic and renal UGT2B7 expression, plasma albumin concentration, age, BSA, GFR, haematocrit and sex. By accounting for these factors, it was possible to explain 87% of the variability in epirubicin in a simulated cohort of 2000 oncology patients. Conclusions: The present study describes the development and evaluation of a full-body PBPK model to assess systemic and individual organ exposure to epirubicin. Variability in epirubicin exposure was primarily driven by hepatic and renal UGT2B7 expression, plasma albumin concentration, age, BSA, GFR, haematocrit and sex. [ABSTRACT FROM AUTHOR]

The role of sex differences in clinical presentation, TB drug pharmacokinetic variables, and treatment outcomes is unclear. What is the effect of sex on TB disease severity, drug exposure, and treatment outcome? This study was a prospective cohort study conducted in India. It assessed TB disease severity; risk of unfavorable treatment outcomes (failure, recurrence, and death) according to sex; and risk factors for unfavorable outcomes stratified according to sex. Effects of sex on the pharmacokinetic variables (maximum concentration and area under the curve) of rifampicin, isoniazid, and pyrazinamide were estimated by using noncompartmental analyses. Of 1,541 people with microbiologically confirmed TB, 567 (37%) were women. Women had a lower risk of high mycobacterial burden (smear grade ≥ 2 and/or time to detection < 7 days) with an adjusted OR of 0.70 (95% CI, 0.56-0.87). Among the 744 participants who were followed up prospectively, 261 (35%) were women. Women had a lower risk of unfavorable treatment outcomes (adjusted incidence risk ratio, 0.60; 95% CI, 0.43-0.85), mostly because recurrence was lower (adjusted incidence risk ratio, 0.45; 95% CI, 0.23-0.86). Isoniazid (but not rifampicin and pyrazinamide) maximum concentration and area under the curve were significantly higher among women (P <.01) than men. Among women, unfavorable outcomes were more likely among those with cavitary disease, but among men, increased risk of unfavorable outcomes was associated with alcohol use, higher BMI, and lower glycated hemoglobin level. Women present with lower mycobacterial burden, achieve higher TB drug exposure, and are less likely to have unfavorable treatment outcomes than men. Strategies to improve TB treatment success should take into account sex differences in risk factors for unfavorable outcomes. [ABSTRACT FROM AUTHOR]

Vincristine (VCR), an effective antitumor drug, has been utilized in several polytherapy regimens for acute lymphoblastic leukemia, neuroblastoma and rhabdomyosarcoma. However, clinical evidence shows that the metabolism of VCR varies greatly among patients. The traditional based body surface area (BSA) administration method is prone to insufficient exposure to VCR or severe VCR-induced peripheral neurotoxicity (VIPN). Therefore, reliable strategies are urgently needed to improve efficacy and reduce VIPN. Due to the unpredictable pharmacokinetic changes of VCR, therapeutic drug monitoring (TDM) may help to ensure its efficacy and to manage VIPN. At present, there is a lot of supporting evidence for the suitability of applying TDM to VCR therapy. Based on the consensus guidelines drafted by the International Association of Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT), this review aimed to summarize various available data to evaluate the potential utility of VCR TDM for cancer patients. Of note, valuable evidence has accumulated on pharmacokinetics variability, pharmacodynamics, drug exposure–clinical response relationship, biomarkers for VIPN prediction, and assays for VCR monitoring. However, there are still many relevant clinical pharmacological questions that cannot yet be answered merely based on insufficient evidence. Currently, we cannot recommend a therapeutic exposure range and cannot yet provide a dose-adaptation strategy for clinicians and patients. In areas where the evidence is not yet sufficient, more research is needed in the future. The precision medicine of VCR cannot rely on TDM alone and needs to consider the clinical, environmental, genetic background and patient-specific factors as a whole. [ABSTRACT FROM AUTHOR]

Introduction: The correlation between total and free polymyxin B (PMB including PMB1 and PMB2) exposure in vivo and acute kidney injury (AKI) remains obscure. This study explores the relationships between plasma exposure of PMB1 and PMB2 and nephrotoxicity, and investigates the risk factors for PMB-induced acute kidney injury (AKI) in critically ill patients. Methods: Critically ill patients who used PMB and met the criteria were enrolled. The total plasma concentration and plasma binding of PMB1 and PMB2 were analysed by liquid chromatography–tandem mass spectrometry and equilibrium dialysis. Results: A total of 89 patients were finally included, and AKI developed in 28.1% of them. The peak concentration of PMB1 (Cmax (B1)) (adjusted odds ratio (AOR) = 1.68, 95% CI 1.08–2.62, p = 0.023), baseline BUN level (AOR = 1.08, 95% CI 1.01–1.16, p = 0.039) and hypertension (AOR = 3.73, 95% CI 1.21–11.54, p = 0.022) were independent risk factors for PMB-induced AKI. The area under the ROC curve of the model was 0.799. When Cmax (B1) was 5.23 μg/ml or more, the probability of AKI was higher than 50%. The ratio of PMB1/PMB2 decreased after PMB preparation entered into the body. The protein binding rate in critically ill patients indicated significant individual differences. Free Cmax (B) and free Cmax (B1) levels in the AKI group were significantly (p < 0.05) higher than those in the non-AKI group. Total and free concentrations of PMB in patients showed a positive correlation. Conclusions: Both the ROC curve and logistic regression model showed that Cmax (B1) was a good predictor for the probability of PMB-induced AKI. Early therapeutic drug monitoring (TDM) of PMB should be considered in critically ill patients. Compared with Cmin (B), Cmax (B) and Cmax (B1) may be helpful for the early prediction of PMB-induced AKI in critically ill patients. [ABSTRACT FROM AUTHOR]

Abstract Background Cerebrovascular disorders have occurred more frequently in some Central Nervous System (CNS) disorders, such as epilepsy. Some CNS drugs have been associated with increased stroke risk. Our aim was to estimate the risk of ischaemic stroke in patients exposed to antiepileptic drugs (AED). Methods Population-based matched case-control study using SIDIAP database, based in electronic health records from primary healthcare from Catalonia, Spain. Cases were those patients with a registered diagnosis of first stroke during 2009–2014. Up to 10 controls were selected for each case and matched by sex, age, and geographic area and without a prior diagnosis of stroke. We considered global drug exposure to AED, past and current exposure and exposure in monotherapy to each AED. Results 2,865 cases and 19,406 controls were exposed to AED during the study period. Global exposure to levetiracetam [(ORadj3.3, CI95 % 2.8-4.0)], phenytoin [ORadj1.5, CI95 % 1.2–41.9)], and valproic acid [(ORadj 1.3, CI95 % 1.1–1.6)], showed significantly association to ischaemic stroke that was also maintained with current exposure of levetiracetam [ORadj4.1, CI95 % 3.3–5.2)] and valproic acid [ORadj1.4, CI95 % 1.1–1.9)]. Current levetiracetam monotherapy showed a very high risk of ischaemic stroke [(ORadj 5.1, CI95 % 3.7–6.9)]. Conclusions Drugs used for other conditions than epilepsy (pregabalin, gabapentin) were the most used AED and both did not show a risk. Levetiracetam shows a risk for stroke even when assessed in current monotherapy. The lack of data regarding the link with diagnosis and severity in our study makes it necessary to conduct further studies to confirm or dismiss our results, focussing on levetiracetam.

Background: Epirubicin is an anthracycline antineoplastic drug that is primarily used in combination therapies for the treatment of breast, gastric, lung and ovarian cancers and lymphomas. Epirubicin is administered intravenously (IV) over 3 to 5 min once every 21 days with dosing based on body surface area (BSA; mg/m2). Despite accounting for BSA, marked inter-subject variability in circulating epirubicin plasma concentration has been reported. Methods: In vitro experiments were conducted to determine the kinetics of epirubicin glucuronidation by human liver microsomes in the presence and absence of validated UGT2B7 inhibitors. A full physiologically based pharmacokinetic model was built and validated using Simcyp® (version 19.1, Certara, Princeton, NJ, USA). The model was used to simulate epirubicin exposure in 2000 Sim-Cancer subjects over 158 h following a single intravenous dose of epirubicin. A multivariable linear regression model was built using simulated demographic and enzyme abundance data to determine the key drivers of variability in systemic epirubicin exposure. Results: Multivariable linear regression modelling demonstrated that variability in simulated systemic epirubicin exposure following intravenous injection was primarily driven by differences in hepatic and renal UGT2B7 expression, plasma albumin concentration, age, BSA, GFR, haematocrit and sex. By accounting for these factors, it was possible to explain 87% of the variability in epirubicin in a simulated cohort of 2000 oncology patients. Conclusions: The present study describes the development and evaluation of a full-body PBPK model to assess systemic and individual organ exposure to epirubicin. Variability in epirubicin exposure was primarily driven by hepatic and renal UGT2B7 expression, plasma albumin concentration, age, BSA, GFR, haematocrit and sex.

Amphetamine-Type Stimulants (ATS), such as amphetamines, MDMA, and methamphetamine are a commonly used class of illicit drugs in Europe. There is a large existing literature on motives for the use of illicit drugs, often focusing on initiation.However, few studies have explored the reasons why some people choose not to use drugs (non-use), and even fewer focus on the social processes influencing non-use of ATS specifically. We explored social processes related to normalization, and how persistent non-users negotiate their non-use in social contexts where ATS is used, using qualitative interview (n = 21) and survey questionnaire (n = 126) data from a mixed-method study conducted in the Netherlands and England. Our findings showed that in both countries, most participants were repeatedly exposed to ATS use, often in social or nightlife settings. Participants abstained from use for a number of reasons, including: lack of interest in illicit drug use in general; desire to maintain control over their own behavior and environment; and to avoid the associated health risks. Social processes also shaped persistent non-use of ATS, via conscious socialization with, and selection of, other non-using peers over time.Our findings contribute to the literature on the normalization thesis, showing that recreational ATS use is only partly socially accommodated and normalized among persistent non-users, suggesting differentiated normalization. [ABSTRACT FROM AUTHOR]

This study examines the lifetime prevalence of illicit drug use and illicit drug exposure in disadvantaged ("Roma") and more affluent neighborhoods in Czechia. The results of a survey among populations of both types of neighborhoods suggest no statistically significant difference between the two in terms of the overall lifetime prevalence of illicit drug use; however, lifetime prevalence of methamphetamine use proved higher in disadvantaged neighborhoods. The population of disadvantaged neighborhoods has also lower chances to use LSD during their lifetime. Further differences were identified in drug exposure, with the population of more affluent neighborhoods being more frequently exposed to illicit drugs than the population of disadvantaged neighborhoods. The predictors of drug use and drug exposure were partially different for both populations. In the disadvantaged population, drug use was revealed, among other predictors, to be associated with housing conditions. [ABSTRACT FROM AUTHOR]

Objectives: To explore the association between drug exposure and SARS-CoV-2 prognosis among elderly people living in long-term care facilities (LTC) Design: We carried out a cross-sectional study among old people living in LTC that had a proven SARS-CoV-2 infection, including socio-demographic data, comorbidities and drug intake at the moment of the diagnosis. The study was focused on ACE2 inhibitors, ARA-II blockers, inhaled bronchodilators, oral corticoids, platelet antiaggregants, oral anti-coagulants, statins and Vitamin D. Results: 1 306 individuals were included, with a mean age of 86.7 years, and 72.3% were females. The case fatality rate was 24.4%. Among the studied exposures platelet antiaggregants were the most prevalent (24.7%). After adjusting for propensity score, the intake of inhaled corticoids (OR 0.73; p=0.03) and statins (OR 0.65; p=0.03) were found to be protective factors of death, whereas ACE2 inhibitor showed an almost significant association (OR 0.73, p=0.07). Conclusions: Considering the high prevalence of drug intake among elderly people, drug exposure may be an important Covid-19 disease modifier in LTC residents and should be considered when exploring prognostic risk factors associated to Covid-19.

Remdesivir has displayed pharmacological activity against SARS-CoV-2. However, no pharmacometabolomics (PM) or correlation analysis with pharmacokinetics (PK) was revealed. Rats were intravenously administered remdesivir, and a series of blood samples were collected before and after treatment. Comprehensive metabolomics profile and PK were investigated and quantitated simultaneously using our previous reliable HPLC-MS/MS method. Both longitudinal and transversal metabolic analyses were conducted, and the correlation between PM and PK parameters was evaluated using Pearson's correlation analysis and the PLS model. Multivariate statistical analysis was employed for discovering candidate biomarkers which predicted drug exposure or toxicity of remdesivir. The prominent metabolic profile variation was observed between pre- and posttreatment, and significant changes were found in 65 metabolites. A total of 15 metabolites—12 carnitines, one N-acetyl-D-glucosamine, one allantoin, and one corticosterone—were significantly correlated with the concentration of Nuc (active metabolite of remdesivir). Adenosine, spermine, guanosine, sn-glycero-3-phosphocholine, and l-homoserine may be considered potential biomarkers for predicting drug exposure or toxicity. This study is the first attempt to apply PM and PK to study remdesivir response/toxicity, and the identified candidate biomarkers might be used to predict the AUC and Cmax, indicating capability of discriminating good or poor responders. Currently, this study originally offers considerable evidence to metabolite reprogramming of remdesivir and sheds light on precision therapy development in fighting COVID-19. [ABSTRACT FROM AUTHOR]

Remdesivir has displayed pharmacological activity against SARS-CoV-2. However, no pharmacometabolomics (PM) or correlation analysis with pharmacokinetics (PK) was revealed. Rats were intravenously administered remdesivir, and a series of blood samples were collected before and after treatment. Comprehensive metabolomics profile and PK were investigated and quantitated simultaneously using our previous reliable HPLC-MS/MS method. Both longitudinal and transversal metabolic analyses were conducted, and the correlation between PM and PK parameters was evaluated using Pearson’s correlation analysis and the PLS model. Multivariate statistical analysis was employed for discovering candidate biomarkers which predicted drug exposure or toxicity of remdesivir. The prominent metabolic profile variation was observed between pre- and posttreatment, and significant changes were found in 65 metabolites. A total of 15 metabolites—12 carnitines, one N-acetyl-D-glucosamine, one allantoin, and one corticosterone—were significantly correlated with the concentration of Nuc (active metabolite of remdesivir). Adenosine, spermine, guanosine, sn-glycero-3-phosphocholine, and l-homoserine may be considered potential biomarkers for predicting drug exposure or toxicity. This study is the first attempt to apply PM and PK to study remdesivir response/toxicity, and the identified candidate biomarkers might be used to predict the AUC and Cmax, indicating capability of discriminating good or poor responders. Currently, this study originally offers considerable evidence to metabolite reprogramming of remdesivir and sheds light on precision therapy development in fighting COVID-19.

Background: Eltrombopag (EPAG) is an oral thrombopoietin receptor agonist, approved for refractory primary immune thrombocytopenia (ITP) in pediatric patients. In two pediatric RCTs, EPAG led to an improvement of platelet counts and a reduction in bleeding severity. However, a significant number of pediatric patients did not achieve the primary endpoints. We performed a pharmacokinetic evaluation of EPAG in pediatric patients with refractory ITP. Methods: Outpatients aged from 1 to 17 y, affected by refractory ITP to first-line treatment, were enrolled for a pharmacokinetic assessment. The analysis of drug plasma concentration was performed by the LC-MS/MS platform. Non-compartmental and statistical subgroup analyses were carried out using the R package ncappc. Results: Among 36 patients eligible for PK analysis, the median dose of EPAG given once daily was 50 mg. The EPAG peak occurs between 2 and 4 h with a population Cmax and AUC 0–24 geo-mean of 23, 38 μg/ml, and 275, 4 µg*h/mL, respectively. The pharmacokinetic profile of EPAG did not show a dose proportionality. Female patients showed a statistically significant increase of dose-normalized exposure parameters, increasing by 110 and 123% for Cmax and AUC 0–24, respectively, when compared to male patients. Patients aged 1–5 y showed values increased by more than 100% considering both exposure parameters, compared to older children. Furthermore, patients presenting complete response (83%), showed augmented EPAG exposure parameters compared to subjects with partial or no response. Conclusion: These data highlight the need to further explore the variability of EPAG exposure and its pharmacokinetic/pharmacodynamic profile in pediatric patients also in a real-life setting. [ABSTRACT FROM AUTHOR]

Background: Drug exposure assessment based on dispensing data can be misclassified when patients do not adhere to their therapy or when information about over‐the‐counter drugs is not captured in the study database. Previous research has considered hypothetical sensitivity and specificity values, whereas this study aims to assess the impact of literature‐based real values of exposure misclassification. Methods: A synthetic cohort study was constructed based on the proportion of exposure theoretically captured in a database (range 0.5–1.0) and the level of adherence (0.5–1.0). Three scenarios were explored: nondifferential misclassification, differential misclassification (misclassifications dependent on an unmeasured risk factor doubling the outcome risk), and nondifferential misclassification in a comparative effectiveness study (RRA and RRB both 2.0 compared to nonuse, RRA‐B 1.0). Results: For the scenarios with nondifferential misclassification, 25% nonadherence or 25% uncaptured exposure changed the RR from 2.0 to 1.75, and 1.95, respectively. Applying different proportions of nonadherence or uncaptured use (20% vs. 40%) for subgroups with and without the risk factor, an RR of 0.95 was observed in the absence of a true effect (i.e., true RR = 1). In the comparative effectiveness study, no effect on RR was seen for different proportions of uncaptured exposure; however, different levels of nonadherence for the drugs (20% vs. 40%) led to an underestimation of RRA‐B (0.89). Discussion: All scenarios led to biased estimates, but the magnitude of the bias differed across scenarios. When testing the robustness of findings of pharmacoepidemiologic studies, we recommend using realistic values of nonadherence and uncaptured exposure based on real‐world data. [ABSTRACT FROM AUTHOR]

Similar to the general population, elite athletes are exposed to a complex set of environmental factors including chemicals and radiation and also biological and physical stressors, which constitute an exposome that is, unlike for the general population, subjected to specific scrutiny for athletes due to applicable antidoping regulations and associated (frequent) routine doping controls. Hence, investigations into the athlete's exposome and how to distinguish between deliberate drug use and different contamination scenarios has become a central topic of antidoping research, as a delicate balance is to be managed between the vital and continually evolving developments of sensitive analytical techniques on the one hand, and the risk of the athletes' exposome potentially causing adverse analytical findings on the other. [ABSTRACT FROM AUTHOR]

Abstract Trial data support an absence of an exposure–survival relationship for pembrolizumab. As these relationships remain unexamined in a real‐world setting, we determined them in metastatic melanoma prospectively in an observational study. Translational objectives included identifying biomarkers of progressive disease (PD). Checkpoint blockade naïve patients receiving 2 mg/kg Q3W pembrolizumab had pharmacokinetic and clinical outcome data collected. Trough, a valid surrogate for drug exposure, was assessed using ELISA. T‐cell exhaustion and chemokine markers were determined using flow cytometry. Geometric means of exposures and biomarkers were tested against objective response groups using one‐way ANOVA. The cohort was split by the median into high versus low pembrolizumab exposure groups. Kaplan–Meier progression‐free survival (PFS) and overall survival (OS) curves were estimated for high versus low exposure, compared using the log rank test. The high pembrolizumab exposure group (n = 14) experienced substantially longer median OS (not reached vs. 48 months, p = .014), than the low exposure group (n = 14). A similar positive exposure PFS relationship was found (median not reached vs. 48 months, p = .045). The frequency of TIM‐3 expression on CD4+ T cells was significantly higher in PD (mean 27.8%) than complete response (CR) (13.38%, p = .01) and partial response (12.4%, p = .05). There was a near doubling of CXCR6 and TIM‐3 co‐expression on CD4+ T cells in PD (mean 23.3%) versus CR (mean 11.4, p = .003) and partial response (9.8%, p = .0001). We describe positive exposure‐PFS and exposure‐OS relationships for pembrolizumab in metastatic melanoma. TIM‐3, alongside co‐expression of CXCR6 and TIM‐3 on circulating CD4+ T cells are potential bio markers of treatment failure.

Trial data support an absence of an exposure--survival relationship for pembrolizumab. As these relationships remain unexamined in a real-world setting, we determined them in metastatic melanoma prospectively in an observational study. Translational objectives included identifying biomarkers of progressive disease (PD). Checkpoint blockade naïve patients receiving 2 mg/kg Q3W pembrolizumab had pharmacokinetic and clinical outcome data collected. Trough, a valid surrogate for drug exposure, was assessed using ELISA. T-cell exhaustion and chemokine markers were determined using flow cytometry. Geometric means of exposures and biomarkers were tested against objective response groups using one-way ANOVA. The cohort was split by the median into high versus low pembrolizumab exposure groups. Kaplan--Meier progression-free survival (PFS) and overall survival (OS) curves were estimated for high versus low exposure, compared using the log rank test. The high pembrolizumab exposure group (n = 14) experienced substantially longer median OS (not reached vs. 48 months, p = .014), than the low exposure group (n = 14). A similar positive exposure PFS relationship was found (median not reached vs. 48 months, p = .045). The frequency of TIM-3 expression on CD4+ T cells was significantly higher in PD (mean 27.8%) than complete response (CR) (13.38%, p = .01) and partial response (12.4%, p = .05). There was a near doubling of CXCR6 and TIM-3 co-expression on CD4+ T cells in PD (mean 23.3%) versus CR (mean 11.4, p = .003) and partial response (9.8%, p = .0001). We describe positive exposure-PFS and exposure-OS relationships for pembrolizumab in metastatic melanoma. TIM-3, alongside co-expression of CXCR6 and TIM-3 on circulating CD4+ T cells are potential bio markers of treatment failure. [ABSTRACT FROM AUTHOR]

Purpose: Acetaminophen (APAP) is available over-the-counter and widely regarded as safe for use in pregnancy. APAP has been used to close a persistently patent ductus arteriosus. Fetal constriction/closure of the ductus arteriosus (FCCDA), of public health interest given the drug's widespread use during pregnancy, is being monitored globally, including by the European Medicines Agency Pharmacovigilance Risk Assessment Committee. Our objective was to share a comprehensive signal evaluation of FCCDA with in utero APAP exposure to determine if the totality of evidence is sufficiently more consistent with one of the following two possibilities: (1) APAP never contributes to FCCDA (null hypothesis or HO) versus (2) APAP may in some cases be at least a contributory cause of in utero DA narrowing (alternative hypothesis or HA) to justify risk communication. Methods: To assess the relative support for HO versus HA, we synthesize and interpret within an Austin Bradford Hill criteria framework a comprehensive, cross-disciplinary set of published information and de novo analysis, including toxicology, epidemiology, clinical pharmacology, and clinical and quantitative pharmacovigilance analysis of spontaneous reports. Results: While residual uncertainty remains, the totality of information is more compatible with HA than H0, to the extent that it is reasonably possible that APAP may sometimes be at least a contributory cause of FCCDA. Conclusion: It is reasonably possible that APAP may sometimes be at least a contributory cause of FCCDA, and this should therefore be communicated to stakeholders. Trial registration: ClinicalTrials.gov registration: Not applicable [ABSTRACT FROM AUTHOR]

Human immunodeficiency virus (HIV) infection remains one of the most severe problems for humanity, particularly due to the development of HIV resistance. To evaluate an association between viral sequence data and drug combinations and to estimate an effect of a particular drug combination on the treatment results, collection of the most representative drug combinations used to cure HIV and the biological data on amino acid sequences of HIV proteins is essential. We have created a new, freely available web database containing 1,651 amino acid sequences of HIV structural proteins [reverse transcriptase (RT), protease (PR), integrase (IN), and envelope protein (ENV)], treatment history information, and CD4+ cell count and viral load data available by the user’s query. Additionally, the biological data on new HIV sequences and treatment data can be stored in the database by any user followed by an expert’s verification. The database is available on the web at http://www.way2drug.com/rhivdb.

Abstract Recognize that delayed hypersensitivity reactions to sulfonamides may present as urticated plaques with hyperpigmentation and purpura for which a diagnosis of urticarial vasculitis should be considered.

Human immunodeficiency virus (HIV) infection remains one of the most severe problems for humanity, particularly due to the development of HIV resistance. To evaluate an association between viral sequence data and drug combinations and to estimate an effect of a particular drug combination on the treatment results, collection of the most representative drug combinations used to cure HIV and the biological data on amino acid sequences of HIV proteins is essential. We have created a new, freely available web database containing 1,651 amino acid sequences of HIV structural proteins [reverse transcriptase (RT), protease (PR), integrase (IN), and envelope protein (ENV)], treatment history information, and CD4+ cell count and viral load data available by the user's query. Additionally, the biological data on new HIV sequences and treatment data can be stored in the database by any user followed by an expert's verification. The database is available on the web at http://www.way2drug.com/rhivdb. [ABSTRACT FROM AUTHOR]

Background: Cerebrovascular disorders have occurred more frequently in some Central Nervous System (CNS) disorders, such as epilepsy. Some CNS drugs have been associated with increased stroke risk. Our aim was to estimate the risk of ischaemic stroke in patients exposed to antiepileptic drugs (AED).Methods: Population-based matched case-control study using SIDIAP database, based in electronic health records from primary healthcare from Catalonia, Spain. Cases were those patients with a registered diagnosis of first stroke during 2009-2014. Up to 10 controls were selected for each case and matched by sex, age, and geographic area and without a prior diagnosis of stroke. We considered global drug exposure to AED, past and current exposure and exposure in monotherapy to each AED.Results: 2,865 cases and 19,406 controls were exposed to AED during the study period. Global exposure to levetiracetam [(ORadj3.3, CI95 % 2.8-4.0)], phenytoin [ORadj1.5, CI95 % 1.2-41.9)], and valproic acid [(ORadj 1.3, CI95 % 1.1-1.6)], showed significantly association to ischaemic stroke that was also maintained with current exposure of levetiracetam [ORadj4.1, CI95 % 3.3-5.2)] and valproic acid [ORadj1.4, CI95 % 1.1-1.9)]. Current levetiracetam monotherapy showed a very high risk of ischaemic stroke [(ORadj 5.1, CI95 % 3.7-6.9)].Conclusions: Drugs used for other conditions than epilepsy (pregabalin, gabapentin) were the most used AED and both did not show a risk. Levetiracetam shows a risk for stroke even when assessed in current monotherapy. The lack of data regarding the link with diagnosis and severity in our study makes it necessary to conduct further studies to confirm or dismiss our results, focussing on levetiracetam. [ABSTRACT FROM AUTHOR]