Acetaminophen (APAP) is a ubiquitous antipyretic and analgesic used in children in the United States (US), including those with cancer. The effects of US Food & Drug Administration (FDA) guidance on APAP prescribing have been described for healthy adults and children; however, APAP use patterns in neonates, infants, children, adolescents, and young adults (CAYA) with cancer are unknown. Considering their increased risk of liver injury, APAP's potential for causing hepatoxicity, and FDA guidance changes, this study examined the recent evolution of APAP use in CAYA with cancer. This retrospective, multi-center analysis extracted APAP prescribing data from the Pediatric Health Information System® (PHIS). Eligible patients were aged 0-26 years, had a cancer diagnosis per International Classification of Diseases (ICD) codes, and were prescribed a chemotherapeutic. APAP and APAP-opioid combination prescribing were assessed at hospital, regional, and national levels. APAP and APAP-opioid combination use changes were assessed using the non-parametric Mann-Kendall test. PHIS records for the complete years of 2004-2021 yielded 388,364 inpatient encounters for 50,779 unique patients. Of these, 87.3% of patients received APAP. Although APAP-opioid combination use was infrequent overall, CAYA receiving APAP were more likely to receive APAP-opioid combination medications (N=25,880, 13.4%, p < 0.001) compared to those not receiving APAP. Among specialty children's hospitals, national APAP use was stable over the study period. Regionally, APAP use increased among Northeastern hospitals. APAP-opioid combination use decreased nationally with regional variation. In contrast to the steady decline in other regions, Southern APAP-opioid combination use was consistently elevated before declining in 2014.

Objectives: Voriconazole is a triazole antifungal used to treat fungal infections in children with cancer. However, previous research reports by our group1 and others2 have shown that voriconazole pharmacokinetics (PK) is highly variable in this population, and many patients fail to achieve therapeutic target levels. Subtherapeutic levels of voriconazole in this immunocompromised population can be fatal. This study aims to develop a pediatric PBPK model that incorporates observed interpatient variability as well as cytochrome P450 (CYP) enzyme ontogeny. The simulated data was compared to the antifungal pharmacodynamics (PD) of voriconazole against multiple organisms to optimize the dose regimen in this population. Methods: Initially, an adult PBPK model of voriconazole that incorporated hepatic clearance by CYP2C19, CYP2C9, and CYP3A4 enzymes was developed. The adult model was verified with oral (10 studies) and intravenous (4 studies) PK datasets of voriconazole in adults. The PBPK modeling was performed using PK Sim® software, and the PD analysis was performed using R. The adult model was then extrapolated to children with and without cancer using ontogeny equations of CYP maturation. The pediatric PBPK model was then verified using the observed PK data of voriconazole in children with (Nf14) and without cancer (Nf11). For both models, bias and precision were evaluated by calculating the average fold error (AFE) and absolute average fold error (AAFE), respectively. The final pediatric PBPK model of voriconazole was used to simulate the levels of voriconazole in virtual pediatric patients (Nf1000) across the age continuum using dosing regimens used in children with cancer. The probability of target attainment (PTA) for different pre-clinical and clinical PK/PD indices of efficacy for voriconazole was considered (fAUC24/MIC ≥25, Ctrough > 2 µg/mL, and Ctrough, SS/MIC >2) to understand the overall benefit in each pediatric sub-population group.Results: The adult PBPK model successfully predicted the PK of voriconazole after IV and oral administration. The adult model was successfully extrapolated to the pediatric model by incorporating ontogeny equations of CYP maturation. For both adult and pediatric models, more than 90% of adult observed PK data were captured within the 90% prediction interval of the model-simulated data. The AFE and AAFE values for observed versus predicted voriconazole concentrations in adult and pediatric models were within 0.5 and 2. The outcomes of the PBPK model-based simulations indicated that the pediatric dosing regimens need to be tailored based on the child’s age and the specific infectious fungal species involved. Conclusions: A PBPK model to predict the PK of voriconazole in children with cancer was developed and verified. In clinical settings, the infectious fungal species must be considered. Additionally, further research with large sample sizes is necessary to validate the current findings.Citations: 1. Biltaji E et al. American College of Clinical Pharmacology (ACCP) Annual Meeting, Sep 17-19, 2017, San Diego, CA. (2017)2. Tucker L, et al. J Pediatr Pharmacol Ther. 20 17-23. (2015)

OBJECTIVES:To describe the efficacy of atropine in controlling salivary flow in patients with sialorrhea or drooling.MATERIALS AND METHODS:We included randomized controlled studies, quasi-randomized trials, case reports, clinical trials, systematic reviews, and meta-analyses assessing the use of atropine in patients with sialorrhea or drooling. The endpoints were reduction in salivary flow rate, amount of saliva secreted, reduction in clinical symptoms of sialorrhea, death rattle intensity, or reduction in drooling intensity as measured by an objective scale such as the drooling intensity scale.RESULTS:A total of 56 studies with 2,378 patients were included in the systematic review. The underlying disease states included brain injury, amyotrophic lateral sclerosis, cerebral palsy, clozapine- and perphenazine-induced sialorrhea, Parkinson's disease, and terminal illness. The routes of atropine administration included sublingual, intravenous, subcutaneous, oral tablet or solution, and direct injection of atropine into parotid glands or at the base of the tongue. The generalized estimated equation regression models showed that sublingual administration is superior to oral and subcutaneous routes.CONCLUSION:Atropine is efficacious in managing sialorrhea in most disease states. Sublingual administration of atropine is superior to other routes of administration in reducing salivary flow in patients with sialorrhea.

Abstract Study question Does the proposed fertoprotective agent melatonin interfere with the anti-cancer activity of imatinib chemotherapy in a chronic myelogenous leukemia (CML) cell line? Summary answer At low concentrations, melatonin demonstrates mild inhibition of imatinib activity, however this is overcome at therapeutic concentrations. Melatonin also shows anti-tumor activity against CML. What is known already A harmful consequence of cancer therapy is a resultant loss of fertility. Pharmacologic interventions that reduce radiation or chemotherapy-induced gonadotoxicity are a major unmet medical need. Several ‘fertoprotective’ agents have shown promise in protecting the gonads from injury during treatment, including melatonin. However, melatonin is not currently applied in humans for this purpose. Key safety and efficacy data are needed to move potential fertoprotective agents into clinical trials. Study design, size, duration We evaluated the interaction of varying combined concentrations of melatonin and imatinib, a tyrosine kinase inhibitor, within an in-vitro matrix experiment. The interaction was be evaluated within K562, a cell line derived from human chronic myelogenous leukemia (CML). This chemotherapy and cell line were selected due to CML’s dependence on BCR-ABL for survival, which is inhibited by imatinib, permitting direct evaluation of melatonin-imatinib cross-interaction. Participants/materials, setting, methods K562 were seeded in 384-well plates into which increasing concentrations of imantinib and melatonin were progressively dispensed. The cells were cultured for 48 hours. Viable cell concentrations were then determined using a cell luminescent assay. Drug interaction was then determined using drug synergy analysis software.The expected drug combination responses were calculated based on ZIP reference model using SynergyFinder 3.0. Deviations between observed and expected responses with positive and negative values denote synergy and antagonism respectively. Main results and the role of chance Melatonin demonstrated toxicity to K562 CML cell lines independent of imatinib, with a mean inhibition of cell growth of 74.7% at 1uM, CI [69.6%, 79.7%]. This anti-tumor activity was progressively seen at concentrations >0.1 uM. At low imatinib concentrations (<0.2 uM), melatonin decreased the anti-cancer potency of imatinib. This effect was overcome at higher concentrations of imatinib. The overall mean synergy score was -5.87, CI [-7.145, -4.588]. Limitations, reasons for caution These experiments were carried out in an in-vitro setting in a tightly controlled environment. In a clinical setting, the complexity of potential interactions between melatonin and chemotherapy will increase (i.e. metabolism, distribution), thus animal models will be a necessary next step of evaluation before clinical safety trials may proceed. Wider implications of the findings Melatonin may serve as an inexpensive, well-tolerated adjuvant to help protect the gonad from chemotherapy, while additionally exhibiting its own anti-cancer effects in certain settings. Our preliminary data suggests that the risk of melatonin to impair active imatinib treatment may be low, however continued investigation is necessary. Trial registration number Not applicable

BACKGROUND:Numerous reports contend opioids can augment or inhibit malignancy. At present, there is no consensus on the risk or benefit posed by opioids on malignancy or chemotherapeutic activity. Distinguishing the consequences of opioid use from pain and its management is challenging. Additionally, opioid concentration data is often lacking in clinical studies. A scoping review approach inclusive of preclinical and clinical data will improve our understanding of the risk-benefit relationship concerning commonly prescribed opioids and cancer and cancer treatment. OBJECTIVE:The aim of the study is to map diverse studies spanning from preclinical to clinical regarding opioids with malignancy and its treatment. METHODS:This scoping review will use the Arksey six stages framework to (1) identify the research question; (2) identify relevant studies; (3) select studies meeting criteria; (4) extract and chart data; (5) collate, summarize, and report results; and (6) conduct expert consultation. An initial pilot study was undertaken to (1) parameterize the extent and scale of existing data for an evidence review, (2) identify key factors to be extracted in systematic charting efforts, and (3) assess opioid concentration as a variable for its relevance to the central hypothesis. Six databases will be searched with no filters: MEDLINE, Embase, CINAHL Complete, Cochrane Library, Biological Sciences Collection, and International Pharmaceutical Abstracts. Trial registries will include ClinicalTrials.gov, Cochrane CENTRAL, International Standard Randomised Controlled Trial Number Registry, European Union Clinical Trials Register, and World Health Organization International Clinical Trials Registry. Eligibility criteria will include preclinical and clinical study data on opioids effects on tumor growth or survival, or alteration on the antineoplastic activity of chemotherapeutics. We will chart data on (1) opioid concentration from human subjects with cancer, yielding a "physiologic range" to better interpret available preclinical data; (2) patterns of opioid exposure with disease and treatment-related patient outcomes; and (3) the influence of opioids on cancer cell survival, as well as opioid-related changes to cancer cell susceptibility for chemotherapeutics. RESULTS:This scoping review will present results in narrative forms as well as with the use of tables and diagrams. Initiated in February 2021 at the University of Utah, this protocol is anticipated to generate a scoping review by August 2023. The results of the scoping review will be disseminated through scientific conference proceedings and presentations, stakeholder meetings, and by publication in a peer-reviewed journal. CONCLUSIONS:The findings of this scoping review will provide a comprehensive description of the consequences of prescription opioids on malignancy and its treatment. By incorporating preclinical and clinical data, this scoping review will invite novel comparisons across study types that could inform new basic, translational, and clinical studies regarding risks and benefits of opioid use among patients with cancer. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID):PRR1-10.2196/38167.

Purpose: The therapeutic utility of Cannabis in cancer is a topic of intense interest. Dronabinol is synthetic Δ9-tetrahydrocannabinol (THC), the primary psychoactive component of Cannabis sativa, and is approved for treating refractory chemotherapy-induced nausea and vomiting. Little is known about dronabinol prescribing in children and young adults, and no published concentration data are available. This study evaluated national level dronabinol use and assessed concentrations of THC and its primary metabolites in patients with cancer <27 years of age prescribed dronabinol. Methods: Observational review of records from the Pediatric Health Information System (PHIS) and a regional network of hospitals in the Intermountain West, including a tertiary care children's hospital, Primary Children's Hospital (PCH), for inpatients <27 years of age prescribed dronabinol. Prospective blood samples were collected from children with cancer at PCH. Results: Across PHIS institutions, overall dronabinol prescribing aligned with the pharmacy records for those with cancer (p < 0.0001), and of these, 10.4% received dronabinol as inpatients. Blood collected within 72 hours of dronabinol administration was available from 10 children with a median age of 12.5 (range 6-17) years. Quantifiable concentrations were found in 4 (13%), 6 (20%), and 1 (3%) samples assayed for THC, 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (COOH-THC), and 11-hydroxy-Δ9-tetrahydrocannabinol (OH-THC), respectively. THC concentrations ranged between 0.100 and 0.128 ng/mL and were not associated with dose. Conclusion: Dronabinol prescribing appears exclusive to patients diagnosed with cancer, and its use has increased steadily in the past decade. In a small sample of children administered dronabinol, THC and metabolite concentrations were consistently low or undetectable.

Sjögren’s syndrome (SS) is an autoimmune disease with no effective treatment options. Resolvin D1 (RvD1) belongs to a class of lipid‐based specialized pro‐resolving mediators that showed efficacy in preclinical models of SS. We developed a physiologically‐based pharmacokinetic (PBPK) model of RvD1 in mice and optimized the model using plasma and salivary gland pharmacokinetic (PK) studies performed in NOD/ShiLtJ mice with SS‐like features. The predictive performance of the PBPK model was also evaluated with two external datasets from the literature reporting RvD1 PKs. The PBPK model adequately captured the observed concentrations of RvD1 administered at different doses and in different species. The PKs of RvD1 in virtual humans were predicted using the verified PBPK model at various doses (0.01–10 mg/kg). The first‐in‐human predictions of RvD1 will be useful for the clinical trial design and translation of RvD1 as an effective treatment strategy for SS.

Pharmacokinetic (PK) conflicts can arise between supportive care medications (SCM) and chemotherapy in children with hematologic malignancy (HM). In this retrospective study, medical records for children (28 days-18 years) diagnosed with HM and receiving an SCM antimicrobial were collected from a hospital network between 1 May 2000 and 31 December 2014. PK drug-gene associations were obtained from a curated pharmacogenomics database. Among 730 patients (median age of 7.5 (IQR 3.7-13.9) years), primarily diagnosed with lymphoid leukemia (52%), lymphoma (28%), or acute myeloid leukemia (16%), chemotherapy was administered in 2846 hospitalizations. SCM accounted for 90.5% (n = 448) of distinct drugs with 93% (n = 679) of children, receiving >= 5 different SCM/hospitalization. Same-day SCM/chemotherapeutic PK gene overlap occurred in 48.3% of hospitalizations and was associated with age (p = 0.026), number of SCM, HM subtype, surgery, and hematopoietic stem cell transplant (p < 0.0001). A high and variable SCM burden among children with HM receiving chemotherapy poses a risk for unanticipated PK conflicts.

For many drugs, clearance is the primary factor driving dosing regimens. In young children, hepatic metabolic clearance is influenced by maturational changes in the expression and activity of drug-metabolizing enzymes, as well as by changes in hepatic blood flow and perfusion, plasma protein binding, and active transport processes. The largest maturational changes in the different determinants of hepatic metabolic clearance are observed in the first months and years of life with largest interindividual variability in the youngest age ranges. Together, the physiochemical properties of a given drug and the interplay of the aforementioned factors in a developmental context determine the drug's total hepatic clearance. Knowledge on the maturational processes influencing hepatic drug clearance is limited. Centrally, an understanding of the ontogeny of drug-metabolizing enzymes is critical for sound clinical judgment regarding the use of certain drugs in young children.

OBJECTIVE:To evaluate the risk of nonsteroidal anti-inflammatory drug (NSAID) therapy-associated acute kidney injury (AKI) among neonates diagnosed with patent ductus arteriosus (PDA) who are treated with gentamicin.STUDY DESIGN:Multicenter retrospective observational study of patients ⩽44 postmenstrual weeks of age diagnosed with PDA who received gentamicin during hospitalization between January 2006 and December 2014. Patients with and without NSAID exposure were matched on covariates associated with AKI and NSAID therapy. The primary end point, AKI, was defined according to Kidney Disease Improving Global Outcomes neonatal criteria.RESULTS:The rate of AKI for the entire cohort (n=594) was 12% (n=71). Among neonates receiving NSAIDS, 14.8% (n=44) experienced an AKI as compared to 9.1% (n=27) for those who were not exposed (relative risk, 1.6; 95% confidence interval, 1.0 to 2.6). Therefore, the attributable risk of NSAID use was 5.7% (95% confidence interval, 0.5 to 11.0).CONCLUSION:Among neonates with PDA and receiving gentamicin, NSAID therapy increases the risk of AKI by about 6%.

Introduction: Advancing appropriate and adequate analgesic pharmacotherapy in pediatric patients with cancer is an area of clinical need. Few studies have been performed to evaluate the selection of an analgesic and appropriate dosing corresponding to analgesic effect among pediatric cancer patients. This review describes information related to pharmacokinetic, pharmacodynamic, and pharmacogenomic (when applicable) considerations for analgesics that are commonly used to manage pain experienced by pediatric patients with cancer.Areas covered: Analgesics commonly used to treat pediatric patients with malignancy patterned after the World Health Organization's 'analgesic ladder' for cancer pain management.Expert opinion: Addressing pain management safely and effectively in pediatric patients with cancer will require advances in both drug development, to increase the armament of analgesics available for children, and our pharmacologic understanding of those analgesics in current use. However, performing the necessary types of studies to develop new analgesics, or gain knowledge of existing therapy, within a population that is relatively small, diverse, and who experience pain originating from a variety of sources, is a tremendous challenge.

Introduction: Voriconazole is a broad-spectrum antifungal agent commonly used to treat invasive fungal infections (IFI), including aspergillosis, candidiasis, Scedosporium infection, and Fusarium infection. IFI often occur in immunocompromised patients, leading to increased morbidity and mortality.Areas covered: The objective of this review is to summarize the pharmacodynamic properties of voriconazole and to provide considerations for potential optimal dosing strategies. Studies have demonstrated superior clinical response when an AUC/MIC >25 or C-min/MIC >1 is attained in adult patients, correlating to a trough concentration range as narrow as 2-4.5mg/L; however, these targets are poorly established in the pediatric population. Topics in this discussion include voriconazole use in multiple age groups, predisposing patient factors for IFI, and considerations for clinicians managing IFI.Expert commentary: The relationship between voriconazole dosing and exposure is not well defined due to the large inter- and intra-subject variability. Development of comprehensive decision support tools for individualizing dosing, particularly in children who require higher dosing, will help to increase the probability of achieving therapeutic efficacy and decrease sub-therapeutic dosing and adverse events.

Background The incidence of nephrotoxicity among vancomycin-treated neonates has been reported to range from 2% to 20%. These widely varying estimates have led to confusion and controversy regarding the safety of vancomycin among neonates.Objective Evaluate the incidence of nephrotoxicity among neonates receiving vancomycin concomitantly with gentamicin.Design Retrospective observational cohort study using propensity score matching to provide covariate balance between neonates who did or did not receive vancomycin based on factors known to be related to the development of renal dysfunction.Setting Hospitals (n=22) throughout the Intermountain West, including a quaternary care children's hospital.Patients Neonates 44 postmenstrual weeks (median gestational age: 31 (IQR 28-36) weeks) receiving intravenous gentamicin with or without exposure to vancomycin from January 2006 to December 2012.Main outcome measures Nephrotoxicity based on the modified Acute Kidney Injury Network criteria for acute kidney injury (AKI) or serum creatinine concentration 1.5mg/dL persisting for 48h.Results The final cohort was comprised of 1066 neonates (533 receiving vancomycin and gentamicin vs 533 receiving gentamicin). In a propensity score-matched cohort that was well balanced across 16 covariates, AKI was not associated with vancomycin use (16 neonates receiving vancomycin vs 7 controls experienced AKI; OR 1.5; 95% CI 0.6 to 4.0). However, the presence of a patent ductus arteriosus, concomitant non-steroidal anti-inflammatory drug use, 1 positive blood cultures, low birth weight and higher severity of illness and risk of mortality scores were associated with an increased risk of nephrotoxicity.Conclusions These results corroborate several earlier reports and much anecdotal evidence describing the infrequent occurrence of nephrotoxicity in neonates receiving concomitant vancomycin and gentamicin.

Growth and maturational changes have been identified as significant covariates in describing variability in clearance of renally excreted drugs such as vancomycin. Because of immaturity of clearance mechanisms, quantification of renal function in neonates is of importance. Several serum creatinine (SCr)‐based renal function descriptors have been developed in adults and children, but none are selectively derived for neonates. This review summarizes development of the neonatal kidney and discusses assessment of the renal function regarding estimation of glomerular filtration rate using renal function descriptors. Furthermore, identification of the renal function descriptors that best describe the variability of vancomycin clearance was performed in a sample study of a septic neonatal cohort. Population pharmacokinetic models were developed applying a combination of age‐weight, renal function descriptors, or SCr alone. In addition to age and weight, SCr or renal function descriptors significantly reduced variability of vancomycin clearance. The population pharmacokinetic models with Léger and modified Schwartz formulas were selected as the optimal final models, although the other renal function descriptors and SCr provided reasonably good fit to the data, suggesting further evaluation of the final models using external data sets and cross validation. The present study supports incorporation of renal function descriptors in the estimation of vancomycin clearance in neonates.

Introduction: Similar to other nations North American people used herbs for thousands of years to treat diseases and purify their spirits. By the middle of the 1900s, evidence-based conventional medicine received wide acceptance in Canada and the United States (US). Nowadays, people are going back to their roots and actively using herbal medicines (HMs) and natural health products (NHPs).Areas covered: This article is focusing on use and regulation of the HMs and NHPs in Canada and the US, raises concerns regarding HM and NHP safety and efficacy, offers suggestions on how to overcome these problems. Materials available from legislative and governmental websites, PubMed and news media were used.Expert commentary: Use of HMs, especially dietary supplements is widespread among adults in Canada and US. HMs and NHPs are regulated in both countries, but minimum criteria for product approval and post-market surveillance have been set. Concerns of quality, contamination, adulteration, and efficacy in are of central importance in the discussion of HMs and NHPs. Detailed product description and research are of vital importance to ensure safety and efficacy of these products. Additionally, herbal' education of healthcare providers and patients is needed to guarantee further successful integration of HM and conventional medicines.