Pharmacokinetic Target Research Articles

Dolutegravir dosing for children with HIV weighing less than 20 kg: pharmacokinetic and safety substudies nested in the open-label, multicentre, randomised, non-inferiority ODYSSEY trial

SummaryBackgroundDolutegravir-based antiretroviral therapy is a preferred first-line treatment for adults and children living with HIV; however, very little pharmacokinetic data for dolutegravir use are available in young children. We therefore aimed to evaluate dolutegravir dosing and safety in children weighing 3 kg to less than 20 kg by assessing pharmacokinetic parameters and safety data in children taking dolutegravir within the ODYSSEY trial.MethodsWe did pharmacokinetic substudies nested within the open-label, multicentre, randomised, non-inferiority ODYSSEY trial. We enrolled children from seven research centres in South Africa, Uganda, and Zimbabwe. Children weighing 3 kg to less than 14 kg received 5 mg dispersible tablets of dolutegravir according to WHO weight bands: 5 mg for children weighing 3 kg to less than 6 kg and younger than 6 months, 10 mg for children weighing 3 kg to less than 6 kg and aged 6 months or older, 15 mg for children weighing 6 kg to less than 10 kg, and 20 mg for children weighing 10 kg to less than 14 kg. Children weighing 14 kg to less than 20 kg received a 25 mg film-coated tablet once per day early in the trial or 25 mg dispersible tablets (five 5 mg tablets once per day) later in the trial. A minimum of eight children per weight band or dose was targeted for 24 h pharmacokinetic profiling at steady state. The primary pharmacokinetic parameter was the trough concentration 24 h after observed dolutegravir intake (Ctrough). Pharmacokinetic targets were based on adult dolutegravir Ctrough and the 90% effective concentration (EC90; ie, 0·32 mg/L). Safety was evaluated in eligible children consenting to pharmacokinetic substudies.FindingsBetween May 25, 2017, and Aug 15, 2019, we enrolled 72 children aged between 3 months and 11 years. 71 children were included in the safety population and 55 (76%) of 72 children contributed 65 evaluable pharmacokinetic profiles. Geometric mean Ctrough in children on dispersible tablets in weight bands between 3 kg and less than 20 kg ranged between 0·53–0·87 mg/L, comparable to the adult geometric mean Ctrough of 0·83 mg/L. Variability was high with coefficient of variation percentages ranging between 50% and 150% compared with 26% in adults. Ctrough below EC90 was observed in four (31%) of 13 children weighing 6 kg to less than 10 kg taking 15 mg dispersible tablets, and four (21%) of 19 weighing 14 kg to less than 20 kg taking 25 mg film-coated tablets. The lowest geometric mean Ctrough of 0·44 mg/L was observed in children weighing 14 kg to less than 20 kg on 25 mg film-coated tablets. Exposures were 1·7–2·0 times higher on 25 mg dispersible tablets versus 25 mg film-coated tablets. 19 (27%) of 71 children had 29 reportable grade 3 or higher adverse events (13 serious adverse events, including two deaths), none of which were related to dolutegravir.InterpretationWeight-band dosing of paediatric dolutegravir dispersible tablets provides appropriate drug exposure in most children weighing 3 kg to less than 20 kg, with no safety signal. 25 mg film-coated tablets did not achieve pharmacokinetic parameters in children weighing 14 kg to less than 20 kg, which were comparable to adults, suggesting dosing with dispersible tablets is preferable or a higher film-coated tablet dose is required.FundingPaediatric European Network for Treatment of AIDS Foundation, ViiV Healthcare, and UK Medical Research Council.

Assessment of Nasal-Brain-Targeting Efficiency of New Developed Mucoadhesive Emulsomes Encapsulating an Anti-Migraine Drug for Effective Treatment of One of the Major Psychiatric Disorders Symptoms.

Migraine is one of the major symptoms of many psychiatric and mental disorders like depression and anxiety. Eletriptan Hydrobromide (EH) is a well-tolerated drug in migraine treatment, but suffers from low oral bioavailability and low brain targeting after oral delivery. New nasal mucoadhesive EH-emulsomes development could be a new means to direct the drug from the nose-to-brain to achieve rapid onset of action and high drug concentration in the brain for acute migraine treatment. Eletriptan mucoadhesive emulsomes formulations were prepared using thin-film hydration method and 23 full factorial design was adopted to study different formulation factors’ effect on the emulsomes characters. The emulsomes were characterized for entrapment efficiency (EE%), zeta potential (ZP), particle size (PS), morphology, and ex-vivo permeation through the nasal mucosa. The selected formula was evaluated in mice for its in-vivo bio-distribution in comparison with EH intranasal and intravenous solutions. Drug targeting efficacy (DTE%) and nose-to-brain direct transport percentage (DTP%) were calculated. The optimization formulation showed a nanoparticle size of 177.01 nm, EE 79.44%, and ZP = 32.12 ± 3.28 mV. In addition, in-vitro permeability studies revealed enhanced drug permeability with suitable mean residence time up to 120 ± 13 min. EH-emulsomes were stable under different storage conditions for three months. In vivo examination and pharmacokinetic drug targeting parameters revealed EH transport to the CNS after EH nanoparticle nasal administration. Histopathology study showed no ciliotoxic effect on the nasal mucosa. From the results, it can be confirmed that the emulsomes formulation of EH proved safe direct nose-to-brain transport of EH after nasal administration of EH emulsomes.

Antibiotic Stewardship and Therapeutic Drug Monitoring of β-Lactam Antibiotics: Is There a Link? An Opinion Paper.

In critically ill patients, changes in the pharmacokinetics (PK) of β-lactams can lead to significant variations in serum concentrations, with possibly detrimental effects on outcomes. The utilization of individually calculated doses, extended infusion regimen, and therapeutic drug monitoring (TDM)-guided dose adjustments can mitigate the PK changes and help to achieve and attain an individual PK target. We reviewed relevant literature from 2004 to 2021 using 4 search engines (PubMed, Web of Science, Scopus, and Google Scholar). Unpublished clinical data were also examined. TDM-guided, individualized dosing strategies facilitated PK target attainment and improved patient outcomes. TDM-guided therapy is a core concept of individualized dosing that increases PK target attainment and identifies possible toxic β-lactam concentrations. Individualized dosing and TDM facilitate the rational use of β-lactams and are integral for antibiotic stewardship interventions in critical care, affording the optimal exposure of both pathogen and drugs, along with enhanced treatment efficacy and reduced emergence of antimicrobial resistance.

Altitudinal and geographical variations in phytochemical composition and biological activities of Curcuma longa accession from Uttarakhand, the Himalayan region

The aim of the present study was to assess the variations in chemical composition and biological activities of essential oil of Curcuma longa rhizome local cultivars collected from four varied altitudes and habitats of Kumaun and Garhwal regions of Uttarakhand, India. The essential oil was collected from the rhizomes by hydrodistillation extraction using the Clevenger apparatus. Yields of essential oil from rhizomes varied from 0.180% to 0.273%. The GC–MS analysis of the essential oil revealed the presence of turmerone, germacrone, eucalyptol, caryophyllene, ß-sesquiphellandrene, hedycaryol, α-zingiberene, α-curcumene as some of the major compounds. The biological activities were performed by different methods, that is, the antioxidant activities via DPPH assay, reducing power assay, and Fe2+ chelating activity showing varied activities in different local cultivars of turmeric. Moreover, in vitro anti-inflammatory activity and the antidiabetic activity of essential oil also showed comparable results among local cultivars of turmeric samples vis-à-vis standards. Practical applications Curcuma longa, a magical natural herb, is used as a rich food flavoring agent and possess vivid medicinal properties against several disease and ailments. Varied scientific investigations proved the application of C. longa in pharmaceuticals is a rich source of antioxidants, antibacterial, and anti-inflammatory drugs. Interestingly, the essential oil of C. longa possesses volatile compounds that have different pharmacological and biological activities reliant upon habitat, elevation, and several edaphic factors. Moreover, further investigation concerning the phytochemical variation, pharmacodynamics, as well as pharmacokinetic targets can lead to clinical trials that can help to develop rich antioxidant, anticancer, anti-inflammatory, and antidiabetic drugs. Finally, the results of the findings of this research pave the path for several more pharmacological and medicinal research illuminating the path toward natural medication.

Treating children with tuberculosis—Using pharmacometrics to do better

Treating children with tuberculosis—Using pharmacometrics to do better

Risk Factors Associated with Suboptimal Tobramycin Levels in the Medical Intensive Care Unit.

Optimal aminoglycoside dosing in critically ill patients represents a challenge for practitioners, especially in the medical intensive care unit (MICU). MICU patients exhibit altered pharmacokinetics due to pathophysiological changes the body undergoes in critical illness, leading to possible treatment failure. The literature surrounding optimal dosing and therapeutic drug monitoring strategies of aminoglycosides in MICU patients is scarce and conflicting. Additionally, only a few studies have investigated risk factors for suboptimal pharmacokinetic target obtainment. Currently, no definitive risk factors have been identified to predict suboptimal aminoglycoside target obtainment in MICU patients. The objective of this study was to determine risk factors for suboptimal pharmacokinetic target obtainment in patients receiving tobramycin in the MICU. This single-center, retrospective cohort study included patients 18-89 years old who received at least one 7 mg/kg tobramycin dose in the MICU from January, 1 2015 to September, 30 2020. Patients also had to have at least two detectable drug levels obtained at least one half-life apart following the first tobramycin dose. The primary outcome was to determine the incidence of optimal pharmacokinetic target obtainment, defined as a tobramycinmaximum concentration (Cmax)≥10 mcg/ml, and to identify the risk factors for suboptimal (Cmax < 10 mcg/mL) pharmacokinetic target obtainment, in MICU patients. Secondary outcomes were compared between suboptimal and optimal target obtainment in patients with culture confirmed gram-negative infection susceptible to tobramycin. These secondary outcomes included all-cause in-hospital mortality, ICU length of stay (LOS), hospital LOS, and vasopressor duration in those with shock. A total of 230 patients were included in this retrospective study. For the primary outcome, 187 (81.3%) patients achieved optimal target obtainment. Through multivariate logistic regression, female sex and serum albumin <2.5 g/dL were identified as independent risk factors for suboptimal target obtainment; [OR = 2.14; 95% CI (1.05-4.37), p = 0.037], [OR = 2.50; 95% CI (1.21-5.19), p = 0.014], respectively. Fifty-four (23%) patients had culture-confirmed gram-negative infections susceptible to tobramycin and were included in the subgroup analysis. Of these 54 patients, 11 (20.4%) did not achieve optimal target concentrations. In patients with culture-confirmed gram-negative infection, there was no difference between patients with optimal target obtainment and suboptimal target obtainment in ICU LOS, hospital LOS, all-cause mortality, or vasopressor duration in those with shock. Among patients receiving their first dose of tobramycin in the MICU, 81.3% obtained an optimal serum concentration. Female sex and serum albumin <2.5 g/dL were identified as risk factors for suboptimal target obtainment; however, further research is warranted to assess the utility of using these two covariates as risk factors for more aggressive dosing in critically ill MICU patients.

1159. Pharmacokinetics, Safety, and Tolerability of Imipenem/Cilastatin/Relebactam in Pediatric Participants With Confirmed or Suspected Gram-negative Bacterial Infections: A Phase 1b, Open-label, Single-Dose Clinical Trial

BackgroundImipenem/cilastatin/relebactam (IMI/REL) is approved for treating hospital-acquired/ventilator-associated bacterial pneumonia, complicated urinary tract infection, and complicated intra-abdominal infection in adults. This study assessed single-dose pharmacokinetics (PK), safety, and tolerability of IMI/REL in neonatal and pediatric participants with confirmed or suspected gram-negative bacterial infections.MethodsThis was a phase 1, open-label, non-comparative study (NCT03230916). Age- and weight-adjusted dosing is summarized in Table 1. The primary objective was to characterize the PK profiles for imipenem and relebactam after a single intravenous dose of IMI/REL. PK parameters were analyzed using population modeling. The PK target for imipenem was the percent time of the dosing interval that the unbound plasma concentration exceeded the minimum inhibitory concentration (%fT >MIC) of ≥30% (MIC used, 2 µg/mL). The PK target for relebactam was an area under the curve (AUC)/MIC ratio >8 (MIC used, 2 µg/mL), corresponding to AUC0-24h >58.88 μM∙h. Safety and tolerability were assessed for up to 14 days after drug infusion. ResultsOf the 46 participants who received IMI/REL, 42 were included in the PK analysis. The mean plasma concentration-time profiles for imipenem and relebactam were generally comparable across age cohorts (Figure). For imipenem, the geometric mean %ƒT >MIC ranged from 50% to 94% and the mean maximum concentration (Cmax) ranged from 65 μM to 126 μM (Table 2). For relebactam, the geometric Cmax ranged from 33 μM to 87 μM and mean AUC0-6h ranged from 51 μM·h to 159 μM·h across the age cohorts (Table 2). IMI/REL was well tolerated with 8 (17.4%) participants experiencing ≥1 adverse events (AE) and 2 (4.3%) participants experiencing AE that were deemed drug related by the investigator. Drug-related AE were increased alanine aminotransferase, increased aspartate aminotransferase, anemia, and diarrhea, which were non-serious, mild in severity, and resolved within the follow-up period of 14 days.Figure 1 ConclusionImipenem and relebactam exceeded the pediatric plasma PK targets across pediatric age cohorts in the study; the single doses of IMI/REL were well tolerated. These results will inform IMI/REL dose selection for further pediatric clinical evaluation.Disclosures Camilla Tøndel, MD, PhD, Merck & Co., Inc., (Grant/Research Support) Emmanuel Roilides, MD, PhD, FIDSA, FAAM, FESCMID, FECMM, FISAC, Merck Sharp & Dohme Corp. (Consultant, Grant/Research Support) Matthew S. Kelly, MD, MPH, Merck Sharp & Dohme Corp. (Consultant, Grant/Research Support) Munjal Patel, PhD, Merck Sharp & Dohme Corp. (Employee, Shareholder) Pavan Vaddady, PhD, Merck Sharp & Dohme Corp. (Employee) Alok Maniar, MD, MPH, Merck Sharp & Dohme Corp. (Employee, Shareholder) Ying Zhang, PhD, Merck & Co., Inc. (Employee, Shareholder) Amanda Paschke, MD MSCE, Merck Sharp & Dohme Corp. (Employee, Shareholder) Joan R. Butterton, MD, Merck Sharp & Dohme Corp. (Employee, Shareholder) Luke F. Chen, MBBS MPH MBA FRACP FSHEA FIDSA, Merck (Employee)

1071. Efficacy of Anti-Staphylococcal Lysin, LSVT-1701, in Combination with Daptomycin in Experimental Left-Sided Infective Endocarditis (IE) Due to Methicillin-Resistant Staphylococcus aureus (MRSA)

BackgroundAnti-staphylococcal phage lysins, such as LSVT-1701, represent important candidate adjunctive agents against invasive MRSA infections because of both their microbicidal and anti-biofilm properties. We, thus, sought to examine the in vivo efficacy of LSVT-1701 combination with daptomycin, a standard-of-care anti-MRSA agent with proven efficacy against bacteremia and IE in humans.MethodsWe utilized the rabbit model of aortic valve infective endocarditis (using the prototype MRSA strain, MW2) to examine the combined efficacy of LSVT-1701 plus daptomycin. We examined microbiologic outcomes in distinct target tissues (cardiac vegetations, spleen and kidney) in this model, as well as the pharmacokinetic and pharmacodynamic drivers and target attainment values most predictive of treatment outcomes. LSVT-1701 was given at two dose-regimens (32.5 mg/kg and 50 mg/kg) with different dose-durations (single dose vs daily dose for 2 d vs daily dose for 4 d); daptomycin was administered in combination with daptomycin at a sub-lethal daily dose of 4 mg/kg for 4 d to maximize potential synergistic interaction outcomes.ResultsThe Table below shows all LSVT-1701 regimens in combination with daptomycin significantly reduced MRSA burdens in all target tissue as compared to untreated controls. The reduction in MRSA counts was statistically significant in instances of both increasing LSVT-1701 dose level (i.e., single doses of 50 mg/kg vs 32.5 mg/kg iv), as well as increased numbers of lysin doses (i.e., four daily doses vs a single-dose or two daily-doses) in combination with daptomycin. Of note, both the LSVT-1701 50 mg/kg and 32.5 mg/kg daily dose-strategies given for four days in combination with daptomycin sterilized all target tissues (i.e., quantitative cultures ≤ the lower limit of detection of 1 log10 CFU/g. tissue). MRSA bio-burdens in blood, vegetations, kidneys and spleen in rabbit IE modelConclusionLSVT-1701 administered at 32.5 or 50 mg/kg in a 4 d daily-dose regimen in combination with daptomycin resulted in microbiologic sterilization of all target organs in this MRSA IE model. These data support further clinical development of LSVT-1701 for the treatment of MRSA endovascular infections including IE.Disclosures David Huang, MD, PhD, Lysovant (Consultant) Eric Gaukel, BS, Lysovant (Employee) Katyna Borroto-Esoda, PhD, Lysovant (Consultant) Arnold Bayer, MD, PhD, Lysovant (Grant/Research Support)

A System Pharmacology Model for Decoding the Synergistic Mechanisms of Compound Kushen Injection in Treating Breast Cancer.

Breast cancer (BC) is one of the most common malignant tumors among women worldwide and can be treated using various methods; however, side effects of these treatments cannot be ignored. Increasing evidence indicates that compound kushen injection (CKI) can be used to treat BC. However, traditional Chinese medicine (TCM) is characterized by “multi-components” and “multi-targets”, which make it challenging to clarify the potential therapeutic mechanisms of CKI on BC. Herein, we designed a novel system pharmacology strategy using differentially expressed gene analysis, pharmacokinetics synthesis screening, target identification, network analysis, and docking validation to construct the synergy contribution degree (SCD) and therapeutic response index (TRI) model to capture the critical components responding to synergistic mechanisms of CKI in BC. Through our designed mathematical models, we defined 24 components as a high contribution group of synergistic components (HCGSC) from 113 potentially active components of CKI based on ADME parameters. Pathway enrichment analysis of HCGSC targets indicated that Rhizoma Heterosmilacis and Radix Sophorae Flavescentis could synergistically target the PI3K-Akt signaling pathway and the cAMP signaling pathway to treat BC. Additionally, TRI analysis showed that the average affinity of HCGSC and targets involved in the key pathways reached -6.47 kcal/mmol, while in vitro experiments proved that two of the three high TRI-scored components in the HCGSC showed significant inhibitory effects on breast cancer cell proliferation and migration. These results demonstrate the accuracy and reliability of the proposed strategy.

Thinking Quantitatively of RNA-Based Information Transfer via Extracellular Vesicles: Lessons to Learn for the Design of RNA-Loaded EVs.

Extracellular vesicles (EVs) are 50–1000 nm vesicles secreted by virtually any cell type in the body. They are expected to transfer information from one cell or tissue to another in a short- or long-distance way. RNA-based transfer of information via EVs at long distances is an interesting well-worn hypothesis which is ~15 years old. We review from a quantitative point of view the different facets of this hypothesis, ranging from natural RNA loading in EVs, EV pharmacokinetic modeling, EV targeting, endosomal escape and RNA delivery efficiency. Despite the unique intracellular delivery properties endowed by EVs, we show that the transfer of RNA naturally present in EVs might be limited in a physiological context and discuss the lessons we can learn from this example to design efficient RNA-loaded engineered EVs for biotherapies. We also discuss other potential EV mediated information transfer mechanisms, among which are ligand–receptor mechanisms.

Systems pharmacology to reveal multi-scale mechanisms of traditional Chinese medicine for gastric cancer

Because of the complex etiology, the treatment of gastric cancer is a formidable challenge for contemporary medical. The current treatment method focuses on traditional surgical procedures, supplemented by other treatments. Among these other treatments, Traditional Chinese Medicine (TCM) plays an important role. Here, we used the systems pharmacology approach to reveal the potential molecular mechanism of PRGRC on gastric cancer which composes of Pinellia ternata(Thunb.) Breit., Rheum palmatumL., Gentiana scabraBunge, Radix Aucklandiae and Citrus aurantium L. This approach combines pharmacokinetics analysis with pharmacodynamics evaluation for the active compounds screening, targets prediction and pathways assessing. Firstly, through pharmacokinetic evaluation and target prediction models, 83 potential compounds and 184 gastric cancer-related targets were screened out. Then, the results of network analysis suggested that the targets of PRGRC were mainly involved two aspects: apoptosis and inflammation. Finally, we verified the reliability of the above analysis at the cellular level by using naringenin and luteolin with good pharmacokinetic activity as representative compounds. Overall, we found that PRGRC could influence the development of gastric cancer from a multi-scale perspective. This study provided a new direction for analyzing the mechanism of TCM.

Nose to brain delivery of Efavirenz nanosuspension for effective neuro AIDS therapy: in-vitro, in-vivo and pharmacokinetic assessment

Efavirenz is inhibitor of non-nucleoside reverse transcriptase enzyme; BCS class II drug. The objective of the present research was to prepare and evaluate nanosuspension of Efavirenz for the treatment of neuro-AIDS. Efavirenz is the substrate for drug resistant proteins at BBB prone to efflux and could not reach brain with effective levels. Current need of the therapy is to develop drug delivery systems targeting viral reservoirs at effective concentration in the brain. With this need we developed Efavirenz nanosuspension for nose to brain drug transport to bypass blood brain barrier. Nanosuspension prepared with high-pressure homogenization had a mean particle size of 223 nm, PDI of 0.2 and -21.2 mV zeta potential. Histopathology study on goat nasal mucosa showed no adverse effects of formulation on nasal tissues. Gamma scintigraphy study and in-vivo study on Wistar rat model reveals drug transport to the CNS after nasal administration. Pharmacokinetic parameters and drug targeting potential of 99.46 % suggest direct nose to brain transport of Efavirenz nanoparticle. Results reveal that nose to brain delivery of Efavirenz is the best possible alternative for neuro –AIDS treatment.

Optimizing Dosing and Fixed-Dose Combinations of Rifampicin, Isoniazid, and Pyrazinamide in Pediatric Patients With Tuberculosis: A Prospective Population Pharmacokinetic Study.

In 2010, the World Health Organization (WHO) revised dosing guidelines for treatment of childhood tuberculosis. Our aim was to investigate first-line antituberculosis drug exposures under these guidelines, explore dose optimization using the current dispersible fixed-dose combination (FDC) tablet of rifampicin/isoniazid/pyrazinamide; 75/50/150mg, and suggest a new FDC with revised weight bands. Children with drug-susceptible tuberculosis in Malawi and South Africa underwent pharmacokinetic sampling while receiving first-line tuberculosis drugs as single formulations according the 2010 WHO recommended doses. Nonlinear mixed-effects modeling and simulation was used to design the optimal FDC and weight-band dosing strategy for achieving the pharmacokinetic targets based on literature-derived adult AUC0-24h for rifampicin (38.7-72.9), isoniazid (11.6-26.3), and pyrazinamide (233-429 mg ∙ h/L). In total, 180 children (42% female; 13.9% living with human immunodeficiency virus [HIV]; median [range] age 1.9 [0.22-12] years; weight 10.7 [3.20-28.8] kg) were administered 1, 2, 3, or 4 FDC tablets (rifampicin/isoniazid/pyrazinamide 75/50/150mg) daily for 4-8, 8-12, 12-16, and 16-25kg weight bands, respectively. Rifampicin exposure (for weight and age) was up to 50% lower than in adults. Increasing the tablet number resulted in adequate rifampicin but relatively high isoniazid and pyrazinamide exposures. Administering 1, 2, 3, or 4 optimized FDC tablets (rifampicin/isoniazid/pyrazinamide 120/35/130mg) to children < 6, 6-13, 13-20. and 20-25kg, and 0.5 tablet in < 3-month-olds with immature metabolism, improved exposures to all 3 drugs. Current pediatric FDC doses resulted in low rifampicin exposures. Optimal dosing of all drugs cannot be achieved with the current FDCs. We propose a new FDC formulation and revised weight bands.

Population pharmacogenomics: an update on ethnogeographic differences and opportunities for precision public health.

Both safety and efficacy of medical treatment can vary depending on the ethnogeographic background of the patient. One of the reasons underlying this variability is differences in pharmacogenetic polymorphisms in genes involved in drug disposition, as well as in drug targets. Knowledge and appreciation of these differences is thus essential to optimize population-stratified care. Here, we provide an extensive updated analysis of population pharmacogenomics in ten pharmacokinetic genes (CYP2D6, CYP2C19, DPYD, TPMT, NUDT15 and SLC22A1), drug targets (CFTR) and genes involved in drug hypersensitivity (HLA-A, HLA-B) or drug-induced acute hemolytic anemia (G6PD). Combined, polymorphisms in the analyzed genes affect the pharmacology, efficacy or safety of 141 different drugs and therapeutic regimens. The data reveal pronounced differences in the genetic landscape, complexity and variant frequencies between ethnogeographic groups. Reduced function alleles of CYP2D6, SLC22A1 and CFTR were most prevalent in individuals of European descent, whereas DPYD and TPMT deficiencies were most common in Sub-Saharan Africa. Oceanian populations showed the highest frequencies of CYP2C19 loss-of-function alleles while their inferred CYP2D6 activity was among the highest worldwide. Frequencies of HLA-B*15:02 and HLA-B*58:01 were highest across Asia, which has important implications for the risk of severe cutaneous adverse reactions upon treatment with carbamazepine and allopurinol. G6PD deficiencies were most frequent in Africa, the Middle East and Southeast Asia with pronounced differences in variant composition. These variability data provide an important resource to inform cost-effectiveness modeling and guide population-specific genotyping strategies with the goal of optimizing the implementation of precision public health.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00439-021-02385-x.

Pharmacokinetic Variability and Target Attainment of Fluconazole in Critically Ill Patients.

Background: Fluconazole is one of the oldest antifungal drugs. Previous studies have raised concerns considering variability in exposure and inadequate target attainment in critically ill patients. The current study aims to define variability and target attainment for fluconazole exposure in a large group of critically ill patients. Methods: In this pharmacokinetic study, daily plasma trough samples and, if possible, 24 h urine samples were collected to determine fluconazole concentration. A minimum target trough concentration of 10–15 mg/L was selected, corresponding to a free area under the concentration–time curve above the minimum inhibitory concentration (fAUC/MIC) of at least 100 for an MIC of 4 mg/L. Covariates that significantly influenced fluconazole exposure were identified. Results: In total, 288 plasma samples from 43 patients, with a median age of 66 years, were included. The median fluconazole trough concentration was 22.9 mg/L. A notable component of the measured concentrations was below the target trough concentrations (13% <10 mg/L and 27% <15 mg/L). The intra- and intersubject variability were 28.3% and 50.5%, respectively. The main covariates determining fluconazole exposure were the administered dose (mg/kg), augmented renal clearance, and renal replacement therapy. Conclusions: Fluconazole trough concentrations are variable in critically ill patients and a considerable number of these concentrations was below the predefined target trough concentrations.

Assessment of the Effects of a High Amikacin Dose on Plasma Peak Concentration in Critically Ill Children.

This study aimed to assess the incidence of amikacin plasma peak concentration (Cmax) below 60 mg·L-1 in critically ill children receiving an amikacin dosing regimen of 30 mgkg-1·day-1. Secondary objectives were to identify factors associated with low Cmax and to assess the incidence of acute kidney injury (AKI). A retrospective observational study was performed in two French pediatric intensive care units. All admitted children who received 30 mg·kg-1 amikacin and had a Cmax measurement were eligible. Clinical and biological data, amikacin dose, and concentrations were collected. In total, 30 patients were included, aged from 3 weeks to 7 years. They received a median amikacin dosage of 30 mgkg-1·day-1 (range 29-33) based on admission body weight (BW), corresponding to 27 mgkg-1·day-1 (range 24-30) based on actual BW. Cmax was < 60 mg·L-1 in 21 (70%) children and none had a Cmax ≥ 80 mg·L-1. Among the 15 patients with a measured minimum inhibitory concentration (MIC), 13 (87%) had a Cmax/MIC ratio > 8. Univariate analysis showed that factors associated with Cmax < 60 mg·L-1 were high estimated glomerular filtration rate (p = 0.015) and low blood urea concentration (p = 0.001). AKI progression or occurrence was observed after amikacin administration in two (7%) and six (21%) patients, respectively. Despite the administration of the maximal recommended amikacin dose, Cmax was below the pharmacokinetic target in 70% of our pediatric population. Further studies are needed to develop a pharmacokinetic model in a population of critically ill children to optimize target attainment.

Chemical Compounds and Pharmacological Activities of Mangosteen (Garcinia mangostana L.) – Updated Review

Mangosteen (Garcinia mangostana L.) is a tropical fruit belonging to Guttiferae (syn. Clusiaceae) family. Research on mangosteen has been widely conducted. Also, numerous in vitro and in vivo studies related to mangosteen have been published, indicating its significance and potential usefulness in the research field. This review was constructed by collecting and analyzing more than 50 research articles to explore the phytochemical contents and the medicinal benefits of mangosteen. A significant level of xanthones greatly contributes to the extensive pharmacological activities of mangosteen. Apart from xanthones, mangosteen also contained benzophenones, flavonoids, and anthocyanins. Mangosteen had a wide range of pharmacological effects, including antioxidant, anti-acne, anti-aging, anti-hyperpigmentation, antibacterial, antidiabetic, anti-obesity, anti-inflammatory, antimalarial, antiparasitic, and antitumor. Additionally, mangosteen has shown an advantageous activity toward pathological conditions such as Alzheimer's, bipolar disorder, schizophrenia, neuropathic pain, and pulmonary fibrosis. This literature review indicated that xanthone in mangosteen had potential and promising to be developed as a drug candidate. More extensive explorations, especially in pharmacokinetic, pharmacodynamic, and xanthone targeting effects, are widely open to be carried out for future research.

Meropenem Pharmacokinetics and Target Attainment in Critically Ill Patients Are Not Affected by Extracorporeal Membrane Oxygenation: A Matched Cohort Analysis.

Existing evidence is inconclusive whether meropenem dosing should be adjusted in patients receiving extracorporeal membrane oxygenation (ECMO). Therefore, the aim of this observational matched cohort study was to evaluate the effect of ECMO on pharmacokinetic (PK) variability and target attainment (TA) of meropenem. Patients admitted to the intensive care unit (ICU) simultaneously treated with meropenem and ECMO were eligible. Patients were matched 1:1, based on renal function and body weight, with non-ECMO ICU patients. Meropenem blood sampling was performed over one or two dosing intervals. Population PK modelling was performed using NONMEM7.5. TA was defined as free meropenem concentrations >2 or 8 mg/L (i.e., 1 or 4× minimal inhibitory concentration, respectively) throughout the whole dosing interval. In total, 25 patients were included, contributing 27 dosing intervals. The overall TA was 56% and 26% for the 2 mg/L and 8 mg/L target, respectively. Population PK modelling identified estimated glomerular filtration rate according to the Chronic Kidney Disease Epidemiology equation and body weight, but not ECMO, as significant predictors. In conclusion, TA of meropenem was confirmed to be poor under standard dosing in critically ill patients but was not found to be influenced by ECMO. Future studies should focus on applying dose optimisation strategies for meropenem based on renal function, regardless of ECMO.

Personalized ß-lactam dosing in patients with coronavirus disease 2019 (COVID-19) and pneumonia: A retrospective analysis on pharmacokinetics and pharmacokinetic target attainment.

Pathophysiological changes are important risk factors for critically ill patients with pneumonia manifesting sub-therapeutic antibiotic exposures during empirical treatment. The effect of coronavirus disease 2019 (COVID-19) on antibiotic dosing requirements is uncertain. We aimed to determine the effect of COVID-19 on ß-lactam pharmacokinetics (PK) and PK target attainment in critically ill patients with a personalized dosing strategy.Retrospective, single-center analysis of COVID-19 ± critically ill patients with pneumonia (community-acquired pneumonia or hospital-acquired pneumonia) who received continuous infusion of a ß-lactam antibiotic with dosing personalized through dosing software and therapeutic drug monitoring. A therapeutic exposure was defined as serum concentration between (css) 4 to 8 times the EUCAST non-species related breakpoint).Data from 58 patients with pneumonia was analyzed. Nineteen patients were tested COVID-19-positive before the start of the antibiotic therapy for community-acquired pneumonia or hospital-acquired pneumonia. Therapeutic exposure was achieved in 71% of COVID-19 patients (68% considering all patients). All patients demonstrated css above the non–species-related breakpoint. Twenty percent exceeded css above the target range (24% of all patients). The median ß-lactam clearance was 49% compared to ß-lactam clearance in a standard patient without a significant difference regarding antibiotic, time of sampling or present COVID-19 infection. Median daily doses were 50% lower compared to standard bolus dosing.COVID-19 did not significantly affect ß-lactam pharmacokinetics in critically ill patients. Personalized ß-lactam dosing strategies were safe in critically ill patients and lead to high PK target attainment with less resources.

Toxicity and pharmacokinetics of actinomycin-D and vincristine in children and adolescents: Children's Oncology Group Study ADVL06B1.

Actinomycin-D and vincristine are cytotoxic drugs commonly used to treat cancers in children. This prospective study assessed pharmacokinetic variability and toxicity of these drugs in children. Blood samples were collected in 158 patients. Actinomycin-D or vincristine concentrations were quantified using high-performance liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were estimated using non-compartmental methods. Target toxicities were collected prospectively. Actinomycin-D pharmacokinetics (n = 52 patients) were highly variable. The median (coefficient of variation, CV%) area under the concentration-time curve (AUC) was 332ng/mL·h.(110%); clearance was 4.6 L/h/m2 (90%); half-life was 25h (60%). No patient met the defined criteria for myelosuppression. In multivariate analysis, none of the demographic nor pharmacokinetic parameters was predictors of acute hepatotoxicity. Vincristine pharmacokinetics (n = 132 patients) demonstrated substantial variability. The median (CV%) AUC was 78ng/mL·h(98%); clearance was 17.2L/h/m2 (67%); half-life was 14.6h (73%). In multivariate analysis, the effect of increasing age for a given BSA was an increase in neuropathy while the effect of increasing BSA for a given age was a decrease in neuropathy. Conclusion: Pharmacokinetics of both drugs were highly variable. For actinomycin-D, there was no correlation between demographic or pharmacokinetic parameters and target toxicities. For vincristine, the correlations of age and BSA and neuropathy are confounded by the correlation between age and BSA in children and the ability to ascertain neuropathy in infants. Variability may be attributed to dose reductions and capped doses for both drugs. Investigation of BSA-based dosing in young children is warranted to decrease variability of exposure.