Model Based Estimation of Posaconazole Tablet and Suspension Bioavailability in Hospitalized Children Using Real-World Therapeutic Drug Monitoring Data in Patients Receiving Intravenous and Oral Dosing.

Invasive fungal infections are a major cause of morbidity and mortality for immunocompromised patients. Posaconazole is approved for treatment and prophylaxis of invasive fungal infection in adult patients, with intravenous, oral suspension, and gastroresistant/delayed-released tablet formulations available. In Europe, until very recently, posaconazole was used off-label in children, although a new delayed-release suspension approved for pediatric use is expected to become available soon. A population pharmacokinetic model was developed which uses posaconazole therapeutic drug monitoring data following intravenous and oral dosing in hospitalized children, thus enabling estimation of pediatric suspension and tablet oral bioavailability. In total, 297 therapeutic drug monitoring plasma levels from 104 children were included in this analysis. The final model was a one-compartment model with first-order absorption and nonlinear elimination. Allometric scaling on clearance and volume of distribution was included a priori. Tablet bioavailability was estimated to be 66%. Suspension bioavailability was estimated to decrease with increasing doses, ranging from 3.8% to 32.2% in this study population. Additionally, concomitant use of proton pump-inhibitors was detected as a significant covariate, reducing suspension bioavailability by 41.0%. This is the first population pharmacokinetic study to model posaconazole data from hospitalized children following intravenous, tablet, and suspension dosing simultaneously. The incorporation of saturable posaconazole clearance into the model has been key to the credible joint estimation of tablet and suspension bioavailability. To aid rational posaconazole dosing in children, this model was used alongside published pharmacodynamic targets to predict the probability of target attainment using typical pediatric dosing regimen.

Voriconazole plasma concentrations and dosing in paediatric patients below 24 months of age.

Voriconazole (VCZ) is an important first-line option for management of invasive fungal diseases and approved in paediatric patients ≥24 months at distinct dosing schedules that consider different developmental stages. Information on dosing and exposures in children <24 months of age is scarce. Here we report our experience in children <24 months who received VCZ due to the lack of alternative treatment options. This retrospective analysis includes 50 distinct treatment episodes in 17 immunocompromised children aged between 3 and <24 months, who received VCZ between 2004 and 2022 as prophylaxis (14 patients; 47 episodes) or as empirical treatment (3 patients; 3 episodes) by mouth (46 episodes) or intravenously (4 episodes) based on contraindications, intolerance or lack of alternative options. Trough concentrations were measured as clinically indicated, and tolerability was assessed based on hepatic function parameters and discontinuations due to adverse events (AEs). VCZ was administered for a median duration of 10 days (range: 1-138). Intravenous doses ranged from 4.9 to 7.0 mg/kg (median: 6.5) twice daily, and oral doses from 3.8 to 29 mg/kg (median: 9.5) twice daily, respectively. The median trough concentration was 0.63 mg/L (range: 0.01-16.2; 38 samples). Only 34.2% of samples were in the recommended target range of 1-6 mg/L; 57.9% had lower and 7.9% higher trough concentrations. Hepatic function parameters analysed at baseline, during treatment and at end of treatment did not show significant changes during VCZ treatment. There was no correlation between dose and exposure or hepatic function parameters. In three episodes, VCZ was discontinued due to an AE (6%; three patients). In conclusion, this retrospective analysis reveals no signal for increased toxicity in paediatric patients <24 months of age. Empirical dosing resulted in mostly subtherapeutic exposures which emphasises the need for more systematic study of the pharmacokinetics of VCZ in this age group.

Pharmacokinetic modelling of caspofungin to develop an extended dosing regimen in paediatric patients.

BACKGROUND: Echinocandins are commonly used in treatment and prophylaxis of invasive fungal diseases. Intravenous daily dosing for prophylaxis in the outpatient setting can however become a hurdle for adequate compliance in the paediatric population. OBJECTIVES: Simulations were performed to assess extended twice-weekly dosing for antifungal prophylaxis using caspofungin. METHODS: A population pharmacokinetic model was developed based on previously published data from children aged 3 months to 17 years. Using the final model, Monte Carlo simulations were performed to assess the dose needed for adequate exposure in a twice-weekly setting. Mean weekly AUC0-24 h/MIC together with reported AUC0-24 h from previously reported paediatric trials were used to guide adequate exposure. RESULTS AND CONCLUSIONS: A two-compartment model with linear elimination and allometric scaling using fixed exponents was found most adequate to describe the given paediatric populations. Simulations showed that a 200 mg/m2 twice-weekly regimen with maximal 200 mg total dose should result in exposures matching registered daily dosing as well as commonly used pharmacokinetic/pharmacodynamic targets.

Simultaneous pharmacokinetic/pharmacodynamic (PKPD) assessment of ampicillin and gentamicin in the treatment of neonatal sepsis.

OBJECTIVES: This study aimed to simultaneously investigate the pharmacokinetics of ampicillin and gentamicin, currently the WHO standard of care for treating neonatal sepsis. METHODS: Pharmacokinetic data were collected in 59 neonates receiving ampicillin and gentamicin for suspected or proven sepsis in the NeoFosfo trial (NCT03453177). A panel of 23 clinical Escherichia coli isolates from neonates with sepsis, resistant to either ampicillin, gentamicin or both, were tested for susceptibility using chequerboards. Pharmacokinetic/pharmacodynamic (PKPD) modelling and simulations were used to compare single-agent (EUCAST MIC) and combination (chequerboard MIC) target attainment with standard dosing regimens. RESULTS: A model was established that simultaneously estimated parameters of a one-compartment ampicillin model and a two-compartment gentamicin model. A common clearance for both drugs was used (6.89 L/h/70 kg) relating to glomerular filtration (CLGFR), with an additional clearance term added for ampicillin (5.3 L/h/70 kg). Covariate modelling included a priori allometric weight and post-menstrual age scaling of clearance. Further covariate relationships on renal clearance were postnatal age and serum creatinine.Simulation-based PKPD assessments suggest good Gram-positive (MIC ≤ 0.25 mg/L) cover. However, less than one-quarter of neonates were predicted to receive efficacious coverage against Enterobacterales (MIC ≤ 2 mg/L). The benefit of the ampicillin/gentamicin combination was limited, with only 2/23 E. coli clinical strains showing FIC index < 0.5 (synergy) and most in the range 0.5-1 (suggesting additivity). Simulations showed that feasible dosing strategies would be insufficient to cover resistant strains. CONCLUSIONS: PKPD simulations showed ampicillin and gentamicin combination therapy was insufficient to cover Enterobacterales, suggesting the need for alternative empirical treatment options for neonatal sepsis.

Pharmacokinetic modeling and simulation to understand diamorphine dose-response in neonates, children, and adolescents.

Pharmacokinetic-pharmacodynamic modeling and simulation can facilitate understanding and prediction of exposure-response relationships in children with acute or chronic pain. The pharmacokinetics of diamorphine (diacetylmorphine, heroin), a strong opioid, remain poorly quantified in children and dose is often guided by clinical acumen. This tutorial demonstrates how a model to describe intranasal and intravenous diamorphine pharmacokinetics can be fashioned from a model for diamorphine disposition in adults and a model describing morphine disposition in children. Allometric scaling and maturation models were applied to clearances and volumes to account for differences in size and age between children and adults. The utility of modeling and simulation to gain insight into the analgesic exposure-response relationship is demonstrated. The model explains reported observations, can be used for interrogation, interpolated to determine equianalgesia and inform future clinical studies. Simulation was used to illustrate how diamorphine is rapidly metabolized to morphine via its active metabolite 6-monoacetylmorphine, which mediates an early dopaminergic response accountable for early euphoria. Morphine formation is then responsible for the slower, prolonged analgesic response. Time-concentration profiles of diamorphine and its metabolites reflected disposition changes with age and were used to describe intravenous and intranasal dosing regimens. These indicated that morphine exposure in children after intranasal diamorphine 0.1 mg.kg-1 was similar to that after intranasal diamorphine 5 mg in adults. A target concentration of morphine 30 µg.L-1 can be achieved by a diamorphine intravenous infusion in neonates 14 µg.kg-1 .h-1 , in a 5-year-old child 42 µg.kg-1 .h-1 and in an 15 year-old-adolescent 33 µg.kg-1 .h-1 .

Pharmacodynamics of Posaconazole in Experimental Invasive Pulmonary Aspergillosis: Utility of Serum Galactomannan as a Dynamic Endpoint of Antifungal Efficacy.

Aspergillus galactomannan antigenemia is an accepted tool for the diagnosis of invasive pulmonary aspergillosis (IPA) in neutropenic patients. Little is known, however, about the utility of this biomarker to assess the efficacy of antifungal therapies. The pharmacokinetics (PK) and pharmacodynamics (PD) of posaconazole in treatment and prophylaxis were investigated in the persistently neutropenic rabbit model of Aspergillus fumigatus IPA at doses between 2 and 20 mg/kg per day. Sparse plasma sampling was used to obtain PK data at steady state, and the serum galactomannan index (GMI), as a dynamic endpoint of antifungal response, was obtained every other day, in addition to conventional outcome parameters including survival and fungal tissue burden. Nonparametric PK/PD model building was performed using the Pmetrics package in R. A one-compartment model with linear elimination best described the PK of posaconazole. The PD effect of posaconazole exposure in plasma on the GMI in serum was best described by dynamic Hill functions reflecting growth and killing of the fungus. Through calculations of the area under the concentration-time curve from 0 to 24 h (AUC0-24) at steady state, the exposure-response relationship between posaconazole and the GMI for treatment followed a sigmoidal function with an asymptote forming above an AUC0-24 of 30 mg · h/liter. All prophylactic doses were able to control the fungal burden. A nonparametric population PK/PD model adequately described the effect of posaconazole in prophylaxis and treatment of experimental IPA. An AUC0-24 greater than 30 mg · h/liter was associated with adequate resolution of the GMI, which well supports previously suggested exposure-response relationships in humans.

Amikacin Combined with Fosfomycin for Treatment of Neonatal Sepsis in the Setting of Highly Prevalent Antimicrobial Resistance.

Antimicrobial resistance (particularly through extended-spectrum ß-lactamase and aminoglycoside-modifying enzyme production) in neonatal sepsis is a global problem, particularly in low- and middle-income countries, with significant mortality rates. High rates of resistance are reported for the current WHO-recommended first-line antibiotic regimen for neonatal sepsis, i.e., ampicillin and gentamicin. We assessed the utility of fosfomycin and amikacin as a potential alternative regimen to be used in settings of increasingly prevalent antimicrobial resistance. The combination was studied in a 16-arm dose-ranged hollow-fiber infection model (HFIM) experiment. The combination of amikacin and fosfomycin enhanced bactericidal activity and prevented the emergence of resistance, compared to monotherapy with either antibiotic. Modeling of the experimental quantitative outputs and data from checkerboard assays indicated synergy. We further assessed the combination regimen at clinically relevant doses in the HFIM with nine Enterobacterales strains with high fosfomycin and amikacin MICs and demonstrated successful kill to sterilization for 6/9 strains. From these data, we propose a novel combination breakpoint threshold for microbiological success for this antimicrobial combination against Enterobacterales strains, i.e., MICF × MICA < 256 (where MICF and MICA are the fosfomycin and amikacin MICs, respectively). Monte Carlo simulations predict that a standard fosfomycin-amikacin neonatal regimen would achieve >99% probability of pharmacodynamic success for strains with MICs below this threshold. We conclude that the combination of fosfomycin with amikacin is a viable regimen for the empirical treatment of neonatal sepsis and is suitable for further clinical assessment in a randomized controlled trial.

Clinical pharmacokinetics and dose recommendations for posaconazole gastroresistant tablets in children with cystic fibrosis.

OBJECTIVES: To investigate the population pharmacokinetics of posaconazole gastroresistant tablets in children with cystic fibrosis (CF) and perform simulations to recommend optimal doses. PATIENTS AND METHODS: Children from a paediatric CF centre who had received posaconazole tablets and underwent therapeutic drug monitoring were identified from pharmacy records. Relevant clinical data were collated from case notes and electronic patient records and used to develop an allometrically scaled population pharmacokinetic model. A stepwise covariate model-building exercise evaluated the influence of interacting medicines and liver function. RESULTS: One hundred posaconazole serum concentrations were collected from 37 children with a median age of 14 years (range 7-17). Posaconazole pharmacokinetics were adequately described by a one-compartment model with inter-individual variability on clearance. Dose simulations demonstrated a 77%-83% probability of attaining a trough target of 1 mg/L with a dose of 300 mg every 12 h for two doses then 300 mg once daily (OD) in children aged 6-11 years; and 86%-88% with a dose of 400 mg every 12 h for two doses then 400 mg OD in adolescents aged 12-17 years. This dose scheme also yielded a 90% probability of achieving an AUC of 30 mg·h/L. AUC and trough concentration were highly correlated (r2 = 0.98). Simulations showed that trough concentrations of >0.75 mg/L would exceed an AUC of 30 mg·h/L in 90% of patients. CONCLUSIONS: A starting dose of 300 mg OD in those aged 6-11 years and 400 mg OD in those aged 12-17 years (following loading doses) yields a 90% probability of attaining an AUC of 30 mg·h/L.

IV and oral fosfomycin pharmacokinetics in neonates with suspected clinical sepsis.

BACKGROUND: Fosfomycin has the potential to be re-purposed as part of a combination therapy to treat neonatal sepsis where resistance to current standard of care (SOC) is common. Limited data exist on neonatal fosfomycin pharmacokinetics and estimates of bioavailability and CSF/plasma ratio in this vulnerable population are lacking. OBJECTIVES: To generate data informing the appropriate dosing of IV and oral fosfomycin in neonates using a population pharmacokinetic analysis of plasma and CSF data. METHODS: The NeoFosfo study (NCT03453177) was a randomized trial that examined the safety and pharmacokinetics of fosfomycin comparing SOC versus SOC plus fosfomycin. Sixty-one neonates received fosfomycin (100 mg/kg IV q12h for 48 h) and then they converted to oral therapy at the same dose. Two plasma pharmacokinetic samples were taken following the first IV and oral doses, sample times were randomized to cover the whole pharmacokinetic profile and opportunistic CSF pharmacokinetic samples were collected. A population pharmacokinetic model was developed in NONMEM and simulations were performed. RESULTS: In total, 238 plasma and 15 CSF concentrations were collected. A two-compartment disposition model, with an additional CSF compartment and first-order absorption, best described the data. Bioavailability was estimated as 0.48 (95% CI = 0.347-0.775) and the CSF/plasma ratio as 0.32 (95% CI = 0.272-0.409). Allometric weight and postmenstrual age (PMA) scaling was applied; additional covariates included postnatal age (PNA) on clearance and CSF protein on CSF/plasma ratio. CONCLUSIONS: Through this analysis a population pharmacokinetic model has been developed that can be used alongside currently available pharmacodynamic targets to select a neonatal fosfomycin dose based on an infant's PMA, PNA and weight.

Population pharmacokinetics and probability of target attainment in patients with sepsis under renal replacement therapy receiving continuous infusion of meropenem: Sustained low-efficiency dialysis and continuous veno-venous haemodialysis.

AIMS: To describe the population pharmacokinetics (PK) and probability of target attainment (PTA) of continuous infusion (CI) of meropenem in septic patients receiving renal replacement therapy (RRT). METHODS: Fifteen patients without RRT, 13 patients receiving sustained low-efficiency dialysis and 12 patients receiving continuous veno-venous haemodialysis were included. Population PK analysis with Monte Carlo simulations for different dosing regimens was performed. For minimum inhibitory concentration 2 mg/L was chosen. The target was set as 50% time ≥4× minimum inhibitory concentration. RESULTS: The PK of meropenem was best described by a 1-compartment model with linear elimination. Serum creatinine, residual diuresis and time on RRT, with no difference between sustained low-efficiency dialysis and continuous veno-venous haemodialysis, were found to be significant covariates affecting clearance, explaining >20% of the clearance between subject variability. PTA analysis showed that in patients with RRT, 2 g/24 h, meropenem CI achieved a PTA of 95%. In patients without RRT, the target was achieved with 3 g/24 h CI or prolonged infusion of 1 g meropenem over 8 hours but not with bolus application of 1 g meropenem for 8 hours. Only 2 patients (both without RRT) had meropenem concentrations below the target level. However, approximately half of the patients with RRT receiving CI 3 g/24 h meropenem had toxic concentrations. CONCLUSION: We found relevant PK variability for meropenem CI in septic patients with or without RRT, leading to a substantial risk for overdosing in patients with RRT. This finding highlights the strong demand for personalized dosing in critically ill patients.

Population pharmacokinetics of vancomycin in patients with external ventricular drain-associated ventriculitis.

BACKGROUND: To determine the distribution of vancomycin into the cerebrospinal fluid (CSF) in patients with external ventricular drain (EVD)-associated ventriculitis, the pharmacokinetics of vancomycin were evaluated and covariate relationships explored. METHODS: For the population pharmacokinetic model patients were recruited in a neurocritical care unit at the University Hospital of Muenster in the period between January 2014 and June 2015. All patients had a clinical evidence of EVD-associated ventriculitis. Population pharmacokinetic analysis of vancomycin was performed using NONMEM. RESULTS: A total of 184 blood and 133 CSF samples were collected from 29 patients. The final population pharmacokinetic model is a three-compartment model with linear elimination. Creatinine clearance (ClCr ) and CSF-lactate were detected as significant covariates, showing that the total vancomycin plasma clearance (Cl) depends on ClCr and furthermore the clearance (Cldif ) between the central and CSF compartment correlates with CSF lactate concentration. Based on the final model, the following values were estimated by NONMEM: Cl = 5.15 L/h, Q (intercompartmental clearance) = 3.31 L/h, Cldif  = 0.0031 L/h, Vcentral  = 42.1 L, VCSF  = 0.32 L and the value of Vperipheral was fixed to 86.2 L. With the developed pharmacokinetic model, area under the curve (AUC) values as well as CSF trough levels were simulated. CONCLUSION: Based on our analysis, the dosing of vancomycin should be referred to the degree of inflammation (derived from the CSF lactate concentration) and renal function (derived from ClCr ).

Extended Dosing Regimens for Fungal Prophylaxis.

Invasive fungal diseases carry high morbidity and mortality in patients undergoing chemotherapy for hematological malignancies or allogeneic hematopoietic stem cell transplantation. In order to prevent these life-threatening infections, antifungal chemoprophylaxis plays an important role in daily clinical practice. Broad-spectrum antifungal triazoles are widely used but exhibit disadvantages such as relevant drug-drug interactions. Therefore, amphotericin B products or echinocandins can be an alternative in selected patient populations. As these compounds are available as intravenous formulations only, there is growing interest in extended dosing regimens. Although not approved for these agents, this strategy is a rational option, as these compounds have properties suitable for this strategy, including dose-proportional pharmacokinetics, prolonged elimination half-life, and a large therapeutic window. As the use of extended dosing regimens in antifungal prophylaxis is expanding in clinical practice, we reviewed the pharmacokinetic and pharmacodynamic rationale for this strategy, animal model data, dose escalation studies, and clinical trials supporting this concept.

Plasma exposures following posaconazole delayed-release tablets in immunocompromised children and adolescents.

BACKGROUND: Posaconazole is a recommended option for antifungal prophylaxis in paediatric patients >12 years of age. However, little is known about plasma exposures and safety following administration of the delayed-release tablets (DRTs) in children and adolescents. METHODS: In a retrospective observational study, we analysed steady-state trough concentrations of posaconazole in all paediatric patients who had received the DRT formulation between May 2015 and December 2018 for antifungal prophylaxis. Dosing was guided by a published population pharmacokinetic model with weight-based dosing. Drug concentrations in plasma were measured by a validated tandem MS method. Liver function and drug discontinuations due to adverse effects were also assessed. RESULTS: A total of 34 patients (21 male, 13 female; median age 12 years, range 5-17 years; median body weight 43.5 kg, range 16-84 kg) undergoing treatment for haemato-oncological disorders (n=23) or immunosuppression for polyarthritis (n=1) or post-allogeneic HSCT (n=11) received posaconazole DRTs for a median of 70 days (range 9-391 days). The median first steady-state trough plasma concentration following model-derived dosing was 1607 ng/mL (range 501-8485 ng/mL) with trough concentrations being above the dosing target of ≥700 ng/mL in 32/34 patients (94%). Considering all (first and subsequent) trough concentrations, target attainment was 90% (63/70 samples). Posaconazole was well tolerated without adverse event-related discontinuations or breakthrough infections. CONCLUSIONS: Administration of posaconazole DRTs to paediatric patients guided by a population pharmacokinetic-derived dosing algorithm resulted in predictable and potentially effective exposures and was well tolerated over prolonged time periods.

Pharmacokinetic Modeling of Voriconazole To Develop an Alternative Dosing Regimen in Children.

The pharmacokinetic variability of voriconazole (VCZ) in immunocompromised children is high, and adequate exposure, particularly in the first days of therapy, is uncertain. A population pharmacokinetic model was developed to explore VCZ exposure in plasma after alternative dosing regimens. Concentration data were obtained from a pediatric phase II study. Nonlinear mixed effects modeling was used to develop the model. Monte Carlo simulations were performed to test an array of three-times-daily (TID) intravenous dosing regimens in children 2 to 12 years of age. A two-compartment model with first-order absorption, nonlinear Michaelis-Menten elimination, and allometric scaling best described the data (maximal kinetic velocity for nonlinear Michaelis-Menten clearance [Vmax] = 51.5 mg/h/70 kg, central volume of distribution [V1] = 228 liters/70 kg, intercompartmental clearance [Q] = 21.9 liters/h/70 kg, peripheral volume of distribution [V2] = 1,430 liters/70 kg, bioavailability [F] = 59.4%, Km = fixed value of 1.15 mg/liter, absorption rate constant = fixed value of 1.19 h-1). Interindividual variabilities for Vmax, V1, Q, and F were 63.6%, 45.4%, 67%, and 1.34% on a logit scale, respectively, and residual variability was 37.8% (proportional error) and 0.0049 mg/liter (additive error). Monte Carlo simulations of a regimen of 9 mg/kg of body weight TID simulated for 24, 48, and 72 h followed by 8 mg/kg two times daily (BID) resulted in improved early target attainment relative to that with the currently recommended BID dosing regimen but no increased rate of accumulation thereafter. Pharmacokinetic modeling suggests that intravenous TID dosing at 9 mg/kg per dose for up to 3 days may result in a substantially higher percentage of children 2 to 12 years of age with adequate exposure to VCZ early during treatment. Before implementation of this regimen in patients, however, validation of exposure, safety, and tolerability in a carefully designed clinical trial would be needed.

Improving the efficacy of plant-made anti-HIV monoclonal antibodies for clinical use.

Introduction: Broadly neutralising antibodies are promising candidates for preventing and treating Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome (HIV/AIDS), as an alternative to or in combination with antiretroviral therapy (ART). These mAbs bind to sites on the virus essential for virus attachment and entry, thereby inhibiting entry into the host cell. However, the cost and availability of monoclonal antibodies, especially combinations of antibodies, hampers implementation of anti-HIV bNAb therapies in low- to middle- income countries (LMICs) where HIV-1 prevalence is highest. Methods: We have produced three HIV broadly neutralizing antibodies (bNAbs), 10-1074, VRC01 and 3BNC117 in the Nicotiana benthamiana transient expression system. The impact of specific modifications to enhance potency and efficacy were assessed. To prolong half-life and increase bioavailability, a M252Y/S254T/T256E (YTE) or M428L/N434S (LS) mutation was introduced. To increase antibody dependent cellular cytotoxicity (ADCC), we expressed an afucosylated version of each antibody using a glycoengineered plant line. Results: The majority of bNAbs and their variants could be expressed at yields of up to 47 mg/kg. Neither the expression system nor the modifications impacted the neutralization potential of the bNAbs. Afucosylated bNAbs exhibit enhanced ability to bind to FcγRIIIa and trigger ADCC, regardless of the presence of Fc amino acid mutations. Lastly, we demonstrated that Fc-modified variants expressed in plants show enhanced binding to FcRn, which results in a favourable in vivo pharmacokinetic profile compared to their unmodified counterparts. Conclusion: Tobacco plants are suitable expression hosts for anti-HIV bNAbs with increased efficacy and an improved pharmacokinetic profile.

Randomised controlled trial of fosfomycin in neonatal sepsis: pharmacokinetics and safety in relation to sodium overload.

OBJECTIVE: To assess pharmacokinetics and changes to sodium levels in addition to adverse events (AEs) associated with fosfomycin among neonates with clinical sepsis. DESIGN: A single-centre open-label randomised controlled trial. SETTING: Kilifi County Hospital, Kenya. PATIENTS: 120 neonates aged ≤28 days admitted being treated with standard-of-care (SOC) antibiotics for sepsis: ampicillin and gentamicin between March 2018 and February 2019. INTERVENTION: We randomly assigned half the participants to receive additional intravenous then oral fosfomycin at 100 mg/kg two times per day for up to 7 days (SOC-F) and followed up for 28 days. MAIN OUTCOMES AND MEASURES: Serum sodium, AEs and fosfomycin pharmacokinetics. RESULTS: 61 and 59 infants aged 0-23 days were assigned to SOC-F and SOC, respectively. There was no evidence of impact of fosfomycin on serum sodium or gastrointestinal side effects. We observed 35 AEs among 25 SOC-F participants and 50 AEs among 34 SOC participants during 1560 and 1565 infant-days observation, respectively (2.2 vs 3.2 events/100 infant-days; incidence rate difference -0.95 events/100 infant-days (95% CI -2.1 to 0.20)). Four SOC-F and 3 SOC participants died. From 238 pharmacokinetic samples, modelling suggests an intravenous dose of 150 mg/kg two times per day is required for pharmacodynamic target attainment in most children, reduced to 100 mg/kg two times per day in neonates aged <7 days or weighing <1500 g. CONCLUSION AND RELEVANCE: Fosfomycin offers potential as an affordable regimen with a simple dosing schedule for neonatal sepsis. Further research on its safety is needed in larger cohorts of hospitalised neonates, including very preterm neonates or those critically ill. Resistance suppression would only be achieved for the most sensitive of organisms so fosfomycin is recommended to be used in combination with another antimicrobial. TRIAL REGISTRATION NUMBER: NCT03453177.

Diamorphine pharmacokinetics and conversion factor estimates for intranasal diamorphine in paediatric breakthrough pain:systematic review.

BACKGROUND: Intranasal diamorphine is a potential treatment for breakthrough pain but few paediatric data are available to assist dose estimation. AIM: To determine an intranasal diamorphine dose in children through an understanding of pharmacokinetics. DESIGN: A systematic review of the literature was undertaken to seek diamorphine pharmacokinetic parameters in neonates, children and adults. Parenteral and enteral diamorphine bioavailability were reviewed with respect to formation of the major metabolite, morphine. Clinical data quantifying equianalgesic effects of diamorphine and morphine were reviewed. REVIEW SOURCES: PubMed (1960-2020); EMBASE (1980-2020); IPA (1973-2020) and original human research studies that reported diacetylmorphine and metabolite after any dose or route of administration. RESULTS: The systematic review identified 19 studies: 16 in adults and 1 in children and 2 neonatal reports. Details of study participants were extracted. Age ranged from premature neonates to 67 years and weight 1.4-88 kg. Intranasal diamorphine bioavailability was predicted as 50%. The equianalgesic intravenous conversion ratio of morphine:diamorphine was 2:1. There was heterogeneity between pharmacokinetic parameter estimates attributed to routes of administration, lack of size standardisation, methodology and pharmacokinetic analysis. Estimates of the pharmacokinetic parameters clearance and volume of distribution were reduced in neonates. There were insufficient paediatric data to characterise clearance or volume maturation of either diamorphine or its metabolites. CONCLUSIONS: We estimate equianalgesic ratios of intravenous morphine:diamorphine 2:1, intravenous morphine:intranasal diamorphine 1:1 and oral morphine:intranasal diamorphine of 1:3. These ratios are based on adult literature, but are reasonable for deciding on an initial dose of 0.1 mg/kg in children 4-13 years.

Favipiravir and/or nitazoxanide: a randomized, double-blind, 2×2 design, placebo-controlled trial of early therapy in COVID-19 in health workers, their household members, and patients treated at IMSS (FANTAZE).

BACKGROUND: The 2020 pandemic of SARS-CoV-2 causing COVID-19 disease is an unprecedented global emergency. COVID-19 appears to be a disease with an early phase where the virus replicates, coinciding with the first presentation of symptoms, followed by a later 'inflammatory' phase which results in severe disease in some individuals. It is known from other rapidly progressive infections such as sepsis and influenza that early treatment with antimicrobials is associated with a better outcome. The hypothesis is that this holds for COVID-19 and that early antiviral treatment may prevent progression to the later phase of the disease. METHODS: Trial design: Phase IIA randomised, double-blind, 2 × 2 design, placebo-controlled, interventional trial. RANDOMISATION: Participants will be randomised 1:1 by stratification, with the following factors: gender, obesity, symptomatic or asymptomatic, current smoking status presence or absence of comorbidity, and if the participant has or has not been vaccinated. BLINDING: Participants and investigators will both be blinded to treatment allocation (double-blind). DISCUSSION: We propose to conduct a proof-of-principle placebo-controlled clinical trial of favipiravir plus or minus nitazoxanide in health workers, their household members and patients treated at the Mexican Social Security Institute (IMSS) facilities. Participants with or without symptomatic COVID-19 or who tested positive will be assigned to receive favipiravir plus nitazoxanide or favipiravir plus nitazoxanide placebo. The primary outcome will be the difference in the amount of virus ('viral load') in the upper respiratory tract after 5 days of therapy. Secondary outcomes will include hospitalization, major morbidity and mortality, pharmacokinetics, and impact of antiviral therapy on viral genetic mutation rate. If favipiravir with nitazoxanide demonstrates important antiviral effects without significant toxicity, there will be a strong case for a larger trial in people at high risk of hospitalization or intensive care admission, for example older patients and/or those with comorbidities and with early disease. TRIAL REGISTRATION: ClinicalTrials.gov NCT04918927 . Registered on June 9, 2021.

LaTeX tutorial for the standardization and automation of population analysis reports.

Writing population analysis reports that fulfilling the specifications of submission readiness is a time-consuming process and prone to human error. Thus, there is a need to streamline the creation of these reports through elements of standardization and automation. LaTeX is considered a suitable program package capable of creating long, modular, structured documents, and, because of its typographic quality, includes formula typesetting. The presented automation scripts together with easily adjustable LaTeX templates are designed to enable the reader to understand and reproduce a typical workflow from analysis to reporting. The focus of this tutorial is to use an example of a population pharmacokinetic analysis to show how to work with the proposed automated structures allowing even a reader new to the concept of LaTeX to automatize the reporting workflow and customize the templates for their specific needs.

Variation in Target Attainment of Beta-Lactam Antibiotic Dosing Between International Pediatric Formularies.

As antimicrobial susceptibility of common bacterial pathogens decreases, ensuring optimal dosing may preserve the use of older antibiotics in order to limit the spread of resistance to newer agents. Beta-lactams represent the most widely prescribed antibiotic class, yet most were licensed prior to legislation changes mandating their study in children. As a result, significant heterogeneity persists in the pediatric doses used globally, along with quality of evidence used to inform dosing. This review summarizes dosing recommendations from the major pediatric reference sources and tries to answer the questions: Does beta-lactam dose heterogeneity matter? Does it impact pharmacodynamic target attainment? For three important severe clinical infections-pneumonia, sepsis, and meningitis-pharmacokinetic models were identified for common for beta-lactam antibiotics. Real-world demographics were derived from three multicenter point prevalence surveys. Simulation results were compared with minimum inhibitory concentration distributions to inform appropriateness of recommended doses in targeted and empiric treatment. While cephalosporin dosing regimens are largely adequate for target attainment, they also pose the most risk of neurotoxicity. Our review highlights aminopenicillin, piperacillin, and meropenem doses as potentially requiring review/optimization in order to preserve the use of these agents in future.