Interpreting hydroxychloroquine blood levels for medication non-adherence: a pharmacokinetic study.

OBJECTIVE: Characterise the relationship between hydroxychloroquine (HCQ) blood levels and the number of missed doses, accounting for dosage, dose timing and the large variability in pharmacokinetics (PK) between patients. METHODS: We externally validated a published PK model and then conducted dosing simulations. We developed a virtual population of 1000 patients for each dosage across a range of body weights and PK variability. Using the model, 10 Monte Carlo simulations for each patient were conducted to derive predicted whole blood concentrations every hour over 24 hours (240 000 HCQ levels at steady state). To determine the impact of missed doses on levels, we randomly deleted a fixed proportion of doses. RESULTS: For patients receiving HCQ 400 mg daily, simulated random blood levels <200 ng/mL were exceedingly uncommon in fully adherent patients (<0.1%). In comparison, with 80% of doses missed, approximately 60% of concentrations were <200 ng/mL. However, this cut-off was highly insensitive and would miss many instances of severe non-adherence. Average levels quickly dropped to <200 ng/mL after 2-4 days of missed doses. Additionally, mean levels decreased by 29.9% between peak and trough measurements. CONCLUSIONS: We propose an algorithm to optimally interpret HCQ blood levels and approximate the number of missed doses, incorporating the impact of dosage, dose timing and pharmacokinetic variability. No single cut-off has adequate combinations of both sensitivity and specificity, and cut-offs are dependent on the degree of targeted non-adherence. Future studies should measure trough concentrations to better identify target HCQ levels for non-adherence and efficacy.

Abatacept Pharmacokinetics and Exposure Response in Patients Hospitalized With COVID-19: A Secondary Analysis of the ACTIV-1 IM Randomized Clinical Trial.

Importance: The pharmacokinetics of abatacept and the association between abatacept exposure and outcomes in patients with severe COVID-19 are unknown. Objective: To characterize abatacept pharmacokinetics, relate drug exposure with clinical outcomes, and evaluate the need for dosage adjustments. Design, Setting, and Participants: This study is a secondary analysis of data from the ACTIV-1 (Accelerating COVID-19 Therapeutic Interventions and Vaccines) Immune Modulator (IM) randomized clinical trial conducted between October 16, 2020, and December 31, 2021. The trial included hospitalized adults who received abatacept in addition to standard of care for treatment of COVID-19 pneumonia. Data analysis was performed between September 2022 and February 2024. Exposure: Single intravenous infusion of abatacept (10 mg/kg with a maximum dose of 1000 mg). Main Outcomes and Measures: Mortality at day 28 was the primary outcome of interest, and time to recovery at day 28 was the secondary outcome. Drug exposure was assessed using the projected area under the serum concentration time curve over 28 days (AUC0-28). Logistic regression modeling was used to analyze the association between drug exposure and 28-day mortality, adjusted for age, sex, and disease severity. The association between time to recovery and abatacept exposure was examined using Fine-Gray modeling with death as a competing risk, and was adjusted for age, sex, and disease severity. Results: Of the 509 patients who received abatacept, 395 patients with 848 serum samples were included in the population pharmacokinetic analysis. Their median age was 55 (range, 19-89) years and most (250 [63.3%]) were men. Abatacept clearance increased with body weight and more severe disease activity at baseline. Drug exposure was higher in patients who survived vs those who died, with a median AUC0-28 of 21 428 (range, 8462-43 378) mg × h/L vs 18 262 (range, 9628-27 507) mg × h/L (P < .001). Controlling for age, sex, and disease severity, an increase of 5000 units in AUC0-28 was associated with lower odds of mortality at day 28 (OR, 0.52 [95% CI, 0.35-0.79]; P = .002). For an AUC0-28 of 19 400 mg × h/L or less, there was a higher probability of recovery at day 28 (hazard ratio, 2.63 [95% CI, 1.70-4.08] for every 5000-unit increase; P < .001). Controlling for age, sex, and disease severity, every 5000-unit increase in AUC0-28 was also associated with lower odds of a composite safety event at 28 days (OR, 0.46 [95% CI, 0.33-0.63]; P < .001). Using the dosing regimen studied in the ACTIV-1 IM trial, 121 of the 395 patients (30.6%) would not achieve an abatacept exposure of at least 19 400 mg × h/L, particularly at the extremes of body weight. Using a modified, higher-dose regimen, only 12 patients (3.0%) would not achieve the hypothesized target abatacept exposure. Conclusions and Relevance: In this study, patients who were hospitalized with severe COVID-19 and achieved higher projected abatacept exposure had reduced mortality and a higher probability of recovery with fewer safety events. However, abatacept clearance was high in this population, and the current abatacept dosing (10 mg/kg intravenously with a maximum of 1000 mg) may not achieve optimal exposure in all patients. Trial Registration: ClinicalTrials.gov Identifier: NCT04593940.

Comparative Effectiveness of a Second Tumor Necrosis Factor Inhibitor Versus a Non-Tumor Necrosis Factor Biologic in the Treatment of Patients With Polyarticular-Course Juvenile Idiopathic Arthritis.

OBJECTIVE: The objective of this study was to compare the effectiveness of a second tumor necrosis factor inhibitor (TNFi) versus a non-TNFi biologic following discontinuation of a TNFi for patients with polyarticular-course juvenile idiopathic arthritis (pJIA). METHODS: Using the Childhood Arthritis and Rheumatology Research Alliance Registry, patients with pJIA who started receiving a second biologic following a first TNFi were identified. Patients were required to have no active uveitis on the index date and a visit six months after the index date. Outcome measures included Clinical Juvenile Arthritis Disease Activity Score with a maximum of 10 active joints (cJADAS10), cJADAS10 inactive disease (ID; ≤2.5) and cJADAS10 minimal disease activity (MiDA; ≤5). Multiple imputation was used to account for missing data. Adjusted odds ratios (aORs) were calculated using propensity score quintiles to compare outcomes at six months following second biologic initiation. RESULTS: There were 216 patients included, 84% initially received etanercept, and most patients stopped receiving it because of its ineffectiveness (74%). A total of 183 (85%) started receiving a second TNFi, and 33 (15%) started receiving a non-TNFi. Adalimumab was the most common second biologic received (71% overall, 84% of second TNFi), and tocilizumab was the most common non-TNFi second biologic received (9% overall, 58% of non-TNFi). There was no difference between receiving TNFi versus non-TNFi in cJADAS10 ID (29% vs 25%; aOR 1.23, 95% confidence interval [CI] 0.47-3.20) or at least MiDA (43% vs 39%; aOR 1.11, 95% CI 0.47-2.62) at six months. CONCLUSION: Most patients with pJIA started receiving TNFi rather than non-TNFi as their second biologic, and there were no differences in disease activity at six months.

Using Real-World Data to Externally Evaluate Population Pharmacokinetic Models of Dexmedetomidine in Children and Infants.

Dexmedetomidine is a sedative used in both adults and off-label in children with considerable reported pharmacokinetic (PK) interindividual variability affecting drug exposure across populations. Several published models describe the population PKs of dexmedetomidine in neonates, infants, children, and adolescents, though very few have been externally evaluated. A prospective PK dataset of dexmedetomidine plasma concentrations in children and young adults aged 0.01-19.9 years was collected as part of a multicenter opportunistic PK study. A PubMed search of studies reporting dexmedetomidine PK identified five population PK models developed with data from demographically similar children that were selected for external validation. A total of 168 plasma concentrations from 102 children were compared with both population (PRED) and individualized (IPRED) predicted values from each of the five published models by quantitative and visual analyses using NONMEM (v7.3) and R (v4.1.3). Mean percent prediction errors from observed values ranged from -1% to 120% for PRED, and -24% to 60% for IPRED. The model by James et al, which was developed using similar "real-world" data, nearly met the generalizability criteria from IPRED predictions. Other models developed using clinical trial data may have been limited by inclusion/exclusion criteria and a less racially diverse population than this study's opportunistic dataset. The James model may represent a useful, but limited tool for model-informed dosing of hospitalized children.

Opportunistic dried blood spot sampling validates and optimizes a pediatric population pharmacokinetic model of metronidazole.

Pharmacokinetic models rarely undergo external validation in vulnerable populations such as critically ill infants, thereby limiting the accuracy, efficacy, and safety of model-informed dosing in real-world settings. Here, we describe an opportunistic approach using dried blood spots (DBS) to evaluate a population pharmacokinetic model of metronidazole in critically ill preterm infants of gestational age (GA) ≤31 weeks from the Metronidazole Pharmacokinetics in Premature Infants (PTN_METRO, NCT01222585) study. First, we used linear correlation to compare 42 paired DBS and plasma metronidazole concentrations from 21 preterm infants [mean (SD): post natal age 28.0 (21.7) days, GA 26.3 (2.4) weeks]. Using the resulting predictive equation, we estimated plasma metronidazole concentrations (ePlasma) from 399 DBS collected from 122 preterm and term infants [mean (SD): post natal age 16.7 (15.8) days, GA 31.4 (5.1) weeks] from the Antibiotic Safety in Infants with Complicated Intra-Abdominal Infections (SCAMP, NCT01994993) trial. When evaluating the PTN_METRO model using ePlasma from the SCAMP trial, we found that the model generally predicted ePlasma well in preterm infants with GA ≤31 weeks. When including ePlasma from term and preterm infants with GA >31 weeks, the model was optimized using a sigmoidal Emax maturation function of postmenstrual age on clearance and estimated the exponent of weight on volume of distribution. The optimized model supports existing dosing guidelines and adds new data to support a 6-hour dosing interval for infants with postmenstrual age >40 weeks. Using an opportunistic DBS to externally validate and optimize a metronidazole population pharmacokinetic model was feasible and useful in this vulnerable population.

Indomethacin Pharmacokinetics and Pharmacodynamics in Pregnancies With Preterm Labor: The Need for Dose-Ranging Trials.

The use of indomethacin to delay delivery in preterm labor (PTL) is widely accepted; however, the optimal dosage of indomethacin in pregnancy is unknown. Here, we perform population pharmacokinetic (PK) and pharmacodynamic (PD) analyses, characterize the plasma disposition of indomethacin in pregnant women with PTL, and relate indomethacin exposure to delayed delivery and maternal/neonatal safety. We analyzed plasma and urine samples collected from a multicenter, prospective, opportunistic PK/PD study of indomethacin in pregnant women 12-32 weeks gestation admitted with PTL. Ninety-four participants with 639 plasma concentrations for indomethacin were included in the analysis. The final population PK (popPK) model for indomethacin was a 2-compartment structural model with first-order absorption and elimination and a covariate effect of body mass index on apparent oral clearance. We observed a 21%-60% increase in apparent oral clearance observed during pregnancy. There was no clear association between indomethacin exposure and maternal or neonatal safety outcomes, or with the magnitude of delayed delivery; however, 96.7% of women treated with indomethacin had a delivery that was delayed at least 48 hours. Given the changes to indomethacin apparent oral clearance during pregnancy, and the lack of relationship between indomethacin exposure and safety, dose-finding studies of indomethacin in pregnant women with PTL may help clarify the most safe and efficacious dosage and duration of indomethacin.

Azathioprine metabolite levels and outcomes during pregnancies with rheumatic disease.

OBJECTIVE: Despite widespread use of azathioprine (AZA) during pregnancy, no studies evaluated the impact of pregnancy on AZA metabolites 6-thioguanine nucleotide (6-TGN) and 6-methylmercaptopurine nucleotide (6-MMPN) disposition in rheumatic diseases. This study characterises changes in AZA metabolite concentrations throughout pregnancy in women with rheumatic disease and explores relationships between metabolite concentrations, maternal disease activity, and neonatal outcomes. METHODS: Patients with rheumatic disease from a single centre prescribed AZA prior to pregnancy and ≥1 blood sample during pregnancy (5/2016 to 4/2022) were included. Commercial laboratories quantified AZA metabolite concentrations. The upper safety limit for 6-MMPN was >5700 pmol/8×108 RBC. The therapeutic target for 6-TGN was ≥159 pmol/8×108 RBC. Repeated correlation measures were used to evaluate the relationship between metabolite concentrations and pregnancy duration, and the relationship between 6-TGN concentration and SLE Physician Global Assessment (PGA). The relationship between pregnancy average 6-TGN and neonatal gestational age at birth was analysed using linear regression. RESULTS: Thirty-seven pregnancies in 35 women with 108 serum samples were included. There was no significant difference in dose-adjusted 6-TGN concentrations across pregnancy and peripartum, whereas 6-MMPN concentrations appeared higher during pregnancy. No elevated transaminases or cholestasis were observed concurrently with 6-MMPN above 5700 pmol/8×108 RBC. Metabolite concentrations were related to total AZA dosage, weight-based dosage and TPMT phenotype. In pregnant women with SLE achieving average 6-TGN in the therapeutic range, we observed a non-significant reduction in PGA and increase in neonatal gestational age at birth. CONCLUSIONS: In this exploratory study, we did not observe systematic changes in 6-TGN concentrations throughout pregnancy and peripartum, whereas 6-MMPN concentrations were higher during pregnancy. Monitoring AZA metabolite concentrations in pregnancy is a potential tool to identify medication non-adherence as well as patients with high 6-MMPN in whom dosage adjustment or close laboratory monitoring may optimise safety.

Pharmacokinetics of Oral Vitamin D in Children with Obesity and Asthma.

BACKGROUND AND OBJECTIVE: Vitamin D insufficiency is common in several pediatric diseases including obesity and asthma. Little data exist describing the pharmacokinetics of oral vitamin D in children or the optimal dosing to achieve therapeutic 25(OH)D targets. Describe the pharmacokinetics of oral Vitamin D in children with asthma. METHODS: This was a multi-center, randomized, open-label, oral supplementation study to describe the pharmacokinetics of vitamin D in children aged 6-17 years who have asthma and were overweight/obese. Participants had a serum 25(OH)D concentration between 10 and < 30 ng/mL at baseline. In Part 1 of the study, we assessed four 16-week dosing regimens for their ability to achieve 25(OH)D concentrations ≥ 40 ng/mL. Using serial serum 25(OH)D sampling over 28 weeks, we created a population pharmacokinetic model and performed dosing simulations to achieve 25(OH)D concentrations ≥ 40 ng/mL. In Part 2, the optimal regimen chosen from Part 1 was compared (2:1) to a standard-of-care control dose (600 international units [IU] daily) over 16 weeks. A final population pharmacokinetic model using both parts was developed to perform dosing simulations and determine important co-variates in the pharmacokinetics of vitamin D. RESULTS: Based on empiric and simulation data, the daily dose of 8000 IU and a loading dose of 50,000 IU were chosen; this regimen raised 25(OH)D concentrations above 40 ng/mL in the majority of participants while avoiding concentrations > 100 ng/mL. A 50,000-IU loading dose led to faster achievement of 25(OH)D therapeutic concentrations (≥ 40 ng/mL). The estimated median (5th-95th percentiles) apparent clearance of vitamin D from the final population pharmacokinetic model was 0.181 (0.155-0.206) L/h. The body mass index z-score was a significant covariate on apparent clearance and was associated with a significantly decreased median half-life in 25(OH)D (body mass index z-score 1.00-1.99: 97.7 days, body mass index z-score 2.00-2.99: 65.9 days, body mass index z-score ≥ 3.00: 39.1 days, p < 0.001). CONCLUSIONS: Obesity impacts vitamin D clearance and the half-life, but serum concentrations > 40 ng/mL can be reached in most children using a loading dose of 50,000 IU followed by a daily dose of 8000 IU. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier number NCT03686150.

Using Pharmacokinetic Modeling and Electronic Health Record Data to Predict Clinical and Safety Outcomes after Methylprednisolone Exposure during Cardiopulmonary Bypass in Neonates.

Background: Infants undergoing cardiac surgery with cardiopulmonary bypass (CPB) frequently receive intraoperative methylprednisolone (MP) to suppress CPB-related inflammation; however, the optimal dosing strategy and efficacy of MP remain unclear. Methods: We retrospectively analyzed all infants under 90 days-old who received intra-operative MP for cardiac surgery with CPB from 2014-2017 at our institution. We combined real-world dosing data from the electronic health record (EHR) and two previously developed population pharmacokinetic/pharmacodynamic models to simulate peak concentration (Cmax) and area under the concentration-time curve for 24 h (AUC24) for MP and the inflammatory cytokines interleukin-6 (IL-6) and interleukin-10 (IL-10). We evaluated the relationships between post-operative, safety, and other clinical outcomes obtained from the EHR with each predicted exposure using non-parametric tests. Results: A total of 142 infants with median post-natal age 8 (interquartile range [IQR]: 5, 37) days received a total dose of 30 (19, 49) mg/kg of MP. Twelve (8%) died, 37 (26%) met the composite post-operative outcome, 114 (80%) met the composite safety outcome, and 23 (16%) had a major complication. Predicted median Cmax and AUC24 IL-6 exposure was significantly higher for infants meeting the composite post-operative outcome and those with major complications. Predicted median Cmax and AUC24 MP exposure was significantly higher for infants requiring insulin. No exposure was associated with death or other safety outcomes. Conclusions: Pro-inflammatory IL-6, but not MP exposure, was associated with post-operative organ dysfunction, suggesting current MP dosing may not adequately suppress IL-6 or increase IL-10 to impact clinical outcomes. Prospective study will be required to define the optimal exposure-efficacy and exposure-safety profiles in these infants.

Occurrence of adverse events and change in disease activity after initiation of etanercept in paediatric patients with juvenile psoriatic arthritis in the CARRA Registry.

OBJECTIVE: Etanercept is commonly used to treat juvenile idiopathic arthritis, including juvenile psoriatic arthritis (JPsA); however, information on etanercept's safety and effectiveness in clinical practice is limited. We used data from the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry to evaluate etanercept's safety and effectiveness in JPsA in clinical practice. METHODS: We analysed safety and effectiveness data for paediatric patients enrolled in the CARRA Registry who had a JPsA diagnosis and had used etanercept. Safety was assessed by calculating rates of prespecified adverse events of special interest (AESIs) and serious adverse events (SAEs). Effectiveness was assessed by a variety of disease activity measures. RESULTS: Overall, 226 patients had JPsA and received etanercept; 191 met criteria for safety analysis and 43 met criteria for effectiveness analysis. AESI and SAE incidence rates were low. There were five events: three uveitis, one new-onset neuropathy and one malignancy. Incidence rates were 0.55 (95% CI: 0.18, 1.69), 0.18 (95% CI: 0.03, 1.29) and 0.13 (95% CI: 0.02, 0.09) per 100 patient-years for uveitis, neuropathy and malignancy, respectively. Etanercept showed effectiveness for JPsA treatment; 7 of 15 (46.7%) had an American College of Rheumatology-Pediatric Response 90, 9 of 25 (36.0%) had a clinical Juvenile Arthritis Disease Activity Score 10-joint ≤1.1 and 14 of 27 (51.9%) had clinically inactive disease at the 6-month follow-up. CONCLUSION: Data in the CARRA Registry showed that etanercept treatment was safe in treating children with JPsA, with low AESIs and SAEs. Etanercept was also effective, even when assessed in a small sample size.

Population Pharmacokinetics of Piperacillin/Tazobactam Across the Adult Lifespan.

BACKGROUND AND OBJECTIVE: Piperacillin/tazobactam is one of the most frequently used antimicrobials in older adults. Using an opportunistic study design, we evaluated the pharmacokinetics of piperacillin/tazobactam as a probe drug to evaluate changes in antibacterial drug exposure and dosing requirements, including in older adults. METHODS: A total of 121 adult patients were included. The population pharmacokinetic models that best characterized the observed plasma concentrations of piperacillin and tazobactam were one-compartment structural models with zero-order input and linear elimination. RESULTS: Among all potential covariates, estimated creatinine clearance had the most substantial impact on the elimination clearance for both piperacillin and tazobactam. After accounting for renal function and body size, there was no remaining impact of frailty on the pharmacokinetics of piperacillin and tazobactam. Monte Carlo simulations indicated that renal function had a greater impact on the therapeutic target attainment than age, although these covariates were highly correlated. Frailty, using the Canadian Study of Health and Aging Clinical Frailty Scale, was assessed in 60 patients who were ≥ 65 years of age. CONCLUSIONS: The simulations suggested that adults ≤ 50 years of age infected with organisms with higher minimum inhibitory concentrations may benefit from continuous piperacillin/tazobactam infusions (12 g/day of piperacillin component) or extended infusions of 4 g every 8 hours. However, for a target of 50% fT + minimum inhibitory concentration, dosing based on renal function is generally preferable to dosing by age, and simulations suggested that patients with creatinine clearance ≥ 120 mL/min may benefit from infusions of 4 g every 8 hours for organisms with higher minimum inhibitory concentrations.

Dosing Variation at Initiation of Adalimumab and Etanercept and Clinical Outcomes in Juvenile Idiopathic Arthritis: A Childhood Arthritis and Rheumatology Research Alliance Registry Study.

OBJECTIVE: To determine the dose-response relationship of tumor necrosis factor (TNF) inhibition in the treatment of juvenile idiopathic arthritis (JIA). METHODS: Participants of the Childhood Arthritis and Rheumatology Research Alliance Registry were eligible for inclusion in the analyses if they started TNF inhibition treatment for JIA. The primary treatment response was determined 3 to 7 months after the start of treatment, based on the JIA American College of Rheumatology Pediatric criteria for improvement, clinical Juvenile Arthritis Disease Activity Score, and persistence of treatment after 6 months. Subsequently, pooled logistic regression models were performed to include long-term follow-up data. The models were adjusted for risk factors associated with poor treatment response. Dosing was expressed by body weight, body surface area, ideal body weight, fat free mass, and lean body mass. RESULTS: Participants treated with adalimumab (n = 328) and etanercept (n = 437) were included in the analyses (median dose 0.82 mg/kg body weight [interquartile range (IQR) 0.66-1.04] and 0.83 mg/kg body weight [IQR 0.75-0.95], respectively). The majority of analyses did not show a relationship between dose and outcome. Where associations were found, results were conflicting. Alternative dosing characteristics based on ideal body weight, fat free mass, and lean body mass did not result in stronger or more consistent associations. CONCLUSION: This study was not able to confirm our hypothesis that increased dosing of TNF inhibitors results in improved treatment outcomes. Although adjustment was performed for risk factors of impaired treatment response, residual confounding by indication likely explains the negative associations found in this study.

Extrapolation of Adult Efficacy Data to Pediatric Systemic Lupus Erythematosus: Evaluating Similarities in Exposure-Response.

To streamline drug development, the United States Food and Drug Administration (FDA) can consider the extrapolation of adult efficacy data to children when the disease and drug effects are sufficiently similar. This study explored whether the relationship between drug exposure and response for selected drugs in systemic lupus erythematosus (SLE) was sufficiently similar to support a consideration of the extrapolation of adult efficacy data to children of ≥5 years of age. An exposure-response analysis of drugs used to treat SLE was conducted using published exposure versus response and efficacy versus time data. Statistical analyses included noncompartmental analysis of a drug's area under the effect curve and direct Imax pharmacodynamic (PD) modeling. Six drugs were included: azathioprine, belimumab, cyclophosphamide, hydroxychloroquine, mycophenolate/mycophenolic acid, and rituximab. For belimumab, the net change in responders at week 52 (the primary end point) was nearly identical between 1 adult trial and the pediatric trial. For mycophenolate, PD modeling suggested no significant differences in exposure and SLE disease activity between adults and children. For azathioprine, cyclophosphamide, hydroxychloroquine, and rituximab the data were not sufficient to quantitatively characterize the exposure-response relationship, but the clinical or pharmacologic response between children and adults was similar overall. Adult SLE data should be leveraged to guide pediatric drug development programs and identify areas with residual uncertainty regarding the effectiveness or safety of a drug in children. The degree to which efficacy extrapolation can reduce clinical trial requirements in pediatric SLE should be individualized for each new drug product, depending in part on the mechanism of action of the drug and the similarity of disease manifestations in children and adults.

Pharmacokinetics of hydroxychloroquine in paediatric lupus: data from a novel, direct-to-family clinical trial.

OBJECTIVE: Determine the pharmacokinetics (PK) and exposure-response of hydroxychloroquine (HCQ) and desethylhydroxychloroquine (DHCQ) in paediatric SLE (pSLE). METHODS: We conducted an exploratory phase 2, direct-to-family trial. Children enrolled in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry with a diagnosis of pSLE were eligible if they were receiving HCQ as standard of care for ≥3 months. Biological samples were collected at up to four visits over a 6-month period. At each visit, plasma was obtained to measure the concentrations of HCQ and DHCQ, as well as cytokines. HCQ and DHCQ plasma PK data were analysed using a population PK modelling approach. RESULTS: Twenty-five subjects provided a total of 88 plasma concentrations for PK analysis. There was a poor linear fit between HCQ concentrations and total body weight (R2=0.03). There was a decline in both interferon (IFN)-alpha and IFN-gamma with higher concentrations of HCQ and DHCQ. Volume of distribution for HCQ in plasma was higher in children compared with published values in adults (73 000 L vs 44 000 L), but clearance values in children were similar to adults. CONCLUSIONS: We report the first population PK model for HCQ and DHCQ in children using data from a novel direct-to-family clinical trial. We observed high interindividual variability in HCQ PK and found that weight-based dosing for HCQ is poorly correlated with drug concentrations, suggesting the need to use therapeutic drug monitoring to individualise dosing. Furthermore, our results suggest that the current weight-based dosing paradigm for HCQ may result in suboptimal drug exposures, particularly for children with obesity. Accordingly, additional studies of HCQ are needed in pSLE to determine the optimal drug concentration and dosing to reduce disease activity and improve outcomes. TRIAL REGISTRATION NUMBER: NCT04358302.

Safety of Ceftazidime-Avibactam in Combination with Aztreonam (COMBINE) in a Phase I, Open-Label Study in Healthy Adult Volunteers.

This phase I study evaluated the safety of the optimal ceftazidime-avibactam (CZA) with aztreonam (ATM) regimens identified in hollow fiber infection models of MBL-producing Enterobacterales. Eligible healthy subjects aged 18 to 45 years were assigned to one of six cohorts: 2.5 g CZA over 2 h every 8 h (approved dose), CZA continuous infusion (CI) (7.5 g daily), 2 g ATM over 2 h every 6 h, ATM CI (8 g daily), CZA (approved dose) with 1.5 g ATM over 2 h every 6 h, and CZA (approved dose) with 2 g ATM over 2 h every 6 h. Study drug(s) were administered for 7 days. The most frequently observed adverse events (AEs) were hepatic aminotransferase (ALT/AST) elevations (n = 19 subjects). Seventeen of the 19 subjects with ALT/AST elevations received ATM alone or CZA-ATM. The incidence of ALT/AST elevations was comparable between the ATM-alone and CZA-ATM cohorts. Two subjects in the ATM CI cohort experienced severe ALT/AST elevation AEs. All subjects with ALT/AST elevations were asymptomatic with no other findings suggestive of liver injury. Most other AEs were of mild to moderate severity and were similar across cohorts, except for prolonged prothrombin time (more frequent in CZA-ATM cohorts). These results suggest that CZA-ATM administered as 2-h intermittent infusions is safe and that some caution should be exercised with the use of ATM CI at an ATM dose of 8 g daily. If CZA-ATM is prescribed, clinicians are advised to monitor liver function, hematologic, and coagulation parameters. Future controlled studies are required to better define the safety and efficacy of the CZA-ATM regimens evaluated in this phase I study.

Pharmacokinetics of Ceftazidime-Avibactam in Combination with Aztreonam (COMBINE) in a Phase 1, Open-Label Study of Healthy Adults.

Scant pharmacokinetic (PK) data are available on ceftazidime-avibactam (CZA) and aztreonam (ATM) in combination, and it is unknown if CZA-ATM exacerbates alanine aminotransferase (ALT)/aspartate aminotransferase (AST) elevations relative to ATM alone. This phase 1 study sought to describe the PK of CZA-ATM and assess the associations between ATM exposures and ALT/AST elevations. Subjects (n = 48) were assigned to one of six cohorts (intermittent infusion [II] CZA, continuous infusion [CI] CZA, II ATM, CI ATM [8 g/daily], II CZA with II ATM [6 g/daily], and II CZA with II ATM [8 g/daily]), and study product(s) were administered for 7 days. A total of 19 subjects (40%) had ALT/AST elevations, and most (89%) occurred in the ATM/CZA-ATM cohorts. Two subjects in the CI ATM cohort experienced severe ALT/AST elevations, which halted the study. All subjects with ALT/AST elevations were asymptomatic with no other signs of liver injury, and all ALT/AST elevations resolved without sequalae after cessation of dosing. In the population PK (PopPK) analyses, CZA-ATM administration reduced total ATM clearance by 16%, had a negligible effect on total ceftazidime clearance, and was not a covariate in the avibactam PopPK model. In the exposure-response analyses, coadministration of CZA-ATM was not found to augment ALT/AST elevations. Modest associations were observed between ATM exposure (maximum concentration of drug in serum [Cmax] and area under the concentration-time curve [AUC]) and ALT/AST elevations in the analysis of subjects in the II ATM/CZA-ATM cohorts. The findings suggest that administration of CZA-ATM reduces ATM clearance but does not exacerbate AST/ALT elevations relative to ATM alone. The results also indicate that CI ATM should be used with caution.

Exposure-safety relationship for acyclovir in the treatment of neonatal herpes simplex virus disease.

BACKGROUND: Neonatal herpes simplex virus (HSV) disease has been treated with high-dose (20 mg/kg/dose) acyclovir since 1991. AIMS: Determine the safety of acyclovir in infants with neonatal HSV treated with high-dose acyclovir; examine the association between acyclovir dose and exposure with adverse events (AEs). STUDY DESIGN: We obtained demographic information and acyclovir dosing via medical records. Acyclovir exposure was calculated using an established pharmacokinetic model. SUBJECTS: Infants <120 days of age with neonatal HSV discharged from four academic children's hospitals. OUTCOME MEASURES: We identified clinical and laboratory adverse events (AEs). RESULTS AND CONCLUSIONS: We identified 49 infants with neonatal HSV treated with acyclovir; 42 infants had complete 21-day dosing information. Median mean daily dose was 59 mg/kg/day. Clinical AEs were common among all gestational and postnatal age groups. Rash was the most common clinical AE (37 %). Mild laboratory AEs occurred in 2-37 % of infants. The median maximum doses (mg/kg/day) were higher among infants with hypokalemia, elevated blood urea nitrogen, and thrombocytosis. For all other laboratory AEs, the median maximum doses for infants without events were higher or equal to the median maximum dose of infants with the AE. The odds of experiencing any clinical or laboratory AE did not differ by predicted acyclovir exposure for either area under the curve (AUC) or maximum concentration (Cmax) (odds ratio [OR] = 1.00 [0.98, 1.03] and OR = 1.01 [0.93, 1.12], respectively). Although AEs were common with high-dose acyclovir exposure, severe AEs were rare. Acyclovir exposure was not associated with AEs.

Characterizing Pharmacokinetics in Children With Obesity-Physiological, Drug, Patient, and Methodological Considerations.

Childhood obesity is an alarming public health problem. The pediatric obesity rate has quadrupled in the past 30 years, and currently nearly 20% of United States children and 9% of children worldwide are classified as obese. Drug distribution and elimination processes, which determine drug exposure (and thus dosing), can vary significantly between patients with and without obesity. Obesity-related physiological changes, such as increased tissue volume and perfusion, altered blood protein concentrations, and tissue composition can greatly affect a drug's volume of distribution, which might necessitate adjustment in loading doses. Obesity-related changes in the drug eliminating organs, such as altered enzyme activity in the liver and glomerular filtration rate, can affect the rate of drug elimination, which may warrant an adjustment in the maintenance dosing rate. Although weight-based dosing (i.e., in mg/kg) is commonly practiced in pediatrics, choice of the right body size metric (e.g., total body weight, lean body weight, body surface area, etc.) for dosing children with obesity still remains a question. To address this gap, the interplay between obesity-related physiological changes (e.g., altered organ size, composition, and function), and drug-specific properties (e.g., lipophilicity and elimination pathway) needs to be characterized in a quantitative framework. Additionally, methodological considerations, such as adequate sample size and optimal sampling scheme, should also be considered to ensure accurate and precise top-down covariate selection, particularly when designing opportunistic studies in pediatric drug development. Further factors affecting dosing, including existing dosing recommendations, target therapeutic ranges, dose capping, and formulations constraints, are also important to consider when undergoing dose selection for children with obesity. Opportunities to bridge the dosing knowledge gap in children with obesity include modeling and simulating techniques (i.e., population pharmacokinetic and physiologically-based pharmacokinetic [PBPK] modeling), opportunistic clinical data, and real world data. In this review, key considerations related to physiology, drug parameters, patient factors, and methodology that need to be accounted for while studying the influence of obesity on pharmacokinetics in children are highlighted and discussed. Future studies will need to leverage these modeling opportunities to better describe drug exposure in children with obesity as the childhood obesity epidemic continues.

External Evaluation of Risperidone Population Pharmacokinetic Models Using Opportunistic Pediatric Data.

Risperidone is approved to treat schizophrenia in adolescents and autistic disorder and bipolar mania in children and adolescents. It is also used off-label in younger children for various psychiatric disorders. Several population pharmacokinetic models of risperidone and 9-OH-risperidone have been published. The objectives of this study were to assess whether opportunistically collected pediatric data can be used to evaluate risperidone population pharmacokinetic models externally and to identify a robust model for precision dosing in children. A total of 103 concentrations of risperidone and 112 concentrations of 9-OH-risperidone, collected from 62 pediatric patients (0.16-16.8 years of age), were used in the present study. The predictive performance of five published population pharmacokinetic models (four joint parent-metabolite models and one parent only) was assessed for accuracy and precision of the predictions using statistical criteria, goodness of fit plots, prediction-corrected visual predictive checks (pcVPCs), and normalized prediction distribution errors (NPDEs). The tested models produced similarly precise predictions (Root Mean Square Error [RMSE]) ranging from 0.021 to 0.027 nmol/ml for risperidone and 0.053-0.065 nmol/ml for 9-OH-risperidone). However, one of the models (a one-compartment mixture model with clearance estimated for three subpopulations) developed with a rich dataset presented fewer biases (Mean Percent Error [MPE, %] of 1.0% vs. 101.4, 146.9, 260.4, and 292.4%) for risperidone. In contrast, a model developed with fewer data and a more similar population to the one used for the external evaluation presented fewer biases for 9-OH-risperidone (MPE: 17% vs. 69.9, 47.8, and 82.9%). None of the models evaluated seemed to be generalizable to the population used in this analysis. All the models had a modest predictive performance, potentially suggesting that sources of inter-individual variability were not entirely captured and that opportunistic data from a highly heterogeneous population are likely not the most appropriate data to evaluate risperidone models externally.