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Supplemental Table 1. IMC-A12 trough serum concentrations during cycle 1 and cycle 2

Supplemental Figure 1. Graph of IMC-A12 trough serum concentrations versus time.

Purpose: To determine the MTD, dose-limiting toxicities (DLT), pharmacokinetics, and biologic effects of cixutumumab administered in combination with temsirolimus to children with refractory solid tumors.Experimental Design: Cixutumumab and temsirolimus were administered intravenously once every 7 days in 28-day cycles. Pharmacokinetic and biology studies, including assessment of mTOR downstream targets in peripheral blood mononuclear cells, were performed during the first cycle.Results: Thirty-nine patients, median age 11.8 years (range, 1–21.5), with recurrent solid or central nervous system tumors were enrolled, of whom 33 were fully assessable for toxicity. There were four dose levels, which included two dose reductions and a subsequent intermediated dose escalation: (i) IMC-A12 6 mg/kg, temsirolimus 15 mg/m2; (ii) IMC-A12 6 mg/kg, temsirolimus 10 mg/m2; (iii) IMC-A12 4 mg/kg, temsirolimus 8 mg/m2; and (iv) IMC-A12 6 mg/kg, temsirolimus 8 mg/m2. Mucositis was the predominant DLT. Other DLTs included hypercholesterolemia, fatigue, thrombocytopenia, and increased alanine aminotransferase. Target inhibition (decreased S6K1 and PAkt) in peripheral blood mononuclear cells was noted at all dose levels. Marked interpatient variability in temsirolimus pharmacokinetic parameters was noted. At 8 mg/m2, the median temsirolimus AUC was 2,946 ng • h/mL (range, 937–5,536) with a median sirolimus AUC of 767 ng • h/mL (range, 245–3,675).Conclusions: The recommended pediatric phase II doses for the combination of cixutumumab and temsirolimus are 6 mg/kg and 8 mg/m2, respectively. Clin Cancer Res; 21(7); 1558–65. ©2014 AACR.

Introduction: Early sepsis results in pharmacokinetic (PK) changes due to physiologic alterations. PK changes can lead to suboptimal drug target attainment, risking inadequate coverage from antibiotics like ceftriaxone. Little is known about how ceftriaxone PK and target attainment quantitatively change over time in patients with sepsis or the association between target attainment and outcomes in critically ill children and young adults. Methods: A retrospective analysis of a prospective study was conducted in a single-center pediatric intensive care unit. Septic patients given at least one ceftriaxone dose (commonly as 50 mg/kg every 12 h) and who had blood obtained in both the first 48 h of therapy (early) and afterwards (late) were included. Normalized clearance and central volume were estimated and compared in both sepsis phases. We evaluated target attainment, defined as concentrations above 1× or 4× the minimum inhibitory concentration (MIC) for 100% of dosing intervals, and investigated the association between target attainment and clinical outcomes. Results: Fifty-five septic patients (median age: 7.5 years) were included. Normalized clearance and central volume were similar in both phases (6.18 ± 1.48 L/h/70 kg early vs. 6.10 ± 1.61 L/h/70 kg late, p = 0.60; 26.6 [IQR 22.3, 31.3] L/70 kg early vs. 24.5 [IQR 22.0, 29.4] L/70 kg late, p = 0.18). Individual percent differences in normalized clearance and central volume between sepsis phases ranged from −39% to 276% and −51% to 212% (reference, late sepsis), respectively. Fewer patients attained the 1× MIC target in late sepsis (82% late vs. 96% early, p = 0.013), which was associated with transition to once daily dosing, typically done due to transfer from the pediatric intensive care unit (PICU) to a lower acuity unit. Failure to attain either target in late sepsis was associated with antibiotic broadening. Conclusion: Ceftriaxone PK parameters were similar between early and late sepsis, but there were large individual differences. Fewer patients attained MIC targets in late sepsis and all who did not attain the less stringent target received once daily dosing during this period. The failure to attain targets in late sepsis was associated with antibiotic broadening and could be an area for antibiotic stewardship intervention.

BACKGROUND: Antibodies to infliximab (ATI) are associated with secondary loss of response and increased risk for drug reactions. Limited studies have associated ATI with increased infliximab clearance. AIMS: We assessed the impact of ATI on infliximab clearance and loss of response in an inception paediatric Crohn’s disease cohort with 1-year follow-up. METHODS: This multi-centre prospective cohort study collected peak and trough serum infliximab/ATI concentrations from 660 infusions (78 patients) during the first year of therapy. Clinicians were blinded to these research labs. The primary outcome was the difference in infliximab clearance between ATI-positive (ATI) and ATI-negative (no-ATI) patients. Secondary outcomes included pre-treatment predictors of ATI (including HLA-DQA1 genotyping). Clinical remission, loss of response and infliximab clearance were compared between pre-ATI, during ATI and following ATI resolution with MANOVA. Time to ATI was calculated by Cox proportional Hazards model. RESULTS: ATI were detected in 68% (53/78) patients with a median concentration of 76 ng/mL (range 23–1828). Maximum ATI concentration was 6 and starting dose

Low‐dose methotrexate (MTX) is a first‐line therapy for the treatment of arthritis. However, there is considerable interindividual variability in MTX exposure following standard dosing. Polymorphisms in SLCO1B1 significantly effect MTX clearance, altering therapeutic response. One decreased function variant, rs4149056 (c.521T>C, Val174Ala), slows MTX clearance and in vitro uptake of MTX. This phenotype was recapitulated in a mouse model using a knockout (KO) of the murine orthologue, Slco1b2. Our objective was to investigate the impact of this phenotype on the pharmacokinetics and therapeutic outcomes of low‐dose MTX in a murine model of collagen‐induced arthritis (CIA). We evaluated response to MTX in mice with CIA using wildtype (WT), heterozygous, and KO Slco1b2 mice on a DBA1/J background. Arthritis was macroscopically evaluated daily to quantify disease progression. Mice received 2 mg/kg or a pharmacogenetically guided MTX dose subcutaneously 3 times a week for 2 weeks. MTX concentrations were collected at the end of the study and exposure (day*µM) was estimated using a two‐compartment model. Mice displayed a seven‐fold range in MTX exposure and revealed a significant exposure‐response relationship (p = 0.0027). KO mice receiving the 2 mg/kg dosing regimen had 2.3‐fold greater exposure to MTX (p < 0.0001) and a 66% reduction in overall disease progression (p = 0.011) compared to WT mice. However, exposure and response were equivalent when pharmacogenetically guided dosing was used. These studies demonstrate that an exposure‐response relationship exists for MTX and that Slco1b2 genotype affects MTX exposure and therapeutic response. Such evidence supports the use of SLCO1B1‐pharmacogenetic dosing of low‐dose MTX for patients with arthritis.

Lay Summary It is increasingly recognized that inconsistent biologic therapeutic response is related to pharmacokinetic variability (drug clearance) between patients. This study highlights a multidisciplinary effort to integrate a precision dosing dashboard within the electronic health record to individualize biologic exposure starting and during induction.

Background Piperacillin/tazobactam, a commonly used antibiotic, is associated with acute kidney injury (AKI). The relationship between piperacillin concentrations and AKI remains unknown. Objective Estimate piperacillin exposures in critically ill children and young adults administered piperacillin/tazobactam to identify concentrations and clinical factors associated with piperacillin-associated AKI. Patients and methods We assessed piperacillin pharmacokinetics in 107 patients admitted to the paediatric ICU who received at least one dose of piperacillin/tazobactam. Piperacillin AUC, highest peak (Cmax) and highest trough (Cmin) in the first 24 hours of therapy were estimated. Piperacillin-associated AKI was defined as Kidney Disease: Improving Global Outcomes (KDIGO) Stage 2/3 AKI present >24 hours after initial piperacillin/tazobactam dose. Likelihood of piperacillin-associated AKI was rated using the Naranjo Adverse Drug Reaction Probability Scale. Multivariable logistic regression was performed to identify patient and clinical predictors of piperacillin-associated AKI. Results Out of 107 patients, 16 (15%) were rated as possibly or probably having piperacillin-associated AKI. Estimated AUC and highest Cmin in the first 24 hours were higher in patients with piperacillin-associated AKI (2042 versus 1445 mg*h/L, P = 0.03; 50.1 versus 10.7 mg/L, P Conclusions We show a relationship between estimated piperacillin AUC and highest Cmin in the first 24 hours of piperacillin/tazobactam therapy and piperacillin-associated AKI, suggesting total piperacillin exposure early in the course is associated with AKI development. These data could serve as the foundation for implementation of model-informed precision dosing to reduce AKI incidence in patients given piperacillin/tazobactam.

AIMS We studied melphalan pharmacokinetics (PK) and feasibility of melphalan full-dose adjustment based on test-dose PK in children and young adults with non-malignant disorders (NMD) undergoing allogeneic hematopoietic cell transplantation (HCT) using reduced intensity conditioning (RIC) containing alemtuzumab, fludarabine and melphalan. METHODS Patients received test-dose melphalan (10% of planned full-dose) prior to conditioning. Blood samples for PK were obtained around test and full-dose melphalan (140 mg/m2 or 4.7 mg/kg in patients

Neurologic complications are common in patients with sickle cell anemia (SCA), but conventional tools such as MRI and transcranial Doppler ultrasonography (TCD) do not fully assess cerebrovascular pathology. Cerebral tissue oximetry measures mixed oxygen saturation in the frontal lobes (SCT O2 ) and provides early prognostic information about tissue at risk of ischemic injury. Untreated patients with SCA have significantly lower SCT O2 than healthy controls that declines with age. Hydroxyurea is effective in preventing many SCA-related complications, but the degree to which it preserves normal neurophysiology is unclear. We analyzed participants enrolled in the Therapeutic Response Evaluation and Adherence Trial (TREAT, NCT02286154), which enrolled participants initiating hydroxyurea using individualized dosing (New Cohort) and those previously taking hydroxyurea (Old Cohort) and was designed to monitor the long-term benefits of hydroxyurea. Cerebral oximetry was performed at baseline and annually. For the New Cohort (median starting age = 12 months, n = 55), mean baseline SCT O2 was normal before starting hydroxyurea (mean 65%, 95% CI 58-72%) and significantly increased after two years (mean 72%, 95% CI 65-79%, p = 0.00001). The SCT O2 for patients receiving long-term hydroxyurea (median age = 9.6 years) was normal at study entry (mean 66%, 95% CI 58-74%) and remained stable across two years. Both cohorts had significantly higher SCT O2 than published data from predominantly untreated SCA patients. Cerebral oximetry is a non-invasive method to assess cerebrovascular pathology that complements conventional imaging. Our results indicate that hydroxyurea suggests protection against neurophysiologic changes seen in untreated SCA. This article is protected by copyright. All rights reserved.

Chronic intrauterine exposure to psychoactive drugs often results in neonatal opioid withdrawal syndrome (NOWS). When nonpharmacologic measures are insufficient in controlling NOWS, morphine, methadone, and buprenorphine are first-line medications commonly used to treat infants with NOWS because of in utero exposure to opioids. Research suggests that buprenorphine may be the leading drug therapy used to treat NOWS when compared with morphine and methadone. Currently, there are no consensus or standardized treatment guidelines for medications prescribed for NOWS. Opioids used to treat NOWS exhibit large interpatient variability in pharmacokinetics (PK) and pharmacodynamic (PD) response in neonates. Organ systems undergo rapid maturation after birth that may alter drug disposition and exposure for any given dose during development. Data regarding the PK and PD of opioids in neonates are sparse. Pharmacometric methods such as physiologically based pharmacokinetic and population pharmacokinetic modeling can be used to explore factors predictive of some of the variability associated with the PK/PD of opioids in newborns. This review discusses the utility of pharmacometric techniques for enhancing precision dosing in infants requiring opioid treatment for NOWS. Applying these approaches may contribute to optimizing the outcome by reducing cumulative drug exposure, mitigating adverse drug effects, and reducing the burden of NOWS in neonates.

Background Sturge-Weber syndrome is a rare neurovascular disorder associated with capillary malformation, seizures, cognitive impairments, and stroke-like episodes (SLEs), arising from a somatic activating mutation in GNAQ. Studies suggest this mutation may cause hyperactivation of the mammalian target of rapamycin pathway. Sirolimus is an mammalian target of rapamycin inhibitor studied in other vascular anomalies and a potentially promising therapy in Sturge-Weber syndrome. Methods Ten patients with Sturge-Weber syndrome brain involvement and cognitive impairments were enrolled. Oral sirolimus was taken for six months (maximum dose: 2 mg/day, target trough level: 4-6 ng/mL). Neuropsychological testing, electroencephalography, and port-wine score were performed at baseline and after six months on sirolimus. Neuroquality of life, adverse events, and Sturge-Weber Syndrome Neurological Score (neuroscore) were recorded at each visit. Results Sirolimus was generally well tolerated; one subject withdrew early. Adverse events considered related to sirolimus were mostly (15/16) grade 1. A significant increase in processing speed was seen in the overall group (P = 0.031); five of nine patients with available data demonstrated statistically rare improvement in processing speed. Improvements were seen in the neuroquality of life subscales measuring anger (P = 0.011), cognitive function (P = 0.015), and depression (P = 0.046). Three subjects experiencing SLEs before and during the study reported shortened recovery times while on sirolimus. Conclusions Sirolimus was well tolerated in individuals with Sturge-Weber syndrome and may be beneficial for cognitive impairments, especially in patients with impaired processing speed or a history of SLE. A future, randomized, placebo-controlled trial of sirolimus in patients with Sturge-Weber syndrome is needed to further understand these potentially beneficial effects.

Alemtuzumab is used as part of reduced-intensity and reduced-toxicity transplant conditioning regimens for nonmalignant diseases. Prior studies identified an ideal target concentration range of 0.15-0.6 mcg/mL at day 0. However, only 24% of patients fall within this window using standard intermediate dosing. We performed a pilot study of a novel target concentration intervention strategy to target day 0 alemtuzumab concentrations to 0.15-0.6 mcg/mL. Twelve patients received model-informed alemtuzumab dosing of 0.5-0.6 mcg/kg divided over days -14 to -12. Alemtuzumab concentrations were measured, and pharmacokinetic (PK) modeling was performed on day -5 to predict day 0 concentrations. If the day 0 alemtuzumab concentration was predicted to fall below 0.15 mcg/mL, simulations were performed to identify the individual "top-up" dose needed to achieve the target day 0 concentration window. Six (50%) patients achieved day 0 alemtuzumab concentrations between 0.15 and 0.6 mcg/mL (4 received a top-up dose). Five patients had day 0 concentrations above the target window (no top-up doses). One patient had a day 0 concentration below the target range in the presence of anti-alemtuzumab antibodies. A concentration intervention strategy approach to alemtuzumab treatment can successfully target a greater proportion of patients into the ideal therapeutic window. Additional dose-reduction studies are needed to further optimize the initial dosing and achieve target attainment in all patients.

Background Sickle cell disease (SCD) is a severe and devastating hematological disorder that affects over 100,000 persons in the USA and millions worldwide. Hydroxyurea is the primary disease-modifying therapy for the SCD, with proven benefits to reduce both short-term and long-term complications. Despite the well-described inter-patient variability in pharmacokinetics (PK), pharmacodynamics, and optimal dose, hydroxyurea is traditionally initiated at a weight-based dose with a subsequent conservative dose escalation strategy to avoid myelosuppression. Because the dose escalation process is time consuming and requires frequent laboratory checks, many providers default to a fixed dose, resulting in inadequate hydroxyurea exposure and suboptimal benefits for many patients. Results from a single-center trial of individualized, PK-guided dosing of hydroxyurea for children with SCD suggest that individualized dosing achieves the optimal dose more rapidly and provides superior clinical and laboratory benefits than traditional dosing strategies. However, it is not clear whether these results were due to individualized dosing, the young age that hydroxyurea treatment was initiated in the study, or both. The Hydroxyurea Optimization through Precision Study (HOPS) aims to validate the feasibility and benefits of this PK-guided dosing approach in a multi-center trial. Methods HOPS is a randomized, multicenter trial comparing standard vs. PK-guided dosing for children with SCD as they initiate hydroxyurea therapy. Participants (ages 6 months through 21 years), recruited from 11 pediatric sickle cell centers across the USA, are randomized to receive hydroxyurea either using a starting dose of 20 mg/kg/day (Standard Arm) or a PK-guided dose (Alternative Arm). PK data will be collected using a novel sparse microsampling approach requiring only 10 μL of blood collected at 3 time-points over 3 h. A protocol-guided strategy more aggressive protocols is then used to guide dose escalations and reductions in both arms following initiation of hydroxyurea. The primary endpoint is the mean %HbF after 6 months of hydroxyurea. Discussion HOPS will answer important questions about the clinical feasibility, benefits, and safety of PK-guided dosing of hydroxyurea for children with SCD with potential to change the treatment paradigm from a standard weight-based approach to one that safely and effectively optimize the laboratory and clinical response. Trial registration ClinicalTrials.gov NCT03789591. Registered on 28 December 2018.

Neonatal opioid withdrawal syndrome (NOWS) often arises in infants born to mothers who used opioids during pregnancy. Morphine, methadone, and buprenorphine are the most common first-line treatments, whereas clonidine and phenobarbital are generally reserved for adjunctive therapy. These drugs exhibit substantial pharmacokinetic (PK) and pharmacodynamic (PD) variability. Current pharmacological treatments for NOWS are based on institutional protocols and largely rely on empirical treatment of patient symptoms.This article reviews the PK/PD of NOWS pharmacotherapies with a focus on the implication of physiological development and maturation. Body size-standardized clearance is consistently low in neonates, except for methadone. This can be ascribed to underdeveloped metabolic and elimination pathways. The effects of pharmacogenetics have been clarified especially for morphine. The PK/PD relationship of medications used in the treatment of NOWS is generally understudied.Providing an appropriate opioid dose in neonates is challenging. Advancements in quantitative pharmacology and PK/PD modeling approaches facilitate identification of key factors driving PK/PD variability and characterization of exposure-response relationships. PK/PD model-informed simulations have been widely employed to define age-appropriate pediatric dosing regimens. The model-informed approach holds promise to aid more rational use of medications in the treatment of NOWS.

Total pancreatectomy with islet autotransplantation is a complex surgical approach for acute recurrent or chronic pancreatitis that frequently triggers extreme thrombocytosis (platelets ≥ 1000 × 109 /L). Thrombocytosis can be prothrombotic, so cytoreductive hydroxyurea is often initiated after this surgery; however, optimal dosing strategy and efficacy are unknown. This prospective pilot study characterized the pharmacokinetics of hydroxyurea after this procedure in children. It also compared them with previously published pediatric parameters in sickle cell anemia (SCA), the disease in which pediatric hydroxyurea pharmacokinetics have primarily been studied. Plasma hydroxyurea levels were quantified in 14 participants aged 4-19 years using high-performance liquid chromatography. Blood collections were scheduled 20 minutes, 1 hour, and 4 hours after the first dose, on pharmacokinetic day 1 (PK1), and again 2-3 months later if still on hydroxyurea (PK2). Six participants had PK1 and PK2 data at all 3 postdose timed collections, 5 only had PK1 samples, and 3 only had PK2 samples. Total pancreatectomy with islet autotransplantation participants had reduced and delayed absorption compared with sickle cell anemia participant data from the Hydroxyurea Study of Long-Term Effects, regardless of timing or dosing methodology. Total pancreatectomy with islet autotransplantation participants had different pharmacokinetic profiles at PK1 versus PK2, with lower dose-normalized exposures than previously reported in sickle cell anemia. These results suggest variability exists in hydroxyurea absorption and bioavailability in total pancreatectomy with islet autotransplantation patients, suspected to be primarily because of Roux-en-Y reconstruction, and suggest that more pharmacokinetic data are needed for scenarios when hydroxyurea is prescribed to children without sickle cell anemia.

BACKGROUND: Pain control in infants is an important clinical concern, with potential long-term adverse neurodevelopmental effects. Intravenous morphine is routinely administered for post-operative pain management; however, its dose-concentration-response relationship in neonates and infants has not been well characterized. Although the current literature provides dosing guidelines for the average infant, it fails to control for the large unexplained variability in morphine clearance and response in individual patients. Bayesian estimation can be used to control for some of this variability. The authors aimed to evaluate morphine pharmacokinetics and exposure in critically ill neonates and infants receiving standard of care morphine therapy and compare a population-based approach to the model-informed Bayesian techniques. METHODS: The pharmacokinetics and exposure of morphine and its active metabolites were evaluated in a prospective opportunistic pharmacokinetic study using 221 discarded blood samples from 57 critically ill neonates and infants in the neonatal intensive care unit. Thereafter, a population-based pharmacokinetic model was compared to a Bayesian adaptive control strategy to predict an individual’s pharmacokinetic profile and morphine exposure over time. RESULTS: Among the critically ill neonates and infants, morphine clearance showed substantial variability with a 40-fold range (i.e., 2.2 to 87.1, mean 23.7 L/h/70 kg). Compared to the observed morphine concentrations, the population-model based predictions had an R(2) of 0.13 while the model-based Bayesian predictions had an R(2) of 0.61. CONCLUSION: Model-informed Bayesian estimation is a better predictor of morphine exposure than pharmacokinetic models alone in critically ill neonates and infants. A large variability was also identified in morphine clearance. A further study is warranted to elucidate the predictive covariates and precision dosing strategies that use morphine concentration and pain scores as feedbacks.

Buprenorphine has been shown to be effective in treating infants with neonatal opioid withdrawal syndrome. However, an evidence-based buprenorphine dosing strategy has not been established in the treatment of neonatal opioid withdrawal syndrome because of a lack of exposure–response data. The aim of this study was to develop an integrated pharmacokinetic and pharmacodynamic model to predict buprenorphine treatment outcomes in newborns with neonatal opioid withdrawal syndrome. Clinical data were obtained from 19 newborns with a median (range) gestational age of 37 (34–41) weeks enrolled in a pilot pharmacokinetic study of buprenorphine. Sparse blood sampling, comprising three specimens obtained around the second dose of buprenorphine, was performed using heel sticks with dried blood spot technology. Standardized neonatal opioid withdrawal syndrome severity scores (Finnegan scores) were collected every 3–4 h based on symptoms by bedside nursing staff. Mean Finnegan scores were used as a pharmacodynamic marker in the exposure–response modeling. The blood concentration–Finnegan score relationship was described using a physiologic indirect response model with inclusion of natural disease remission. A total of 52 buprenorphine blood concentrations and 780 mean Finnegan scores were available for the pharmacokinetic/pharmacodynamic modeling and exposure–response analysis. A one-compartment model with first-order absorption adequately described the pharmacokinetic data. The buprenorphine blood concentration at 50% of maximum effect for the inhibition of disease progression was 0.77 ng/mL (95% confidence interval 0.32–1.2). The inclusion of natural disease remission described as a function of postnatal age significantly improved the model fit. A buprenorphine pharmacokinetic/pharmacodynamic model was successfully developed. The model could facilitate model-informed optimization of the buprenorphine dosing regimen in the treatment of neonatal opioid withdrawal syndrome.

Background Hydromorphone is an opioid agonist used for pediatric analgesia. Due to lack of data, pediatric dosing (based on adult pharmacokinetic models) is not optimal. Aim This study characterizes hydromorphone population pharmacokinetics in pediatric surgical patients. Methods In this prospective observational study, 34 children (4-18 years, bodyweight 23-89.6 kg) received multiple intravenous hydromorphone boluses followed by postoperative hydromorphone patient-controlled analgesia. Arterial blood samples were collected before and at 3, 10, 30, and 90 (and few samples at 1350) minutes after the first dose. Hydromorphone concentrations were measured by validated LC-MS/MS assay. Nonlinear mixed-effects modeling was used for pharmacokinetic model development. The final population pharmacokinetic model was evaluated by visual predictive check and bootstrap analysis. Monte Carlo simulations based on the final pharmacokinetic model determined optimal patient-controlled analgesia parameters to achieve a target of 20 ng/mL (as the median effective analgesic concentration), using minimum effective analgesic concentration of 4 ng/mL as a proxy for patient-controlled analgesia dose demand, and not exceeding the defined safe upper threshold of 40 ng/mL. Results Hydromorphone pharmacokinetic profiles were adequately described by a two-compartmental model with first-order elimination. Bodyweight was found to be a significant covariate for hydromorphone clearance. Allometrically scaledpharmacokinetic parameter estimates (per 70 kg), systemic clearance (0.748 L/min), volume of distribution (33 L), peripheral clearance (1.57 L/min), and peripheral volume of distribution (146 L) were similar to reported adult parameter estimates. Sex, race, age, and type of surgery were not identified as significant covariates. To identify optimal patient-controlled analgesia dosing parameters, we simulated several initial loading doses, demand doses, and lockout intervals. Our simulations support an initial patient-controlled analgesia loading dose of 15 µg/kg followed by a demand dose of 6 µg/kg with lockout intervals of 20 minutes. Conclusions After intravenous hydromorphone, plasma pharmacokinetic profiles in children undergoing different surgeries were well described by a two-compartment population allometric pharmacokinetic model using bodyweight as the size descriptor. Model informed simulations identified patient-controlled analgesia parameters to inform initial settings, with adjustments as needed based on observed individual effects.

Providing maximal therapeutic efficacy without toxicity is a universal goal of rational drug therapy. However, substantial between-patient variability in drug response often impedes such successful treatments and brings the necessity of tailoring drug dose to individual needs for more precise therapy. In many cases plenty of patient characteristics, such as body size, genetic makeup and environmental factors, need to be taken into consideration to find the optimal dose in clinical practice. A pharmacokinetics and pharmacodynamics (PK/PD) model-informed approach offers integration of various patient information to provide an expectation of drug response and derive practical dose estimates to support clinicians' dosing decisions. Such an approach was pioneered in the late 1970s, but its broad clinical acceptance and implementation have been hampered by the lack of widespread computer technology, including user-friendly software tools. This has significantly changed in recent years. With the advent of electronic health records (EHRs) and the ubiquity of user-friendly software tools, we now experience a convergence of clinical information, pharmacogenetics, systems pharmacology and pharmacometrics, and technology. Advanced pharmacometrics research is now more appliable and implementable to improve health care. This article presents examples of successful development and implementation of pharmacogenetics-guided and PK/PD model-informed decision support to facilitate precision dosing, including the development of an EHR-embedded decision support tool. Through the integration of clinical decision support tools in EHRs, clinical pharmacometrics support can be brought directly to the clinical team and the bedside.

Methotrexate (MTX), an antifolate, is administered at high doses to treat malignancies in children and adults. However, there is considerable interpatient variability in clearance of high-dose (HD) MTX. Patients with delayed clearance are at an increased risk for severe nephrotoxicity and life-threatening systemic MTX exposure. Glucarpidase is a rescue agent for severe MTX toxicity that reduces plasma MTX levels via hydrolysis of MTX into inactive metabolites, but is only indicated when MTX concentrations are > 2 SDs above the mean excretion curve specific for the given dose together with a significant creatinine increase (> 50%). Appropriate administration of glucarpidase is challenging due to the ambiguity in the labeled indication. A recent consensus guideline was published with an algorithm to provide clarity in when to administer glucarpidase, yet clinical interpretation of laboratory results that do not directly correspond to the algorithm prove to be a limitation of its use. The goal of our study was to develop a clinical decision support tool to optimize the administration of glucarpidase for patients receiving HD MTX. Here, we describe the development of a novel 3-compartment MTX population pharmacokinetic (PK) model using 31,672 MTX plasma concentrations from 772 pediatric patients receiving HD MTX for the treatment of acute lymphoblastic leukemia and its integration into the online clinical decision support tool, MTXPK.org. This web-based tool has the functionality to utilize individualized demographics, serum creatinine, and real-time drug concentrations to predict the elimination profile and facilitate model-informed administration of glucarpidase.

Background Activation of the mammalian target of rapamycin (mTOR) pathway is observed in neurofibromatosis type 1 (NF1) associated low-grade gliomas (LGGs), but agents that inhibit this pathway, including mTOR inhibitors, have not been studied in this population. We evaluate the efficacy of the orally administered mTOR inhibitor everolimus for radiographically progressive NF1-associated pediatric LGGs. Methods Children with radiologic-progressive, NF1-associated LGG and prior treatment with a carboplatin-containing chemotherapy were prospectively enrolled on this phase II clinical trial to receive daily everolimus. Whole blood was analyzed for everolimus and markers of phosphatidylinositol-3 kinase (PI3K)/mTOR pathway inhibition. Serial MRIs were obtained during treatment. The primary endpoint was progression-free survival at 48 weeks. Results Twenty-three participants (median age, 9.4 y; range, 3.2–21.6 y) were enrolled. All participants were initially evaluable for response; 1 patient was removed from study after development of a malignant peripheral nerve sheath tumor. Fifteen of 22 participants (68%) demonstrated a response, defined as either shrinkage (1 complete response, 2 partial response) or arrest of tumor growth (12 stable disease). Of these, 10/15 remained free of progression (median follow-up, 33 mo). All remaining 22 participants were alive at completion of therapy. Treatment was well tolerated; no patient discontinued therapy due to toxicity. Pharmacokinetic parameters and pre-dose concentrations showed substantial between-subject variability. PI3K/mTOR pathway inhibition markers demonstrating blood mononuclear cell mTOR pathway inactivation was achieved in most participants. Conclusion Individuals with recurrent/progressive NF1-associated LGG demonstrate significant disease stability/shrinkage during treatment with oral everolimus with a well-tolerated toxicity profile. Everolimus is well suited for future consideration as upfront or combination therapy in this patient population.

Aims Fanconi anaemia (FA) is a rare disorder characterized by progressive bone marrow failure that requires haematopoietic cell transplantation (HCT). Busulfan is used in conditioning regimens prior to HCT. Doses used in non‐FA patients cause life‐threatening toxicities in FA patients and data on busulfan pharmacokinetics (PK) in this population are limited. This study characterized busulfan PK in paediatric FA patients using population PK modelling and evaluated the effect of body composition on steady‐state concentrations (C ss). Methods A total of 200 busulfan plasma concentrations in 29 FA patients from a recent study (http://Clinicaltrials.gov; NCT01082133) were available for population PK modelling. The effect of different body size‐scaled doses and body compositions on C ss was investigated using population PK modelling. Results Fat free mass (FFM) was identified as the best size descriptor in a two‐compartment busulfan PK model in FA patients. Conventional dosing, based on an amount of busulfan per kilogram of total body mass, resulted in higher C ss in FA patients with higher body mass index (BMI). A newly proposed FFM‐based dosing strategy would eliminate the observed trend of higher concentrations in high BMI patients, and achieve consistent C ss across a wide BMI spectrum. Conclusions This is the first study to describe the population PK of busulfan in paediatric FA patients. The proposed model will facilitate PK model‐informed precision dosing. FFM‐based dosing is expected to improve the probability of achieving target C ss, particularly in obese patients, while minimizing the risk of overdosing.

Background: Sotalol is often employed to prevent recurrence of symptomatic atrial flutter/atrial fibrillation. Because sotalol can prolong the QT interval excessively causing ventricular arrhythmias, a 3-day in-hospital loading or dose escalation period is mandated with oral administration in the product label for patient safety. In patients with normal renal function, 3 days (five oral doses) are required to obtain steady state maximum sotalol concentration, which results in maximum QT prolongation. The aim of this study is to develop an intravenous to oral loading regime for sotalol therapy that reduces the 3-day in-hospital initiation or dose escalation with oral administration to 1 day without compromising patient safety. Methods: Using model-informed drug development techniques, simulations were developed for initiation and dose escalation of sotalol therapy by employing an intravenous loading dose followed by oral sotalol administrations. Results: In patients with normal renal function, an initial 1-h loading dose of intravenous sotalol followed by two oral doses in 24 h has been developed permitting attainment of three maximum serum concentrations reflecting maximum QT prolongation in a 1-day observation period. Dosing regimens for patients with impaired renal function are also developed. Conclusions: In patients with normal renal function, using an intravenous loading dose followed by oral administrations permits safe initiation or dose escalation of sotalol in 1 day instead of the 3-day dosing regimen with oral administration. Cardiol Res. 2020;11(5):294-304 doi: https://doi.org/10.14740/cr1143

Critical illness, including sepsis, causes significant pathophysiologic changes that alter the pharmacokinetics (PK) of antibiotics. Ceftriaxone is one of the most prescribed antibiotics in patients admitted to the pediatric intensive care unit (PICU). We sought to develop population PK models of both total ceftriaxone and free ceftriaxone in children admitted to a single-center PICU using a scavenged opportunistic sampling approach. We tested if the presence of sepsis and phase of illness (before or after 48 hours of antibiotic treatment) altered ceftriaxone PK parameters. We performed Monte Carlo simulations to evaluate whether dosing regimens commonly used in PICUs in the United States (50 mg/kg every 12 hours vs. 24 hours) resulted in adequate antimicrobial coverage. We found that a two-compartment model best described both total and free ceftriaxone concentrations. For free concentrations, the population clearance value is 6.54 L/h/70 kg, central volume is 25.4 L/70 kg and the peripheral volume is 19.6 L/70kg. For both models, we found that allometric weight scaling, post-menstrual age, creatinine clearance and daily highest temperature had significant effects on clearance. Presence of sepsis or phase of illness did not have a significant effect on clearance or volume of distribution. Monte Carlo simulations demonstrated that to achieve free concentrations above 1 μg/mL for 100% of the dosing intervals, a dosing regimen of 50 mg/kg every 12 hours is recommended for most patients. A continuous infusion could be considered if the target is to maintain free concentrations four times above the minimum inhibitory concentrations (4 μg/mL).

Background & aims: We aimed to model infliximab (IFX) pharmacokinetics (PK) in pediatric acute severe ulcerative colitis (ASUC) and assess the association between PK parameters, including drug exposure, and clinical response. Methods: We studied a multicenter prospective cohort of hospitalized children initiating IFX for ASUC or IBD-unclassified. Serial IFX serum concentrations over 26 weeks were used to develop a PK model. We tested the association of PK parameter estimates with day 7 clinical response, week 8 clinical remission, week 26 corticosteroid-free clinical remission (CSF-CR) (using the Pediatric Ulcerative Colitis Activity Index), and colectomy-free survival. Results: Thirty-eight participants received IFX (median initial dose, 9.9 mg/kg). Day 7 clinical response, week 8 clinical remission, and week 26 CSF-CR occurred in 71%, 55%, and 43%, respectively. Albumin, C-reactive protein, white blood cell count, platelets, weight, and antibodies to IFX were significant covariates incorporated into a PK model. Week 26 non-remitters exhibited faster IFX clearance than remitters (P =.013). However, cumulative IFX exposure did not differ between clinical response groups. One (2.7%) and 4 (10.8%) participants underwent colectomy by week 26 and 2 years, respectively. Day 3 IFX clearance >0.02 L/h was associated with colectomy (hazard ratio, 58.2; 95% confidence interval, 6.0–568.6; P

Background: Vedolizumab for inflammatory bowel disease (IBD) is often intensified based on distinct pharmacokinetics in children. Prior adult-specific population pharmacokinetic models have identified limited covariates of drug clearance. Aims: To establish a population pharmacokinetic model for children and young adults to identify novel covariates of drug clearance to better account for paediatric-specific inter-patient variability in vedolizumab pharmacokinetics; a key secondary exploratory aim was to identify microbial signatures of pharmacokinetic outcomes in a subset of patients. Methods: The study included data from 463 observed vedolizumab concentrations (59 peaks and 404 troughs) from 74 patients with IBD (52 with Crohn's disease and 22 with ulcerative colitis or unclassified IBD, median age 16 years). Pharmacokinetic analysis was conducted with non-linear mixed effects modelling. For the evaluation of the exposure–response relationship, clinical outcomes were evaluated by trough levels, clearance and vedolizumab exposure. Whole-genome metagenomic sequencing was conducted at baseline and week 2. Results: A two-compartment population pharmacokinetic model was identified with a clear correlation between CL and weight, erythrocyte sedimentation rate, and hypoalbuminemia. Trough concentrations before infusion 3 (37 μg/ml) and before infusion 4 (20 μg/ml) best predicted steroid-free clinical remission at infusion 4. Using faecal metagenomics, we identified an early (baseline and week 2) abundance of butyrate-producing species and pathways that were associated with an infusion 4 trough concentration >20 μg/ml. Conclusions: This novel paediatric vedolizumab pharmacokinetic model could inform precision dosing. While additional studies are needed, an abundance of faecal butyrate producers is associated with early response to vedolizumab, suggesting that microbial analysis may be beneficial to biological selection.

Hydroxyurea, an oral medication with important clinical benefits in the treatment of sickle cell anemia, can be accurately determined in plasma with a transition metal dichalcogenide-based electrochemical sensor. We used a two-dimensional molybdenum sulfide material (MoS2) selectively electrodeposited on a polycrystalline gold electrode via tailored waveform polarization in the gold electrical double layer formation region. The electro-activity of the modified electrode depends on the electrical waveform parameters used to electro-deposit MoS2. The concomitant oxidation of the MoS2 material during its electrodeposition allows for the tuning of the sensor&rsquo, s specificity. Chemometrics, utilizing mathematical procedures such as principal component analysis and multivariable partial least square regression, were used to process the electrochemical data generated at the bare and the modified electrodes, thus allowing the hydroxyurea concentrations to be predicted in human plasma. A limit-of-detection of 22 nM and a sensitivity of 37 nA cm&minus, 2 &micro, M&minus, 1 were found to be suitable for pharmaceutical and clinical applications.

Transplant-associated thrombotic microangiopathy (TA-TMA) is a fatal posttransplant complication of hematopoietic stem cell transplantation. We recently reported that survival for TA-TMA has been improved by early intervention with eculizumab, a complement C5 inhibitor, guided by pharmacokinetic/pharmacodynamic (PK/PD) model-informed precision dosing. However, patients with gastrointestinal bleeding showed poor survival, even when treated with more frequent doses. Our objective was to develop separate models in bleeding and nonbleeding patients with TA-TMA and to propose precision dosing algorithms. Eculizumab PK/PD was analyzed in 19 bleeding and 38 nonbleeding patients (0.5-29.9 years of age). A complement activation biomarker (sC5b-9) and body weight were identified as significant determinants of eculizumab clearance regardless of bleeding. Eculizumab clearance after the first dose was higher in bleeding than in nonbleeding patients (83.8 vs 61.3 mL/h per 70 kg; P = .07). The high clearance was maintained over treatment doses in bleeding patients, whereas nonbleeding patients showed a time-dependent decrease in clearance. sC5b-9 levels were highest before the first dose and decreased over time, regardless of bleeding complications. A Monte Carlo Simulation analysis showed that the current dosing protocols recommended for atypical hemolytic uremic syndrome had 100 μg/mL eculizumab in nonbleeding patients. We identified an intensified loading protocol to reach 80% target attainment. Our data clearly showed the need for individualized dosing for patients with significant bleeding and for ongoing dose adjustments to optimize outcomes. The developed models will be incorporated into a clinical decision guideline for precision dosing to improve outcomes in children and young adults with TA-TMA.