Children represent a large underserved population of "therapeutic orphans," as an estimated 80% of children are treated off-label. However, pediatric drug development often faces substantial challenges, including economic, logistical, technical, and ethical barriers, among others. Among many efforts trying to remove these barriers, increased recent attention has been paid to extrapolation; that is, the leveraging of available data from adults or older age groups to draw conclusions for the pediatric population. The Bayesian statistical paradigm is natural in this setting, as it permits the combining (or "borrowing") of information across disparate sources, such as the adult and pediatric data. In this paper, authored by the pediatric subteam of the Drug Information Association Bayesian Scientific Working Group and Adaptive Design Working Group, we develop, illustrate, and provide suggestions on Bayesian statistical methods that could be used to design improved pediatric development programs that use all available information in the most efficient manner. A variety of relevant Bayesian approaches are described, several of which are illustrated through 2 case studies: extrapolating adult efficacy data to expand the labeling for Remicade to include pediatric ulcerative colitis and extrapolating adult exposure-response information for antiepileptic drugs to pediatrics.

Background: Nivolumab 480 mg every 4 weeks (Q4W) is approved in the European Union, United States, and several other markets across multiple tumor types. Its approval was supported by quantitative efficacy/safety analyses bridging to 3 mg/kg every 2 weeks (Q2W). Patients and methods: The benefiterisk profile of nivolumab 480 mg Q4W relative to 3 mg/kg Q2W was evaluated using population pharmacokinetic modeling and exposureeresponse (EeR) analyses for safety and efficacy. Pharmacokinetic exposures were predicted for 3203 patients with melanoma, non-small-cell lung cancer (NSCLC), renal cell carcinoma (RCC), squamous cell carcinoma of the head and neck, urothelial carcinoma, or classical Hodgkin lymphoma. Quantitative models analyzed EeR to predict 480-mg Q4W safety across all indications and efficacy for melanoma, NSCLC, and RCC. Intratumoral receptor occupancy (RO) was predicted for parameters representing different tumor types. Results: Time-averaged concentrations for 480 mg Q4W versus 3 mg/kg Q2W were higher during the first 28 days (26.8%) and similar at steady state (5.2%). The maximum concentration (C max) after the first dose was higher (110.4%), and the trough concentration at day 28 was lower (À22.1%) with 480 mg Q4W versus 3 mg/kg Q2W. The C max achieved with 480 mg Q4W was lower than the previously established safe dose of 10 mg/kg Q2W. The probability of adverse events for key safety end points was similar for 480 mg Q4W and 3 mg/kg Q2W. The predicted overall survival and objective response rates with 480 mg Q4W were comparable to 3 mg/kg Q2W. The predicted high intratumoral RO provided additional evidence to support 480 mg Q4W across tumor types. Conclusions: The benefiterisk profile for nivolumab 480 mg Q4W was predicted to be similar to that of 3 mg/kg Q2W across tumor types while providing a convenient and flexible option for patients and their caregivers.

The pharmacokinetics of florfenicol were studied in koi carp Cyprinus carpio (hereafter, koi) and threespot gourami Trichogaster trichopterus after oral (50 mg/kg) and intramuscular (25 mg/kg) administration of the drug in warm water conditions (24-25ЊC). The estimates of clearance, volume of distribution, and half-life were 0.05 L · h Ϫ1 · kg Ϫ1 , 1.0 L/kg, and 16 h, respectively, in koi. In threespot gourami, the corresponding estimates were 0.32 L · h Ϫ1 · kg Ϫ1 , 2.0 L/kg, and 4 h. In koi, minimal drug absorption was observed after bath treatment. Analysis of florfenicol leaching from fish feed indicated that about 50-80% of the coated drug is lost and is not available for therapeutic benefit for either species. The minimum inhibitory concentrations of florfenicol, determined for bacterial isolates from tropical fish, ranged from 0.5 to 2 g/mL. For effective dosing regimens in koi and threespot gourami, the differences in pharmacokinetics should be considered in future studies.

Background: Linezolid standard dosing is fixed at 600 mg q12h for adults. Literature suggests critically-ill, obese patients require higher doses. The study aim is two-fold: (i) to describe linezolid PK and (ii) to evaluate if PK/PD target attainment is achieved with standard dosing in critically-ill, obese patients with severe SSTIs. Methods: Adult patients with a body mass index (BMI) ≥ 30 kg/m2 and receiving IV linezolid from August 2018 to April 2019 were eligible for consent in this prospective study. Severe SSTIs were defined as necrotizing fasciitis, myonecrosis, or SSTI with sepsis syndrome. Four blood samples were collected at steady state at 1, 3, 5 hours post-infusion and as a trough. Target attainment was defined as achieving AUC0-24h/MIC ≥ 100 hr*mg/L. Monte Carlo simulations were used to determine probability of target attainment (PTA). Results: Eleven patients were included in the study. The median BMI was 45.7 kg/m2 and median total body weight (TBW) was 136.0 kg. Seven patients received standard linezolid doses and four received 600 mg q8h. A one-compartment model described linezolid PK. Based on AUC0-24h/MIC targets, for non-cirrhotic patients at 140 kg, PTA with standard linezolid doses was 100%, 98.8%, 34.1%, and 0% for MICs 0.5, 1, 2, and 4 mg/L, respectively. Conclusion: Target attainment ≥ 90% is not achieved with standard linezolid doses for non-cirrhotic patients ≥ 140 kg with MICs ≥ 2 mg/L. This study adds to accumulating evidence that standard linezolid doses may not be adequate for all patients.

Limited data exist on the effect of continuous renal replacement therapy (CRRT) methods on anti‐epileptic drug pharmacokinetics (PK). This prospective practice‐based PK study aims to assess the impact of continuous venovenous hemofiltration (CVVH), a modality of CRRT, on levetiracetam PK in critically ill patients and to derive individualized dosing recommendations. Eleven patients receiving oral or intravenous levetiracetam and CVVH in various intensive care units at a large academic medical center were enrolled to investigate the need for dosing adjustments. Prefilter, postfilter, and ultrafiltrate samples were obtained before dosing, after the completion of the infusion or 1‐hour postoral dose, and up to 6 additional time points postinfusion or postoral administration. Patient‐specific blood and ultrafiltrate flow rates and laboratory values were also collected at the time of sampling. The average sieving coefficient (SC) for levetiracetam was 0.89 ± 0.1, indicating high filter efficiency. Six of the 11 patients experienced concentrations outside the reported therapeutic range (12–46 mg/L). The average volume of distribution was 0.73 L/kg. CVVH clearance contributes a major fraction of the total levetiracetam clearance (36–73%) in neurocritically ill patients. The average bias and precision of the estimated vs. observed total clearance value was ~ 10.6% and 21.5%. Major dose determinants were identified to be SC and effluent flow rate. Patients with higher ultrafiltrate rates will have increased drug clearance and, therefore, will require higher doses in order to match exposures seen in patients with normal renal function.

Introduction: The anti-PD-1 checkpoint inhibitor NIVO provides favorable safety and efficacy when administered at 3 mg/kg Q2W across multiple tumor types. Alternative dosing schedules would provide flexibility and offer benefits to patients and prescribers. A well-established understanding of NIVO clinical pharmacology, robust clinical data across multiple tumor types and well characterized, relatively flat E-R relationships for efficacy and safety support the use of model-based approaches to qualify other potential NIVO doses and schedules. Methods: The feasibility of extending the dosing interval of NIVO from Q2W to Q4W was investigated using a combination of quantitative clinical pharmacology analyses and safety assessments. The predicted benefit-risk profile of NIVO 480 mg Q4W relative to 3 mg/kg Q2W was assessed by the following analyses: (1) comparison of NIVO exposures produced by 3 mg/kg Q2W and 480 mg Q4W across tumor types; (2) evaluation of NIVO exposure margins for safety relative to the well-tolerated dose of 10 mg/kg Q2W; (3) comparison of predicted risk of experiencing adverse events (Gr3+ AEs, immune-mediated AEs) with 480 mg Q4W relative to 3 mg/kg Q2W across indications of melanoma, NSCLC, RCC, UC, H&N and cHL; and (4) comparison of predicted objective tumor response (OR) and overall survival with NIVO 480 mg Q4W relative to 3 mg/kg Q2W in patients with melanoma, NSCLC, and RCC. Results: Steady-state peak, time-averaged, and trough NIVO concentrations predicted with 480 mg Q4W were approximately 44% higher, 4% higher, and 18% lower, respectively, compared with 3 mg/kg Q2W. The aggregate of safety data accumulated for NIVO up to a dose level of 10 mg/kg Q2W in multiple tumor types provides a wide safety margin for the maximum concentration values expected with 480 mg Q4W. The steady-state exposures produced by 480 mg Q4W were lower than the corresponding exposures with 10 mg/kg Q2W, which has been shown to have acceptable safety and tolerability. The predicted probabilities of achieving an OR with NIVO 480 mg Q4W were similar to those with 3 mg/kg Q2W (<1% difference) across tumor types. Predicted 1- and 2-year survival probabilities were also similar to that of NIVO 3 mg/kg Q2W (differences ranging between 0%-4.6% at year 1, and 1.9%-6.9% at year 2) across tumor types. Conclusion: With a well-established understanding of NIVO clinical pharmacology, robust clinical data across multiple tumor types and well-characterized E-R relationships for efficacy and safety, the differences in exposures produced by a NIVO schedule of 480 mg Q4W relative to 3 mg/kg Q2W dosing schedule are not expected to result in clinically meaningful differences in the safety and efficacy of NIVO. The proposed 480 mg Q4W schedule has been incorporated into NIVO clinical trials (NCT02713867, NCT02714218) across multiple tumor types. Citation Format: Xiaochen Zhao, Vijay Ivaturi, Mathangi Gopalakrishnan, Jun Shen, Yan Feng, Paul Statkevich, Eric Richards, Michelle Rashford, Vicki Goodman, Joga Gobburu, Akintunde Bello, Amit Roy, Shruti Agrawal. A model-based exposure-response (E-R) assessment of a nivolumab (NIVO) 4-weekly (Q4W) dosing schedule across multiple tumor types [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT101. doi:10.1158/1538-7445.AM2017-CT101

BackgroundCOX-2 inhibitors can be effective for acute migraine, but none is supplied in a rapidly absorbed, ready-to-use oral liquid formulation. DFN-15, a novel oral liquid formulation of celecoxib, is being developed for the acute treatment of migraine with or without aura. Clinical studies with this formulation are ongoing.ObjectivesThe objectives of the present study were to compare the bioavailability of DFN-15 with that of the commercial formulation of celecoxib 400-mg oral capsules (Celebrex®) and to determine the dose proportionality of DFN-15 in healthy fasted volunteers.MethodsThis single-dose randomized crossover study in 16 healthy fasted volunteers evaluated the pharmacokinetics and relative bioavailability of DFN-15 at doses of 120, 180, and 240 mg against the commercial formulation of celecoxib 400-mg oral capsules and determined the dose proportionality of DFN-15.ResultsThe maximum observed plasma concentrations (C max) of celecoxib after the administration of DFN-15 120, 180, and 240 mg (1062–1933 ng/ml) were higher than for the 400-mg oral capsules (611 ng/ml). The median time to peak concentration (T max) was within 1 h for DFN-15 and 2.5 h for the oral capsules. The pharmacokinetics of DFN-15 were dose proportional from 120 to 240 mg. Partial area under the plasma concentration–time curves (AUCs) from 15 min to 2 h for DFN-15 120 mg were at least threefold higher than for the oral capsules, and the relative bioavailability of DFN-15 was approximately 140% that of the oral capsules. DFN-15 was well tolerated, with no new or unexpected adverse events.ConclusionsBased on a faster rate of absorption and increased bioavailability, DFN-15 is being evaluated as an abortive medication for acute treatment in patients with migraine.

Background and Objectives: Currently, no dosing information exists for ceftaroline fosamil in patients undergoing continuous renal replacement therapy (CRRT). The objectives of this study are to characterize the pharmacokinetics of ceftaroline in critically ill patients undergoing CRRT modalities and to derive individualized dosing recommendations. Methods: This pharmacokinetic study aimed to enroll critically ill patients receiving ceftaroline fosamil and any CRRT modality from adult intensive care units. Selection of the specific CRRT modality and dosing regimen was based on clinical discretion. Pre-filter, post-filter, and ultrafiltrate samples were obtained before the administration of the fourth dose, after the completion of the infusion, and up to five additional time points post-infusion. Plasma concentrations were measured using a validated ultra-high performance liquid chromatography assay. Individual pharmacokinetic parameters were calculated using non-compartmental analysis. Results: Four patients were enrolled to investigate the need for dosing adjustments. The average sieving coefficient for ceftaroline was 0.81 ± 0.1, indicating high filter efficiency. The average volume of distribution was 41.8 L (0.48 L/kg) and is within the previously reported range in patients with normal renal function. Non-renal clearance accounted for more than 50% of the total clearance observed in patients. The observed pharmacokinetic profiles suggest that the pharmacodynamic target for 2log 10 CFU reduction from baseline (%fT >1 mg/L of 50%) was met for each patient. Due to the impact of CRRT and non-renal clearance, dosing recommendations were derived for different ranges of effluent flow rates and adjusted body weights. For a patient with an adjusted body weight of 70 kg and receiving CRRT at an effluent flow rate of 3 L/h, a ceftaroline fosamil dosing regimen of 400 mg every 12 h is proposed. Conclusion: Ceftaroline is cleared extensively in critically ill patients receiving CRRT and may impact pharmacodynamic target achievement. Dose adjustments should be based on the intensity of the CRRT regimen, patient weight, and the clinical status of the patient.