AIMS:Canagliflozin was recently approved in type 2 diabetes mellitus (T2DM) patients ≥10 and <18 years old as a single agent dosed once daily (QD) or in a fixed-dose combination with metformin dosed twice daily (BID). We characterize canagliflozin pharmacokinetics in paediatric patients with T2DM, compare estimated individual and simulated exposure metrics for QD and BID doses in paediatric patients and adults, and investigate the relationship between canagliflozin plasma concentrations and change from baseline HbA1c with QD and BID doses. METHODS:Paediatric population pharmacokinetics and pharmacokinetics/pharmacodynamics models were based on the previously developed corresponding adult models, using Phase 1 and 3 study data, evaluating canagliflozin 100- or 300-mg QD doses in paediatric patients with T2DM. Modelling encompassed exploratory analysis, external evaluation, model update and simulation of canagliflozin exposure metrics and HbA1c for QD and BID doses. RESULTS:Estimated and simulated steady-state area under the concentration-time curve during 24 h (AUC24h) and maximum drug concentration were comparable between paediatric patients and adults for canagliflozin 100- or 300-mg QD. Simulated steady-state AUC24h was similar between QD and BID dosing for the same canagliflozin total daily dose in paediatric patients and adults with T2DM. QD to BID bridging was supported by simulated HbA1c and change from baseline in HbA1c in paediatric patients. CONCLUSIONS:No canagliflozin dose adjustments are required alone or in combination with metformin to ensure similar plasma exposures between paediatric and adult patients with T2DM, as well as similar HbA1c lowering between QD and BID dosing in paediatric patients.

Efficacy and safety of ibrutinib 560 mg once daily or placebo combined with bendamustine and rituximab (BR) were assessed in patients with mantle cell lymphoma in a randomized phase 3 study (SHINE). The analysis described explores the ibrutinib population pharmacokinetics (PK) and exposure-response (E-R) relationships of selected efficacy and safety endpoints. Ibrutinib PK was consistent with previous assessments, characterized by an open two-compartment disposition model with sequential zero-first order oral absorption after a lag time. Ibrutinib treatment was efficacious in extending PFS versus placebo (HR: 0.75; 95% CI: 0.59 to 0.96), although similar OS, CRR, and ORR were observed. PFS benefit was similar across the quartiles of ibrutinib exposure, suggesting that systemic exposures obtained provide maximal clinical response. There was no association between ibrutinib exposure and incidence of major hemorrhage, Grade ≥ 3 liver function test abnormalities, Grade ≥ 3 neutropenia, Grade ≥ 2 diarrhea, treatment-emergent adverse events (TEAEs) leading to death, and TEAEs leading to ibrutinib dose reduction. However, the incidence of all Grade ≥ 3 TEAEs, all serious TEAEs, TEAEs leading to ibrutinib discontinuation, Grade ≥ 1 atrial fibrillation, any hemorrhage, and Grade ≥ 3 infection was higher in the ibrutinib than placebo arm. Of these, only atrial fibrillation and any hemorrhage increased with increasing exposure. Overall, ibrutinib 560 mg, combined with BR, consistently improves PFS across the ibrutinib exposure range evaluated. According to the results of the exposure-response analysis, for patients who develop specific toxicities, dose reduction according to the prescribing information may improve the ibrutinib tolerability while keeping adequate exposure to maintain efficacy.

ABSTRACTThis analysis assessed the relationship between the plasma concentrations of loperamide and its N‐desmethyl loperamide meta‐ bolite (M1) and the potential QT interval prolongation at therapeutic and supratherapeutic doses. The exposure–response analysis was performed using the data from healthy adults participating in a randomized, double‐blind, single‐dose, four‐way (placebo; loperamide 8 mg [therapeutic]; loperamide 48 mg [supratherapeutic]; moxifloxacin 400 mg [positive control]) crossover study. The electrocardiographic measurements extracted from 12‐lead digital Holter recordings were time‐matched to pharmacokinetic sampling of loperamide/M1. The primary response variable was placebo‐adjusted change from baseline in Fridericia‐corrected QT interval (ΔΔQTcF); the exposure variable was loperamide and/or M1 concentration. A total of 53 participants with 1408 time‐matched pharmacokinetic and ΔΔQTcF measurements was analyzed. Hysteresis between both loperamide and M1 concentrations and ΔΔQTcF was observed with supratherapeutic dose. The pre‐specified linear concentration‐ΔΔQTcF relationship was driven by M1 concentrations in the effect compartment. The model‐predicted mean ΔΔQTcF at the geometric mean of the maximum concentration in the effect compartment was −0.526 msec (90% CI, −1.51 to 0.462) following 8‐mg dose (2.1 ng/mL) and 6.06 msec (90% CI, 3.86–8.27) following 48‐mg dose (14.2 ng/mL). The upper bound of two‐sided 90% CI was < 10 msec for both doses. The sensitivity analysis considering loperamide concentrations in the effect compartment instead of M1 as input for the concentration‐ΔΔQTcF analysis confirmed these findings. The data showed that loperamide or M1 does not have an effect on cardiac repolarization that exceeds the threshold of regulatory concern in healthy participants at doses of 8 and 48 mg.

Supplementary Figure 2. Goodness-of-Fit Plots for the Tumor Growth Model

Supplementary Figure 1. Goodness-of-Fit Plots for the Pharmacokinetic Model

The efficacy of ponesimod and teriflunomide for the treatment of relapsing multiple sclerosis (MS) was compared in a randomized phase III trial. This study explores the exposure-response (E-R) relationships of efficacy end points (annualized relapse rate [ARR] and combined unique active lesions [CUALs]) of ponesimod observed in this trial. The E-R relationships were described using nonlinear mixed effects models for count data. The effect of baseline covariates (demography and prognostic factors) was also explored. Ponesimod 20 mg reduced ARR (primary end point) by 30.5% (95% confidence interval [CI]: 9.8% to 46.4%) and the number of CUALs by 56% (95% CI: 46% to 64%) between baseline and week 108 compared to teriflunomide 14 mg. The E-R analyses indicated a significant relationship between ARR and CUAL. In turn, CUAL was significantly related to ponesimod systemic exposure. Based on these relationships, the predicted reduction of ARR was relatively flat in the range of ponesimod systemic exposure achieved with the 20 mg clinical dose: the expected ARR decrease ranged from 28% (95% CI: 11% to 42%) at the 5th percentile of ponesimod exposure to 34% (95% CI: 19% to 47%) at the 95th percentile. No significant baseline covariates affected the ponesimod effects and, consequently, dosage adjustments are not warranted by these analyses. Although significant relationships were found between ARR and CUAL and between ponesimod exposure and CUAL, these analyses were supportive of the use of a flat 20 mg maintenance dose for ponesimod in adult patients with MS.

Purpose To model absolute neutrophil count (ANC) suppression in response to acute radiation (AR) exposure and evaluate ANC time course as a predictor of overall survival (OS) in response to AR exposure with or without treatment with granulocyte colony-stimulating factor in nonhuman primates. Methods Source data were obtained from two pivotal studies conducted in rhesus macaques exposed to 750 cGy of whole body irradiation on day 0 that received either placebo, daily filgrastim, or pegfilgrastim (days 1 and 8 after irradiation). Animals were observed for 60 days with ANC measured every 1 to 2 days. The population model of ANC response to AR and the link between observed ANC time course and OS consisted of three submodels characterizing injury due to radiation, granulopoiesis, and a time-to-event model of OS. Results The ANC response model accurately described the effects of AR exposure on the duration of neutropenia. ANC was a valid surrogate for survival because it explained 76% (95% CI, 41%–97%) and 73.2% (95% CI, 38.7%–99.9%) of the treatment effect for filgrastim and pegfilgrastim, respectively. Conclusion The current model linking radiation injury to neutropenia and ANC time course to OS can be used as a basis for translating these effects to humans.

Background: Acute Radiation Syndrome (ARS) is an acute illness caused by exposure to a high dose of penetrating radiation over a short period of time. Hematopoietic subsyndrome of ARS (HS-ARS) is characterized by dose dependent bone marrow depression leading to lymphopenia, neutropenia, thrombocytopenia, and anemia. Death due to HS-ARS from infection or excessive bleeding usually occurs within 2 to 3 weeks. Duration of thrombocytopenia is a predictor of overall survival (OS) in irradiated animal models, suggesting that a treatment for thrombocytopenia may increase survival in humans with HS-ARS. Romiplostim, a thrombopoietin receptor agonist, treatment resulted in prevention of severe thrombocytopenia and increased OS in irradiated animals. As human clinical trials for HS-ARS are not feasible or ethical, a romiplostim pharmacokinetic/pharmacodynamic (PKPD)-OS model for irradiated humans was developed. The model, informed by PKPD data in healthy/irradiated rhesus monkeys (RM) and healthy volunteers (HV), was subsequently used to predict the survival benefit of romiplostim relative to placebo in humans with HS-ARS. Methods: A PKPD model of romiplostim exposure-platelet response in healthy RM was developed and updated with radiation parameters to estimate the radiation effects on thrombopoiesis, on PKPD of romiplostim, and on differences in platelet response due to sex and body weight (Pritchard-Bell, ACoP11, 2020). A parametric time-to-event model relating platelet time course to OS in irradiated RM with/without romiplostim treatment was developed to quantify the impact of platelet response on OS (Jones, ACoP11, 2020). To extrapolate radiation effects to humans, romiplostim PKPD radiation parameters and radiation effects estimated from irradiated RM were applied to a romiplostim HV PKPD model. The extrapolated irradiated human PKPD model and irradiated RM OS model were combined and calibrated against published historical mortality data of humans exposed to acute radiation (Scott BR 1990). Following calibration, the extrapolated irradiated human PKPD and OS models were used to conduct simulations of OS in irradiated humans receiving romiplostim or placebo treatment. Relative survival benefit (RSB) of romiplostim, proportion of romiplostim treated humans surviving relative to placebo treated humans post radiation exposure, was summarized for various romiplostim doses (1 [initiation dose per label], 3, or 10 µg/kg [maximum dose per label]) and treatment scenarios (time after irradiation, adult vs pediatric) based on simulations of 10,000 humans/scenario randomized 1:1 to receive romiplostim or placebo. Results: An HV PKPD model of thrombopoiesis was updated to incorporate radiation specific scaling factors estimated from irradiated RM on romiplostim pharmacokinetic parameters and platelet lifespan, nonlinear inhibitory effect of radiation dose on megakaryocyte production, treatment effect of romiplostim on platelet lifespan, radiation sensitivity and radiation intensity. The extrapolated PKPD model for irradiated humans combined with the OS model from irradiated RM was calibrated with a scaling factor of 1.24 on radiation parameters to result in 50% survival 60 days post radiation exposure for humans exposed to a 3.07 Gy radiation dose (1 Gy/hr over 3.07 hr) consistent with published data. The calibrated OS model was used to simulate OS following romiplostim treatment 24 hours post irradiation and predicted 75% (RSB: 1.5), 80% (RSB: 1.6), and 87% (RSB: 1.7) survival on day 60, for romiplostim doses of at 1, 3, and 10 µg/kg, respectively compared to 50% survival for placebo. Percent survival was >75% when 10 µg/kg romiplostim was administered 24, 48, or 72 hours post irradiation and when administered to pediatric sub-groups (0-2, >2-6, >6-12, >12-18). Conclusions: A PKPD model of romiplostim exposure-response in irradiated humans was used to predict platelet response in humans with HS-ARS with/without treatment with romiplostim and was combined with an OS model to simulate 60-day survival in humans with HS-ARS. Simulations demonstrated the robust survival benefit of a single 10 µg/kg romiplostim dose compared with placebo in both adult and pediatric humans with HS-ARS following an acute radiation event. Selection of a romiplostim dose for treatment of HS-ARS is pending review of the irradiated RM studies and subsequent modeling and simulation analyses by the FDA. Disclosures Doshi: Amgen Inc: Current Employment. Jones:Amgen Inc: Current Employment. Pritchard-Bell:Amgen Inc: Current Employment. Park:Amgen Inc: Current Employment. Olsson Gisleskog:POG Pharmacometrics Ltd: Current Employment.

Acute exposure to high doses of radiation leads to severe myelosuppression, but few treatments are currently available to treat hematopoietic syndrome of acute radiation syndrome. Granulocyte colony stimulating factors (e.g., filgrastim) stimulate proliferation of neutrophil precursors and enhance mature neutrophil function. Owing to ethical constraints on conducting clinical research in lethally irradiated humans, we developed a model‐based strategy to integrate preclinical experience in irradiated nonhuman primates (NHPs) and other clinical myelosuppressive conditions to inform filgrastim dosing to treat hematopoietic syndrome of acute radiation syndrome. Models predicting neutrophil counts and overall survival based on drug exposures were calibrated and scaled from NHPs to adult and pediatric human subjects. Several scenarios were examined investigating variations in filgrastim doses, dose frequency, treatment initiation, and duration, as well as the effect of age and radiation dose rate. Model‐based simulations and established safety profiles supported that a subcutaneous filgrastim dose of 10 µg/kg once daily provides a significant survival benefit (50%) over placebo in both adults and children, provided that the treatment is initiated within 1–14 days after radiation exposure and lasts 2–3 weeks. For treatment durations of longer than 3 weeks, filgrastim treatment is not expected to provide significantly greater benefit. This survival benefit is expected to hold for the wide range of radiation doses and dose rates (0.01–1,000 Gy/hours) examined.

Aims The aims of this study were to develop a pharmacokinetic (PK) and PK‐pharmacodynamic (PK/PD) model of cinacalcet in adults and paediatrics with secondary hyperparathyroidism (SHPT) on dialysis, to test covariates of interest, and to perform simulations to inform dosing in paediatrics with SHPT. Methods Cinacalcet PK, intact parathyroid hormone (iPTH) and corrected calcium (cCa) time courses following multiple daily oral doses (1–300 mg) were modelled using a nonlinear mixed effects modelling approach using data from eight clinical studies. Model‐based trial simulations, using adult or paediatric titration schemas, predicted efficacy (iPTH change from baseline and proportion achieving iPTH decrease ≥30%) and safety (cCa change from baseline and proportion achieving cCa ≤8.4 mg/dL) endpoints at 24 weeks. Results Cinacalcet PK parameters were described by a two‐compartment linear model with delayed first‐order absorption‐elimination (apparent clearance = 287.74 L h −1 ). Simulations suggested that paediatric starting doses (1, 2.5, 5, 10 and 15 mg) would provide PK exposures less than or similar to a 30 mg adult dose. The titrated dose simulations suggested that the mean (prediction interval) proportion of paediatric and adult subjects achieving ≥30% reduction in iPTH from baseline at Week 24 was 49% (36%, 62%), and 70.1% (62.5%, 77%), respectively. Additionally, the mean (confidence interval) proportion of paediatric and adult subjects achieving cCa ≤8.4 mg dL −1 at Week 24 was 8% (2%, 18%) and 23.6% (17.5%, 30.5%), respectively. Conclusions Model‐based simulations showed that the paediatric cinacalcet starting dose (0.2 mg kg −1 ), titrated to effect, would provide the desired PD efficacy (PTH suppression <30%) while minimizing safety concerns (hypocalcaemia).

Objectives: Etelcalcetide is a novel calcium-sensing receptor (CaSR) activator currently in development for the treatment of sHPT. The objectives of this analysis were to develop a population PK/PD model relating etelcalcetide exposure to markers of efficacy (intact PTH, iPTH) and safety (corrected serum calcium, cCa); to evaluate covariate effects on PK/PD parameters; and to perform PK-PD simulations to support intravenous TIW administration of etelcalcetide.

Etelcalcetide is a novel calcimimetic in development for the treatment of secondary hyperparathyroidism (SHPT). A population pharmacokinetic/pharmacodynamic (PK/PD) model was developed relating etelcalcetide exposures to markers of efficacy (parathyroid hormone [PTH]) and safety (calcium) using data from three clinical studies. The semimechanistic model was developed that included allosteric activation pharmacology and understanding of calcium homeostasis. The temporal profiles for all biomarkers were well described by the model. The cooperativity constant was 4.94, confirming allosteric activation mechanism. Subjects with more severe disease (higher PTH baseline) were predicted to experience less pronounced reduction in PTH (percentage change from baseline), but more reduction in calcium (Ca; percentage change from baseline). There was no evidence that dose adjustment by any covariate was needed. Model‐based simulations provided quantitative support to several elements of dosing, such as starting dose, monitoring, and titration timing for registration trials.

Abstract Purpose: Rilotumumab is an investigational, fully human monoclonal antibody to hepatocyte growth factor. In a randomized phase II study, trends toward improved survival were observed with rilotumumab (7.5 or 15 mg/kg) plus epirubicin, cisplatin, and capecitabine (ECX) versus placebo plus ECX in gastric/gastroesophageal junction (GEJ) cancer patients, especially in MET-positive patients. Here, we quantitatively characterized the longitudinal exposure–response [tumor growth (TG) and overall survival (OS)] relationship for rilotumumab. Experimental Design: Rilotumumab concentrations, tumor sizes, and survival time from the phase II study were pooled to develop a longitudinal exposure versus TG model and parametric OS model that explored predictive/prognostic/treatment effects (MET expression, rilotumumab exposure, relative tumor size). Model evaluation included visual predictive checks, nonparametric bootstrap, and normalized prediction distribution errors. Simulations were undertaken to predict the relationship between rilotumumab dose and OS. Results: Rilotumumab exhibited linear time-independent pharmacokinetics not affected by MET expression. The TG model adequately described tumor size across arms. A Weibull distribution best described OS. Rilotumumab exposure and change in tumor size from baseline at week 24 were predictive of OS. MET-positive patients showed shorter survival and responded better to rilotumumab than MET-negative patients. Simulations predicted a median (95% confidence interval) HR of 0.38 (0.18–0.60) in MET-positive patients treated with 15 mg/kg rilotumumab Q3W. Conclusions: Rilotumumab plus ECX demonstrated concentration-dependent effects on OS, influenced by MET expression, and tumor size in gastric/GEJ cancer patients. These findings support the phase II testing of rilotumumab 15 mg/kg every 3 weeks in MET-positive gastric/GEJ cancer (RILOMET-1; NCT01697072). Clin Cancer Res; 21(11); 2453–61. ©2015 AACR.

2585 Background: Inhibitors of apoptosis proteins (IAPs) modulate multiple processes, including caspase activation and NF-kB signaling. Expression and/or overexpression of IAPs have been reported for a variety of tumor types and are correlated with tumor growth and resistance to apoptosis induced by standard chemo and radiation therapies. The small molecule Debio 1143 is an orally-active IAP antagonist able to promote apoptosis in tumor cells. Methods: In a first-in-human Phase I study in patients with advanced cancer, Debio 1143 was given orally once daily on days 1-5 every 2 or 3 weeks. Ten dose levels ranging from 5 mg to 900 mg were explored. Blood samples were taken on days 1-5 for PK (Debio 1143) and PD assessments (IAPs levels, blood markers of apoptosis and inflammation) with rich sampling at day 1 and day 5. A population PK model was built within NONMEM 7.2. Further to a graphical PK vs PD check, population PK/PD models were explored. Results: The PK of Debio 1143 was well described by a two-compartment model with two absorption pathways. Debio 1143 bioavailability appeared to decrease after repeated administrations, suggesting a possible time-dependent PK. Graphically, markers of target engagement (cIAP1 PBMCs levels) and apoptosis (caspase-3 generated cytokeratine-18 fragments plasma levels [CK18-M30]) showed changes with Debio 1143 PK. cIAP1 levels could be fitted using an indirect response model where the elimination of cIAP1 was stimulated by Debio 1143. The CK18-M30 data was best fitted by a model with a delayed effect, onsetting after the first day. Simulations of d14q21 treatment predicted a clear decrease in cIAP1, with small differences between 100 mg and 200 mg dosing. A CK18-M30 increase ranging from 20 to 200% is predicted at day 14 after 200 mg qd. Conclusions: Debio 1143PK is compatible with oral administration q5d21. A clear relationship between PK and markers of target engagement or apoptosis was evidenced over the dose range explored. Findings from the q14d21 simulations indicate a promising PK/PD relationship for such schedule. Results from ongoing studies including PK/safety and PK/efficacy exploration will also feed the model to support Debio 1143 treatment optimization.