Quantification of Radiation Injury on Neutropenia and the Link between Absolute Neutrophil Count Time Course and Overall Survival in Nonhuman Primates Treated with G-CSF.

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.

Prediction of Survival Benefit of Filgrastim in Adult and Pediatric Patients With Acute Radiation Syndrome.

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.

Population Pharmacokinetic and Pharmacodynamic Modeling of Etelcalcetide in Patients with Chronic Kidney Disease and Secondary Hyperparathyroidism Receiving Hemodialysis.

INTRODUCTION: Etelcalcetide is a novel calcimimetic that binds and activates calcium-sensing receptors (CaSRs) for the treatment of secondary hyperparathyroidism (SHPT). METHODS: To assess titrated dosing regimens, population pharmacokinetic (PK) and PK/pharmacodynamic (PKPD) modeling of etelcalcetide was performed using NONMEM 7.2. In this analysis, plasma etelcalcetide, serum parathyroid hormone (PTH) and calcium (Ca) concentration-time data were collected from five phase I, II, and III clinical trials following single or multiple intravenous doses of etelcalcetide ranging from 2.5 to 60 mg. A semi-mechanistic model was used to describe the relationship between etelcalcetide, PTH, and Ca. This model included the role of PTH in Ca regulation, the feedback of Ca onto PTH production via the CaSR, and the activity of etelcalcetide plasma levels in increasing the sensitivity of the CaSR to Ca via the cooperative binding model. The impact of relevant covariates was evaluated by stepwise forward/backward selection. Model evaluation was based on standard goodness-of-fit plots and prediction-corrected visual predictive checks (pcVPCs). Simulation was conducted to evaluate titrated dosing regimens. RESULTS AND DISCUSSION: The time courses of etelcalcetide, PTH, and Ca were well-described by the model. The clearance and central volume of distribution (Vc) of etelcalcetide were 0.472 L/h and 49.9 L, respectively, while estimates of the turnover half-lives of PTH and Ca were 0.36 and 23 h, respectively. The extent of interindividual variability in model parameters was low to moderate (6-67%), and no covariates were identified as significant predictors of PK and PD variability. pcVPCs confirmed the predictive ability of the model. CONCLUSIONS: The current analysis confirms the putative mechanism of action of etelcalcetide as an allosteric activator of CaSR. Simulations showed that dose titration of etelcalcetide, rather than fixed dose, is needed to effectively decrease the PTH level in patient populations.

Rilotumumab exposure-response relationship in patients with advanced or metastatic gastric cancer.

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).

Pharmacokinetics of melagatran and the effect on ex vivo coagulation time in orthopaedic surgery patients receiving subcutaneous melagatran and oral ximelagatran: a population model analysis.

OBJECTIVE: Ximelagatran, an oral direct thrombin inhibitor, is rapidly bioconverted to melagatran, its active form. The objective of this population analysis was to characterise the pharmacokinetics of melagatran and its effect on activated partial thromboplastin time (APTT), an ex vivo measure of coagulation time, in orthopaedic surgery patients sequentially receiving subcutaneous melagatran and oral ximelagatran as prophylaxis for venous thromboembolism. To support the design of a pivotal dose-finding study, the impact of individualised dosage based on bodyweight and calculated creatinine clearance was examined. DESIGN AND METHODS: Pooled data obtained in three small dose-guiding studies were analysed. The patients received twice-daily administration, with either subcutaneous melagatran alone or a sequential regimen of subcutaneous melagatran followed by oral ximelagatran, for 8-11 days starting just before initiation of surgery. Nonlinear mixed-effects modelling was used to evaluate rich data of melagatran pharmacokinetics (3326 observations) and the pharmacodynamic effect on APTT (2319 observations) in samples from 216 patients collected in the three dose-guiding trials. The pharmacokinetic and pharmacodynamic models were validated using sparse data collected in a subgroup of 319 patients enrolled in the pivotal dose-finding trial. The impact of individualised dosage on pharmacokinetic and pharmacodynamic variability was evaluated by simulations of the pharmacokinetic-pharmacodynamic model. RESULTS: The pharmacokinetics of melagatran were well described by a one-compartment model with first-order absorption after both subcutaneous melagatran and oral ximelagatran. Melagatran clearance was correlated with renal function, assessed as calculated creatinine clearance. The median population clearance (creatinine clearance 70 mL/min) was 5.3 and 22.9 L/h for the subcutaneous and oral formulations, respectively. The bioavailability of melagatran after oral ximelagatran relative to subcutaneous melagatran was 23%. The volume of distribution was influenced by bodyweight. For a patient with a bodyweight of 75kg, the median population estimates were 15.5 and 159L for the subcutaneous and oral formulations, respectively. The relationship between APTT and melagatran plasma concentration was well described by a power function, with a steeper slope during and early after surgery but no influence by any covariates. Simulations demonstrated that individualised dosage based on creatinine clearance or bodyweight had no clinically relevant impact on the variability in melagatran pharmacokinetics or on the effect on APTT. CONCLUSIONS: The relatively low impact of individualised dosage on the pharmacokinetic and pharmacodynamic variability of melagatran supported the use of a fixed-dose regimen in the studied population of orthopaedic surgery patients, including those with mild to moderate renal impairment.