Pembrolizumab: Role of Modeling and Simulation in Bringing a Novel Immunotherapy to Patients With Melanoma.

Recently, immunotherapy has yielded promising results in several cancer types. Contrary to the established classical chemotherapy-dosing paradigm, a maximum tolerated dose approach does not always produce better clinical outcomes for novel targeted therapies, as their efficacy is frequently robust at pharmacologically active doses below the maximum tolerated dose. Integrated safety and efficacy assessments are needed to inform clinical dose and trial design, and to support an early identification of potentially safe and efficacious combination treatments.

Using Model-Based "Learn and Confirm" to Reveal the Pharmacokinetics-Pharmacodynamics Relationship of Pembrolizumab in the KEYNOTE-001 Trial.

Evaluation of pharmacokinetic/pharmacodynamic (PK/PD) properties played an important role in the early clinical development of pembrolizumab. Because analysis of data from a traditional 3 + 3 dose-escalation design revealed several critical uncertainties, a model-based approach was implemented to better understand these properties. Based on anticipated scenarios for potency and PK nonlinearity, a follow-up study was designed and thoroughly evaluated. Execution of 14,000 virtual trials led to the selection and implementation of a robust design that extended the low-dose range by 200-fold. Modeling of the resulting data demonstrated that pembrolizumab PKs are nonlinear at <0.3 mg/kg every 3 weeks, but linear in the clinical dose range. Saturation of ex vivo target engagement in blood began at ≥1 mg/kg every 3 weeks, and a steady-state dose of 2 mg/kg every 3 weeks was needed to reach 95% target engagement, supporting examination of 2 mg/kg every 3 weeks in ongoing trials in melanoma and other advanced cancers.

Translational Pharmacokinetic/Pharmacodynamic Modeling of Tumor Growth Inhibition Supports Dose-Range Selection of the Anti-PD-1 Antibody Pembrolizumab.

Pembrolizumab, a humanized monoclonal antibody against programmed death 1 (PD-1), has a manageable safety profile and robust clinical activity against advanced malignancies. The lowest effective dose for evaluation in further dose-ranging studies was identified by developing a translational model from preclinical mouse experiments. A compartmental pharmacokinetic model was combined with a published physiologically based tissue compartment, linked to receptor occupancy as the driver of observed tumor growth inhibition. Human simulations were performed using clinical pharmacokinetic data, literature values, and in vitro parameters for drug distribution and binding. Biological and mathematical uncertainties were included in simulations to generate expectations for dose response. The results demonstrated a minimal increase in efficacy for doses higher than 2 mg/kg. The findings of the translational model were successfully applied to select 2 mg/kg as the lowest dose for dose-ranging evaluations.

Model-Based Characterization of the Pharmacokinetics of Pembrolizumab: A Humanized Anti-PD-1 Monoclonal Antibody in Advanced Solid Tumors.

Pembrolizumab, a potent antibody against programmed death 1 (PD-1) receptor, has shown robust antitumor activity and manageable safety in patients with advanced solid tumors. Its pharmacokinetic (PK) properties were analyzed with population PK modeling using pooled data from the KEYNOTE-001, -002, and -006 studies of patients with advanced melanoma, non-small cell lung cancer (NSCLC), and other solid tumor types. Pembrolizumab clearance was low and the volume of distribution small, as is typical for therapeutic antibodies. Identified effects of sex, baseline Eastern Cooperative Oncology Group performance status, measures of renal and hepatic function, tumor type and burden, and prior ipilimumab treatment on pembrolizumab exposure were modest and lacked clinical significance. Furthermore, simulations demonstrated the model has robust power to detect clinically relevant covariate effects on clearance. These results support the use of the approved pembrolizumab dose of 2 mg/kg every 3 weeks without dose adjustment in a variety of patient subpopulations.

Population Pharmacokinetic/Pharmacodynamic Modeling of Tumor Size Dynamics in Pembrolizumab-Treated Advanced Melanoma.

Pembrolizumab is a potent immune-modulating antibody active in advanced melanoma, as demonstrated in the KEYNOTE-001, -002, and -006 studies. Longitudinal tumor size modeling was pursued to quantify exposure-response relationships for efficacy. A mixture model was first developed based on an initial dataset from KEYNOTE-001 to describe four patterns of tumor growth and shrinkage. For subsequent analyses, tumor size measurements were adequately described by a single consolidated model structure that captured continuous tumor size with a combination of growth and regression terms, as well as a fraction of tumor responsive to therapy. This revised model structure provided a framework to efficiently evaluate the impact of covariates and pembrolizumab exposure. Both models indicated that exposure to the drug was not a significant predictor of tumor size response, demonstrating that the dose range evaluated (2 and 10 mg/kg every 3 weeks) is likely near or at the plateau of maximal response.

[Conservative treatment of open incomplete radial fracture in an adult horse]. / Conservatieve behandeling van een open onvolledige radiusfractuur bij een volwassen paard.

A non-displaced radialfracture of a horse was,diagnosed. The horse had an open fracture resulting from external trauma. A diagnosis was made on radiographs taken 48h after trauma. The horse was treated conservatively by box rest and Robert-Jones bandages. After 7 days the wound was opened to let the wound drainage necrotic material and small sequesters and was washed every other day. After 7 weeks, radiographs showed complete consolidation. Four months after the injury the horse was back to work at his former level and is still working two years after the incident.

Comparison of QTc data analysis methods recommended by the ICH E14 guidance and exposure-response analysis: case study of a thorough QT study of asenapine.

An assessment of the effects of asenapine on QTc interval in patients with schizophrenia revealed a discrepancy between the results obtained by two different methods: an intersection-union test (IUT) (as recommended in the International Conference on Harmonisation E14 guidance) and an exposure-response (E-R) analysis. Simulations were performed in order to understand and reconcile this discrepancy. Although estimates of the time-matched, placebo-corrected mean change in QTc from baseline (ddQTc) at peak plasma concentrations from the E-R analysis ranged from 2 to 5 ms per dose level, the IUT applied to simulated data from the E-R model yielded maximum ddQTc estimates of 7-10 ms for the various doses of asenapine. These results indicate that the IUT can produce biased estimates that may induce a high false-positive rate in individual thorough QTc trials. In such cases, simulations from an E-R model can aid in reconciling the results from the two methods and may support the use of E-R results as a basis for labeling.

Dose selection of corifollitropin alfa by modeling and simulation in controlled ovarian stimulation.

In controlled ovarian stimulation (COS), a single subcutaneous dose of corifollitropin alfa is used to initiate and sustain multifollicular growth for 7 days. The objective of this study was to determine the optimal dose of corifollitropin alfa. A pharmacokinetic model was developed to describe the time profile of corifollitropin alfa concentrations. Multiple parameters reflecting ovarian response were included in a pharmacokinetic-pharmacodynamic (PK-PD) model framework. An early decline in serum inhibin B was shown to be a sensitive marker for COS failure. Simulations were performed to select the lowest corifollitropin alfa dose that would result in a minimal cancellation rate: 100 microg for a group of women weighing 60 kg. With these doses, the predicted mean number of oocytes per started COS cycle was similar in the two groups, i.e., 12.1 and 13.2, respectively. The selected doses were tested in prospective clinical trials and were proven to be adequate.

Modeling and simulation of the time course of asenapine exposure response and dropout patterns in acute schizophrenia.

Modeling and simulation were utilized to characterize the efficacy dose response of sublingual asenapine in patients with schizophrenia and to understand the outcomes of six placebo-controlled trials in which placebo responses and dropout rates varied. The time course of total Positive and Negative Syndrome Scale (PANSS) scores was characterized for placebo and asenapine treatments in a pharmacokinetic-pharmacodynamic model in which the asenapine effect was described by an E(max) model, increasing linearly over the 6-week study period. A logistic regression model described the time course of dropouts, with previous PANSS value being the most important predictor. The last observation carried forward (LOCF) time courses were well described in simulations from the combined PANSS + dropout model. The observed trial outcomes were successfully predicted for all the placebo arms and the majority of the treatment arms. Although simulations indicated that the post hoc probability of success of the performed trials was low to moderate, these analyses demonstrated that 5 and 10 mg twice-daily (b.i.d.) doses of asenapine have similar efficacy.