Population pharmacokinetics and CD20 binding dynamics for mosunetuzumab in relapsed/refractory B-cell non-Hodgkin lymphoma.

Mosunetuzumab (Mosun) is a CD20xCD3 T-cell engaging bispecific antibody that redirects T cells to eliminate malignant B cells. The approved step-up dose regimen of 1/2/60/30 mg IV is designed to mitigate cytokine release syndrome (CRS) and maximize efficacy in early cycles. A population pharmacokinetic (popPK) model was developed from 439 patients with relapsed/refractory B-Cell Non-Hodgkin lymphoma receiving Mosun IV monotherapy, including fixed dosing (0.05-2.8 mg IV every 3 weeks (q3w)) and Cycle 1 step-up dosing groups (0.4/1/2.8-1/2/60/30 mg IV q3w). Prior to Mosun treatment, ~50% of patients had residual levels of anti-CD20 drugs (e.g., rituximab or obinutuzumab) from prior treatment. CD20 receptor binding dynamics and rituximab/obinutuzumab PK were incorporated into the model to calculate the Mosun CD20 receptor occupancy percentage (RO%) over time. A two-compartment model with time-dependent clearance (CL) best described the data. The typical patient had an initial CL of 1.08 L/day, transitioning to a steady-state CL of 0.584 L/day. Statistically relevant covariates on PK parameters included body weight, albumin, sex, tumor burden, and baseline anti-CD20 drug concentration; no covariate was found to have a clinically relevant impact on exposure at the approved dose. Mosun CD20 RO% was highly variable, attributed to the large variability in residual baseline anti-CD20 drug concentration (median = 10 µg/mL). The 60 mg loading doses increased Mosun CD20 RO% in Cycle 1, providing efficacious exposures in the presence of the competing anti-CD20 drugs. PopPK model simulations, investigating Mosun dose delays, informed treatment resumption protocols to ensure CRS mitigation.

Considerations for Industry-Preparing for the FDA Model-Informed Drug Development (MIDD) Paired Meeting Program.

A recent industry perspective published in this journal describes the benefits received by drug companies from participation in the MIDD Pilot Program. Along with the primary objectives of supporting good decision-making in drug development, there were substantial savings in time and development costs. Furthermore, many sponsors reported qualitative benefits such as new learnings and clarity on MIDD strategies and methodology that could be applied to other development programs. Based on the success of the Pilot Program, the FDA recently announced the continuation of the MIDD Paired Meeting Program as part of the Prescription Drug User Fee Act (PDUFA VII). In this report, we describe the collective experiences of industry participants in the MIDD Program to date, including all aspects of the process from meeting request submission to follow-up actions. The purpose is to provide future participants with information to optimize the value of the MIDD Program.

Pharmacologic characterization of atogepant: A potent and selective calcitonin gene-related peptide receptor antagonist.

BACKGROUND: The trigeminal sensory neuropeptide calcitonin gene-related peptide (CGRP) is identified as an essential element in migraine pathogenesis. METHODS: In vitro and in vivo studies evaluated pharmacologic properties of the CGRP receptor antagonist atogepant. Radioligand binding using 125I-CGRP and cyclic adenosine monophosphate (cAMP) accumulation assays were conducted in human embryonic kidney 293 cells to assess affinity, functional potency and selectivity. Atogepant in vivo potency was assessed in the rat nitroglycerine model of facial allodynia and primate capsaicin-induced dermal vasodilation (CIDV) pharmacodynamic model. Cerebrospinal fluid/brain penetration and behavioral effects of chronic dosing and upon withdrawal were evaluated in rats. RESULTS: Atogepant exhibited high human CGRP receptor-binding affinity and potently inhibited human α-CGRP-stimulated cAMP responses. Atogepant exhibited significant affinity for the amylin1 receptor but lacked appreciable affinities for adrenomedullin, calcitonin and other known neurotransmitter receptor targets. Atogepant dose-dependently inhibited facial allodynia in the rat nitroglycerine model and produced significant CIDV inhibition in primates. Brain penetration and behavioral/physical signs during chronic dosing and abrupt withdrawal were minimal in rats. CONCLUSIONS: Atogepant is a competitive antagonist with high affinity, potency and selectivity for the human CGRP receptor. Atogepant demonstrated a potent, concentration-dependent exposure/efficacy relationship between atogepant plasma concentrations and inhibition of CGRP-dependent effects.

Assessment of CYP3A-mediated drug interaction via cytokine (IL-6) elevation for mosunetuzumab using physiologically-based pharmacokinetic modeling.

Mosunetuzumab is a CD3/CD20 bispecific antibody. As an on-target effect, transient elevation of interleukin-6 (IL-6) occurs in early treatment cycles. A physiologically-based pharmacokinetic (PBPK) model was developed to assess potential drug interaction caused by IL-6 enzyme suppression on cytochrome P450 3A (CYP3A) during mosunetuzumab treatment. The model's performance in predicting IL-6 CYP3A suppression and subsequent drug-drug interactions (DDIs) was verified using existing clinical data of DDIs caused by chronic and transient IL-6 elevation. Sensitivity analyses were performed for a complete DDI risk assessment. The IL-6 concentration- and time-dependent CYP3A suppression during mosunetuzumab treatment was simulated using PBPK model with incorporation of in vitro IL-6 inhibition data. At clinically approved doses/regimens, the DDI at maximum CYP3A suppression was predicted to be a midazolam maximum drug concentration in plasma (Cmax ) and area under the plasma drug concentration-time curve (AUC) ratio of 1.17 and 1.37, respectively. At the 95th percentile of IL-6 concentration level or when gut CYP3A suppression was considered, the predicted DDI risk for mosunetuzumab remained low (<2-fold). The PBPK-based DDI predictions informed the mosunetuzumab product label to monitor, in early cycles, the concentrations and toxicities for sensitive CYP3A substrates with narrow therapeutic windows.

Mosunetuzumab monotherapy is active and tolerable in patients with relapsed/refractory diffuse large B-cell lymphoma.

As part of a phase 1 or 2 study, this single-arm expansion cohort established the efficacy and safety of mosunetuzumab monotherapy in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) (received ≥2 previous lines of therapy). Intravenous mosunetuzumab was administered with cycle (C) 1 step-up dosing for cytokine release syndrome (CRS) mitigation: C1 day (D) 1: 1 mg; C1D8 2 mg; C1D15 and C2D1: 60 mg; C3 + D1: 30 mg. Hospitalization was not mandatory. Patients with complete response (CR) completed treatment after C8; those with partial response or stable disease continued treatment for a total of 17 cycles. The primary end point was CR rate (best response), assessed against a historical control CR rate (20%) by independent review facility. Eighty-eight patients (73.9% de novo DLBCL; 26.1% transformed follicular lymphoma) were enrolled; all had received previous anthracycline and anti-CD20 therapy. Overall response and CR rates were 42.0% (95% confidence interval [CI], 31.6-53.1) and 23.9% (95% CI, 15.4-34.1), respectively; CR rate did not reach statistical significance vs the historical control (P = .36). Median time to first response was 1.4 months. Median progression-free survival was 3.2 months (95% CI, 2.2-5.3). The CR rate in 26 patients who received previous chimeric antigen receptor T-cell (CAR-T) therapy was 12%. CRS was one of the most common adverse events (26.1% of patients); predominantly grade 1 to 2 and primarily in C1. Four patients (4.5%) discontinued mosunetuzumab owing to adverse events. Mosunetuzumab demonstrated notable efficacy and a manageable safety profile in patients with R/R DLBCL, including those previously treated with CAR-Ts. This trial was registered at www.clinicaltrials.gov as #NCT02500407.

Systems-based digital twins to help characterize clinical dose-response and propose predictive biomarkers in a Phase I study of bispecific antibody, mosunetuzumab, in NHL.

Phase I oncology clinical trials often comprise a limited number of patients representing different disease subtypes who are divided into cohorts receiving treatment(s) at different dosing levels and schedules. Here, we leverage a previously developed quantitative systems pharmacology model of the anti-CD20/CD3 T-cell engaging bispecific antibody, mosunetuzumab, to account for different dosing regimens and patient heterogeneity in the phase I study to inform clinical dose/exposure-response relationships and to identify biological determinants of clinical response. We developed a novel workflow to generate digital twins for each patient, which together form a virtual population (VPOP) that represented variability in biological, pharmacological, and tumor-related parameters from the phase I trial. Simulations based on the VPOP predict that an increase in mosunetuzumab exposure increases the proportion of digital twins with at least a 50% reduction in tumor size by day 42. Simulations also predict a left-shift of the exposure-response in patients diagnosed with indolent compared to aggressive non-Hodgkin's lymphoma (NHL) subtype; this increased sensitivity in indolent NHL was attributed to the lower inferred values of tumor proliferation rate and baseline T-cell infiltration in the corresponding digital twins. Notably, the inferred digital twin parameters from clinical responders and nonresponders show that the potential biological difference that can influence response include tumor parameters (tumor size, proliferation rate, and baseline T-cell infiltration) and parameters defining the effect of mosunetuzumab on T-cell activation and B-cell killing. Finally, the model simulations suggest intratumor expansion of pre-existing T-cells, rather than an influx of systemically expanded T-cells, underlies the antitumor activity of mosunetuzumab.

Safety and efficacy of mosunetuzumab, a bispecific antibody, in patients with relapsed or refractory follicular lymphoma: a single-arm, multicentre, phase 2 study.

BACKGROUND: Mosunetuzumab is a CD20 × CD3 T-cell-engaging bispecific monoclonal antibody that redirects T cells to eliminate malignant B cells. In a phase 1 study, mosunetuzumab was well tolerated and active in patients with relapsed or refractory B-cell lymphoma. We, therefore, aimed to evaluate the safety and anti-tumour activity of fixed-duration mosunetuzumab in patients with relapsed or refractory follicular lymphoma who had received two or more previous therapies. METHODS: We conducted a single-arm, multicentre, phase 2 study at 49 centres in seven countries (Australia, Canada, Germany, South Korea, Spain, UK, and USA). All patients were aged 18 years or older with histologically confirmed follicular lymphoma (grade 1-3a) and an Eastern Cooperative Oncology Group performance status of 0-1. Patients had disease that was relapsed or refractory to two or more previous lines of treatment, including an anti-CD20 therapy and an alkylating agent. Intravenous mosunetuzumab was administered in 21-day cycles with cycle 1 step-up dosing: 1 mg on cycle 1 day 1, 2 mg on cycle 1 day 8, 60 mg on cycle 1 day 15 and cycle 2 day 1, and 30 mg on day 1 of cycle 3 and onwards. Patients with a complete response by investigator assessment using the International Harmonisation Project criteria completed treatment after cycle 8, whereas patients with a partial response or stable disease continued treatment for up to 17 cycles. The primary endpoint was independent review committee-assessed complete response rate (as best response) in all enrolled patients; the primary efficacy analysis compared the observed IRC-assessed complete response rate with a 14% historical control complete response rate in a similar patient population receiving the pan class I PI3K inhibitor copanlisib. Safety was assessed in all enrolled patients. This study is registered with ClinicalTrials.gov, number NCT02500407, and is ongoing. FINDINGS: Between May 2, 2019, and Sept 25, 2020, we enrolled 90 patients. As of the data cutoff date (Aug 27, 2021), the median follow-up was 18·3 months (IQR 13·8-23·3). According to independent review committee assessment, a complete response was recorded in 54 patients (60·0% [95% CI 49·1-70·2]). The observed complete response rate was significantly higher than the historical control complete response rate with copanlisib of 14% (p<0·0001), thereby meeting the primary study endpoint. Cytokine release syndrome was the most common adverse event (40 [44%] of 90 patients) and was predominantly grade 1 (23 [26%] of 90) and grade 2 (15 [17%]), and primarily confined to cycle 1. The most common grade 3-4 adverse events were neutropenia or neutrophil count decreased (24 [27%] of 90 patients), hypophosphataemia (15 [17%]), hyperglycaemia (seven [8%]), and anaemia (seven [8%]). Serious adverse events occurred in 42 (47%) of 90 patients. No treatment-related grade 5 (ie, fatal) adverse event occurred. INTERPRETATION: Fixed-duration mosunetuzumab has a favourable safety profile and induces high rates of complete remissions, allowing potential administration as an outpatient regimen, in patients with relapsed or refractory follicular lymphoma and two or more previous therapies. FUNDING: F Hoffmann-La Roche and Genentech.

Volumetric additive manufacturing of silica glass with microscale computed axial lithography.

Glass is increasingly desired as a material for manufacturing complex microscopic geometries, from the micro-optics in compact consumer products to microfluidic systems for chemical synthesis and biological analyses. As the size, geometric, surface roughness, and mechanical strength requirements of glass evolve, conventional processing methods are challenged. We introduce microscale computed axial lithography (micro-CAL) of fused silica components, by tomographically illuminating a photopolymer-silica nanocomposite that is then sintered. We fabricated three-dimensional microfluidics with internal diameters of 150 micrometers, free-form micro-optical elements with a surface roughness of 6 nanometers, and complex high-strength trusses and lattice structures with minimum feature sizes of 50 micrometers. As a high-speed, layer-free digital light manufacturing process, micro-CAL can process nanocomposites with high solids content and high geometric freedom, enabling new device structures and applications.

Single-Agent Mosunetuzumab Shows Durable Complete Responses in Patients With Relapsed or Refractory B-Cell Lymphomas: Phase I Dose-Escalation Study.

PURPOSE: Mosunetuzumab is a bispecific antibody targeting CD20 and CD3 that redirects T cells to engage and eliminate malignant B cells and is being developed for relapsed or refractory (R/R) B-cell non-Hodgkin lymphomas (B-NHLs). METHODS: This first-in-human trial (ClinicalTrials.gov identifier: NCT02500407) evaluated the safety and tolerability and efficacy of mosunetuzumab in patients with R/R B-NHL and established the recommended phase II dose. Data from dose escalation are presented. Single-agent mosunetuzumab was administered intravenously in 3-week cycles, at full dose in cycle 1 day 1 (group A) or with ascending (step-up) doses during cycle 1 on days 1, 8, and 15 (group B), for eight or 17 cycles on the basis of tumor response. RESULTS: Two hundred thirty patients were enrolled. Doses up to 2.8 mg and 60 mg were assessed in groups A and B, respectively; maximum tolerated dose was not exceeded. In group B (n = 197), common adverse events (≥ 20% of patients) were neutropenia (28.4%), cytokine release syndrome (27.4%), hypophosphatemia (23.4%), fatigue (22.8%), and diarrhea (21.8%). Cytokine release syndrome was mostly low-grade (grade ≥ 3: 1.0%) and mainly confined to cycle 1. Across the doses investigated (group B), best overall response rates were 34.9% and 66.2% in patients with aggressive and indolent B-NHL, respectively, and complete response rates were 19.4% and 48.5%. Among patients with a complete response, the median duration of response was 22.8 months (95% CI, 7.6 to not estimable) and 20.4 (95% CI, 16 to not estimable) in patients with aggressive and indolent B-NHL, respectively. CONCLUSION: Mosunetuzumab, administered with step-up dosing, has a manageable safety profile and induces durable complete responses in R/R B-NHL. The expansion stage of the study is ongoing at the dose level of 1/2/60/60/30 mg selected for further study.

Quantitative Clinical Pharmacology of T-Cell Engaging Bispecifics: Current Perspectives and Opportunities.

T-cell directing/engaging bispecifics (TDBs) enable a powerful mode of action by activating T-cells through the creation of artificial immune synapses. Their pharmacological response involves the dynamic inter-relationships among T-cells, tumor cells, and TDBs. This results in complex and challenging issues in understanding pharmacokinetics, tissue distribution, target engagement, and exposure-response relationship. Dosing strategy plays a crucial role in determining the therapeutic window of TDBs because of the desire to maximize therapeutic efficacy in the context of known mechanism-related adverse events, such as cytokine release syndrome and neurological adverse events. Such adverse events are commonly reported as the most prominent events during the initial treatment cycles and dissipate over time. Therefore, the kinetic characterization of the inter-relationships between exposure/target engagement and safety/efficacy outcomes is crucial in designing the optimal dosing regimen to maximize the benefit/risk of TDB agents. In this review, we discuss the key clinical pharmacological considerations in drug discovery and development for TDBs and provide a summary of TDBs currently in clinical development. We also propose forward-looking perspectives and opportunities to derive insights through quantitative clinical pharmacology approaches.

Mitigating the risk of cytokine release syndrome in a Phase I trial of CD20/CD3 bispecific antibody mosunetuzumab in NHL: impact of translational system modeling.

Mosunetuzumab, a T-cell dependent bispecific antibody that binds CD3 and CD20 to drive T-cell mediated B-cell killing, is currently being tested in non-Hodgkin lymphoma. However, potent immune stimulation with T-cell directed therapies poses the risk of cytokine release syndrome, potentially limiting dose and utility. To understand mechanisms behind safety and efficacy and explore safety mitigation strategies, we developed a novel mechanistic model of immune and antitumor responses to the T-cell bispecifics (mosunetuzumab and blinatumomab), including the dynamics of B- and T-lymphocytes in circulation, lymphoid tissues, and tumor. The model was developed and validated using mosunetuzumab nonclinical and blinatumomab clinical data. Simulations delineated mechanisms contributing to observed cell and cytokine (IL6) dynamics and predicted that initial step-fractionated dosing limits systemic T-cell activation and cytokine release without compromising tumor response. These results supported a change to a step-fractionated treatment schedule of mosunetuzumab in the ongoing Phase I clinical trial, enabling safer administration of higher doses.

Tumor Time-Course Predicts Overall Survival in Non-Small Cell Lung Cancer Patients Treated with Atezolizumab: Dependency on Follow-Up Time.

The large heterogeneity in response to immune checkpoint inhibitors is driving the exploration of predictive biomarkers to identify patients who will respond to such treatment. We extended our previously suggested modeling framework of atezolizumab pharmacokinetics, IL18, and tumor size (TS) dynamics, to also include overall survival (OS). Baseline and model-derived variables were explored as predictors of OS in 88 patients with non-small cell lung cancer treated with atezolizumab. To investigate the impact of follow-up length on the inclusion of predictors of OS, four different censoring strategies were applied. The time-course of TS change was the most significant predictor in all scenarios, whereas IL18 was not significant. Identified predictors of OS were similar regardless of censoring strategy, although OS was underpredicted when patients were censored 5 months after last dose. The study demonstrated that the tumor-time course-OS relationship could be identified based on early phase I data.

Characterization of Ubrogepant: A Potent and Selective Antagonist of the Human Calcitonin Gene‒Related Peptide Receptor.

A growing body of evidence has implicated the calcitonin gene-related peptide (CGRP) receptors in migraine pathophysiology. With the recent approval of monoclonal antibodies targeting CGRP or the CGRP receptor, the inhibition of CGRP-mediated signaling has emerged as a promising approach for preventive treatments of migraine in adults. However, there are no small-molecule anti-CGRP treatments available for treating migraine. The current studies aimed to characterize the pharmacologic properties of ubrogepant, an orally bioavailable, CGRP receptor antagonist for the acute treatment of migraine. In a series of ligand binding assays, ubrogepant exhibited a high binding affinity for native (K i=0.067 nM) and cloned human (K i=0.070 nM) and rhesus CGRP receptors (K i=0.079 nM), with relatively lower affinities for CGRP receptors from rat, mouse, rabbit and dog. In functional assays, ubrogepant potently blocked human α-CGRP stimulated cAMP response (IC50 of 0.08 nM) and exhibited highly selective antagonist activity for the CGRP receptor compared with other members of the human calcitonin receptor family. Furthermore, the in vivo CGRP receptor antagonist activity of ubrogepant was evaluated in a pharmacodynamic model of capsaicin-induced dermal vasodilation (CIDV) in rhesus monkeys and humans. Results demonstrated that ubrogepant produced concentration-dependent inhibition of CIDV with a mean EC50 of 3.2 and 2.6 nM in rhesus monkeys and humans, respectively. Brain penetration studies with ubrogepant in monkeys showed a CSF/plasma ratio of 0.03 and low CGRP receptor occupancy. In summary, ubrogepant is a competitive antagonist with high affinity, potency, and selectivity for the human CGRP receptor. SIGNIFICANCE STATEMENT: Ubrogepant is a potent, selective, orally delivered, small-molecule competitive antagonist of the human calcitonin generelated peptide receptor. In vivo studies using a pharmacodynamic model of capsaicin-induced dermal vasodilation (CIDV) in rhesus monkeys and humans demonstrated that ubrogepant produced concentration-dependent inhibition of CIDV, indicating a predictable pharmacokinetic-pharmacodynamic relationship.

Ubrogepant Is Not Associated With Clinically Meaningful Elevations of Alanine Aminotransferase in Healthy Adult Males.

Ubrogepant is a novel, oral calcitonin gene-related peptide (CGRP) receptor antagonist intended for the acute treatment of migraine attacks. Ubrogepant has a chemical structure distinct from previous small-molecule CGRP receptor antagonists that were associated with elevated serum alanine aminotransferase (ALT) in clinical trials. Here, we report overall and hepatic safety data from two placebo-controlled phase I trials of ubrogepant, spray-dried oral compressed tablet (SD-OCT) in healthy male volunteers. Trial A was a pharmacokinetic (PK) trial of single (100-400 mg) and multiple (40-400 mg) ascending doses. Trial B was a dedicated hepatic safety trial assessing daily use of ubrogepant 150 mg for 28 days. Serum ALT (as hepatotoxicity biomarker) and PK data are reported. Ubrogepant was well-tolerated in both trials, with a low incidence of adverse events that did not differ greatly from placebo. Changes in mean ALT levels were minimal and similar to placebo. Over 28 days of treatment, the mean percentage change in ALT from baseline was < 5% at all time points. No participant in either trial demonstrated ALT ≥ 3× upper limit of normal at any time. Ubrogepant SD-OCT demonstrated linear PK appropriate for acute treatment of migraine, with rapid uptake (time of maximum plasma concentration (tmax ): 2-3 hours) and no accumulation with daily use. Overall, there was no evidence of ubrogepant-associated hepatotoxicity with daily doses up to 400 mg for 10 days or with daily ubrogepant 150 mg for 28 days. Supratherapeutic dosing is a useful strategy for characterizing hepatic safety in early drug development.

Making Better Dose Decisions: Using Exposure-Response Modeling to Integrate Efficacy Outcome of Two Phase IIb Clinical Trials of Ubrogepant for Migraine Treatment.

Ubrogepant (MK-1602) is a novel, oral, calcitonin gene-related peptide receptor antagonist in clinical development with positive phase III outcomes for acute treatment of migraine. This paper describes the population exposure-response (E-R) modeling and simulations, which were used to inform the phase III dose-selection rationale, based on ~ 800 participants pooled across two phase IIb randomized dose-finding clinical trials. The E-R model describes the placebo and ubrogepant treatment effects based on migraine pain end points (2-hour pain relief and 2-hour pain freedom) at various dose levels. Sensitivity analyses were conducted to evaluate various assumptions of placebo response in light of the high placebo response observed in one phase II trial. A population pharmacokinetic model describing the effect of formulations was included in the E-R simulation framework to assess potential dose implications of a formulation switch from phase II to phase III. Model-based simulations predict that a dose of 25 mg or higher is likely to achieve significantly better efficacy than placebo with desirable efficacy levels. The understanding of E-R helped support the dose selection for the phase III clinical trials.

A PK/PD Analysis of Circulating Biomarkers and Their Relationship to Tumor Response in Atezolizumab-Treated non-small Cell Lung Cancer Patients.

To assess circulating biomarkers as predictors of antitumor response to atezolizumab (anti-programmed death-ligand 1 (PD-L1), Tecentriq) serum pharmacokinetic (PK) and 95 plasma biomarkers were analyzed in 88 patients with relapsed/refractory non-small cell lung cancer (NSCLC) receiving atezolizumab i.v. q3w (10-20 mg/kg) in the PCD4989g phase I clinical trial. Following exploratory analyses, two plasma biomarkers were chosen for further study and correlation with change in tumor size (the sum of the longest diameter) was assessed in a pharmacokinetic/pharmacodynamic (PK/PD) tumor modeling framework. When longitudinal kinetics of biomarkers and tumor size were modeled, tumor shrinkage was found to significantly correlate with area under the curve (AUC), baseline factors (metastatic sites, liver metastases, and smoking status), and relative change in interleukin (IL)-18 level from baseline at day 21 (RCFBIL -18,d21 ). Although AUC was a major predictor of tumor shrinkage, the effect was estimated to dissipate with an average half-life of 80 days, whereas RCFBIL -18,d21 seemed relevant to the duration of the response.

Population PK Analyses of Ubrogepant (MK-1602), a CGRP Receptor Antagonist: Enriching In-Clinic Plasma PK Sampling With Outpatient Dried Blood Spot Sampling.

Merck & Co., Inc. (Kenilworth, New Jersey) has recently published an integrated strategy for implementation of dried blood spots (DBS) in late-stage trials for population pharmacokinetic (PK) modeling. We applied this strategy for another late-stage clinical program: ubrogepant (MK-1602), a novel oral calcitonin gene-related peptide receptor antagonist for acute treatment of migraine. At the time of implementation, ubrogepant was entering phase 2 development. DBS was implemented to acquire PK information proximal to an acute migraine event to enable exposure-response modeling. The clinical endpoint was a spontaneous event, which generally occurs outside a clinic visit. Thus, an innovative feature of this trial was facilitating DBS in an outpatient setting. In vitro and bioanalytical tests established initial method feasibility and suitability for further evaluations in the clinic. A quantitative relationship was developed between blood and plasma concentrations from concurrently collected samples in a phase 1 (healthy subjects) and phase 2 (target patient population) study using graphical and population PK approaches. This integrated information was presented to the Food and Drug Administration for regulatory input. Following regulatory concurrence, DBS was poised for use in further clinical studies. Population PK modeling was used to dissect sources of variability contributing to DBS collection in the outpatient setting. What has been learned from this program has informed the broader integrated strategy of Merck & Co., Inc. (Kenilworth, NJ) for DBS implementation in clinical trials and research to improve the precision of PK data collected in an outpatient setting.

A survey of new oncology drug approvals in the USA from 2010 to 2015: a focus on optimal dose and related postmarketing activities.

The maximally tolerated dose (MTD) of cytotoxic agents has historical precedence in treating cancer, as it was believed that dose and therapeutic effect are intrinsically linked and that the MTD would provide greatest therapeutic value. With molecularly targeted agents, the premise of preventing toxicity to normal tissues while modulating tumor growth provides a potential for an increased therapeutic window. Results from these targeted agents suggest we are entering an era of chronic cancer management, which will require design of regimens with long-term tolerability. A corresponding switch from MTD-based (toxicity-driven) dosing strategies to alternative paradigms is also expected. The challenge with these targeted agents is to fully understand the complex relationship between pharmacokinetics, pharmacodynamics, and safety and efficacy in early-stage trials, so that the optimal dose and schedule for registration trials may be identified. This review provides a systematic survey of the applications submitted to the United States Food and Drug Administration (FDA) for oncology indications, from 2010 through early 2015, and summarizes the dose selection rationale for registrational trials, the relationship of the MTD to outcomes of the final label dose, the postmarketing requirements or commitments related to dose optimization activities, the role of biomarkers, and typical exposure-response modeling methods.