A Phase I, Open-label, Randomized, Crossover Study of the Relative Bioavailability of Capsule and Granule Formulations of Selumetinib.

PURPOSE: Selumetinib (ARRY-142886) is an oral, potent, and highly selective allosteric mitogen-activated protein kinase kinase 1/2 inhibitor approved for the treatment of pediatric patients (≥2 years of age) with neurofibromatosis type 1 who have symptomatic, inoperable plexiform neurofibromas. This Phase I crossover study (NCT03649165) evaluated the pharmacokinetic properties and palatability of a new granule formulation of selumetinib. METHODS: Healthy volunteers were randomized to 1 of 2 sequences; selumetinib granule (25 mg) followed by selumetinib capsules (50 mg [2 × 25 mg]) and vice versa. The primary end point was the pharmacokinetic properties of the 2 formulations. Secondary end points included safety and tolerability of single selumetinib doses and palatability of the granule formulation. FINDINGS: Of the 24 enrolled volunteers (mean age, 33.2 years; range 23-44 years), all were male and 20 (83%) were Black/African American. Under fasted conditions for the granule versus capsule, geometric mean ratios for the dose-normalized Cmax and AUC0-∞ were 0.654 (90% CI, 0.581-0.736) and 0.865 (90% CI, 0.811-0.922), respectively. Absorption of selumetinib was similar between granule and capsule formulation, with a median time to Cmax of 1.73 hours and 1.14 hours, respectively. Adverse event incidence was low (n = 6 in both groups), and most events were mild. Palatability was acceptable, with volunteers indicating that they would take the granule formulation again. IMPLICATIONS: These findings support further research into the selumetinib granule formulation, with the aim of producing an alternative formulation for younger children or patients unable to swallow capsules. CLINICALTRIALS: gov identifier: NCT03649165.

Effect of food on capsule and granule formulations of selumetinib.

Selumetinib is an oral, potent, and highly selective allosteric MEK1/2 inhibitor approved for the treatment of pediatric patients (aged ≥2 years) with neurofibromatosis type 1 who have symptomatic, inoperable plexiform neurofibromas. A granule formulation of selumetinib is under development to improve dosing precision for younger pediatric patients who may be unable to swallow capsules. This phase I crossover study investigated the effect of food on the pharmacokinetic (PK) properties of selumetinib capsule and granule formulations. Healthy male volunteers were randomized to receive selumetinib granules (25 mg) or capsules (50 mg [2 × 25 mg]) under fasted or fed conditions (a low-fat meal). Plasma concentrations and PK parameters were determined less than or equal to 48 h postdose. Safety and tolerability were assessed. Across 24 volunteers, selumetinib was absorbed quickly, with a time to maximum concentration (Tmax ) ranging from ~1-3 h. Geometric mean ratios (90% confidence interval [CI]) for maximum plasma concentration (Cmax ) in the fed versus fasted state were 0.61 (90% CI 0.51-0.72) and 0.40 (90% CI 0.33-0.48) for the granule and capsule formulations, respectively, whereas geometric mean ratios (90% CI) for area under the plasma drug concentration-time curve in the fed versus fasted state were 0.97 (90% CI 0.91-1.02) and 0.62 (90% CI 0.55-0.70), respectively. Levels of less than 10% conversion to the N-desmethyl selumetinib metabolite were observed. Selumetinib was well-tolerated, with only a few adverse events of mild intensity reported. Selumetinib administration with a low-fat meal resulted in lower Cmax and longer Tmax for both formulations versus fasted conditions. However, area under the curve for selumetinib granules was similar under fasted and fed conditions. Overall, these findings support further development of this formulation for pediatric patients.

Concentration-QT modelling in early clinical oncology settings: Simulation evaluation of performance.

AIMS: Concentration-QT modelling (C-QTc) of first-in-human data has been rapidly adopted as the primary evaluation of QTc interval prolongation risk. Here, we evaluate the performance of C-QTc in early oncology settings (i.e., patients, no placebo or supratherapeutic dose, 3 + 3 designs). METHODS: C-QTc performance was evaluated across three oncology scenarios using a simulation-estimation approach: (scen1) typical dose-escalation testing six dose levels (n = 21); (scen2) small dose-escalation testing two dose levels (n = 9); (scen3) expansion cohorts at one dose level (n = 6-140). True ΔΔQTc effects ranged from 3 ms ("no effect") to 20 ms ("large effect"). Performance was assessed based on the upper limit of the ΔQTc two-sided 90% CI against a threshold of 10 or 20 ms. RESULTS: The performance against the 10 ms threshold was limited based on C-QTc data from typical dose escalation (scen1) and acceptable performance was observed only for relatively large expansions (n ≥ 45; scen3). Performance against the 20 ms threshold was acceptable based on C-QTc data from a typical dose escalation (scen1) or dose expansion cohort n > 10 (scen3). In general, pooling C-QTc data from dose escalation and expansion cohorts substantially improved the performance and reduced the ΔQTc 90% CI width. CONCLUSION: C-QTc performance appeared limited using a 10 ms threshold, but acceptable against a 20 ms threshold. Selection of threshold may be informed by the benefit-risk balance in a specific disease area. Acceptable precision (i.e., confidence intervals) of the estimated ΔQTc, regardless of its magnitude, can be facilitated by pooling data from dose escalation and expansion cohorts.

Physiologically Based Pharmacokinetic Modeling for Selumetinib to Evaluate Drug-Drug Interactions and Pediatric Dose Regimens.

Selumetinib (ARRY-142886), an oral, potent and highly selective allosteric mitogen-activated protein kinase kinase 1/2 inhibitor, is approved by the US Food and Drug Administration for the treatment of pediatric patients aged ≥2 years with neurofibromatosis type 1 with symptomatic, inoperable plexiform neurofibromas. A physiologically based pharmacokinetic (PBPK) model was constructed to predict plasma concentration-time profiles of selumetinib, and to evaluate the impact of coadministering moderate cytochrome P450 (CYP) 3A4/2C19 inhibitors/inducers. The model was also used to extrapolate pharmacokinetic exposures from older children with different body surface area to guide dosing in younger children. This model was built based on physiochemical data and clinical in vivo drug-drug interaction (DDI) studies with itraconazole and fluconazole, and verified against data from an in vivo rifampicin DDI study and an absolute bioavailability study. The pediatric model was updated by changing system-specific input parameters using the Simcyp pediatric module. The model captured the observed selumetinib pharmacokinetic profiles and the interactions with CYP inhibitors/inducers. The predictions from the PBPK model showed a DDI effect of 30% to 40% increase or decrease in selumetinib exposure when coadministered with moderate CYP inhibitors or inducers, respectively, which was used to inform dose management and adjustments. The pediatric PBPK model was applied to simulate exposures in specific body surface area brackets that matched those achieved with a 25 mg/m2 dose in SPRINT clinical trials. The pediatric PBPK model was used to guide the dose for younger patients in a planned pediatric clinical study.

Population pharmacokinetics and exposure-response of selumetinib and its N-desmethyl metabolite in pediatric patients with neurofibromatosis type 1 and inoperable plexiform neurofibromas.

PURPOSE: Selumetinib (ARRY-142886) is a potent, selective, MEK1/2 inhibitor approved in the US for the treatment of children (≥ 2 years) with neurofibromatosis type 1 (NF1) and symptomatic, inoperable plexiform neurofibromas (PN). We characterized population pharmacokinetics (PK) of selumetinib and its active N-desmethyl metabolite, evaluated exposure-safety/efficacy relationships, and assessed the proposed therapeutic dose of 25 mg/m2 bid based on body surface area (BSA) in this patient population. METHODS: Population PK modeling and covariate analysis (demographics, formulation, liver enzymes, BSA, patients/healthy volunteers) were based on pooled PK data from adult healthy volunteers (n = 391), adult oncology patients (n = 83) and pediatric patients with NF1-PN (n = 68). Longitudinal selumetinib/metabolite exposures were predicted with the final model. Exposure-safety/efficacy analyses were applied to pediatric patients (dose levels: 20, 25, 30 mg/m2 bid). RESULTS: Selumetinib and metabolite concentration-time courses were modeled using a joint compartmental model. Typical selumetinib plasma clearance was 11.6 L/h (95% CI 11.0-12.2 L/ h). Only BSA had a clinically relevant (> 20%) impact on exposure, supporting BSA-based administration in children. Selumetinib and metabolite exposures in responders (≥ 20% PN volume decrease from baseline) and non-responders were largely overlapping, with medians numerically higher in responders. No clear relationships between exposure and safety events were established; exposure was not associated with key adverse events (AEs) including rash acneiform, diarrhea, vomiting, and nausea. CONCLUSION: Findings support continuous selumetinib 25 mg/m2 bid in pediatric patients. Importantly, the updated dosing nomogram ensures that patients will receive a clinically active, yet tolerable, dose regardless of differences in BSA and allows dose reductions, if necessary.

QT Prolongation Risk Assessment in Oncology: Lessons Learned From Small-Molecule New Drug Applications Approved During 2011-2019.

The International Conference on Harmonisation (ICH) E14 guidance provides recommendations to assess the potential of a drug to delay cardiac repolarization (QT prolongation), including general guidelines for cases in which a conventional thorough QT study (TQT) might not be feasible. These guidelines have been updated through the ICH question-and-answer process, with the last revision in 2015. We conducted a comprehensive analysis of QT prolongation evaluation of small-molecule new drug applications (NDAs) approved in oncology between 2011 and 2019 to extract learning experience. The following information was analysed: (1) methods to assess QT prolongation, (2) electrocardiogram data collection, (3) QT-related label language, and (4) postmarketing requirements. Overall, every NDA included a QT assessment. The concentration-QTc modeling approach (studies in which QT was not the primary objective) was the most common approach (59%), followed by the TQT and the dedicated QT studies (20% and 21%, respectively). The quality and quantity of the QT assessments were different across NDAs, which suggested relatively large flexibility in the designs and approaches to characterizing QT liability. The QT-related label language reflected the QT results, but also the safety events and the study design limitations because of the oncology settings. There was no delay in approval because of less robust QTc studies as long as the benefit-to-risk ratio of the drug was acceptable, and the implications were reflected in the label. This work offers a structured understanding of the QT evaluation criteria by the Food and Drug Administration and can assist in planning QT prolongation assessments in oncology settings.