Use of Pharmacokinetic and Pharmacodynamic Data to Develop the CDK4/6 Inhibitor Ribociclib for Patients with Advanced Breast Cancer.

Ribociclib is an orally bioavailable, selective cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor. CDK4/6 inhibition by ribociclib leads to retinoblastoma tumor suppressor protein (Rb) reactivation, thereby restoring Rb-mediated cell cycle arrest. Ribociclib is approved for the treatment of patients with hormone receptor-positive/human epidermal growth factor receptor-2-negative (HR+/HER2-) advanced breast cancer (ABC), at the dose of 600 mg once daily (QD) during cycles of 21 days on/7 days off, with optional dose reduction to 400 mg and 200 mg. Ribociclib is rapidly absorbed with a median time to reach maximum plasma concentration of 2.4 h, mean half-life of 32.0 h and oral bioavailability of 65.8% at 600 mg. It is eliminated mainly by hepatic metabolism (~ 84% of total elimination), mostly by cytochrome P450 (CYP) 3A4. Age, body weight, race, baseline Eastern Cooperative Oncology Group status, food, mild hepatic impairment, mild-to-moderate renal impairment, proton pump inhibitors, and combination partners (non-steroidal aromatase inhibitors or fulvestrant) have no clinically relevant impact on ribociclib exposure. Ribociclib inhibits CYP3A at 600 mg leading to increased exposure of CYP3A substrates. Strong CYP3A inhibitors or inducers increase or decrease, respectively, ribociclib exposure. Exposure-safety and exposure-efficacy analyses support the clinical benefit of the 600 mg QD starting dose, with potential individualized dose reductions to 400 mg and 200 mg for effective management of the adverse events neutropenia and QTcF interval prolongation, while maintaining efficacy, in patients with HR+/HER2- ABC. Overall, these clinical pharmacology data informed ribociclib dose justification and clinical development, as well as its prescribing information for clinical use in advanced breast cancer patients.

Investigating the value of glucodensity analysis of continuous glucose monitoring data in type 1 diabetes: an exploratory analysis.

Introduction: Continuous glucose monitoring (CGM) devices capture longitudinal data on interstitial glucose levels and are increasingly used to show the dynamics of diabetes metabolism. Given the complexity of CGM data, it is crucial to extract important patterns hidden in these data through efficient visualization and statistical analysis techniques. Methods: In this paper, we adopted the concept of glucodensity, and using a subset of data from an ongoing clinical trial in pediatric individuals and young adults with new-onset type 1 diabetes, we performed a cluster analysis of glucodensities. We assessed the differences among the identified clusters using analysis of variance (ANOVA) with respect to residual pancreatic beta-cell function and some standard CGM-derived parameters such as time in range, time above range, and time below range. Results: Distinct CGM data patterns were identified using cluster analysis based on glucodensities. Statistically significant differences were shown among the clusters with respect to baseline levels of pancreatic beta-cell function surrogate (C-peptide) and with respect to time in range and time above range. Discussion: Our findings provide supportive evidence for the value of glucodensity in the analysis of CGM data. Some challenges in the modeling of CGM data include unbalanced data structure, missing observations, and many known and unknown confounders, which speaks to the importance of--and provides opportunities for--taking an approach integrating clinical, statistical, and data science expertise in the analysis of these data.

Quantitative Assessment of Ribociclib Exposure-Response Relationship to Justify Dose Regimen in Patients with Advanced Breast Cancer.

Ribociclib in combination with endocrine therapy (ET) is a globally approved treatment option for patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) and has demonstrated significantly improved overall survival (OS) in 3 phase 3 clinical trials. To justify the dose regimen and dose modification scheme for patients with ABC, the pharmacokinetic (PK), safety, and efficacy data of ribociclib were analyzed. The data of several phase 1-3 clinical studies were pooled and analyzed to characterize the relationship between exposure (dose or PK) and efficacy (progression-free survival (PFS), time to response, and OS) or safety (neutropenia and QT interval prolongation). The exposure-efficacy analysis showed no apparent relationship between ribociclib exposure and efficacy (PFS and OS), and efficacy analysis by dose reduction showed that patients with ABC continued to benefit from the treatment following dose reduction, supporting the starting dose of 600 mg as well as dose reductions to 400 and 200 mg. The exposure-safety analysis showed that neutropenia and QT prolongation are related to ribociclib exposure that can be effectively managed by individualized dose modification (dose reduction/interruption). Collective evidence from the exposure-response analyses for efficacy and safety support the use of ribociclib in combination with ET partners at the starting dose of 600 mg, and also the effectiveness of individualized dose reductions in managing safety, while maintaining efficacy, in patients with HR+/HER2- ABC. This analysis illustrates the utility of quantitative assessment in justifying dose selection and dose modification for oncology medicines.

Exploratory Food Effect Assessment in Patients in Early Clinical Development of Oncology Drugs.

Instructions for administration with regard to food are a key aspect of how patients experience oral drugs. Through potential effects on pharmacokinetics, the food condition can influence safety and efficacy, and thereby is one of many dimensions of dose optimization. Regulatory guidance from major health authorities advocates for the early investigation of food effect (FE) in clinical development. In oncology, exploratory FE (eFE) evaluation is often incorporated into the first-in-human (FIH) studies in patients to inform food condition of later clinical studies. However, the design aspects of such exploratory assessments are generally under-reported and barely described, and yet complex, due to uniqueness of FIH study design and drug development process in oncology. Herein, we review literature of eFE assessment study design in oncology in patients, and present the Novartis experience in the design, execution, and impact of eFE in FIH oncology studies from 2014 to 2021. Based on this, we propose a roadmap for eFE assessment in early clinical drug development for oncology drugs in patients, including a framework for common study design options with a focus on study- and patient-level timing for typical scenarios. We also provide a broad spectrum of decision-making factors which should be evaluated to drive the design and implementation of eFE assessment, spanning from clinical development strategy, FIH study design, to compound-specific features.

Estimating Shelf Life Through Tolerance Intervals Extended to Nonlinear Response Trends.

Methods for estimating pharmaceutical shelf life based on tolerance intervals are proposed by Schwenke, et al. AAPS PharmSciTech. 2020;21:290, [1] where a critical quality attribute that follows a simple linear (straight line) response trend across storage time is presented as the traditional example. A random coefficient mixed linear regression model is used to characterize the between batch and within batch variation. These methods are further discussed for various stability study scenarios, number of stability batches, and levels of assumed risk in Schwenke, et al. AAPS PharmSciTech. 2021;22:273, [4] through a simulation study, again based on a critical quality attribute assuming a simple linear response. However, in practice, not all stability response profiles conveniently follow straight line or linear trends. The purpose of this paper is to extend the proposed tolerance interval and random coefficient mixed regression methods for estimating pharmaceutical shelf life to critical quality attributes that follow more complex stability response profiles. As an example, a nonlinear response is typically characterized by either an increasing or decreasing response, starting from an initial concentration, trending with storage time towards some limiting response or asymptote. Nonlinear responses cannot be statistically analyzed with linear model methods. Practical information supported by simulation results based on a pharmaceutical stability study are discussed to allow for appropriate statistical analyses and shelf life estimates through random coefficient mixed nonlinear regression and tolerance interval methods.

Justifying Ribociclib Dose in Patients with Advanced Breast Cancer with Renal Impairment Based on PK, Safety, and Efficacy Data: An Innovative Approach Integrating Data from a Dedicated Renal Impairment Study and Oncology Clinical Trials.

BACKGROUND AND OBJECTIVE: Renal impairment is common in patients with cancer and can alter the PK and thus the safety and efficacy of drugs. We assessed the impact of renal impairment during treatment with ribociclib, a cyclin-dependent kinase 4/6 inhibitor, and determined dose recommendations for patients with advanced breast cancer with renal impairment. METHODS: A comprehensive assessment integrating pharmacokinetic, safety, and efficacy data from a phase I dedicated renal impairment study in non-cancer subjects and six phase I-III trials in patients with cancer was performed. RESULTS: Ribociclib showed higher pharmacokinetic exposure in subjects with renal impairment than those with normal renal function following a single 400-mg dose in the dedicated renal impairment study. However, in patient trials, both single-dose and steady­state ribociclib exposure was comparable between patients with cancer with mild/moderate renal impairment and those with normal renal function following the recommended starting dose of 600 mg. Model-predicted steady­state exposure in patients with advanced breast cancer was also similar across the renal function groups. Progression-free survival was similar and safety profiles were generally consistent across the renal cohorts (normal/mild/moderate) in patients with advanced breast cancer, with low-grade and manageable adverse events, demonstrating a positive benefit-risk profile. CONCLUSIONS: From the collective evidence and considering a real-world clinical setting, no dose adjustment is recommended for patients with mild/moderate renal impairment, whereas a reduced dose is recommended for patients with severe renal impairment. This report presented a holistic and innovative strategy to determine dose in patients with renal impairment and demonstrated the effectiveness of integrating the data of both a clinical pharmacology study and patient trials to justify doses in patients with renal impairment. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov identifiers: NCT02431481, NCT01958021, NCT02422615, NCT02278120, NCT01237236, NCT01898845, NCT01872260.

Identifying research priorities with children, youth, and families: A scoping review.

Increased patient advocacy has resulted in a shift toward more active patient engagement in the research. A scoping review was conducted to explore the literature on healthcare research priority settings wherein children, youths, or their families were involved in the priority-setting process. Six databases including MEDLINE, CINAHL, PsycINFO, Embase, Web of Science, and Global Health and the James Lind Alliance website were searched up until September 2019. All primary studies involving children (<18 years of age) or families in developing research priorities in health care were included. All retrieved references were uploaded into Covidence, and two independent reviewers screened the search results. Descriptive thematic analysis was used to identify common themes. A total of 30 studies with 4247 participants were included. Less than half of the participants (n = 1237, (33%) were pediatric patients and their families. A total of 455 research priorities were identified. Three common themes emerged: (i) quality of care delivery, (ii) self-efficacy in health behaviors, and (iii) community engagement in care. This scoping review revealed priority research health topics from the perspectives of children, youths, or their families. The findings may be used as a foundation for future research to improve the health outcomes of children, youths, or their families according to their identified priorities.

Effect of capmatinib on the pharmacokinetics of substrates of CYP3A (midazolam) and CYP1A2 (caffeine) in patients with MET-dysregulated solid tumours.

BACKGROUND: Preclinical studies showed that capmatinib reversibly inhibits cytochrome P450 (CYP) 3A4 and CYP1A2 in a time-dependent manner. In this study, we evaluated the effect of capmatinib on the exposure of sensitive substrates of CYP3A (midazolam) and CYP1A2 (caffeine) in patients with mesenchymal-epithelial transition (MET)-dysregulated solid tumours. Besides pharmacokinetics, we assessed treatment response and safety. METHODS: This open-label, multicentre, single-sequence study consisted of a molecular prescreening period, a screening/baseline period of ≤28 days and a drug-drug interaction (DDI) phase of 12 days. On day 1 of the DDI phase, 37 patients received a single oral dose of midazolam 2.5 mg and caffeine 100 mg as a two-drug cocktail. Capmatinib 400 mg bid was administered from day 4 on a continuous dosing schedule. On day 9 of the DDI phase, patients were re-exposed to midazolam and caffeine. After the DDI phase, patients received capmatinib on continuous 21-day cycles until disease progression at the discretion of the investigator. RESULTS: A 22% (90% confidence interval [CI] 7-38%) increase in the midazolam maximum plasma concentration (Cmax ) was noted when administered with capmatinib, but this was deemed not clinically meaningful. Co-administration with capmatinib resulted in 134% (90% CI 108-163%) and 122% (90% CI 95-153%) increases in the caffeine area under the plasma concentration-time curve from time zero to infinity (AUCinf ) and area under the plasma concentration-time curve from time zero to the last measurable point (AUClast ), respectively, with no change in Cmax . Adverse events were consistent with the known capmatinib safety profile. No new safety signals were reported in this study. CONCLUSION: The data from this study demonstrated that capmatinib is a moderate CYP1A2 inhibitor. Capmatinib administration did not cause any clinically relevant changes in midazolam exposure.

Phase 1 Study Evaluating Pharmacokinetics and Tolerability of Ofatumumab Combined With Bendamustine in Patients With Indolent B-Cell Non-Hodgkin's Lymphoma.

The pharmacokinetics (PK) and safety of ofatumumab and bendamustine alone and in combination were evaluated in patients with treatment-naive or relapsed indolent B-cell non-Hodgkin lymphoma (iNHL). Patients were randomly assigned to ofatumumab and bendamustine or ofatumumab alone. Ofatumumab PK concentration profiles and parameters were similar, alone or in combination with bendamustine. A decrease of 14% in the maximum observed plasma concentration (Cmax ) and 15% in the area under the plasma concentration-time curve (AUC) from time 0 to the last measurable concentration sampling time (AUClast ) was observed for ofatumumab coadministered with bendamustine, which was not considered clinically relevant. Bendamustine PK concentration profiles and parameters were similar with or without ofatumumab. The most frequent treatment-related adverse event was infusion-related reaction in 53% in the combination arm and 47% in the ofatumumab arm. No relevant drug-drug interaction was observed between ofatumumab and bendamustine. Ofatumumab alone or in combination with bendamustine had a manageable safety profile.

Pharmacokinetics of asciminib in the presence of CYP3A or P-gp inhibitors, CYP3A inducers, and acid-reducing agents.

Asciminib is a first-in-class inhibitor of BCR::ABL1, specifically targeting the ABL myristoyl pocket. Asciminib is a substrate of CYP3A4 and P-glycoprotein (P-gp) and possesses pH-dependent solubility in aqueous solution. This report summarizes the results of two phase I studies in healthy subjects aimed at assessing the impact of CYP3A and P-gp inhibitors, CYP3A inducers and acid-reducing agents (ARAs) on the pharmacokinetics (PK) of asciminib (single dose of 40 mg). Asciminib exposure (area under the curve [AUC]) unexpectedly decreased by ~40% when administered concomitantly with the strong CYP3A inhibitor itraconazole oral solution, whereas maximum plasma concentration (Cmax ) decreased by ~50%. However, asciminib exposure was slightly increased in subjects receiving an itraconazole capsule (~3%) or clarithromycin (~35%), another strong CYP3A inhibitor. Macroflux studies showed that cyclodextrin (present in high quantities as excipient [40-fold excess to itraconazole] in the oral solution formulation of itraconazole) decreased asciminib flux through a lipid membrane by ~80%. The AUC of asciminib was marginally decreased by concomitant administration with the strong CYP3A inducer rifampicin (by ~13-15%) and the strong P-gp inhibitor quinidine (by ~13-16%). Concomitant administration of the ARA rabeprazole had little or no effect on asciminib AUC, with a 9% decrease in Cmax . The treatments were generally well tolerated. Taking into account the large therapeutic window of asciminib, the observed changes in asciminib PK following multiple doses of P-gp, CYP3A inhibitors, CYP3A inducers, or ARAs are not considered to be clinically meaningful. Care should be exercised when administering asciminib concomitantly with cyclodextrin-containing drug formulations.

Patient, Caregiver, and Clinician Participation in Prioritization of Research Questions in Pediatric Hospital Medicine.

Importance: The research agenda in pediatric hospital medicine has seldom considered the perspectives of young people, parents and caregivers, and health care professionals. Their perspectives may be useful in identifying questions on topics for research. Objective: To prioritize unanswered research questions in pediatric hospital medicine from the perspectives of young people, parents/caregivers, and health care professionals. Design, Setting, and Participants: Between August 4, 2020, and August 19, 2021, two online surveys and a virtual workshop were conducted, using modified Delphi technique and nominal group technique. Young people, parents/caregivers, and health care professionals with experiences in pediatric hospital medicine in Canada were included. Interventions: The established James Lind Alliance Priority Setting Partnership method was used. In phase 1, a survey collected unanswered questions regarding pediatric hospital medicine via 3 open-ended questions. Survey responses were used to develop summary questions that went through an evidence-checking process. Unanswered questions were brought to a phase 2 interim prioritization survey. The top 10 unanswered research questions in pediatric hospital medicine were established at the final priority setting workshop. Main Outcomes and Measures: Survey responses, top 10 research questions. Results: The phase 1 survey was completed by 188 participants (148 of 167 [89%] females; 17 of 167 [10%] males; mean [SD] age, 39.5 [12.4] years) and generated 495 unanswered research questions and comments, of which 58 were deemed out of scope. The remaining 437 responses were grouped into themes (eg, communication, shared decision-making, health service delivery, and health service management) and then refined to 75 unanswered research questions. Of these 75, only 4 questions had sufficient evidence. To make the number of questions in phase 2 manageable, 21 questions submitted by only 1 respondent were eliminated. Fifty unanswered research questions were included in the phase 2 survey, which was completed by 201 participants (165 of 186 [89%] females; 19 of 186 [10%] males; mean [SD] age, 40.0 [11.0] years). A short list of 16 questions-the top 10 questions from patient partners (youths, parents/caregivers) and clinicians-was presented at the final priority setting workshop and the top 10 questions were prioritized. The top 10 questions focused on the care of special inpatient populations (eg, children with medical complexity), communication, shared decision-making, support strategies in the hospital, mental health supports, shortening length of stay, and supporting Indigenous patients, parents/caregivers, and families. Conclusions and Relevance: This patient-oriented pediatric hospital medicine priority setting partnership identified the most important unanswered research questions focused on the care of children in the hospital. These questions provide a possible roadmap for research on areas deemed important to young people, parents/caregivers, and clinicians.

Prevalence, Cost, and Variation in Cost of Pediatric Hospitalizations in Ontario, Canada.

Importance: Identifying conditions that could be prioritized for research based on health care system burden is important for developing a research agenda for the care of hospitalized children. However, existing prioritization studies are decades old or do not include data from both pediatric and general hospitals. Objective: To assess the prevalence, cost, and variation in cost of pediatric hospitalizations at all general and pediatric hospitals in Ontario, Canada, with the aim of identifying conditions that could be prioritized for future research. Design, Setting, and Participants: This population-based cross-sectional study used health administrative data from 165 general and pediatric hospitals in Ontario, Canada. Children younger than 18 years with an inpatient hospital encounter between April 1, 2014, and March 31, 2019, were included. Main Outcomes and Measures: Condition-specific prevalence, cost of pediatric hospitalizations, and condition-specific variation in cost per inpatient encounter across hospitals. Variation in cost was evaluated using (1) intraclass correlation coefficient (ICC) and (2) number of outlier hospitals. Costs were adjusted for inflation to 2018 US dollars. Results: Overall, 627 314 inpatient hospital encounters (44.8% among children younger than 30 days and 53.0% among boys) at 165 hospitals (157 general and 8 pediatric) costing $3.3 billion were identified. A total of 408 003 hospitalizations (65.0%) and $1.4 billion (43.8%) in total costs occurred at general hospitals. Among the 50 most prevalent and 50 most costly conditions (of 68 total conditions), the top 10 highest-cost conditions accounted for 55.5% of all costs and 48.6% of all encounters. The conditions with highest prevalence and cost included low birth weight (86.2 per 1000 encounters; $676.3 million), preterm newborn (38.0 per 1000 encounters; $137.4 million), major depressive disorder (20.7 per 1000 encounters; $78.3 million), pneumonia (27.3 per 1000 encounters; $71.6 million), other perinatal conditions (68.0 per 1000 encounters; $65.8 million), bronchiolitis (25.4 per 1000 encounters; $54.6 million), and neonatal hyperbilirubinemia (47.9 per 1000 encounters; $46.7 million). The highest variation in cost per encounter among the most costly medical conditions was observed for 2 mental health conditions (other mental health disorders [ICC, 0.28] and anxiety disorders [ICC, 0.19]) and 3 newborn conditions (intrauterine hypoxia and birth asphyxia [ICC, 0.27], other perinatal conditions [ICC, 0.17], and surfactant deficiency disorder [ICC, 0.17]). Conclusions and Relevance: This population-based cross-sectional study of hospitalized children identified several newborn and mental health conditions as having the highest prevalence, cost, and variation in cost across hospitals. Findings of this study can be used to develop a research agenda for the care of hospitalized children that includes general hospitals and to ultimately build a more substantial evidence base and improve patient outcomes.

Pharmacokinetics of capmatinib in participants with hepatic impairment: A phase 1, open-label, single-dose, parallel-group study.

AIMS: Capmatinib, a mesenchymal-epithelial transition factor tyrosine kinase inhibitor, is metabolized by cytochrome P450 (CYP) 3A4 and aldehyde oxidase. In individuals with hepatic impairment, alterations in hepatobiliary excretion and metabolism could lead to higher capmatinib exposure. We compared the pharmacokinetics of a single oral dose of capmatinib 200 mg administered to participants with varying degrees of hepatic impairment vs. matched controls with normal hepatic function. METHODS: This phase 1, multicentre, open-label, parallel-group study enrolled adult participants with normal hepatic function and mild, moderate and severe hepatic impairments. Eligible participants received a single oral dose of 200 mg capmatinib. The pharmacokinetic parameters of capmatinib were analysed and compared across participants with impaired and normal hepatic function. RESULTS: Of 31 enrolled participants, 29 had an evaluable pharmacokinetic profile: normal (n = 9); mild (n = 6); moderate (n = 8); severe (n = 6). Compared with the normal group, geometric mean (GM) maximum (peak) observed plasma drug concentration after single-dose administration decreased by 27.6% in the mild group (GM ratio [GMR] = 0.724; 90% confidence interval [CI]: 0.476-1.10), by 17.2% in the moderate group (GMR = 0.828; 90% CI: 0.563-1.22) and remained unchanged in the severe group (GMR = 1.02; 90% CI: 0.669-1.55). Compared with the normal group, GM area under the plasma concentration-time curve from time zero to infinity decreased by 23.3% in the mild group (GMR = 0.767; 90% CI: 0.532-1.11), by 8.6% in the moderate group (GMR = 0.914; 90% CI: 0.652-1.28) and increased by 24% in the severe group (GMR = 1.24; 90% CI: 0.858-1.78). CONCLUSION: Mild, moderate and severe hepatic impairment did not have a clinically relevant impact on capmatinib pharmacokinetics. No new safety findings are reported in this study.

Pharmacokinetics of Asciminib When Taken With Imatinib or With Food.

Asciminib, a first-in-class, Specifically Targeting the Abelson kinase Myristoyl Pocket (STAMP) inhibitor with the potential to overcome resistance to adenosine triphosphate-competitive tyrosine kinase inhibitors, is being investigated in leukemia as monotherapy and in combination with tyrosine kinase inhibitors including imatinib. This phase 1 study in healthy volunteers assessed the pharmacokinetics of asciminib (40 mg single dose) under 2 conditions: when taken with imatinib (steady state; 400 mg once daily) and a low-fat meal (according to imatinib prescription information), or when taken as single-agent under different food conditions. Asciminib plus imatinib with a low-fat meal increased asciminib area under the plasma concentration-time curve from time 0 to infinity and maximum plasma concentration (geometric mean ratios [90% confidence interval], 2.08 [1.93-2.24] and 1.59 [1.45-1.75], respectively) compared with asciminib alone under the same food conditions. Asciminib plus food decreased asciminib area under the plasma concentration-time curve from time 0 to infinity compared with asciminib taken under fasted conditions (geometric mean ratios: low-fat meal, 0.7 [0.631-0.776]; high-fat meal, 0.377 [0.341-0.417]). Asciminib plus imatinib was well tolerated with no new safety signals. Overall, coadministration of asciminib with imatinib and a low-fat meal results in a moderate increase in asciminib exposure compared with asciminib alone under the same food condition. Food itself decreases asciminib exposure, indicating that single-agent asciminib should be administered in the fasted state to prevent potential suboptimal exposures.

A Practical Discussion on Estimating Shelf Life Through Tolerance Intervals.

This paper is a companion article to the research originally presented in "Estimating Shelf Life through Tolerance Intervals" (Schwenke et al., 21:290, 2020) published in AAPS PharmSciTech where tolerance intervals are introduced as an alternative methodology for estimating pharmaceutical shelf life. An industry stability shelf life example data set was used to demonstrate the proposed methods. Although using industry data does give relevance to examples demonstrating shelf life estimation, measures of how well the proposed methods accurately and effectively estimate shelf life cannot be obtained because the true shelf life values are not known for example data sets. In this current paper, the results of a computer simulation are reported where the tolerance interval estimates of shelf life are compared to theoretically known true shelf life values. Various factors that affect a tolerance interval estimate of pharmaceutical shelf life are investigated. A critical decision factor is the choice of the proportion of the stability distribution allowed out of specification at expiry to define the pharmaceutical risk. The number of stability batches available for shelf life estimation and the storage time at which the estimate is made are also considered in this simulation study. The industry example data are again used as the basis for the simulation study to give relevance to this research.

Pharmacokinetics of Asciminib in Individuals With Hepatic or Renal Impairment.

Asciminib is an investigational, first-in-class, specifically targeting the ABL myristoyl pocket (STAMP) inhibitor of BCR-ABL1 with a new mechanism of action compared with approved ATP-competitive tyrosine kinase inhibitors. This report describes the findings from 2 phase 1 studies assessing the pharmacokinetic (PK) profile of a single dose of asciminib (40 mg) in individuals with impaired renal function (based on absolute glomerular filtration rate; NCT03605277) or impaired hepatic function (based on Child-Pugh classification; NCT02857868). Individuals with severe renal impairment exhibited 49%-56% higher exposure (area under the curve [AUC]), with similar maximum plasma concentration (Cmax ), than matched healthy controls. Based on these findings, as per the protocol, the PK of asciminib in individuals with mild or moderate renal impairment was not assessed. In individuals with mild and severe hepatic impairment, asciminib AUC was 21%-22% and 55%-66% higher, respectively, and Cmax was 26% and 29% higher, respectively, compared with individuals with normal hepatic function. Individuals with moderate hepatic impairment had similar asciminib AUC and Cmax than matched healthy controls. The increase in asciminib AUC and Cmax in the mild hepatic impairment cohort was mainly driven by 1 participant with particularly high exposure. Asciminib was generally well tolerated, and the safety data were consistent with its known safety profile. In summary, these findings indicate that renal or hepatic impairment has no clinically meaningful effect on the exposure or safety profile of asciminib, and support its use in patients with varying degrees of renal or hepatic dysfunction.

Effect of capmatinib on the pharmacokinetics of digoxin and rosuvastatin administered as a 2-drug cocktail in patients with MET-dysregulated advanced solid tumours: A phase I, multicentre, open-label, single-sequence drug-drug interaction study.

AIMS: Capmatinib, an orally bioavailable, highly potent and selective MET inhibitor, was recently approved to treat adult patients with metastatic nonsmall cell lung cancer with METex14 skipping mutations. The study investigated the effect of capmatinib on the pharmacokinetics of a single oral dose of digoxin and rosuvastatin in patients with MET-dysregulated advanced solid tumours. METHODS: This was a multicentre, open-label, single-sequence study. An oral drug cocktail containing 0.25 mg digoxin and 10 mg rosuvastatin was administered to adult patients with MET-dysregulated advanced solid tumours on Day 1, and then on Day 22 with capmatinib. Between Days 11 and 32, capmatinib 400 mg was administered twice daily to ensure the attainment of steady state for drug-drug interaction assessment. Pharmacokinetics of cocktail drugs and safety of capmatinib were evaluated. RESULTS: Thirty-two patients were enrolled. Compared to digoxin alone, the geometric mean ratios (90% confidence interval) of area under the concentration-time curve from time zero to infinity and maximum concentration for digoxin plus capmatinib were 1.47 (1.28, 1.68) and 1.74 (1.43, 2.13), respectively. Compared to rosuvastatin alone, the geometric mean ratios (90% confidence interval) of area under the curve to infinity and maximum concentration for rosuvastatin plus capmatinib were 2.08 (1.56, 2.76) and 3.04 (2.36, 3.92), respectively. Most frequent adverse events (≥25% for all grades) were nausea, asthenia, constipation, vomiting, peripheral oedema and pyrexia. Most frequent Grade 3/4 adverse events (≥5%) were anaemia, pulmonary embolism, asthenia, dyspnoea, nausea and vomiting. CONCLUSION: This study demonstrated that capmatinib is an inhibitor of P-gp and BCRP transporters, with clinically relevant drug-drug interaction potential. Capmatinib was well-tolerated and no unexpected safety concerns were observed.

Estimating Shelf Life Through Tolerance Intervals.

This paper is a continuation of the research published by the Stability Shelf Life Working Group as chartered under the Product Quality Research Institute. The Working Group was formed in 2006 and disbanded in late 2019. Following the philosophy presented by the Working Group on how to characterize the stability shelf life paradigm (Capen et al., 2012), shelf life is estimated here in terms of defining risk as a specified proportion of the pharmaceutical stability distribution of interest being out of specification. Shelf life can be defined for the batch mean distribution for regulatory issues, as well as for the product distributions for patient interests. Estimates of shelf life are proposed corresponding to each stability distribution through the use of statistical tolerance intervals. Appropriate estimates of the between-batch and within-batch variance components are obtained through a random coefficient mixed regression model analysis based on the best fit to batch stability response data. Tolerance interval estimates are computed as part of the mixed model analysis and computed directly using the statistical definition of the stability distributions. A proposed rationale is offered on how to select an appropriate proportion allowed out of specification to define a meaningful shelf life. Examples of the proposed shelf life estimates are presented using industry stability batch data. For each example, the traditional ICH shelf life estimate is given for comparison.

Relative Bioavailability and Food Effect Evaluation for 2 Tablet Formulations of Asciminib in a 2-Arm, Crossover, Randomized, Open-Label Study in Healthy Volunteers.

Asciminib (ABL001) is an orally administered allosteric inhibitor of the BCR-ABL tyrosine kinase. The current study evaluated the relative bioavailability of its 2 tablet variants, AAA and NXA, compared with the capsule CSF and assessed the impact of food in healthy participants in a 2-arm, randomized, open-label, 4-way crossover design. The primary pharmacokinetic parameters analyzed were area under the plasma concentration-time curve (AUC) from time 0 to the time of last measurable concentration (AUClast ), AUC from time 0 to infinity (AUCinf ), and peak concentration (Cmax ). Forty-five healthy volunteers were enrolled, 22 in the AAA arm and 23 in the NXA arm. Under fasting conditions, the AUCinf , AUClast , and Cmax of the AAA tablet were similar to those of the capsule, but slightly higher (∼20%) for NXA and decreased with a high-fat meal (∼65%) and a low-fat meal (∼30%) for both tablet formulations. Overall, 20 participants (9 in the AAA arm; 11 in the NXA arm) experienced at least 1 adverse event, the most common in both arms being headache. The study showed that under fasting conditions, tablet AAA had bioavailability similar to that in the capsule CSF. The bioavailability of both tablet formulations decreased with food, with a more pronounced effect observed with a high-fat meal.

Evaluating Current Practices in Shelf Life Estimation.

The current International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) methods for determining the supported shelf life of a drug product, described in ICH guidance documents Q1A and Q1E, are evaluated in this paper. To support this evaluation, an industry data set is used which is comprised of 26 individual stability batches of a common drug product where most batches are measured over a 24 month storage period. Using randomly sampled sets of 3 or 6 batches from the industry data set, the current ICH methods are assessed from three perspectives. First, the distributional properties of the supported shelf lives are summarized and compared to the distributional properties of the true shelf lives associated with the industry data set, assuming the industry data set represents a finite population of drug product batches for discussion purposes. Second, the results of the ICH "poolability" tests for model selection are summarized and the separate shelf life distributions from the possible alternative models are compared. Finally, the ICH methods are evaluated in terms of their ability to manage risk. Shelf life estimates that are too long result in an unacceptable percentage of nonconforming batches at expiry while those that are too short put the manufacturer at risk of possibly having to prematurely discard safe and efficacious drug product. Based on the analysis of the industry data set, the ICH-recommended approach did not produce supported shelf lives that effectively managed risk. Alternative approaches are required.