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.
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.
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.
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.
Sonidegib selectively inhibits smoothened protein, suppresses the growth of Hedgehog pathway‐dependent tumors, and has recently been approved in the indication of locally advanced basal cell ...carcinoma. A comprehensive exposure‐response analysis was conducted to further characterize the relationship of sonidegib exposure to efficacy and safety. Minimum observed plasma concentration at predose (Cmin), peak concentration (Cmax), and area under the curve were used as exposure endpoints. Exposure‐efficacy analyses included data from 190 patients who received sonidegib 200 mg or 800 mg once daily in the primary efficacy study. Objective response rate (ORR) (complete response CR or partial response PR), progression‐free survival (PFS), and time to tumor response (TTR) were assessed by logistic regression, Cox regression, and Kaplan‐Meier analyses. Exposure‐safety (creatine phosphokinase CK elevation) analyses included data from 336 patients pooled from 4 clinical trials and included doses across ranges of 100 to 3000 mg once daily and 250 to 750 mg twice daily. Similar plasma exposure was observed between responders and nonresponders. The logistic regression model of week 5 Cmin vs ORR indicated no relationship between sonidegib exposure resulting from 200 mg or 800 mg doses and the probability of CR or PR. A similar conclusion of no exposure‐efficacy relationship was drawn from the PFS and TTR analyses. Increased exposure was associated with a greater risk of grade 3 or 4 CK elevation, with lower risk in females than in males when Cmin was used in the model. These analyses support the sonidegib dose recommendation for registration and are consistent with clinical observations.
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.
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 to 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 mg 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. This article is protected by copyright. All rights reserved.
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.
Purpose
Sonidegib prevents activation of the Hedgehog signal transduction pathway. This PK-QT analysis has been performed to test for potential prolongation of the QT/QTc interval during extended ...use, and to understand the exposure-QT relationship for sonidegib in patients and in healthy volunteers (HV).
Methods
A pooled analysis of the change in QT interval corrected for heart rate according to Fridericia’s formula was conducted across four patient studies from a total of 341 patients (
n
= 211, 102, 21, and 7 from the phase II pivotal study A2201, study X2101, study X1101, and study B2209, respectively), and across four healthy volunteer studies from a total of 204 healthy volunteers (
n
= 146, 36, 16, and 6 from study A2114, study A1102, study A2108, and study A2110, respectively). A PK/ECG subgroup of 62 patients from the pivotal study A2201 was also analyzed to assess the QT prolongation risk at steady-state exposures. Sonidigib PK and ECG data were matched to determine the change from baseline in QTcF using a linear mixed-effect model.
Results
Clinical data indicate sonidegib does not cause QTc prolongation. ΔQTcF at steady-state concentrations for both 200 and 800-mg doses were all below 5 ms.
The highest mean ΔQTcF at steady state was −3.9 ms at week 17 pre-dose in the sonidegib 200-mg group and 2.7 ms at 2-h post-dose in the sonidegib 800-mg group. The upper one-sided 95 % confidence interval of the estimated ΔQTcF at steady-state concentrations from the linear mixed-effect models were all <10 ms. No cases of ventricular arrhythmia or torsades de pointes and no deaths associated with QT prolongation have been reported in the sonidegib clinical development program.
Conclusions
Based on these analyses, there is no evidence of QT prolongation associated with sonidegib 200 or 800 mg in solid tumor patients and HV.
Sonidegib is a potent, selective and orally bioavailable inhibitor of the Hedgehog signaling pathway, primarily metabolized by the liver. In order to make dose recommendations for patients with ...hepatic impairment, we have assessed here the pharmacokinetics (PKs) and safety of sonidegib in subjects with varying degrees of hepatic function.
The primary objective of this phase I, multicenter, open-label study was to evaluate the PKs of a single oral 800 mg dose of sonidegib in subjects with impaired hepatic function compared with healthy subjects. PK parameters (e.g. area under the concentration-time curve from time zero to infinity AUC
, area under the concentration-time curve from time zero to the last measurable concentration AUC
, maximum concentration C
, apparent clearance CL/F, and terminal half-life t
) for parent drug and the metabolite were compared with the normal group, as the reference. Metabolite ratio, unbound PK parameters, and the relationship between specific PK parameters and liver function parameters were assessed.
In total, 33 subjects entered the study and received sonidegib. Plasma concentrations peaked at approximately 2-3 h in all groups after dosing. Compared with the normal group, AUC
decreased by 35 and 23% and increased by 14% in the mild, severe, and moderate hepatic impairment groups, respectively. The C
values were lower in all groups with respect to the normal group (decreases of 20, 21 and 60% in the mild, moderate and severe hepatic impairment groups, respectively). Protein binding was independent of hepatic function, and similar trends in the PK parameters were observed for unbound sonidegib and the metabolite. Protein binding was similar across all groups. Weak to no correlation between specific PK and hepatic function parameters was found.
Overall, sonidegib exposures were similar or decreased in the hepatic impairment groups compared with the normal group, and sonidegib was generally well-tolerated in all subjects. Dose adjustment is not considered necessary for subjects with mild, moderate, or severe hepatic impairment.
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