Dostarlimab, an anti-programmed death-1 monoclonal antibody, does not cause QT prolongation in patients with solid tumours: A concentration-QT analysis.

AIMS: Patients with solid tumours were treated with the anti-PD-1 antibody dostarlimab in the Phase I GARNET trial. This study aimed to examine dostarlimab's effect on corrected QT (QTc) interval and the systemic concentration-QTc interval relationship. METHODS: In GARNET Part 2B, patients received 500 mg dostarlimab every 3 weeks (Q3W) for four cycles, then 1000 mg Q6W. Triplicate 12-lead ECGs were recorded and time-matched pharmacokinetic (PK) samples collected at screening, on Day 1 of Cycles 1, 4, 5, 8, 12 (pre-dose and 0.5 h after infusion end), and at treatment end. Concentration-change from baseline QTcF (ΔQTcF) analysis using a linear mixed effects model, summary statistics, incidence of clinically noteworthy ECG values and rhythm abnormalities were evaluated. RESULTS: A total of 377 patients were considered for evaluation (n = 15 excluded from concentration-ΔQTcF). There was a non-significant concentration-ΔQTcF relationship (0.001589 ms/µg/mL; P = .5906). Mean ΔQTcF increase was <6 ms (upper-bound two-sided 90% confidence interval [CI], <10 ms at all post-dose timepoints). Highest geometric mean concentration was 414.1 µg/mL (Cycle 5 Day 1, 0.5 h) with predicted mean ∆QTcF of 3.064 ms (upper-bound two-sided 90% CI: 5.071). Mean QTcF prolongation (all concentrations) was 2.4 ms. QTcF prolongation ≥500 ms occurred in five patients (1.3%); 51 (13.6%) and nine patients (2.4%) had ΔQTcF ≥30 ms and ≥60 ms, respectively. Ten patients (2.7%) reported rhythm abnormalities. No U-wave abnormalities, torsades de pointes, ventricular tachycardia or ventricular fibrillation/flutter were observed. CONCLUSIONS: Dostarlimab does not cause clinically significant QTcF prolongation exceeding the regulatory concern threshold.

Comparative analysis of PD-1 target engagement of dostarlimab and pembrolizumab in advanced solid tumors using ex vivo IL-2 stimulation data.

Dostarlimab (JEMPERLI) is an anti-programmed cell death protein-1 (PD-1) monoclonal antibody (mAb) which is approved by the US Food and Drug Administration for patients with recurrent/advanced mismatch repair-deficient solid tumors, including endometrial cancer, following progression on prior treatment, with approval based on data from the phase I GARNET trial. To support dostarlimab dose regimen recommendations, we estimated and compared the potency of dostarlimab relative to anti-PD-1 mAb pembrolizumab using both data published from the KEYNOTE-001 trial of pembrolizumab and data from the GARNET trial. PD-1 target engagement was assessed ex vivo in blood samples via a super antigen staphylococcal enterotoxin B stimulation assay and interleukin-2 (IL-2) stimulation ratios calculated for dostarlimab. A non-linear mixed-effect sigmoid maximum effect inhibitory model was fitted to dostarlimab IL-2 stimulation ratios using extracted pembrolizumab data as informative priors. The estimated half-maximal effective concentration was 1.95 µg ml-1 (95% credibility interval: 0.21-5.87) for dostarlimab and 1.59 µg ml-1 (95% confidence interval: 0.42-6.12) for pembrolizumab. These findings suggest dostarlimab and pembrolizumab to be equipotent for peripheral PD-1 suppression based on analysis of ex vivo IL-2 stimulation ratios. Accounting for a three-fold dilution between serum and tumor, a target dostarlimab trough concentration of ~54 µg ml-1 would be needed for 90% suppression in the tumor. These data support the use of dostarlimab as a potent PD-1 suppressor and the recommended dostarlimab monotherapy dose regimen of 500 mg Q3W ×4 cycles followed by 1000 mg Q6W thereafter in recurrent/advanced solid tumors.

Transdiagnostic clustering of self-schema from self-referential judgements identifies subtypes of healthy personality and depression.

Introduction: The heterogeneity of depressive and anxiety disorders complicates clinical management as it may account for differences in trajectory and treatment response. Self-schemas, which can be determined by Self-Referential Judgements (SRJs), are heterogeneous yet stable. SRJs have been used to characterize personality in the general population and shown to be prognostic in depressive and anxiety disorders. Methods: In this study, we used SRJs from a Self-Referential Encoding Task (SRET) to identify clusters from a clinical sample of 119 patients recruited from the Institute of Mental Health presenting with depressive or anxiety symptoms and a non-clinical sample of 115 healthy adults. The generated clusters were examined in terms of most endorsed words, cross-sample correspondence, association with depressive symptoms and the Depressive Experiences Questionnaire and diagnostic category. Results: We identify a 5-cluster solution in each sample and a 7-cluster solution in the combined sample. When perturbed, metrics such as optimum cluster number, criterion value, likelihood, DBI and CHI remained stable and cluster centers appeared stable when using BIC or ICL as criteria. Top endorsed words in clusters were meaningful across theoretical frameworks from personality, psychodynamic concepts of relatedness and self-definition, and valence in self-referential processing. The clinical clusters were labeled "Neurotic" (C1), "Extraverted" (C2), "Anxious to please" (C3), "Self-critical" (C4), "Conscientious" (C5). The non-clinical clusters were labeled "Self-confident" (N1), "Low endorsement" (N2), "Non-neurotic" (N3), "Neurotic" (N4), "High endorsement" (N5). The combined clusters were labeled "Self-confident" (NC1), "Externalising" (NC2), "Neurotic" (NC3), "Secure" (NC4), "Low endorsement" (NC5), "High endorsement" (NC6), "Self-critical" (NC7). Cluster differences were observed in endorsement of positive and negative words, latency biases, recall biases, depressive symptoms, frequency of depressive disorders and self-criticism. Discussion: Overall, clusters endorsing more negative words tended to endorse fewer positive words, showed more negative biases in reaction time and negative recall bias, reported more severe depressive symptoms and a higher frequency of depressive disorders and more self-criticism in the clinical population. SRJ-based clustering represents a novel transdiagnostic framework for subgrouping patients with depressive and anxiety symptoms that may support the future translation of the science of self-referential processing, personality and psychodynamic concepts of self-definition to clinical applications.

Positive mental health in psychotherapy: a qualitative study from psychotherapists' perspectives.

BACKGROUND: There is growing evidence in the literature on the use of positive mental health (PMH) interventions among clinical samples. This qualitative study aims to explore the definitions of PMH from psychotherapists' perspectives, and to examine views and attitudes related to the construct. METHODS: Focus group discussions were conducted with psychotherapists at a tertiary psychiatric institute. Focus group sessions were transcribed verbatim and transcripts were analyzed using an inductive thematic approach. RESULTS: Five themes related to psychotherapists' definition of PMH were identified: (1) acceptance; (2) normal functioning and thriving in life; (3) resilience; (4) positive overall evaluation of life; (5) absence of negative emotions and presence of positive emotion states. Themes related to views and attitudes towards PMH were: (1) novel and valuable for psychotherapy; (2) reservations with terminology; (3) factors influencing PMH. CONCLUSION: PMH in psychotherapy is a multidimensional concept that means more than symptom management and distress reduction in clients. There is potential value for its application in psychotherapy practice, though some concerns need to be addressed before it can be well integrated.

Population pharmacokinetics and exposure-response of anti-programmed cell death protein-1 monoclonal antibody dostarlimab in advanced solid tumours.

AIM: Develop a population pharmacokinetic (PopPK) model to characterise the pharmacokinetics (PK) of anti-programmed cell death protein-1 (PD-1) antibody dostarlimab, identify covariates of clinical relevance, and investigate efficacy/safety exposure-response (ER) relationships. METHODS: A PopPK model was developed using Phase 1 GARNET (NCT02715284) trial data for dostarlimab (1, 3 or 10 mg kg-1 every 2 wk; 500 mg every 3 wk or 1000 mg every 6 wk; 500 mg every 3 wk × 4 then 1000 mg every 6 wk [recommended regimen]) serum concentrations over time. Concentration-time data were analysed using nonlinear mixed effects modelling with standard stepwise covariate modelling. ER was explored for treatment-related adverse events and overall response rate (ORR) using logistic regression. RESULTS: PopPK model/adverse event ER analyses included 546 patients (ORR ER analysis n = 362). Dostarlimab PK was well described by a 2-compartment model with time-dependent linear elimination. Time-dependent clearance decreased over time to a maximum of 14.9%. At steady state, estimated dostarlimab geometric mean coefficient of variation % clearance was 0.179 (30.2%) L d-1 ; volume of distribution was 5.3 (14.2%) L; terminal elimination half-life was 23.5 (22.4%) days. Statistically significant covariates were age, body weight, sex, time-varying albumin and alanine aminotransferase for clearance; body weight, albumin and sex for volume of distribution of the central compartment. Hepatic or renal impairment did not affect PK. There were no clinically significant ER relationships. CONCLUSION: Dostarlimab PK parameters are similar to other anti-programmed cell death protein-1 antibodies. The clinical impact of covariates on exposure was limited-to-moderate, supporting recommended dostarlimab monotherapy therapeutic dosing.

IOLite: phase 1b trial of doublet/triplet combinations of dostarlimab with niraparib, carboplatin-paclitaxel, with or without bevacizumab in patients with advanced cancer.

BACKGROUND: Doublet combination therapies targeting immune checkpoints have shown promising efficacy in patients with advanced solid tumors, but it is unknown if rational triplet combinations will be well tolerated and associated with improved antitumor activity. The objective of this trial was to determine the recommended phase 2 doses (RP2Ds) and to assess the safety and efficacy of the programmed cell death protein 1 (PD-1) inhibitor dostarlimab in combination with (1) the poly(ADP-ribose) polymerase inhibitor niraparib with or without vascular endothelial growth factor inhibitor bevacizumab or (2) carboplatin-paclitaxel chemotherapy with or without bevacizumab, in patients with advanced cancer. METHODS: IOLite is a multicenter, open-label, multi-arm clinical trial. Patients with advanced solid tumors were enrolled. Patients received dostarlimab in combination with niraparib with or without bevacizumab or in combination with carboplatin-paclitaxel with or without bevacizumab until disease progression, unacceptable toxicity, or withdrawal from the study. Prespecified endpoints in all parts were to evaluate the dose-limiting toxicities (DLTs), RP2Ds, pharmacokinetics (PKs), and preliminary efficacy for each combination. RESULTS: A total of 55 patients were enrolled; patients received dostarlimab and: (1) niraparib in part A (n=22); (2) carboplatin-paclitaxel in part B (n=14); (3) niraparib plus bevacizumab in part C (n=13); (4) carboplatin-paclitaxel plus bevacizumab in part D (n=6). The RP2Ds of all combinations were determined. All combinations were safe and tolerable, with no new safety signals observed. DLTs were reported in 2, 1, 2, and 0 patients, in parts A-D, respectively. Preliminary antitumor activity was observed, with confirmed Response Evaluation Criteria in Solid Tumors v1.1 complete/partial responses reported in 4 of 22 patients (18.2%), 6 of 14 patients (42.9%), 4 of 13 patients (30.8%), and 3 of 6 (50.0%) patients, in parts A-D, respectively. Disease control rates were 40.9%, 57.1%, 84.6%, and 83.3%, in parts A-D, respectively. Dostarlimab PK was unaffected by any combinations tested. Coadministration of bevacizumab showed no impact on niraparib PKs. The overall mean PD-1 receptor occupancy was 99.0%. CONCLUSIONS: Dostarlimab was well tolerated in both doublet and triplet regimens tested, with promising antitumor activity observed with all combinations. We observed higher disease control rates in the triplet regimens than in doublet regimens. TRIAL REGISTRATION NUMBER: NCT03307785.

Safety, antitumor activity, and pharmacokinetics of dostarlimab, an anti-PD-1, in patients with advanced solid tumors: a dose-escalation phase 1 trial.

PURPOSE: New immuno-oncology therapies targeting programmed cell death receptor 1 (PD-1) have improved patient outcomes in a broad range of cancers. The objective of this analysis was to evaluate the PK, pharmacodynamics (PDy), and safety of dostarlimab monotherapy in adult patients with previously-treated advanced solid tumors who participated in parts 1 and 2A of the phase 1 GARNET study. METHODS: Part 1 featured a 3 + 3 weight-based dose-escalation study, in which 21 patients received dostarlimab 1, 3, or 10 mg/kg intravenously every 2 weeks. The 2 fixed-dose nonweight-based dosing regimens of dostarlimab 500 mg every 3 weeks (Q3W) and 1000 mg every 6 weeks (Q6W) were evaluated using a modified 6 + 6 design in part 2A (n = 13). In parts 1 and 2A, treatment with dostarlimab could continue for up to 2 years or until progression, unacceptable toxicity, patient withdrawal, investigator's decision, or death. RESULTS: The dostarlimab PK profile was dose proportional, and maximal achievable receptor occupancy (RO) was observed at all dose levels in the weight-based and fixed-dose cohorts. Trough dostarlimab concentration after administration of dostarlimab 500 mg Q3W was similar to that after dostarlimab 1000 mg Q6W, the values of which (≈40 µg/mL) projected well above the lowest dostarlimab concentration required for full peripheral RO. No dose-limiting toxicities were observed. CONCLUSIONS: Dostarlimab demonstrated consistent and predictable PK and associated PDy. The observed safety profile was acceptable and characteristic of the anti-PD-1 drug class. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02715284. Registration date: March 9, 2016.

JASPER: Phase 2 trial of first-line niraparib plus pembrolizumab in patients with advanced non-small cell lung cancer.

BACKGROUND: Poly(ADP-ribose) polymerase (PARP) inhibitors may synergize with programmed cell death receptor-1 (PD-1) inhibitors to enhance adaptive and innate antitumor immune responses. In the phase 2 JASPER study (NCT04475939), the PARP inhibitor niraparib was evaluated in combination with the PD-1 inhibitor pembrolizumab in patients with metastatic and/or locally advanced non-small cell lung cancer (NSCLC). METHODS: Patients whose tumors had programmed cell death ligand 1 (PD-L1) tumor proportion scores (TPS) ≥50% (cohort 1) or 1%-49% (cohort 2) received first-line niraparib (200 mg once daily) plus pembrolizumab (200 mg every 3 weeks). The primary end point was investigator-assessed objective response rate (ORR). Secondary end points included duration of response (DoR), progression-free survival (PFS), overall survival (OS), safety, and pharmacokinetics. RESULTS: Thirty-eight patients were enrolled in cohorts 1 and 2. In cohort 1, ORR (95% confidence interval [CI]) was 56.3% (9 of 16 patients; 29.9%-80.2%); 2 of 16 patients had complete responses and 7 of 16 had partial responses (PRs). In cohort 2, ORR was 20.0% (5.7%-43.7%) with 4 of 20 PRs. In cohorts 1 and 2, the median DoR was 19.7 months (95% CI, 4.2 months to not estimable [NE]) and 9.4 months (95% CI, 4.2 months to NE), the median PFS was 8.4 months (95% CI, 3.9-22.1 months) and 4.2 months (95% CI, 2.0-6.2 months), and the median OS was NE (95% CI, 6.0 months to NE) and 7.7 months (95% CI, 4.0-12.5 months), respectively. Grade ≥3 treatment-emergent adverse events occurred in 88.2% and 85.7% of patients in cohorts 1 and 2, respectively. Safety was consistent with known profiles of single-agent niraparib and pembrolizumab. CONCLUSIONS: Niraparib plus pembrolizumab showed clinical activity in patients with advanced and/or metastatic NSCLC. LAY SUMMARY: The JASPER clinical trial studied a new combination treatment for advanced or metastatic non-small cell lung cancer (NSCLC). Pembrolizumab, a drug approved for NSCLC, was given with niraparib. Previous research showed that these 2 drugs together might work better than either drug alone. This study found that more than half of patients with high levels of a tumor marker responded to the combination, and one-fifth of patients with lower levels of the marker responded. The types of side effects from the combination were similar to side effects from both drugs alone. These results support more research on this combination.

"We Are All Trying to Find a Way to Help Ourselves": A Look at Self-Help Strategies Among Psychotherapy Clients.

Objective: This study examined self-help strategies engaged by psychotherapy clients and explored their views on such self-help approach. Methods: Secondary analysis of data from a qualitative research study was conducted. A total of 15 psychotherapy clients were recruited, and data were collected via semi-structured interviews. Thematic analysis of data was conducted using inductive approach to examine the content. Results: Three main themes revolving around self-help strategies were identified: (1) types of self-help strategies, (2) reasons for engaging in self-help activities, and (3) effectiveness of self-help strategies. Conclusion: The self-help approach to manage distress is common among psychotherapy clients. This study provided insights into understanding how and why clients use self-help strategies in their daily lives.

A Randomised Controlled Trial of Clinician-Guided Internet-Based Cognitive Behavioural Therapy for Depressed Patients in Singapore.

This study examined the efficacy and acceptability of a hybrid, clinician-guided internet-based Cognitive Behavioural Therapy (iCBT) programme for outpatients with depression in a psychiatric hospital in Singapore. Fifty three participants were randomly assigned to a treatment or wait-list control group before they underwent a cross-over of conditions. Treatment consisted of a 4-week iCBT with three face-to-face sessions. 60.9% of participants who received treatment completed all six modules. Intention-to-treat analysis showed treatment was associated with significant reductions in symptoms of depression, anxiety and psychological distress but not in functional impairment, while the control condition was not associated with changes in any measures. These reductions had moderate to large effect sizes (ESs) for symptoms of depression and anxiety, and moderate ES for psychological distress. The between-group difference in depression score had a moderate ES. There was a significant between-group treatment effect in depressive symptoms, but not in the other measures. Treatment gains were maintained at 3-month follow-up. Most of the participants were highly satisfied with the programme, with 90 percent stating they would recommend it. This is the first RCT to provide preliminary evidence for the efficacy and acceptability of iCBT for depression in Singapore.

An Integrated Analysis of Dostarlimab Immunogenicity.

Monoclonal antibodies that block the interaction between programmed cell death 1 (PD-1) and its ligand (PD-L1) have revolutionized cancer immunotherapy. However, immunogenic responses to these new therapies-such as the development of antidrug antibodies (ADAs) and neutralizing antibodies (NAbs)-may represent a significant challenge to both efficacy and safety in some patients. Dostarlimab (TSR-042) is an approved, humanized, anti-PD-1 monoclonal antibody that has shown efficacy in multiple solid tumor types. Here, we report the results of an immunogenicity analysis of dostarlimab monotherapy in patients enrolled in the GARNET trial, a multicenter, open-label, single-arm phase 1 study. Overall, 477 of 478 patients (99.8%) were included in the analysis of dostarlimab antibody prevalence, and 349 out of 478 enrolled patients (73.0%) were evaluable for treatment-emergent antibodies to dostarlimab. The incidence of treatment-emergent ADAs was 2.5% at the recommended therapeutic dose (500 mg Q3W for the first 4 doses, 1000 mg Q6W until discontinuation), which is comparable to other anti-PD-(L)1 drugs. NAbs were detected in only 1.3% of patients. In the small percentage of patients who developed ADAs, there was no evidence of altered efficacy or safety of dostarlimab at the recommended dosing regimen. These findings demonstrated that treatment with dostarlimab was associated with a low risk of eliciting clinically meaningful ADAs over the course of this study, and dostarlimab is already approved by health authorities.

Preclinical characterization of dostarlimab, a therapeutic anti-PD-1 antibody with potent activity to enhance immune function in in vitro cellular assays and in vivo animal models.

Inhibitors of programmed cell death protein 1 (PD-1) and its ligand (PD-L1) have dramatically changed the treatment landscape for patients with cancer. Clinical activity of anti-PD-(L)1 antibodies has resulted in increased median overall survival and durable responses in patients across selected tumor types. To date, 6 PD-1 and PD-L1, here collectively referred to as PD-(L)1, pathway inhibitors are approved by the US Food and Drug Administration for clinical use. The availability of multiple anti-PD-(L)1 antibodies provides treatment and dosing regimen choice for patients with cancer. Here, we describe the nonclinical characterization of dostarlimab (TSR-042), a humanized anti-PD-1 antibody, which binds with high affinity to human PD-1 and effectively inhibits its interaction with its ligands, PD-L1 and PD-L2. Dostarlimab enhanced effector T-cell functions, including cytokine production, in vitro. Since dostarlimab does not bind mouse PD-1, its single-agent antitumor activity was evaluated using humanized mouse models. In this model system, dostarlimab demonstrated antitumor activity as assessed by tumor growth inhibition, which was associated with increased infiltration of immune cells. Single-dose and 4-week repeat-dose toxicology studies in cynomolgus monkeys indicated that dostarlimab was well tolerated. In a clinical setting, based on data from the GARNET trial, dostarlimab (Jemperli) was approved for the treatment of adult patients with mismatch repair-deficient recurrent or advanced endometrial cancer that had progressed on or following prior treatment with a platinum-containing regimen. Taken together, these data demonstrate that dostarlimab is a potent anti-PD-1 receptor antagonist, with properties that support its continued clinical investigation in patients with cancer.

A phase 1, open-label, dose-escalation trial of oral TSR-011 in patients with advanced solid tumours and lymphomas.

BACKGROUND: Anaplastic lymphoma kinase (ALK) gene rearrangements are oncogenic drivers in non-small-cell lung cancer (NSCLC). TSR-011 is a dual ALK and tropomyosin-related kinase (TRK) inhibitor, active against ALK inhibitor resistant tumours in preclinical studies. Here, we report the safety, tolerability and recommended phase 2 dose (RP2D) of TSR-011 in patients with relapsed or refractory ALK- and TRK-positive advanced cancers. METHODS: In this sequential, open-label, phase 1 trial (NCT02048488), patients received doses of 30 mg, escalated to 480 mg every 24 hours (Q24h), followed by an expansion cohort of patients with ALK-positive cancers. The primary objective was to evaluate safety and tolerability. Secondary objectives included pharmacokinetics. RESULTS: TSR-011 320- and 480-mg Q24h doses exceeded the maximum tolerated dose. At the RP2D of 40 mg every 8 hours (Q8h), the most common grade 3-4 treatment-emergent adverse events occurred in 3.2-6.5% of patients. Of 14 ALK inhibitor-naive patients with ALK-positive NSCLC, 6 experienced partial responses and 8 had stable disease. CONCLUSIONS: At the RP2D (40 mg Q8h), TSR-011 demonstrated a favourable safety profile with acceptable QTc changes. Limited clinical activity was observed. Based on the competitive ALK inhibitor landscape and benefit/risk considerations, further TSR-011 development was discontinued. CLINICAL TRIAL REGISTRATION NUMBER: NCT02048488.

Salvage Cryoablation for Radiorecurrent Prostate Cancer: Initial Experience at a Regional Health Care System.

CONTEXT: Local recurrence after radiotherapy for prostate cancer remains challenging to treat effectively. Although oncologic control is highest with salvage prostatectomy, the procedure is associated with substantial morbidity. OBJECTIVE: To identify factors associated with successful salvage cryoablation for radiorecurrent prostate cancer. DESIGN: We retrospectively reviewed the medical records of patients who underwent salvage cryoablation at our institution between 2005 and 2015. All patients had biopsy-proven local recurrence after radiotherapy. Patients with seminal vesicle invasion or metastases were excluded. Complete follow-up was obtained for all patients. MAIN OUTCOME MEASURES: Primary study endpoint was biochemical progression-free survival based on the Phoenix criteria. RESULTS: Seventy-five patients underwent salvage cryotherapy. Mean patient age was 69.3 years. The overall biochemical salvage rate was 50.7% at a median follow-up of 3.9 years. The following factors were independently associated with successful cryotherapy: Precryotherapy Gleason score of 3 + 3 or 3 + 4, low precryotherapy prostate-specific antigen (PSA), low precryotherapy PSA density, longer time to PSA nadir after radiotherapy, and low postcryotherapy PSA nadir. A postcryotherapy PSA nadir of 0.5 ng/mL or less was associated with a biochemical progression-free survival of 79.7% at 3 years and 64.7% at 5 years, whereas a postcryotherapy PSA nadir above 0.5 was associated with a biochemical progression-free survival of 5.6% at 3 years and 0% at 5 years (p < 0.0001). CONCLUSION: Approximately 50% of the patients achieved biochemical salvage with cryoablation at 5 years. Nadir PSA after salvage was the strongest predictor of biochemical progression-free survival in our cohort.

An Open-Label, Randomized, Pivotal Bioequivalence Study of Oral Rolapitant.

Rolapitant, a selective and long-acting neurokinin-1 receptor antagonist, is approved in an oral formulation for prevention of delayed chemotherapy-induced nausea and vomiting in adults. This pivotal open-label, randomized, single-dose, multicenter, parallel-group study assessed the bioequivalence of a single oral dose of 180 mg of rolapitant administered in tablet (2 × 90-mg tablets) or capsule (4 × 45-mg capsules) form in healthy male and female subjects. Blood samples for pharmacokinetic analysis were collected predose and at times up to 912 hours postdose. The rolapitant tablet was considered bioequivalent to the rolapitant capsule if the 90% confidence intervals for the ratios of the geometric means for rolapitant, observed maximum plasma concentration (Cmax ), and area under the curve from time 0 extrapolated to infinity (AUC0-∞ ) were within the 0.80-1.25 range. The pharmacokinetic profiles of the capsule group (n = 43) and tablet group (n = 44) were similar. The geometric mean ratios of Cmax and AUC0-∞ were 0.99 (0.89-1.11) and 1.05 (0.92-1.19), respectively, establishing bioequivalence of the rolapitant tablet and capsule formulations. Both formulations were well tolerated, with a similar incidence of treatment-emergent adverse events in the 2 groups.

Effects of rolapitant administered orally on the pharmacokinetics of dextromethorphan (CYP2D6), tolbutamide (CYP2C9), omeprazole (CYP2C19), efavirenz (CYP2B6), and repaglinide (CYP2C8) in healthy subjects.

PURPOSE: Rolapitant is a neurokinin-1 receptor antagonist indicated in combination with other antiemetic agents in adults for the prevention of delayed chemotherapy-induced nausea and vomiting. We evaluated the effects of rolapitant oral on the pharmacokinetics of probe substrates for cytochrome P450 (CYP) 2D6 (dextromethorphan), 2C9 (tolbutamide), 2C19 (omeprazole), 2B6 (efavirenz), and 2C8 (repaglinide) in healthy subjects. METHODS: This open-label, multipart, randomized, phase 1 study assessed cohorts of 20-26 healthy subjects administered dextromethorphan, tolbutamide plus omeprazole, efavirenz, or repaglinide with and without single, oral doses of rolapitant. Maximum plasma analyte concentrations (Cmax) and area under the plasma analyte concentration-time curves (AUC) were estimated using noncompartmental analysis, and geometric mean ratios (GMRs) and 90% confidence intervals for the ratios of test (rolapitant plus probe substrate) to reference (probe substrate alone) treatment were calculated. RESULTS: Rolapitant significantly increased the systemic exposure of dextromethorphan in terms of Cmax and AUC0-inf by 2.2- to 3.3-fold as observed in GMRs on days 7 and 14. Rolapitant did not affect systemic exposure of tolbutamide, and minor excursions outside of the 80-125% no effect limits were detected for omeprazole, efavirenz, and repaglinide. CONCLUSIONS: Inhibition of dextromethorphan by a single oral dose of rolapitant 180 mg is clinically significant and can last at least 7 days. No clinically significant interaction was observed between rolapitant and substrates of CYP2C9, CYP2C19, CYP2B6, or CYP2C8. CYP2D6 substrate drugs with a narrow therapeutic index may require monitoring for adverse reactions if given concomitantly with rolapitant.

Pharmacokinetic Interactions of Rolapitant With Cytochrome P450 3A Substrates in Healthy Subjects.

Rolapitant (Varubi) is a neurokinin-1 receptor antagonist approved for the prevention of chemotherapy-induced nausea and vomiting. Rolapitant is primarily metabolized by the cytochrome P450 3A4 (CYP3A4) enzyme. Unlike other neurokinin-1 receptor antagonists, rolapitant is neither an inhibitor nor an inducer of CYP3A4 in vitro. The objective of this analysis was to examine the pharmacokinetics of rolapitant in healthy subjects and assess drug-drug interactions between rolapitant and midazolam (a CYP3A substrate), ketoconazole (a CYP3A inhibitor), or rifampin (a CYP3A4 inducer). Three phase 1, open-label, drug-drug interaction studies were conducted to examine the pharmacokinetic interactions of orally administered rolapitant with midazolam, rolapitant with ketoconazole, and rolapitant with rifampin. The pharmacokinetic profiles of midazolam and 1-hydroxy midazolam metabolites were essentially unchanged when coadministered with rolapitant, indicating the lack of a clinically relevant inhibition or induction of CYP3A by rolapitant. Coadministration of ketoconazole with rolapitant had no effects on rolapitant maximum concentration and resulted in an approximately 20% increase in the area under the concentration-time curve of rolapitant, suggesting that strong CYP3A inhibitors have minimal inhibitory effects on rolapitant exposure. Repeated administrations of rifampin appeared to reduce rolapitant exposure, resulting in a 33% decrease in maximum concentration and 87% decrease in area under the concentration-time curve from time zero to infinity. Coadministration of rolapitant did not affect the exposure of midazolam. Rifampin coadministration resulted in lower concentrations of rolapitant, and ketoconazole coadministration had no or minimal effects on rolapitant exposure. Rolapitant was safe and well tolerated when coadministered with ketoconazole, rifampin, or midazolam. No new safety signals were reported compared with previous studies of rolapitant.

Pharmacokinetics, Safety, and Tolerability of Rolapitant Administered Intravenously Following Single Ascending and Multiple Ascending Doses in Healthy Subjects.

Rolapitant is a selective and long-acting neurokinin-1 receptor antagonist approved in an oral formulation in combination with dexamethasone and a 5-hydroxytryptamine type 3 receptor antagonist for the prevention of delayed chemotherapy-induced nausea and vomiting in adults. The pharmacokinetic and safety profiles of intravenous (IV) rolapitant were evaluated in two open-label, phase 1 trials in healthy subjects. Single ascending dose (SAD) and multiple ascending dose studies were conducted in one trial (PR-11-5012-C), and a supratherapeutic SAD study was conducted in a separate trial (PR-11-5022-C). In the SAD and supratherapeutic studies, rolapitant maximum plasma concentration, area under the plasma drug concentration-time curve (AUC) from time zero to time of last measured concentration, and AUC from time zero to infinity increased dose-proportionally following single IV infusions of 18 to 270 mg. In the multiple ascending dose study, following 10 daily IV infusions of rolapitant 18, 36, or 54 mg, the mean day 10:day 1 maximum concentration ratio was 1.97, 1.52, and 2.07, respectively, and the mean day 10:day 1 ratio of AUC from 0 to 24 hours was 4.30, 4.59, and 5.38, respectively, indicating drug accumulation over time. Across all studies, rolapitant was gradually eliminated from plasma, with a half-life of 135-231 hours. Rolapitant was safe and well tolerated across all studies, with no serious or severe rolapitant-related treatment-emergent adverse events. The most common rolapitant-related treatment-emergent adverse events were headache, dry mouth, and dizziness, which were predominantly mild in severity. Overall, the pharmacokinetic and safety profiles of IV rolapitant were consistent with those of the oral formulation.

Effects of Rolapitant Administered Intravenously on the Pharmacokinetics of a Modified Cooperstown Cocktail (Midazolam, Omeprazole, Warfarin, Caffeine, and Dextromethorphan) in Healthy Subjects.

Rolapitant is a selective, long-acting neurokinin-1 receptor antagonist, approved in the United States and Europe for prevention of delayed chemotherapy-induced nausea and vomiting in adults. This open-label study evaluated the effects of a new intravenous formulation of rolapitant on cytochrome P450 (CYP) enzyme (CYP3A, CYP1A2, CYP2C9, CYP2C19, and CYP2D6) activity. On days 1 and 14, 36 healthy volunteers received a modified Cooperstown cocktail (midazolam 3 mg [CYP3A substrate], caffeine 200 mg [CYP1A2 substrate], S-warfarin 10 mg [CYP2C9 substrate] + vitamin K 10 mg, omeprazole 40 mg [CYP2C19 substrate], and dextromethorphan 30 mg [CYP2D6 substrate]). On day 7, subjects received the modified Cooperstown cocktail after 166.5-mg rolapitant infusion. On days 21, 28, and 35, subjects received oral dextromethorphan. Maximum plasma concentration (Cmax ) and area under the plasma concentration-time curve (AUC0-last ) of probe drugs post- vs pre-rolapitant administration were assessed using geometric least-squares mean ratios (GMRs) with 90%CIs. The 90%CIs of the GMRs were within the 0.80-1.25 no-effect limits for caffeine and S-warfarin Cmax and AUC0-last . For midazolam Cmax and AUC0-last and omeprazole Cmax , the 90%CIs of the GMRs were marginally outside these limits. Intravenous rolapitant coadministration increased dextromethorphan exposure, peaking 14 days post-rolapitant administration (GMRs: Cmax , 2.74, 90%CI 2.21-3.40; AUC0-last , 3.36, 90%CI 2.74-4.13). Intravenous rolapitant 166.5 mg and probe drugs were well tolerated when coadministered. These data suggest that intravenous rolapitant is not an inhibitor of CYP3A, CYP2C9, CYP2C19, or CYP1A2 but is a moderate inhibitor of CYP2D6.

Pharmacokinetics of Rolapitant in Patients With Mild to Moderate Hepatic Impairment.

Rolapitant is a selective and long-acting neurokinin-1 receptor antagonist approved in an oral formulation in combination with other antiemetic agents for the prevention of delayed chemotherapy-induced nausea and vomiting in adults. This was a phase 1 open-label, parallel-group pharmacokinetic and safety study of a single oral dose of 180 mg of rolapitant and its major active metabolite, M19, in subjects with mild and moderate hepatic impairment compared with healthy matched controls. Pharmacokinetics were assessed by a mixed-model analysis of variance of log-transformed values for maximum observed plasma concentration (Cmax ), observed time at Cmax (tmax ), area under the plasma concentration-time curve (AUC) from time 0 to the time of the last quantifiable concentration (AUC0-t ), and AUC from time 0 to 120 hours (AUC0-120 ), with hepatic group as a fixed effect. Mean rolapitant Cmax , AUC0-t , and AUC0-120 were similar in the mild hepatic impairment and healthy control groups. In subjects with moderate hepatic impairment, AUC0-t was similar and Cmax was 25% lower than in healthy controls. Mean M19 Cmax and AUC0-t were similar in the mild hepatic impairment group and healthy controls, but <20% lower in those with moderate hepatic impairment versus healthy controls. Fraction of unbound rolapitant was comparable in all groups for rolapitant and M19. Rolapitant was well tolerated in all groups, without serious adverse events. Pharmacokinetic differences between healthy subjects and those with mild or moderate hepatic impairment are unlikely to pose a safety risk and do not warrant predefined dosage adjustment in the presence of hepatic impairment.