Richard Labotka

Pharmacokinetics of ixazomib, an oral proteasome inhibitor, in solid tumour patients with moderate or severe hepatic impairment

Aim The aim of the present study was to characterize the pharmacokinetics of the oral proteasome inhibitor, ixazomib, in patients with solid tumours and moderate or severe hepatic impairment, to provide posology recommendations. Methods Eligible adults with advanced malignancies for which no further effective therapy was available received a single dose of ixazomib on day 1 of the pharmacokinetic cycle; patients with normal hepatic function, moderate hepatic impairment or severe hepatic impairment received 4 mg, 2.3 mg or 1.5 mg, respectively. Blood samples for single‐dose pharmacokinetic characterization were collected over 336 h postdose. After sampling, patients could continue to receive ixazomib on days 1, 8 and 15 in 28‐day cycles. Results Of 48 enrolled patients (13, 15 and 20 in the normal, moderate and severe groups, respectively), 43 were pharmacokinetics‐evaluable. Ixazomib was rapidly absorbed (median time to reach peak concentration was 0.95–1.5 h) and highly bound to plasma proteins, with a similar mean fraction bound (~99%) across the three groups. In patients with moderate/severe hepatic impairment (combined group), the geometric least squares mean ratios (90% confidence interval) for unbound and total dose‐normalized area under the plasma concentration vs. time curve from time zero to the time of the last quantifiable concentration in reference to the normal hepatic function group were 1.27 (0.75, 2.16) and 1.20 (0.79, 1.82), respectively. Seven (15%) of the 48 patients experienced a grade 3 drug‐related adverse event; there were no drug‐related grade 4 adverse events. Conclusions In patients with moderate/severe hepatic impairment, unbound and total systemic exposures of ixazomib were 27% and 20% higher, respectively, vs. normal hepatic function. A reduced ixazomib starting dose of 3 mg is recommended for patients with moderate or severe hepatic impairment.

Disease burden of systemic light-chain amyloidosis: a systematic literature review

Abstract Introduction: A systematic literature review on systemic light chain (AL) amyloidosis was conducted in order to understand the disease burden, and identify unmet medical needs and knowledge gaps. Methods: MEDLINE, Embase and Cochrane databases were searched for English language studies published in the last 10 years using search terms that focused on the clinical, economic, and patient-reported outcome (PRO) aspects of AL amyloidosis. There was a low yield of articles in the economic and PRO categories and additional searches were conducted in clinical conference proceedings, and using Google and Google Scholar. After review, there were 65 articles included for data extraction. Results: AL amyloidosis is a rare disorder without any FDA or EMA approved indications for drug therapy. Using off-label therapies, there is a high rate, 42–64%, of non-response or progression, and an associated high mortality. Toxicities during therapy are common with estimates of up to 30–40% of patients experiencing severity of grade 3 or higher. Patients with AL amyloidosis report severe psychological distress, anxiety and clinical depression. Conclusions: There is a deficiency in the literature on the economic costs associated with AL amyloidosis, and information on costs has been derived from studies that examined multiple myeloma or other disease or treatment components common to AL amyloidosis.

Model‐Informed Drug Development for Ixazomib, an Oral Proteasome Inhibitor

Model‐informed drug development (MIDD) was central to the development of the oral proteasome inhibitor ixazomib, facilitating internal decisions (switch from body surface area (BSA)‐based to fixed dosing, inclusive phase III trials, portfolio prioritization of ixazomib‐based combinations, phase III dose for maintenance treatment), regulatory review (model‐informed QT analysis, benefit–risk of 4 mg dose), and product labeling (absolute bioavailability and intrinsic/extrinsic factors). This review discusses the impact of MIDD in enabling patient‐centric therapeutic optimization during the development of ixazomib.

Model‐Based Meta‐Analysis for Multiple Myeloma: A Quantitative Drug‐Independent Framework for Efficient Decisions in Oncology Drug Development

The failure rate for phase III trials in oncology is high; quantitative predictive approaches are needed. We developed a model‐based meta‐analysis (MBMA) framework to predict progression‐free survival (PFS) from overall response rates (ORR) in relapsed/refractory multiple myeloma (RRMM), using data from seven phase III trials. A Bayesian analysis was used to predict the probability of technical success (PTS) for achieving desired phase III PFS targets based on phase II ORR data. The model demonstrated a strongly correlated (R2 = 0.84) linear relationship between ORR and median PFS. As a representative application of the framework, MBMA predicted that an ORR of ∼66% would be needed in a phase II study of 50 patients to achieve a target median PFS of 13.5 months in a phase III study. This model can be used to help estimate PTS to achieve gold‐standard targets in a target product profile, thereby enabling objectively informed decision‐making.

The impact of age and comorbidities on practice patterns and outcomes in patients with relapsed/refractory multiple myeloma in the era of novel therapies

OBJECTIVES One-third of patients with multiple myeloma (MM) are diagnosed at age≥75years. Older patients have increased incidence of cardiovascular disease (CVD) and renal insufficiency (RI), hallmark complications of MM. We examined cumulative incidence of CVD and RI in relapsed/refractory MM (RRMM) and outcomes by age and RI/CVD. MATERIALS AND METHODS Retrospective cohort study using a large US electronic medical records database of adult patients with RRMM initiating first- and second-line therapy (2LT) between 1/2008-06/2015. RI and CVD comorbidities were based on diagnosis codes and/or lab values. RESULTS Among 628 patients, 37.1% were ≥75years. Cumulative incidence of CVD and/or RI increased from 47.7% at MM diagnosis to 67.8% at first relapse. Age≥75years had a trend toward higher risk of relapse post 2LT, proxied by time to next treatment (TTNT), (adjusted HR: 1.28; 95% CI: 1.00, 1.65; P=0.05). TTNT was significantly higher with comorbid CVD+RI (adjusted HR: 1.50; 95% CI: 1.11, 2.02; P<0.01). Age≥75years, RI, CVD, and CVD+RI were associated with increased mortality risk from 2LT initiation; adjusted HR: 1.66 (95% CI: 1.19, 2.33; P<0.01), 1.51 (95% CI: 1.01, 2.26; P=0.04), 1.75 (95% CI: 1.03, 2.96; P=0.04), and 1.95 (95% CI: 1.29, 2.93; P<0.01), respectively. CONCLUSION Despite treatment with novel agents for RRMM in 86% of patients, an outcome gap persists for older patients and those with RI and/or CVD. Personalized treatment approaches that account for age and comorbidities, and further evaluation of innovative regimens and dosing schedules, are needed to improve outcomes for these patients.