Model-Informed Selection of the Recommended Phase III Dose of the Inhibitor of Apoptosis Protein Inhibitor, Xevinapant, in Combination with Cisplatin and Concurrent Radiotherapy in Patients with Locally Advanced Squamous Cell Carcinoma of the Head and Neck.

Xevinapant, an oral inhibitor of apoptosis protein (IAP) inhibitor, demonstrated efficacy in combination with chemoradiotherapy in a randomized phase II study (NCT02022098) in patients with locally advanced squamous cell carcinoma of the head and neck at 200 mg/day on days 1-14 of a 3-week cycle. To confirm 200 mg/day as the recommended phase III dose (RP3D), we integrated preclinical, clinical, pharmacokinetic/pharmacodynamic (PK/PD), and exposure-response modeling results. Population PK/PD modeling of IAP inhibition in peripheral blood mononuclear cells in 21 patients suggested the pharmacologically active dose range was 100-200 mg/day, with a trend for more robust inhibition at the end of the dosing interval at 200 mg/day based on an indirect response model. Additionally, the unbound average plasma concentration at 200 mg/day was similar to that associated with efficacy in preclinical xenograft models. Logistic regression exposure-response analyses of data from 62 patients in the phase II study showed exposure-related increases in probabilities of locoregional control at 18 months (primary end point), overall response, complete response, and the radiosensitization mechanism-related composite safety end point "mucositis and/or dysphagia" (P < 0.05). Exposure-response relationships were not discernible for 12 of 13 evaluated safety end points, incidence of dose reductions, and time to first dose reduction. Quantitative integration of all available data, including model-derived target inhibition profiles, positive exposure-efficacy relationships, and lack of discernible exposure-safety relationships for most safety end points, supports selection of xevinapant 200 mg/day on days 1-14 of a 3-week cycle as the RP3D, allowing for successive dose reductions to 150 and 100 mg/day to manage adverse events.

Population pharmacokinetic analyses for belzutifan to inform dosing considerations and labeling.

Belzutifan (Welireg, Merck & Co., Inc., Rahway, NJ, USA) is an oral, potent inhibitor of hypoxia-inducible factor 2α, approved for the treatment of certain patients with von Hippel-Lindau (VHL) disease-associated renal cell carcinoma (RCC), central nervous system hemangioblastomas, and pancreatic neuroendocrine tumors. It is primarily metabolized by the polymorphic uridine 5'-diphospho-glucuronosyltransferase (UGT) 2B17 and cytochrome (CYP) 2C19. A population pharmacokinetic (PK) model was built, using NONMEM version 7.3, based on demographics/PK data from three clinical pharmacology (food effect, formulation bridging, and genotype/race effect) and two clinical studies (phase I dose escalation/expansion in patients with RCC and other solid tumors; phase II in patients with VHL). Median (range) age for the combined studies was 55 years (19-84) and body weight was 73.6 kg (42.1-165.8). Belzutifan plasma PK was well-characterized by a linear two-compartment model with first-order absorption and elimination. For patients with VHL, the predicted geometric mean (% coefficient of variation) apparent clearance was 7.3 L/h (51%), apparent total volume of distribution was 130 L (35%), and half-life was 12.39 h (42%). There were no clinically relevant differences in belzutifan PK based on the individual covariates of age, sex, ethnicity, race, body weight, mild/moderate renal impairment, or mild hepatic impairment. In this model, dual UGT2B17 and CYP2C19 poor metabolizers (PMs) were estimated to have a 3.2-fold higher area under the plasma concentration-time curve compared to UGT2B17 extensive metabolizer and CYP2C19 non-PM patients. This population PK analysis enabled an integrated assessment of PK characteristics with covariate effects in the overall population and subpopulations for belzutifan labeling.

Predicted Bezlotoxumab Exposure in Patients Who Have Received a Hematopoietic Stem Cell Transplant.

PURPOSE: Bezlotoxumab is approved for prevention of recurrent Clostridioides (Clostridium) difficile infection (CDI) in adults receiving antibacterial treatment for CDI who are at high risk for recurrent CDI. Previous studies have shown that although serum albumin levels are an important predictor for bezlotoxumab exposure, this has no clinically meaningful impact on efficacy. This pharmacokinetic modeling study assessed whether hematopoietic stem cell transplant (HSCT) recipients, at increased risk of CDI and exhibiting decreased albumin levels within the first month posttransplant, are at risk of clinically relevant reductions in bezlotoxumab exposure. METHODS: Observed bezlotoxumab concentration-time data pooled from participants in Phase III trials MODIFY I and II (ClinicalTrials.gov identifiers NCT01241552/NCT01513239) and three Phase I studies (PN004, PN005, and PN006) were used to predict bezlotoxumab exposures in two adult post-HSCT populations: A Phase Ib study of posaconazole including allogeneic HSCT recipients (ClinicalTrials.gov identifier NCT01777763; posaconazole-HSCT population); and a Phase III study of fidaxomicin for CDI prophylaxis (ClinicalTrials.gov identifier NCT01691248; fidaxomicin-HSCT population). The bezlotoxumab PK model used the minimum albumin level for each individual in post-HSCT populations to mimic a "worst-case scenario." FINDINGS: Predicted worst-case bezlotoxumab exposures for the posaconazole-HSCT population (N = 87) were decreased by 10.8% versus bezlotoxumab exposures observed in the pooled Phase III/Phase I data set (N = 1587). No further decrease was predicted for the fidaxomicin-HSCT population (N = 350). IMPLICATIONS: Based on published population pharmacokinetic data, the predicted decrease in bezlotoxumab exposure in the post-HSCT populations is not expected to have a clinically meaningful effect on bezlotoxumab efficacy at the recommended 10 mg/kg dose. Dose modification is therefore not required in the hypoalbuminemia setting expected post-HSCT.

Population pharmacokinetic and exposure-response analyses of ivosidenib in patients with IDH1-mutant advanced hematologic malignancies.

Ivosidenib is a once daily (q.d.), orally available, potent mutant isocitrate dehydrogenase 1 (mIDH1) inhibitor approved for treatment of patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) and intensive chemotherapy ineligible AML with a susceptible IDH1 mutation. Population pharmacokinetics (PKs; N = 253), exposure-response (efficacy [n = 201] and safety [n = 253]), and concentration-corrected electrocardiogram QT interval (QTc; n = 171) analyses were performed using phase I data (100 mg twice daily and 300-1200 mg q.d.). Ivosidenib disposition was well-described by a two-compartment PK model with first-order absorption and elimination. Between-subject variability was moderate for PK parameters. Intrinsic factors did not affect ivosidenib PKs. Moderate/strong CYP3A4 inhibitors increased the area under the plasma ivosidenib concentration-time curve at steady state (AUCss ) by 60%. Efficacy responders and nonresponders had similar ivosidenib exposures. Based on AUCss , there was no apparent relationship between ivosidenib exposure and efficacy or adverse events. The plasma ivosidenib concentration-QT analysis showed a mean change in QTc using Fridericia's method (ΔQTcF) of 17.2 msec at the approved 500 mg q.d. dose. Because of the direct association between ivosidenib exposure and QTcF, patients should have their electrocardiograms and electrolytes monitored, and comedications that increase ivosidenib exposure or prolong the QT interval should be avoided. These model-based analyses quantitatively provide a framework to describe the relationship among ivosidenib dose, exposure, and clinical end points. With precautions for QTc prolongation, the exposure-response analyses support the 500 mg q.d. dose in patients with AML with a susceptible IDH1 mutation.