Physiologically Based Pharmacokinetic Modeling of Oral Absorption, pH, and Food Effect in Healthy Volunteers to Drive Alpelisib Formulation Selection

A physiologically based pharmacokinetic (PBPK) human model for alpelisib, an oral α-specific class I phosphatidylinositol-3-kinase (PI3K) inhibitor, was established to simulate oral absorption and plasma pharmacokinetics of healthy subjects to allow model-informed drug development. The GastroPlus™ model consisted of an advanced absorption gut model, which was linked to a 2-compartmental model. Systemic clearance and volume of distribution were estimated using population pharmacokinetics (popPK). Various food effect and pH-mediated absorption drug–drug interaction (DDI) scenarios were modeled. In fasted healthy subjects, simulated absorption was lower (ca. 70% for a 300-mg dose) due to pH and bile acid concentration-dependent solubility. Ranitidine showed a significant pH-mediated DDI effect only in the fasted but not fed state. The PBPK model identified that more drug is absorbed in the fed state, and alpelisib intestinal permeability is rate limiting to systemic exposure. Simulations for healthy subject showed a positive food effect with ca. 2-fold increase in plasma Cmax and 1.5-fold increase in AUC0-inf with a meal compared with fasted conditions. The PBPK model was verified using clinical food effect data with pivotal clinical formulation (PCF) and then applied to predict the performance of a commercial formulation (CF) in healthy volunteers. The model successfully predicted the outcome of a clinical bioequivalence study for PCF and CF with included in vitro dissolution data, both fasted and fed state. Estimated predictive errors (based on plasma Cmax, AUC0-t) were equal or below 30%. The alpelisib model for healthy subjects enables future bioequivalence formulation assessments, in fasted, fed, or altered pH conditions. [Figure not available: see fulltext.

Efficacy and safety of Everolimus plus Exemestane combinaison therapy versus monotherapy with Everolimus or Capecitabine in HR+, HER2- breast cancer : a multicenter, open-label, phase 2 trial BOLERO-6

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Phase I, open-label, multicentre study of buparlisib in combination with temozolomide or with concomitant radiation therapy and temozolomide in patients with newly diagnosed glioblastoma

Most glioblastoma tumours exhibit intrinsic phosphatidylinositol 3-kinase (PI3K) pathway activation. Preclinical in vitro and in vivo models suggest that buparlisib (an oral pan-PI3K inhibitor) can have an effect on glioblastoma directly and by enhancing the activity of radiation and of temozolomide. This was a phase I, two-stage, multicentre, open-label, dose-escalation study of buparlisib in combination with temozolomide and radiotherapy in patients with newly diagnosed glioblastoma. In stage I, patients who completed the concomitant phase of combination of temozolomide and radiation prior to study entry received buparlisib in combination with temozolomide. In stage II, patients received buparlisib in combination with temozolomide and radiotherapy in the concomitant phase and temozolomide in the adjuvant treatment phase. The primary objective was to estimate the maximum tolerated dose (MTD) of buparlisib when combined with the approved first-line treatment of temozolomide and radiotherapy. The MTD of buparlisib in combination with temozolomide at stage I (adjuvant phase only) was 80 mg/day, which was used as the starting dose in stage II. The MTD of buparlisib in combination with temozolomide and radiotherapy in stage II (concomitant + adjuvant phase) was not determined due to the observed dose-limiting toxicities and treatment discontinuations due to adverse events (AEs). In stage I, the most commonly reported AEs were nausea (72.7%) and fatigue (59.1%). In stage II, the most commonly reported AEs were fatigue and nausea (56.3% each). No on-treatment deaths were reported during the study. Considering that the primary objective of estimating the MTD was not achieved in addition to the observed challenging safety profile of buparlisib in combination with radiotherapy and temozolomide, Novartis decided not to pursue the development of buparlisib in newly diagnosed glioblastoma.Trial registration numberClinicalTrials.gov identifier: NCT01473901

Buparlisib plus carboplatin or lomustine in patients with recurrent glioblastoma: a phase Ib/II, open-label, multicentre, randomised study

International audienceGlioblastoma relapse is associated with activation of phosphatidylinositol 3-kinase (PI3K) signalling pathway. In preclinical studies, the pan-PI3K inhibitor buparlisib showed antitumour activity in glioma models

Buparlisib plus carboplatin or lomustine in patients with recurrent glioblastoma: a phase Ib/II, open-label, multicentre, randomised study

BACKGROUND: Glioblastoma relapse is associated with activation of phosphatidylinositol 3-kinase (PI3K) signalling pathway. In preclinical studies, the pan-PI3K inhibitor buparlisib showed antitumour activity in glioma models. METHODS: This was a two-part, multicentre, phase Ib/II study in patients with recurrent glioblastoma pretreated with radiotherapy and temozolomide standard of care. Patients received buparlisib (80 mg or 100 mg once daily) plus carboplatin (area under the curve (AUC)=5 every 3 weeks), or buparlisib (60 mg once daily) plus lomustine (100 mg/m2 every 6 weeks). The primary endpoint was to determine the maximum tolerable dose (MTD) and/or recommended phase II dose of buparlisib plus carboplatin or lomustine. RESULTS: Between 28 February 2014 and 7 July 2016, 35 patients were enrolled and treated with buparlisib plus carboplatin (n=17; buparlisib (80 mg) plus carboplatin, n=3; and buparlisib (100 mg) plus carboplatin, n=14), or buparlisib (60 mg) plus lomustine (n=18). The MTD of buparlisib was determined to be 100 mg per day in combination with carboplatin at an AUC of 5 every 3 weeks. The MTD of buparlisib in combination with lomustine could not be determined as it did not satisfy the MTD criteria per the Bayesian logistic regression model. CONCLUSION: The overall safety profile of buparlisib remained unchanged, and no new or unexpected safety findings were reported in this study. Preliminary assessment for both combinations did not demonstrate sufficient antitumour activity compared with historical data on single-agent carboplatin or lomustine. TRIAL REGISTRATION NUMBER: NCT01934361.status: publishe