Integrated modeling of biomarkers, survival and safety in clinical oncology drug development.

Model-based approaches, including population pharmacokinetic-pharmacodynamic modeling, have become an essential component in the clinical phases of oncology drug development. Over the past two decades, models have evolved to describe the temporal dynamics of biomarkers and tumor size, treatment-related adverse events, and their links to survival. Integrated models, defined here as models that incorporate at least two pharmacodynamic/ outcome variables, are applied to answer drug development questions through simulations, e.

Pharmacokinetic-pharmacodynamic analysis of drug liking blockade by buprenorphine subcutaneous depot (CAM2038) in participants with opioid use disorder.

Buprenorphine is used to treat opioid use disorder (OUD). Weekly and monthly subcutaneous long-acting buprenorphine injections (CAM2038) provide more stable buprenorphine plasma levels and reduce the treatment burden, misuse, and diversion associated with sublingual transmucosal buprenorphine formulations. To characterize the pharmacokinetic/pharmacodynamic (PK/PD) relationship, a maximum inhibition (I) model was developed relating CAM2038 buprenorphine plasma concentration to drug liking maximum effect (E) visual analog scale (VAS; bipolar) score after intramuscular hydromorphone administration.

How to Successfully Generate an Alternative Approach to a Thorough QT Study: GLPG1972 as an Example.

During development of a drug, the requirement of evaluating the proarrhythmic risk and delayed repolarization needs to be fulfilled. Would it be possible to create an alternative to a thorough QT (TQT) study or is there a need to perform a dedicated TQT study? How is an alternative approach generated, what information is available, and which instructions are considered missing today to generate such an approach? This tutorial describes the considerations and path followed to create an early and feasible alternative to a TQT study using experience-based insights from a successful application to the US Food and Drug Administration for GLPG1972, an ADAMTS-5 inhibitor, and discusses the approach used in light of the current guidelines and literature.

Exposure-safety analyses of nintedanib in patients with chronic fibrosing interstitial lung disease.

Background: Nintedanib reduces the rate of decline in forced vital capacity in patients with idiopathic pulmonary fibrosis (IPF), other chronic fibrosing interstitial lung diseases (ILDs) with a progressive phenotype and systemic sclerosis-associated ILD (SSc-ILD). The recommended dose of nintedanib is 150 mg twice daily (BID).

Methods: Data from Phase II and III trials in IPF and Phase III trials in SSc-ILD and progressive fibrosing ILDs other than IPF were analyzed to investigate the relationship between nintedanib plasma concentrations (exposure) and safety (liver enzyme elevations [defined as transaminase elevations equal or greater than 3 times the upper limit of normal] and diarrhea).

Open innovation: Towards sharing of data, models and workflows.

Sharing of resources across organisations to support open innovation is an old idea, but which is being taken up by the scientific community at increasing speed, concerning public sharing in particular. The ability to address new questions or provide more precise answers to old questions through merged information is among the attractive features of sharing. Increased efficiency through reuse, and increased reliability of scientific findings through enhanced transparency, are expected outcomes from sharing.

Phase I dose-escalation and -expansion study of buparlisib (BKM120), an oral pan-Class I PI3K inhibitor, in patients with advanced solid tumors.

Purpose: The pan-Class I PI3K inhibitor buparlisib (BKM120) has shown activity in a range of preclinical cancer models. This first-in-man study was initiated to identify the maximum tolerated dose (MTD) of buparlisib (100 mg/day) and to assess safety and preliminary efficacy.

Methods: Patients with advanced solid tumors (N = 83) enrolled in a Phase I dose-escalation and -expansion study of single-agent buparlisib.

Dynamic tumor modeling of the dose-response relationship for everolimus in metastatic renal cell carcinoma using data from the phase 3 RECORD-1 trial.

Background: The phase 3 RECORD-1 trial (NCT00410124) established the efficacy and safety of everolimus in patients with metastatic renal cell carcinoma (mRCC) who progress on sunitinib or sorafenib. In RECORD-1, patients received 10 mg everolimus daily, with dose reduction to 5 mg daily allowed for toxicity. We have developed a model of tumor growth dynamics utilizing serial measurements of the sum of the longest tumor diameters (SLD) from individual RECORD-1 patients to define the dose-response relationship of everolimus.