Understanding and Streamlining Dose Finding: From Dose Simulation to Dose Estimation.

Understanding drug dosing to fulfill safety and efficacy requirements in a patient population is an essential part of dose finding in clinical practice and drug development. The majority of current dose finding methods are simulation-based, which can be time consuming and resource intensive. Model-based simulations also do not guarantee that the dose, that will optimally fulfill the safety and efficacy endpoints, will be found.

Donor-derived cell-free DNA monitoring for early diagnosis of antibody-mediated rejection after kidney transplantation: a randomized trial.

Background And Hypothesis: Donor-derived cell-free DNA (dd-cfDNA) shows good diagnostic performance for the detection of antibody-mediated rejection (AMR) in kidney transplant recipients (KTR). However, the clinical benefits of dd-cfDNA monitoring need to be established. Early diagnosis of AMR at potentially reversible stages may be increasingly important due to emerging treatment options for AMR.

Kidney transplantation in patients with polycystic kidney disease: increased risk of infection does not compromise graft and patient survival.

Background: Patients with autosomal dominant polycystic kidney disease (ADPKD) represent >10% of patients awaiting kidney transplantation. These patients are prone to potentially severe urinary tract (UTI) and liver cyst infections after transplantation. Whether such infections compromise outcome is unclear.

Computing optimal drug dosing regarding efficacy and safety: the enhanced OptiDose method in NONMEM.

Recently, an optimal dosing algorithm (OptiDose) was developed to compute the optimal drug doses for any pharmacometrics model for a given dosing scenario. In the present work, we enhance the OptiDose concept to compute optimal drug dosing with respect to both efficacy and safety targets. Usually, these are not of equal importance, but one is a top priority, that needs to be satisfied, whereas the other is a secondary target and should be achieved as good as possible without failing the top priority target.

Dual TTK/PLK1 inhibition has potent anticancer activity in TNBC as monotherapy and in combination.

Background: Threonine tyrosine kinase (TTK) and polo-like kinase 1 (PLK1) are common essential kinases that collaborate in activating the spindle assembly checkpoint (SAC) at the kinetochore, ensuring appropriate chromosome alignment and segregation prior to mitotic exit. Targeting of either TTK or PLK1 has been clinically evaluated in cancer patients; however, dual inhibitors have not yet been pursued. Here we present the and characterization of a first in class, dual TTK/PLK1 inhibitor (BAL0891).