A phase 1/2 ascending dose study and open-label extension study of voxelotor in patients with sickle cell disease

New treatments directly targeting polymerization of sickle hemoglobin (HbS), the proximate event in the pathophysiology of sickle cell disease (SCD), are needed to address the severe morbidity and early mortality associated with the disease. Voxelotor (GBT440) is a first-in-class, oral therapy specifically developed to treat SCD by modulating the affinity of hemoglobin for oxygen, thus inhibiting HbS polymerization and the downstream adverse effects of hemolytic anemia and vaso-occlusion. GBT440-001 was a phase 1/2 randomized, double-blind, placebo-controlled, single and multiple ascending dose study of voxelotor in adult healthy volunteers and patients with SCD which was followed by a single-arm, open-label extension study. This report describes results of voxelotor (500-1000 mg/day) in patients with sickle cell anemia (HbSS). The study evaluated the safety, tolerability, pharmacokinetic, and pharmacodynamic properties of voxelotor and established proof-of-concept by improving clinical measures of anemia, hemolysis, and sickling. Thirty-eight patients with SCD received 28 days of voxelotor 500, 700, or 1000 mg/day, or placebo; 16 patients received 90 days of voxelotor 700 or 900 mg/day, or placebo. Four patients from the 90-day cohort were subsequently enrolled in an extension study and treated with voxelotor 900 mg/day for 6 months. All patients who received multiple doses of voxelotor for ≥28 days experienced hematologic improvements including increased hemoglobin and reduction in hemolysis and percent of sickled red cells, supporting the potential of voxelotor to serve as a disease-modifying therapy for SCD. Voxelotor was well tolerated with no treatment-related serious adverse events and no evidence of tissue hypoxia. ClinicalTrials.gov identification: #NCT02285088 and #NCT03041909

Physiologically Based Pharmacokinetic Model of Amphotericin B Disposition in Rats Following Administration of Deoxycholate Formulation (Fungizone®): Pooled Analysis of Published Data

The time course of tissue distribution of amphotericin B (AmB) has not been sufficiently characterized despite its therapeutic importance and an apparent disconnect between plasma pharmacokinetics and clinical outcomes. The goals of this work were to develop and evaluate a physiologically based pharmacokinetic (PBPK) model to characterize the disposition properties of AmB administered as deoxycholate formulation in healthy rats and to examine the utility of the PBPK model for interspecies scaling of AmB pharmacokinetics. AmB plasma and tissue concentration–time data, following single and multiple intravenous administration of Fungizone® to rats, from several publications were combined for construction of the model. Physiological parameters were fixed to literature values. Various structural models for single organs were evaluated, and the whole-body PBPK model included liver, spleen, kidney, lung, heart, gastrointestinal tract, plasma, and remainder compartments. The final model resulted in a good simultaneous description of both single and multiple dose data sets. Incorporation of three subcompartments for spleen and kidney tissues was required for capturing a prolonged half-life in these organs. The predictive performance of the final PBPK model was assessed by evaluating its utility in predicting pharmacokinetics of AmB in mice and humans. Clearance and permeability–surface area terms were scaled with body weight. The model demonstrated good predictions of plasma AmB concentration–time profiles for both species. This modeling framework represents an important basis that may be further utilized for characterization of formulation- and disease-related factors in AmB pharmacokinetics and pharmacodynamics