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1.  Preclinical Studies in the mdx Mouse Model of Duchenne Muscular Dystrophy with the Histone Deacetylase Inhibitor Givinostat 
Molecular Medicine  2013;19(1):79-87.
Previous work has established the existence of dystrophin–nitric oxide (NO) signaling to histone deacetylases (HDACs) that is deregulated in dystrophic muscles. As such, pharmacological interventions that target HDACs (that is, HDAC inhibitors) are of potential therapeutic interest for the treatment of muscular dystrophies. In this study, we explored the effectiveness of long-term treatment with different doses of the HDAC inhibitor givinostat in mdx mice—the mouse model of Duchenne muscular dystrophy (DMD). This study identified an efficacy for recovering functional and histological parameters within a window between 5 and 10 mg/kg/d of givinostat, with evident reduction of the beneficial effects with 1 mg/kg/d dosage. The long-term (3.5 months) exposure of 1.5-month-old mdx mice to optimal concentrations of givinostat promoted the formation of muscles with increased cross-sectional area and reduced fibrotic scars and fatty infiltration, leading to an overall improvement of endurance performance in treadmill tests and increased membrane stability. Interestingly, a reduced inflammatory infiltrate was observed in muscles of mdx mice exposed to 5 and 10 mg/kg/d of givinostat. A parallel pharmacokinetic/pharmacodynamic analysis confirmed the relationship between the effective doses of givinostat and the drug distribution in muscles and blood of treated mice. These findings provide the preclinical basis for an immediate translation of givinostat into clinical studies with DMD patients.
PMCID: PMC3667212  PMID: 23552722
2.  A Phase I Dose-Escalation Study of Danusertib (PHA-739358) Administered as a 24-hour Infusion With and Without G-CSF in a 14-day Cycle in Patients with Advanced Solid Tumors 
This study was conducted to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of the intravenous pan-aurora kinase inhibitor PHA-739358, danusertib, in patients with advanced solid tumors.
Experimental Design
In Part 1, patients received escalating doses of danusertib (24-h infusion every 14 days) without filgrastim (G-CSF). Febrile neutropenia was the dose-limiting toxicity without G-CSF. Further dose escalation was performed in part 2 with G-CSF. Blood samples were collected for danusertib pharmacokinetics and pharmacodynamics. Skin biopsies were collected to assess histone H3 phosphorylation (pH3).
Fifty-six patients were treated, 40 in part 1 and 16 in part 2. Febrile neutropenia was the dose limiting toxicity in Part 1 without G-CSF. Most other adverse events were grade 1–2, occurring at doses ≥360 mg/m2 with similar incidence in parts 1 and 2. The MTD without G-CSF is 500 mg/m2. The recommended phase 2 dose (RP2D) in Part 2 with G-CSF is 750 mg/m2. Danusertib demonstrated dose-proportional pharmacokinetics in parts 1 and 2 with a median half-life of 18–26 hours. pH3 modulation in skin biopsies was observed at ≥500 mg/m2. One patient with refractory small cell lung cancer (1000 mg/m2 with G-CSF) had an objective response lasting 23 weeks. One patient with refractory ovarian cancer had 27% tumor regression and 30% CA125 decline.
Danusertib was well tolerated with target inhibition in skin at ≥500 mg/m2. Preliminary evidence of anti-tumor activity, including a PR and several occurrences of prolonged stable disease (SD), was seen across a variety of advanced refractory cancers. Phase II studies are ongoing.
PMCID: PMC2826106  PMID: 19825950
Danusertib; PHA-739358; Aurora Kinase Inhibitor; phase I trial; solid tumors
3.  A predictive model for exemestane pharmacokinetics/pharmacodynamics incorporating the effect of food and formulation 
Exemestane (Aromasin®) is an irreversible aromatase inactivator used for the treatment of postmenopausal women with advanced breast cancer. The objective of this study was to evaluate the effect of formulation comparing a sugar-coated tablet (SCT) with a suspension and food on the pharmacokinetics (PK) and pharmacodynamics (PD) with respect to plasma estrone sulphate (E1S) concentrations of exemestane, using a PK/PD approach.
This was an open, three-period, randomized, crossover study. Twelve healthy postmenopausal women received single oral doses of 25 mg exemestane as a SCT after fasting or food and as a suspension after fasting. Exemestane and E1S concentrations were determined before and up to 14 days after drug administration. Population analysis was performed in two steps: (i) a compartmental PK model was selected incorporating the effect of food and formulation; (ii) conditional on the PK model, a PD model was developed employing indirect response models. Model selection was performed using standard statistical tests. Validation and assessment of the predictive capability of the selected model was performed using real test data sets obtained from the literature.
A three-compartment model with first-order elimination rate best described exemestane disposition (k12 0.454, k21 0.158, k13 0.174, k31 0.016 and k 0.738 h−1). Absorption was described by a mono-exponential function [ka 2.3 (SCT after fasting), 1.1 (SCT after food) and 7.6 h−1 (suspension); lag time 0.2 h]. The PD model assumed that E1S plasma concentrations are determined by a zero-order synthesis rate (6.5 pg ml−1 h−1) and a first-order elimination constant (0.032 h−1). Exemestane inhibited E1S synthesis with a C50 value of 22.1 pg ml−1. The mean population estimates were used to simulate the administration of different doses of the drug (0.5, 1, 2.5, 5 and 25 mg day−1). The model predictions were in agreement with historical data.
Exemestane absorption is influenced by the formulation of the drug and by food, but its disposition is independent of both. PK differences do no translate into clinically important differences in the PD. The PK/PD model developed was able to predict successfully the response to different doses and administration schedules with respect to oestrogen suppression.
PMCID: PMC1884784  PMID: 15752382
exemestane; model; NONMEM; pharmacokinetic/pharmacodynamic; population

Results 1-3 (3)