Duchenne Muscular Dystrophy (DMD) is caused by mutations in the dystrophin gene leading to dystrophin deficiency, muscle fiber degeneration and progressive fibrotic replacement of muscles. Givinostat, a histone deacetylase (HDAC) inhibitor, significantly reduced fibrosis and promoted compensatory muscle regeneration in mdx mice. This study was conducted to evaluate whether the beneficial histological effects of Givinostat could be extended to DMD boys. Twenty ambulant DMD boys aged 7 to <11 years on stable corticosteroid treatment were enrolled in the study and treated for ≥12 months with Givinostat. A muscle biopsy was collected at the beginning and at the end of treatment to evaluate the amount of muscle and fibrotic tissue. Histological effects were the primary objectives of the study. Treatment with Givinostat significantly increased the fraction of muscle tissue in the biopsies and reduced the amount of fibrotic tissue. It also substantially reduced tissue necrosis and fatty replacement. Overall the drug was safe and tolerated. Improvement in functional tests was not observed in this study, but the sample size of the study was not sufficient to draw definitive conclusions. This study showed that treatment with Givinostat for more than 1 year significantly counteracted histological disease progression in ambulant DMD boys aged 7 to 10 years.

Health authorities carefully evaluate any change in the batch manufacturing process of a drug before and after regulatory approval. In the absence of an adequate in vitro–in vivo correlation (Level A IVIVC), an in vivo bioequivalence (BE) study is frequently required, increasing the cost and time of drug development. This study focused on developing a Level A IVIVC for progesterone vaginal rings (PVRs), a dosage form designed for the continuous delivery in vivo. The pharmacokinetics (PK) of four batches of rings charged with 125, 375, 750 and 1500 mg of progesterone and characterized by different in vitro release rates were evaluated in two clinical studies. In vivo serum concentrations and in vitro release profiles were used to develop a population IVIVC progesterone ring (P-ring) model through a direct differential-equation-based method and a nonlinear-mixed-effect approach. The in vivo release, ${\mathrm{R}}_{\mathrm{vivo}}\left(\mathrm{t}\right)$, was predicted from the in vitro profile through a nonlinear relationship. ${\mathrm{R}}_{\mathrm{vivo}}\left(\mathrm{t}\right)$ was used as the input of a compartmental PK model describing the in vivo serum concentration dynamics of progesterone. The proposed IVIVC P-ring model was able to correctly predict the in vivo concentration–time profiles of progesterone starting from the in vitro PVR release profiles. Its internal and external predictability was carefully evaluated considering the FDA acceptance criteria for IVIVC assessment of extended-release oral drugs. Obtained results justified the use of the in vitro release testing in lieu of clinical studies for the BE assessment of any new PVRs batches. Finally, the possible use of the developed population IVIVC model as a simulator of virtual BE trials was explored through a case study.

During amyotrophic lateral sclerosis progression, up to 85% of patients develop dysphagia. Riluzole oral suspension 50 mg/10 mL is bioequivalent to riluzole 50-mg film-coated tablets administered orally under fasting conditions. Here, we compare the bioavailability of a single 50-mg dose of riluzole oral suspension via intragastric tube, a proxy for percutaneous endoscopic gastrostomy administration, with that of oral administration in healthy volunteers under fasting conditions. Secondary objectives included the plasma pharmacokinetic and safety profiles of each administration route. This was a single-center, single-dose, open-label, randomized, 2-period, 2-sequence, crossover bioequivalence/bioavailability study. Healthy volunteers were randomized to riluzole oral suspension 50 mg/10 mL either via nasogastric tube or orally, with a 5-day washout before crossover. A total of 32 subjects were randomized (safety population); 30 were eligible for pharmacokinetic analysis. The ratios (nasogastric tube/oral) of the geometric least squares means and the geometric 90% CIs of AUC_0-t, AUC_0-inf, and C_max were calculated to be 90.60% (85.66%-95.82%), 90.43% (85.47%-95.67%), and 96.99% (89.40%-105.23%), respectively, indicating bioequivalence. No significant differences in C_max, T_max, K_el, and t_1/2el between treatments were found. Overall, riluzole oral suspension was well tolerated. No deaths or other serious adverse events were reported. In this study, riluzole oral suspension was bioequivalent when administered intragastrically and orally in healthy subjects under fasting conditions. Both administration methods were well tolerated. These results show that intragastric administration of riluzole oral suspension may provide an important formulation option in people with amyotrophic lateral sclerosis who have a percutaneous endoscopic gastrostomy tube.

Galactosyl hydroxylysine and deoxypyridinoline are at present the most promising markers of bone resorption. Various studies have indeed shown that these two markers discriminate with high accuracy subjects with different rates of bone turnover and that their accuracies and discriminate power are very similar. The aim of this paper is to compare the practicality and the reproducibility of the HPLC galactosyl hydroxylysine and deoxypyridinoline assays. In summary, this review shows that the galactosyl hydroxylysine and deoxypyridinoline HPLC assays differ mainly in the need, in using deoxypyridinoline, for an acid hydrolysis and a preextraction of the urine samples. This implies two major problems for deoxypyridinoline: 1) more time is required due to the cumbersome preanalytical procedures; and 2) a lower reproducibility. Our data, in fact, show that both the intra-assay and inter-assay coefficient of variation of the deoxypyridinoline assay are almost 100% higher than those of the galactosyl hydroxylysine assay.