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Plazomicin is an FDA-approved aminoglycoside for the treatment of complicated urinary tract infections. In this open-label study, 24 adults with normal renal function or mild, moderate, or severe renal impairment (n = 6 per group) received a single 7.5-mg/kg of body weight dose of plazomicin as a 30-min intravenous infusion.

Nrf2 (nuclear factor [erythroid-derived 2]-like 2; the transcriptional master regulator of the antioxidant stress response) is regulated through interaction with its cytoplasmic inhibitor Keap1 (Kelch-like ECH-associated protein 1), which under basal conditions targets Nrf2 for proteasomal degradation. Sequestosome 1 (SQSTM1)/p62–a multifunctional adapter protein that accumulates following autophagy inhibition and can serve as a diagnostic marker for human autophagic vacuolar myopathies (AVMs)–was recently shown to compete with Nrf2 for Keap1 binding, resulting in activation of the Nrf2 pathway. In this study, we used 55 human muscle biopsies divided into five groups [normal control, hydroxychloroquine- or colchicine-treated non-AVM control, hydroxychloroquine- or colchicine-induced toxic AVM, polymyositis, and inclusion body myositis (IBM)] to evaluate whether Keap1-SQSTM1 interaction led to increased Nrf2 signaling in human AVMs. In toxic AVMs and IBM, but not in control muscle groups or polymyositis, Keap1 antibody labeled sarcoplasmic protein aggregates that can be used as an alternate diagnostic marker for both AVM types; these Keap1-positive aggregates were co-labeled with the antibody against SQSTM1 but not with the antibody against autophagosome marker LC3 (microtubule-associated protein 1 light chain 3). In human AVM muscle, sequestration of Keap1 into the SQSTM1-positive protein aggregates was accompanied by an increase in mRNA and protein levels of Nrf2 target genes; similarly, treatment of differentiated C2C12 myotubes with autophagy inhibitor chloroquine led to an increase in the nuclear Nrf2 protein level and an increase in expression of the Nrf2-regulated genes. Taken together, our findings demonstrate that Nrf2 signaling is upregulated in autophagic muscle disorders and raise the possibility that autophagy disruption in skeletal muscle leads to dysregulation of cellular redox homeostasis.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-016-0384-6) contains supplementary material, which is available to authorized users.

Plazomicin is an aminoglycoside that was engineered to overcome aminoglycoside‐modifying enzymes, which are the most common aminoglycoside resistance mechanism in Enterobacteriaceae. Because plazomicin is predominantly eliminated via renal pathways, an in vitro study was conducted to determine whether plazomicin inhibits the organic cation transporter 2 (OCT2) and the multidrug and toxin extrusion (MATE1 and MATE2‐K) transporters, using metformin as a probe substrate. Plazomicin inhibited OCT2, MATE1, and MATE2‐K transporters with half‐maximal inhibition of the transporter values of 5120, 1300, and 338 µg/mL, respectively. To determine whether this in vitro inhibition translates in vivo, an open‐label, randomized, 2‐period, 2‐treatment crossover study (NCT03270553) was carried out in healthy subjects (N = 16), who received a single oral dose of metformin 850 mg alone and in combination with a single intravenous infusion of plazomicin 15 mg/kg. Geometric least‐squares mean ratios of the test treatment (combination) vs the reference treatment (metformin alone) and 90% confidence intervals were within the equivalence interval of 80% to 125% (peak plasma concentration, 104.5 [95.1–114.9]; area under the plasma concentration–time curve from time zero to time of last quantifiable concentration, 103.7 [93.5–115.0]; area under the plasma concentration–time curve from time zero to infinity, 104.0 [94.2–114.8]). The results demonstrate that there is no clinically significant drug‐drug interaction resulting from coadministration of single doses of intravenous plazomicin 15 mg/kg and oral metformin 850 mg in healthy subjects. Coadministration of plazomicin and metformin was well tolerated in healthy subjects.

Introduction. The phase 3 fliGHt Trial evaluated the safety and tolerability of once-weekly lonapegsomatropin, a long-acting prodrug, in children with growth hormone deficiency (GHD) who switched from daily somatropin therapy to lonapegsomatropin. Methods. This multicenter, open-label, 26-week phase 3 trial took place at 28 sites across 4 countries (Australia, Canada, New Zealand, and the United States). The trial enrolled 146 children with GHD, 143 of which were previously treated with daily somatropin. All subjects received once-weekly lonapegsomatropin 0.24 mg hGH/kg/week. The primary outcome measure was safety and tolerability of lonapegsomatropin over 26 weeks. Secondary outcome measures assessed annualized height velocity (AHV), height standard deviation score (SDS), and IGF-1 SDS at 26 weeks. Results. Subjects had a mean prior daily somatropin dose of 0.29 mg/kg/week. Treatment-emergent adverse events (AEs) reported were similar to the published AE profile of daily somatropin therapies. After switching to lonapegsomatropin, the least-squares mean (LSM) AHV was 8.7 cm/year (95% CI: 8.2, 9.2) at Week 26 and LSM height SDS change from baseline to Week 26 of +0.25 (95% CI: 0.21, 0.29). Among switch subjects, the LSM for average IGF-1 SDS was sustained at Week 13 and Week 26, representing an approximate 0.7 increase from baseline (prior to switching from daily somatropin therapy). Conclusions. Lonapegsomatropin treatment outcomes were as expected across a range of ages and treatment experiences. Switching to lonapegsomatropin resulted in a similar AE profile to daily somatropin therapy.

Purpose The objectives of the ongoing, Phase 3, open-label extension trial enliGHten are to assess the long-term safety and efficacy of weekly administered long-acting growth hormone (LAGH) lonapegsomatropin in children with growth hormone deficiency (GHD). Methods Eligible subjects completing a prior Phase 3 lonapegsomatropin parent trial (heiGHt or fliGHt) were invited to participate. All subjects were treated with lonapegsomatropin. Subjects in the US switched to the TransCon hGH Auto-Injector when available.​ Endpoints were long-term safety, annualized height velocity (AHV), pharmacodynamics (insulin-like growth factor-1 standard deviation score [IGF-1 SDS] values), and patient- and caregiver-reported assessments of convenience and tolerability. Results Lonapegsomatropin treatment during enliGHten was associated with continued improvements in height SDS through Week 104 in treatment-naïve subjects from the heiGHt trial (−2.89 to −1.37 for- the lonapegsomatropin group; −3.0 to −1.52 for the daily somatropin group). Height SDS also continued to improve among switch subjects from the fliGHt trial (−1.42 at fliGHt baseline to −0.69 at Week 78). After 104 weeks, the average bone age/chronological age ratio for each treatment group was 0.8 (0.1), showing only minimal advancement of bone age relative to chronological age with continued lonapegsomatropin treatment among heiGHt subjects. Fewer local tolerability reactions were reported with the TransCon hGH Auto-Injector compared with syringe/needle. Conclusions Treatment with lonapegsomatropin continued to be safe and well-tolerated, with no new safety signals identified. Children treated with once-weekly lonapegsomatropin showed continued improvement of height SDS through the 2nd year of therapy without excess advancement of bone age.

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