Immunologic investigations into transgene directed immune-mediated myositis following delandistrogene moxeparvovec gene therapy.

Delandistrogene moxeparvovec is an rAAVrh74 vector-based gene transfer therapy that delivers a transgene encoding delandistrogene moxeparvovec micro-dystrophin, an engineered, functional form of dystrophin shown to stabilize or slow disease progression in DMD. It is approved in the US and in other select countries. Two serious adverse event cases of immune-mediated myositis (IMM) were reported in the phase Ib ENDEAVOR trial (NCT04626674).

Practical Considerations for Delandistrogene Moxeparvovec Gene Therapy in Patients With Duchenne Muscular Dystrophy.

Background: Delandistrogene moxeparvovec is a gene transfer therapy approved in the United States, United Arab Emirates, and Qatar for the treatment of ambulatory patients aged four through five years with a confirmed Duchenne muscular dystrophy (DMD)-causing mutation in the DMD gene. This therapy was developed to address the underlying cause of DMD through targeted skeletal, respiratory, and cardiac muscle expression of delandistrogene moxeparvovec micro-dystrophin, an engineered, functional dystrophin protein.

Methods: Drawing on clinical trial experience from Study 101 (NCT03375164), Study 102 (NCT03769116), and ENDEAVOR (Study 103; NCT04626674), we outline practical considerations for delandistrogene moxeparvovec treatment.

Delandistrogene Moxeparvovec Gene Therapy in Ambulatory Patients (Aged ≥4 to <8 Years) with Duchenne Muscular Dystrophy: 1-Year Interim Results from Study SRP-9001-103 (ENDEAVOR).

Objective: Delandistrogene moxeparvovec is approved in the USA for the treatment of ambulatory patients (4-5 years) with Duchenne muscular dystrophy. ENDEAVOR (SRP-9001-103; NCT04626674) is a single-arm, open-label study to evaluate delandistrogene moxeparvovec micro-dystrophin expression, safety, and functional outcomes following administration of commercial process delandistrogene moxeparvovec.

Methods: In cohort 1 of ENDEAVOR (N = 20), eligible ambulatory males, aged ≥4 to <8 years, received a single intravenous infusion of delandistrogene moxeparvovec (1.

Balovaptan vs Placebo for Social Communication in Childhood Autism Spectrum Disorder: A Randomized Clinical Trial.

Importance: There are no approved medications for the core symptoms of autism spectrum disorder (ASD), socialization and communication difficulties.

Objective: To evaluate the efficacy and safety of balovaptan, an oral selective vasopressin 1a receptor antagonist, compared with placebo in children and adolescents with ASD.

Design, Setting, And Participants: The aV1ation study was a randomized, double-blind, 24-week, parallel-group, placebo-controlled phase 2 trial.

Efficacy and safety of balovaptan for socialisation and communication difficulties in autistic adults in North America and Europe: a phase 3, randomised, placebo-controlled trial.

Background: There are no approved pharmacological therapies to support treatment of the core communication and socialisation difficulties associated with autism spectrum disorder in adults. We aimed to assess the efficacy, safety, and pharmacokinetics of balovaptan, a vasopressin 1a receptor antagonist, versus placebo in autistic adults.

Methods: V1aduct was a phase 3, randomised, placebo-controlled, double-blind trial, conducted at 46 sites across six countries (the USA, the UK, France, Italy, Spain, and Canada).

A randomized, double-blind, placebo-controlled phase II trial to explore the effects of a GABA-α5 NAM (basmisanil) on intellectual disability associated with Down syndrome.

Background: There are currently no pharmacological therapies to address the intellectual disability associated with Down syndrome. Excitatory/inhibitory imbalance has been hypothesized to contribute to impairments in cognitive functioning in Down syndrome. Negative modulation of the GABA-α5 receptor is proposed as a mechanism to attenuate GABAergic function and restore the excitatory/inhibitory balance.

Bioavailability and pharmacokinetic profile of balovaptan, a selective, brain-penetrant vasopressin 1a receptor antagonist, in healthy volunteers.

Background: Balovaptan is a potent, selective vasopressin 1a receptor antagonist. The early-phase pharmacokinetics (PK) of balovaptan are reported.

Research Design And Methods: Two Phase 1 studies (overall = 93) assessed single- and multiple-dose balovaptan PK in healthy adults.

Basmisanil, a highly selective GABA-α5 negative allosteric modulator: preclinical pharmacology and demonstration of functional target engagement in man.

GABA-α5 subunit-containing receptors have been shown to play a key modulatory role in cognition and represent a promising drug target for cognitive dysfunction, as well as other disorders. Here we report on the preclinical and early clinical profile of a novel GABA-α5 selective negative allosteric modulator (NAM), basmisanil, which progressed into Phase II trials for intellectual disability in Down syndrome and cognitive impairment associated with schizophrenia. Preclinical pharmacology studies showed that basmisanil is the most selective GABA-α5 receptor NAM described so far.

Open-Label Assessment of the Effects of Itraconazole and Rifampicin on Balovaptan Pharmacokinetics in Healthy Volunteers.

Introduction: Balovaptan, an investigational vasopressin 1a receptor antagonist that has been evaluated for improvement of social communication and interaction, is primarily metabolized by cytochrome P450 3A4 (CYP3A4).

Methods: Two single-center, non-randomized, two-period, phase 1 studies assessed the effect of the strong CYP3A4 inhibitor itraconazole (study NCT03579719) or the strong CYP3A4 inducer rifampicin (study NCT03586726) at steady state on the pharmacokinetics (PK) of steady-state balovaptan in healthy volunteers. Participants received balovaptan (5 or 10 mg/day) alone for 10 days, or in combination with itraconazole (200 mg/day) for 15 days, or rifampicin (600 mg/day) for 10 days, following balovaptan washout and itraconazole/rifampicin pre-dosing.

PKPD and cardiac single cell modeling of a DDI study with a CYP3A4 substrate and itraconazole to quantify the effects on QT interval duration.

Plasma drug concentration and electrocardiogram (ECG) data from a drug-drug interaction (DDI) study employing the metabolic inhibitor itraconazole have been used as part of a prospectively defined pharmacokinetic/pharmacodynamic modelling strategy to quantify the potential for QT interval prolongation from basmisanil, an investigational compound. ECG data were collected on multiple days during repeat dosing treatment regimens, thereby allowing the capture of QT data across a wide range of drug concentrations in each study participant and encompassing both "therapeutic" and "supra-therapeutic" exposures. The data were used to develop a non-linear mixed effect concentration-QT (C-QT) model that differentiated drug-induced QT prolongation from other factors altering QT interval duration.

A phase 2 clinical trial of a vasopressin V1a receptor antagonist shows improved adaptive behaviors in men with autism spectrum disorder.

There are no approved pharmacological therapies to address the core symptoms of autism spectrum disorder (ASD), namely, persistent deficits in social communication and social interaction and the presence of restricted, repetitive patterns of behaviors, interests, or activities. The neuropeptide vasopressin has been implicated in the regulation of social behaviors, and its modulation has emerged as a therapeutic target for ASD. The phase 2 VANILLA clinical trial reported here evaluated balovaptan, an orally administered selective vasopressin V1a receptor antagonist, in 223 men with ASD and intelligence quotient ≥70.

A Framework Proposal to Follow-Up on Preclinical Convulsive Signals of a New Molecular Entity in First-in-Human Studies Using Electroencephalographic Monitoring.

Traditionally, in dose-escalating first-in-human (FiH) studies, a dose cap with a 10-fold safety margin to the no observed effect level in animals is implemented if convulsive events are observed in animals. However, the convulsive risk seen in animals does not generally translate to humans. Several lines of evidence are summarized indicating that in a dose-escalating setting, electroencephalographic epileptiform abnormalities occur at lower doses than clinical convulsive events.

First-in-man study with a novel PEGylated recombinant human insulin-like growth factor-I.

Objective: This study is a first time assessment of safety and tolerability, pharmacokinetics, and pharmacodynamics of RO5046013 in human, in comparison with unmodified rhIGF-I.

Design: The study was conducted as a single-center, randomized, double-blinded, placebo-controlled, single ascending dose, parallel group study in a clinical research unit in France. A total of 62 healthy volunteers participated in this clinical trial.

Clinical trial considerations on male contraception and collection of pregnancy information from female partner: update.

Background: This is an update to our 2012 publication on clinical trial considerations on male contraception and collection of pregnancy information from female partner, after critical review of recent (draft) guidances released by the International Council for Harmonisation [ICH] the Clinical Trial Facilitation Group [CTFG] and the US Food & Drug Administration [FDA].

Methods: Relevant aspects of the new guidance documents are discussed in the context of male contraception and pregnancy reporting from female partner in clinical trials and the approach is updated accordingly.

Results: Genotoxicity The concept of a threshold is introduced using acceptable daily intake/permissible daily exposure to define genotoxicity requirements, hence highly effective contraception in order to avoid conception.

Population prevalence of Down's syndrome in the United Kingdom.

Background: Aim was to estimate the age and sex-stratified prevalence of Down's syndrome (DS) in the United Kingdom (UK) general population using a large primary care database.

Method: Data source was the Clinical Practice Research Datalink. We divided the number of individuals with a record of DS present on 01/07/2014 by the total number of individuals, and computed Wilson's confidence intervals.

Morbidity and medication in a large population of individuals with Down syndrome compared to the general population.

Aim: The aim of this study was to describe the incidence of morbidities and the prevalence of medical prescriptions in a large Down syndrome population.

Method: A retrospective cohort study was carried out using the UK Clinical Practice Research Datalink from 1 January 2004 to 31 December 2013. We matched individuals with Down syndrome to randomly selected control participants by practice site, sex, birth year, and recording period.

Clinical trial considerations on male contraception and collection of pregnancy information from female partners.

Background: There is little guidance regarding the risk of exposure of pregnant women/ women of childbearing potential to genotoxic or teratogenic compounds via vaginal dose delivered through seminal fluid during sexual intercourse.

Method: We summarize current thinking and provide clinical trial considerations for a consistent approach to contraception for males exposed to genotoxic and/or teratogenic compounds or to compounds of unknown teratogenicity, and for collection of pregnancy data from their female partners.

Results: Where toxicity testing demonstrates genotoxic potential, condom use is required during exposure and for 5 terminal plasma half-lives plus 74 days (one human spermatogenesis cycle) to avoid conception.

Nursing interventions to improve the health of men with prostate cancer undergoing radiotherapy: a review.

The aim of this study was to investigate what nurses do to improve the health of men who are receiving radiotherapy treatment due to prostate cancer. The method was a literature review using a systematic approach. The Cochrane Library, Medline and CINAHL databases were used in a search that covered the period from January 1994 to April 2006.

Interaction of morphine, fentanyl, sufentanil, alfentanil, and loperamide with the efflux drug transporter P-glycoprotein.

Background: The efflux transporter P-glycoprotein, a member of the adenosine triphosphate-binding cassette superfamily, is a major determinant of the pharmacokinetics and pharmacodynamics of the opioid loperamide, a well-recognized antidiarrheal agent. Animal studies indicate that P-glycoprotein limits morphine entry into the brain. In this study, the authors examined whether other opioids of importance to anesthesiologists such as fentanyl, sufentanil, and alfentanil, and also morphine-6-glucuronide and morphine-3-glucuronide, are P-glycoprotein substrates and whether, in turn, these opioids act also as P-glycoprotein inhibitors.

Cyclosporine pharmacokinetics and pharmacodynamics in African American and white subjects.

Background: Renal allograft survival is lower in African American patients compared with white patients. Interethnic differences in cyclosporine (INN, ciclosporin) pharmacokinetics in renal transplant recipients have been described but have not been well characterized. Pharmacodynamic responses to cyclosporine have not been compared among ethnic groups.

Effect of calcium supplements on the oral bioavailability of moxifloxacin in healthy male volunteers.

Objective: To investigate the effect of concomitant calcium administration on the pharmacokinetics and tolerability of moxifloxacin.

Design: This was a nonblinded, randomised, single dose, crossover study in healthy male volunteers.

Participants: 12 healthy male Caucasians (age 24 to 45 years) were enrolled in the study.

Increased drug delivery to the brain by P-glycoprotein inhibition.

Background: Although the antidiarrheal loperamide is a potent opiate, it does not produce opioid central nervous system effects at usual doses in patients. On the basis of in vitro studies demonstrating that loperamide is a substrate for the adenosine triphosphate-dependent efflux membrane transporter P-glycoprotein, we postulated that inhibition of P-glycoprotein with quinidine would increase entry of loperamide into the central nervous system with resultant respiratory depression.

Methods: To test this hypothesis, a 16-mg dose of loperamide was administered to eight healthy male volunteers in the presence of either 600 mg quinidine, a known inhibitor of P-glycoprotein, or placebo.