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. RESULTS: Before infusion, the following are recommended: (1) screen for anti-adeno-associated virus rhesus isolate serotype 74 total binding antibody titers <1:400; (2) assess liver function, platelet count, and troponin-I; (3) ensure patients are up to date with vaccinations and avoid vaccine coadministration with infusion; (4) administer additional corticosteroids starting one day preinfusion (for patients already on corticosteroids); and (5) postpone dosing patients with any infection or acute liver disease until event resolution. Postinfusion, the following are recommended: (1) monitor liver function weekly (three months postinfusion) and, if indicated, continue until results are unremarkable; (2) monitor troponin-I levels weekly (first month postinfusion, continuing if indicated); (3) obtain platelet counts weekly (two weeks postinfusion), continuing if indicated; and (4) maintain the corticosteroid regimen for at least 60 days postinfusion, unless earlier tapering is indicated. CONCLUSIONS: Although the clinical safety profile of delandistrogene moxeparvovec has been consistent, monitorable, and manageable, these practical considerations may mitigate potential risks in a real-world clinical practice setting.

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 (1.33 × 1014 vg/kg). The primary endpoint was change from baseline (CFBL) to week 12 in delandistrogene moxeparvovec micro-dystrophin by western blot. Additional endpoints evaluated included: safety; vector genome copies; CFBL to week 12 in muscle fiber-localized micro-dystrophin by immunofluorescence; and functional assessments, including North Star Ambulatory Assessment, with comparison with a propensity score-weighted external natural history control. RESULTS: The 1-year safety profile of commercial process delandistrogene moxeparvovec in ENDEAVOR was consistent with safety data reported in other delandistrogene moxeparvovec trials (NCT03375164 and NCT03769116). Delandistrogene moxeparvovec micro-dystrophin expression was robust, with sarcolemmal localization at week 12; mean (SD) CFBL in western blot, 54.2% (42.6); p < 0.0001. At 1 year, patients demonstrated stabilized or improved North Star Ambulatory Assessment total scores; mean (SD) CFBL, +4.0 (3.5). Treatment versus a propensity score-weighted external natural history control demonstrated a statistically significant difference in least squares mean (standard error) CFBL in North Star Ambulatory Assessment, +3.2 (0.6) points; p < 0.0001. INTERPRETATION: Results confirm efficient transduction of muscle by delandistrogene moxeparvovec. One-year post-treatment, delandistrogene moxeparvovec was well tolerated, and demonstrated stabilized or improved motor function, suggesting a clinical benefit for patients with Duchenne muscular dystrophy. ANN NEUROL 2023;94:955-968.

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. Between November 22, 2016, and September 3, 2019, individuals were screened and randomly assigned to treatment groups. The primary efficacy analysis population comprised participants taking age-adjusted balovaptan equivalent to a 10-mg adult dose and participants from the concurrently randomized placebo group. This multicenter trial took place across 41 sites in the US. Participants were aged 5 to 17 years with diagnosed ASD and an IQ of 70 or greater. Data were analyzed from April 8 to November 16, 2020. Interventions: Participants were randomly assigned to daily 4-mg or 10-mg adult-equivalent balovaptan or placebo, until the 4-mg group was discontinued. Main Outcomes and Measures: The primary end point was change from baseline on the Vineland-II two-domain composite (2DC; socialization and communication domains) score at week 24. Results: Between November 2016 and September 2019, a total of 599 individuals were screened and 339 participants were randomly assigned to receive 4-mg balovaptan adult-equivalent dose (91 [26.8%]), 10-mg balovaptan adult-equivalent dose (126 [37.2%]), or placebo (122 [36.0%]). Primary analysis included 86 participants assigned to receive 10-mg balovaptan adult-equivalent dose and 81 assigned to receive placebo (mean [SD] age, 12.1 [3.4] years; 139 male participants [83.2%]). No statistically significant differences were observed between the balovaptan and placebo groups in change from baseline on the Vineland-II 2DC score at week 24 (difference in adjusted least-squares mean, -0.16; 90% CI, -2.56 to 2.23; P = .91). No improvements for balovaptan vs placebo were observed at week 24 for any secondary end points. Balovaptan was well tolerated with no emerging safety concerns. Similar proportions of participants reported adverse events (balovaptan, 66 of 86 [76.7%] vs placebo, 61 of 81 [75.3%]) and serious adverse events (balovaptan, 1 of 86 [1.2%] vs placebo, 4 of 81 [4.9%]). Conclusions and Relevance: In this randomized clinical trial, balovaptan did not demonstrate efficacy in improvement of socialization and communication in this population with pediatric ASD. Balovaptan was well tolerated in children 5 years or older. Further development of robust, sensitive, and objective outcome measures may help to improve future studies in the assessment of therapies targeting communication and socialization in pediatric ASD. Trial Registration: ClinicalTrials.gov Identifier: NCT02901431.

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). Eligible participants were aged 18 years or older with an intelligence quotient (IQ) of 70 or higher, and met the criteria for moderate-to-severe autism spectrum disorder (DSM-5 and Autism Diagnostic Observation Schedule). Participants were randomly allocated (1:1), with an independent interactive voice or web-based response system, to receive balovaptan (10 mg) or placebo daily for 24 weeks. Randomisation was stratified by an individual's baseline Vineland-II two-domain composite (2DC) score (<60 or ≥60), sex, region (North America or rest of world), and age (<25 years or ≥25 years). Participants, study site personnel, and the sponsor were masked to treatment assignment. The primary endpoint was change from baseline in Vineland-II 2DC score (the mean composite score across the Vineland-II socialisation and communication domains) at week 24. The primary analysis was done with ANCOVA in the intention-to-treat population. The V1aduct study was terminated for futility after around 50% of participants completed the week 24 visit. This trial is registered with ClinicalTrials.gov (NCT03504917). FINDINGS: Between Aug 8, 2018, and July 1, 2020, 540 people were screened for eligibility, of whom 322 were allocated to receive balovaptan (164 [51%]) or placebo (158 [49%]). One participant from the balovaptan group was not treated before trial termination and was excluded from the analysis. 60 participants in the balovaptan group and 55 in the placebo group discontinued treatment before week 24. The sample consisted of 64 (20%) women and 257 (80%) men, with 260 (81%) participants from North America and 61 (19%) from Europe. At baseline, mean age was 27·6 years (SD 9·7) and mean IQ score was 104·8 (18·1). Two (1%) participants were American Indian or Alaska Native, eight (2%) were Asian, 15 (5%) were Black or African American, 283 (88%) were White, four (1%) were of multiple races, and nine (3%) were of unknown race. Mean baseline Vineland-II 2DC scores were 67·2 (SD 15·3) in the balovaptan group and 66·2 (17·7) in the placebo group. The interim futility analysis showed no improvement for balovaptan versus placebo in terms of Vineland-II 2DC score at week 24 compared with baseline, with a least-squares mean change of 2·91 (SE 1·52) in the balovaptan group (n=79) and 4·75 (1·60) in the placebo group (n=71; estimated treatment difference -1·84 [95% CI -5·15 to 1·48]). In the final analysis, mean change from baseline in Vineland-II 2DC score at week 24 was 4·56 (SD 10·85) in the balovaptan group (n=111) and 6·83 (12·18) in the placebo group (n=99). Balovaptan was well tolerated, with similar proportions of participants with at least one adverse event in the balovaptan group (98 [60%] of 163) and placebo group (104 [66%] of 158). The most common adverse events were nasopharyngitis (14 [9%] in the balovaptan group and 19 [12%] in the placebo group), diarrhoea (11 [7%] and 14 [9%]), upper respiratory tract infection (ten [6%] and nine [6%]), insomnia (five [3%] and eight [5%]), oropharyngeal pain (five [3%] and eight [5%]), and dizziness (two [1%] and ten [6%]). Serious adverse events were reported for two (1%) participants in the balovaptan group (one each of suicidal ideation and schizoaffective disorder), and five (3%) participants in the placebo group (one each of suicidal ideation, panic disorder, limb abscess, urosepsis, colitis [in the same participant with urosepsis], and death by suicide). No treatment-related deaths occurred. INTERPRETATION: Balovaptan did not improve social communication in autistic adults. This study provides insights into challenges facing autism spectrum disorder trials, including the considerable placebo response and the selection of appropriate outcome measures. FUNDING: F Hoffmann-La Roche.

A randomized, double-blind, placebo-controlled phase II trial to explore the effects of a GABAA-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 GABAA-α5 receptor is proposed as a mechanism to attenuate GABAergic function and restore the excitatory/inhibitory balance. METHODS: Basmisanil, a selective GABAA-α5 negative allosteric modulator, was evaluated at 120 mg or 240 mg BID (80 or 160 mg for 12-13 years) in a 6-month, randomized, double-blind, placebo-controlled phase II trial (Clematis) for efficacy and safety in adolescents and young adults with Down syndrome. The primary endpoint was based on a composite analysis of working memory (Repeatable Battery for the Assessment of Neuropsychological Scale [RBANS]) and independent functioning and adaptive behavior (Vineland Adaptive Behavior Scales [VABS-II] or the Clinical Global Impression-Improvement [CGI-I]). Secondary measures included the Behavior Rating Inventory of Executive Functioning-Preschool (BRIEF-P), Clinical Evaluation of Language Fundamentals (CELF-4), and Pediatric Quality of Life Inventory (Peds-QL). EEG was conducted for safety monitoring and quantitatively analyzed in adolescents. RESULTS: Basmisanil was safe and well-tolerated; the frequency and nature of adverse events were similar in basmisanil and placebo arms. EEG revealed treatment-related changes in spectral power (increase in low ~ 4-Hz and decrease in high ~ 20-Hz frequencies) providing evidence of functional target engagement. All treatment arms had a similar proportion of participants showing above-threshold improvement on the primary composite endpoint, evaluating concomitant responses in cognition and independent functioning (29% in placebo, 20% in low dose, and 25% in high dose). Further analysis of the individual measures contributing to the primary endpoint revealed no difference between placebo and basmisanil-treated groups in either adolescents or adults. There were also no differences across the secondary endpoints assessing changes in executive function, language, or quality of life. CONCLUSIONS: Basmisanil did not meet the primary efficacy objective of concomitant improvement on cognition and adaptive functioning after 6 months of treatment, despite evidence for target engagement. This study provides key learnings for future clinical trials in Down syndrome. TRIAL REGISTRATION: The study was registered on December 31, 2013, at clinicaltrials.gov as NCT02024789.

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 N = 93) assessed single- and multiple-dose balovaptan PK in healthy adults. One (N = 16) assessed absolute oral bioavailability (10 mg or 50 mg) vs a [13C]-balovaptan microdose. The other (N = 77) explored single- (0.5-76 mg) and multiple-dose (14 days; 12-52 mg/day) - randomized 6:2 balovaptan:placebo per dose - PK, dose proportionality, and the effect of food on single-dose (32 mg) Cmax and AUCinf. RESULTS: Absolute balovaptan bioavailability was high (103-116%). Steady-state (Day 14) balovaptan PK was approximately dose proportional with a half-life of 45-47 hours, but single-dose Cmax increased more than dose proportionally and half-life was inversely dose-proportional - a discordance partially attributable to a dose-and-time-dependent volume of distribution. Accumulation (Day 1-Day 14) was inversely dose-proportional (~3.5 [12 mg] to ~1.8 [52 mg]). There was no relevant effect of a high-fat meal on single-dose balovaptan exposure. There were no safety signals: 2/93 subjects discontinued for adverse events. CONCLUSIONS: Balovaptan was well tolerated at single (≤76 mg) and multiple (≤52 mg/day) doses, with a PK profile supportive of once-daily administration without food restrictions. TRIAL REGISTRATION: ClinicalTrials.gov NCT03764449; NCT01418963.

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

GABAA-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 GABAA-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 GABAA-α5 receptor NAM described so far. Basmisanil bound to recombinant human GABAA-α5 receptors with 5 nM affinity and more than 90-fold selectivity versus α1, α2, and α3 subunit-containing receptors. Moreover, basmisanil inhibited GABA-induced currents at GABAA-α5 yet had little or no effect at the other receptor subtypes. An in vivo occupancy study in rats showed dose-dependent target engagement and was utilized to establish the plasma exposure to receptor occupancy relationship. At estimated receptor occupancies between 30 and 65% basmisanil attenuated diazepam-induced spatial learning impairment in rats (Morris water maze), improved executive function in non-human primates (object retrieval), without showing anxiogenic or proconvulsant effects in rats. During the Phase I open-label studies, basmisanil showed good safety and tolerability in healthy volunteers at maximum GABAA-α5 receptor occupancy as confirmed by PET analysis with the tracer [11C]-Ro 15-4513. An exploratory EEG study provided evidence for functional activity of basmisanil in human brain. Therefore, these preclinical and early clinical studies show that basmisanil has an ideal profile to investigate potential clinical benefits of GABAA-α5 receptor negative modulation.

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. Geometric mean ratios (GMRs) and 90% confidence intervals (90% CIs) for the area under the concentration-time curve over the dosing interval (AUC) and maximum plasma concentration (Cmax) of balovaptan dosed with vs. without itraconazole/rifampicin were estimated from a mixed effects model. RESULTS: Both studies comprised 15-16 healthy male and female volunteers. Itraconazole 200 mg/day elevated steady-state exposure to 5 mg/day balovaptan approximately 4.5-5.5-fold (Day 15 GMR [90% CI], 4.46 [4.06-4.90] for Cmax and 5.57 [5.00-6.21] for AUC) and extended the time to steady state from ~ 5 days to ~ 13-14 days. Rifampicin 600 mg/day resulted in ~ 90% reductions in both the Cmax (Day 10 GMR [90% CI], 0.14 [0.12-0.15]) and AUC (0.07 [0.06-0.07]) of balovaptan 10 mg/day. Time to balovaptan steady state could not be determined with rifampicin. There were no clinically significant safety findings in either study. CONCLUSIONS: Strong modulators of CYP3A4 activity will significantly alter the PK of balovaptan, with the effect of CYP3A4 induction greater than that of inhibition. Caution should be taken when concomitantly dosing balovaptan with moderate or strong CYP3A4 inducers or strong CYP3A4 inhibitors. TRIAL REGISTRATION NUMBER: NCT03579719; NCT03586726.

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. Food effects were accounted by quantitating their influences on the parameters describing the diurnal variation of QT. The final model demonstrated that itraconazole does not cause QT prolongation, while for basmisanil, the 1-sided upper 95% CI of the QT interval at 240 mg (the highest dose tested in ongoing phase 2 studies) with DDI, was below the 10 ms threshold considered to be of clinical significance by regulatory authorities. The empirical modelling was complemented with a human mechanistic cardiac single cell model that was used to simulate the change in action potential duration as a function of drug concentration. The results of the two approaches were in agreement, suggesting that the effect of basmisanil on QT interval duration can be attributed to the effect on hERG alone. The C-QT model for basmisanil can be used to derive the QT interval corrected changes in heart rate (QTc) and thus inform cardiac safety strategy in later development without the need for a separate, dedicated study.

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. The drug was administered daily for 12 weeks and was compared with placebo. Participants were randomized to placebo (n = 75) or one of three balovaptan dose arms (1.5 mg, n = 32; 4 mg, n = 77; 10 mg, n = 39). Balovaptan treatment was not associated with a change from baseline compared with placebo at 12 weeks in the primary efficacy endpoint (Social Responsiveness Scale, 2nd Edition). However, dose-dependent and clinically meaningful improvements on the Vineland-II Adaptive Behavior Scales composite score were observed for participants treated with balovaptan 4 or 10 mg compared with placebo. This was driven principally by improvements in the Vineland-II socialization and communication scores. Balovaptan was well tolerated across all doses, and no drug-related safety concerns were identified. These results support further study of balovaptan as a potential treatment for the socialization and communication deficits in ASD.

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. Therefore, we propose to consider the occurrence of epileptiform abnormalities in toxicology studies as premonitory signals for convulsions in dose-escalating FiH studies. Compared with the traditional dose-cap approach, this may allow the exploration of higher doses in FiH and, subsequently, phase II studies without compromising human safety. Similarly, the presence or absence of electroencephalographic epileptiform abnormalities may also aid the assessment of proconvulsive risk in situations of increased perpetrator burden as potentially present in pharmacokinetic and/or pharmacodynamic drug-drug interactions.

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. The duration for highly effective contraception has been extended from 74 to 90 days from the end of relevant systemic exposure. Teratogenicity Pharmacokinetic considerations to estimate safety margins have been contextualized with regard to over- and underestimation of the risk of teratogenicity transmitted by a vaginal dose. The duration of male contraception after the last dose takes into account the end of relevant systemic exposure if measured, or a default period of five half-lives after last dose for small molecules and two half-lives for immunoglobulins (mAbs). Measures to prevent exposure of the conceptus via a vaginal dose apply to reproductively competent or vasectomized men, unless measurements fail to detect the compound in seminal fluid. CONCLUSION: Critical review of new guidance documents provides a comparison across approaches and resulted in an update of our previous publication. Separate algorithms for small molecules and monoclonal antibodies are proposed to guide the recommendations for contraception for male trial participants and pregnancy reporting from female partners. No male contraception is required if the dose is below a defined threshold for genotoxic concern applicable to small molecules. For men treated with teratogenic mAbs, condom use to prevent exposure of a potentially pregnant partner is unlikely to be recommended because of the minimal female exposure anticipated following a vaginal dose. The proposed safety margins for teratogenicity may evolve with further knowledge.

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. RESULTS: A total of 6430 individuals with Down syndrome (3009 females, 3421 males) and 19 176 controls (8966 females, 10,210 males) were included in the study. The incidence of cardiovascular disorders, gastrointestinal diseases (incidence rate ratio [IRR] 7.9 at 3 to <6y: yearly prevalence ratio [YPR] for laxatives 4.7), and sleeping disorders (IRR 4.8 in 3 to <6y) was increased in children with Down syndrome versus control participants. New onset of congenital heart malformation, ear diseases, eye disorders, autism, hypothyroidism, diabetes, and obesity were more frequent in childhood and remained elevated in adulthood (overall IRR 35.5, 1.7, 3.1, 4.4, 13.1, 1.3, and 2.6 respectively), whereas the gap widened in adulthood for epilepsy and intellectual disability (IRR 15.2 and 158 respectively, in participants older than 30y). At ≥ 30 years, the incidence of hypotension and dementia was raised (IRR 3.0 and 92.1 respectively; YPR for dementia drugs: 76.3); and that of hypertension, depression and anxiety was lowered (IRR 0.2, 0.5, and 0.4 respectively). INTERPRETATION: The profile of newly occurring morbidities in Down syndrome varies across the developmental lifespan.

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.For non-genotoxic small molecules and immunoglobulins with unknown teratogenic potential or without a no observed adverse effect level (NOAEL) from embryo-fetal development (EFD) studies and no minimal anticipated biological effect level (MABEL), condom use is recommended for males with pregnant partner/female partner of childbearing potential. For teratogenic small molecules with estimated seminal fluid concentration and a margin between projected maternal area under the curve (AUC) and NOAEL AUC from EFD studies of ≥300 (≥100 for immunoglobulins) or in the absence of a NOAEL with a margin between MABEL plasma concentration and maternal Cmax of ≥300 (≥10 for immunoglobulins), condom use is not required. However, condom use is required for margins below the thresholds previously indicated. For small molecules with available seminal fluid concentrations, condom use is required if margins are <100 instead of <300. Condom use should continue for as long as the projected margin is at or above the defined thresholds. Pregnancy data should be proactively collected if pregnancy occurs during the condom use period required for males exposed to first-in-class molecules or to molecules with a target/class shown to be teratogenic, embryotoxic or fetotoxic in human or preclinical experiments. CONCLUSION: These recommendations, based on a precaution principle, provide a consistent approach for minimizing the risk of embryo-fetal exposure to potentially harmful drugs during pregnancy of female partners of males in clinical trials. Proactive targeted collection of pregnancy information from female partners should help determine the teratogenic potential of a drug and minimize background noise and ethical/logistical issues.

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. METHODS: The transcellular movement of the various opioids, including loperamide and morphine, was assessed in L-MDR1 (expressing P-glycoprotein) and LLC-PK1 cell monolayers (P-glycoprotein expression absent). A preferential basal-to-apical versus apical-to-basal transport in the L-MDR cells but not the LLC-PK1 cells is seen for P-glycoprotein substrates. In addition, the effect of the various opioids on the transcellular movement of the prototypical P-glycoprotein substrate digoxin was examined in Caco-2 cell monolayers. IC50 values were calculated according to the Hill equation. RESULTS: Loperamide was a substrate showing high dependence on P-glycoprotein in that basal-apical transport was nearly 10-fold greater than in the apical-basal direction in L-MDRI cells. Morphine also showed a basal-to-apical gradient in the L-MDR1 cell monolayer, indicating that it too is a P-glycoprotein substrate, but with less dependence than loperamide in that only 1.5-fold greater basal-apical directional transport was observed. Fentanyl, sufentanil, and alfentanil did not behave as P-glycoprotein substrates, whereas the morphine glucuronides did not cross the cell monolayers at all, whether P-glycoprotein was present or not. Loperamide, sufentanil, fentanyl, and alfentanil inhibited P-glycoprotein-mediated digoxin transport in Caco-2 cells with IC50 values of 2.5, 4.5, 6.5, and 112 microm, respectively. Morphine and its glucuronides (20 microm) did not inhibit digoxin (5 microm) transport in Caco-2 cells, and therefore IC50 values were not determined. CONCLUSIONS: Opioids have a wide spectrum of P-glycoprotein activity, acting as both substrates and inhibitors, which might contribute to their varying central nervous system-related effects.