Reevaluating safety pharmacology respiratory studies within the ICH S7A core battery: A multi-company evaluation of preclinical utility and clinical translation.

Optimization of ICH safety guideline studies for inclusion into regulatory submissions is critical for resource conservation, animal use reduction, and efficient drug development. The ICH S7A guidance for Safety Pharmacology (SP) studies adopted in 2001 identified the core battery of studies to evaluate the acute safety of putative pharmaceutical molecules prior to First in Human (FIH) trials. To assess the utility of respiratory studies in predicting clinical AE's, seven pharmaceutical companies pooled preclinical and clinical respiratory findings.

Industry perspective on a holistic container closure integrity approach to parenteral combination products.

Biologics are being developed more and more as parenteral combination products with drug delivery devices. The maintenance of sterility is imperative for such medical devices throughout their life cycle. Therefore, the container closure integrity (CCI) should, preferably, be built into the overall process, and not just demonstrated during the final testing of the combination product.

Antibody apparent solubility prediction from sequence by transfer learning.

Developing therapeutic monoclonal antibodies (mAbs) for the subcutaneous administration requires identifying mAbs with superior solubility that are amenable for high-concentration formulation. However, experimental screening is often material and labor intensive. Here, we present a strategy (named solPredict) that employs the embeddings from pretrained protein language modeling to predict the apparent solubility of mAbs in histidine (pH 6.

Estimation of group means in generalized linear mixed models.

In this study, we investigate the concept of the mean response for a treatment group mean as well as its estimation and prediction for generalized linear models with a subject-wise random effect. Generalized linear models are commonly used to analyze categorical data. The model-based mean for a treatment group usually estimates the response at the mean covariate.

Why are we failing to implement imaging studies with radiolabelled new molecular entities in early oncology drug development?

In early drug development advanced imaging techniques can help with progressing new molecular entities (NME) to subsequent phases of drug development and thus reduce attrition. However, several organizational, operational, and regulatory hurdles pose a significant barrier, potentially limiting the impact these techniques can have on modern drug development. Positron emission tomography (PET) of radiolabelled NME is arguably the best example of a complex technique with a potential to deliver unique decision-making data in small cohorts of subjects.

A randomised phase II study of pemetrexed versus pemetrexed+erlotinib as second-line treatment for locally advanced or metastatic non-squamous non-small cell lung cancer.

Introduction: Pemetrexed and erlotinib have been approved as second-line monotherapy for locally advanced or metastatic non-small cell lung cancer (NSCLC). This multicentre, randomised, open-label, parallel phase II study assessed efficacy and safety of pemetrexed versus pemetrexed+erlotinib in patients with advanced non-squamous NSCLC.

Methods: NSCLC stage III-IV patients who failed one prior platinum-based chemotherapy regimen, ≥ 1 measurable lesion by Response Evaluation Criteria in Solid Tumors, and Eastern Cooperative Oncology Group performance status ≤ 2 were eligible.

Influence of improved FcRn binding on the subcutaneous bioavailability of monoclonal antibodies in cynomolgus monkeys.

Engineering monoclonal antibodies (mAbs) with improved binding to the neonatal Fc receptor (FcRn) is a strategy that can extend their in vivo half-life and slow their systemic clearance. Published reports have predominantly characterized the pharmacokinetics of mAbs after intravenous administration. Recently, studies in mice suggest FcRn may also play a role in affecting the subcutaneous bioavailability of mAbs.

Regulation of rat cortical 5-hydroxytryptamine2A receptor-mediated electrophysiological responses by repeated daily treatment with electroconvulsive shock or imipramine.

Down-regulation of 5-hydroxytryptamine(2A) (5-HT(2A)) receptors has been a consistent effect induced by most antidepressant drugs. In contrast, electroconvulsive shock (ECS) up-regulates the number of 5-HT(2A) receptor binding sites. However, the effects of antidepressants on 5-HT(2A) receptor-mediated responses on identified cells of the cerebral cortex have not been examined.

Effect of double antigen bridging immunoassay format on antigen coating concentration dependence and implications for designing immunogenicity assays for monoclonal antibodies.

The double antigen bridging immunoassay has been used extensively for detection of immunogenicity responses to therapeutic monoclonal antibodies. We have analyzed parameters affecting performance of this type of immunoassay including microtiter plate antigen coating concentration, enzyme-labeled antigen conjugate dilution and assay format (one-step versus two-step). We present results demonstrating that the format of the assay has a significant impact on the optimal parameters to maximize assay performance.

Duloxetine Treatment of Stress Urinary Incontinence in Women Does Not Induce Mania or Hypomania.

BACKGROUND: Mania is a rare but unwelcome side effect of treating depressed patients with antidepressants. This research sought to determine the risk of treatment-emergent mania or hypomania in women with stress urinary incontinence treated with duloxetine, a balanced dual serotonin-norepinephrine reuptake inhibitor currently under investigation for the treatment of both stress urinary incontinence and major depressive disorder. METHOD: Data were obtained from 4 double-blind, randomized, placebo-controlled studies involving 1913 women aged 22 to 83 years and 4 ongoing uncontrolled longer-term studies involving 1877 women aged 20 to 87 years.

Urinary Side Effects of Duloxetine in the Treatment of Depression and Stress Urinary Incontinence.

BACKGROUND: The efficacy and safety of duloxetine, a dual reuptake inhibitor of serotonin and norepinephrine at the recommended starting dose, have been demonstrated in the treatment of major depressive disorder (MDD) in men and women and in the treatment of stress urinary incontinence (SUI) in women. Since the mechanism of action of duloxetine in the treatment of SUI is believed to be related to enhanced urethral closure forces, it is important to clarify the risk of acute urinary retention. METHOD: The relationship between duloxetine and obstructive voiding symptoms was examined in 8 double-blind, 8- to 9-week, placebo-controlled studies and 1 open-label study in men and women treated for MDD with duloxetine 40 to 120 mg/day and in 4 double-blind, 12-week, placebo-controlled studies and 4 ongoing open-label studies in women treated for SUI with duloxetine 80 mg/day.

Synthesis and evaluation of tylosin-related macrolides modified at the aldehyde function: a new series of orally effective antibiotics.

Modification of the aldehyde group in tylosin and related macrolide antibiotics dramatically enhanced the oral efficacy of the derivatives against experimental infections caused by susceptible bacteria in laboratory animals. A large number and wide variety of aldehyde-modified macrolide derivatives were prepared, utilizing the Mitsunobu reaction and other chemical transformations. Evaluation of in vitro and in vivo antimicrobial activity indicated that derivatives of demycarosyltylosin (desmycosin) combined the broadest spectrum of antimicrobial activity with the best efficacy and bioavailability after oral administration.