Phase 1 Clinical Trials of Small Molecules: Evolution and State of the Art.

BACKGROUND: Phase 1 studies comprise the first exposure of a promising new chemical entity in healthy volunteers or, when appropriate, in patients. To assure a solid foundation for subsequent drug development, this first step must carefully assess the safety and tolerance of a new compound and often provide some indication of potential effect, so that a safe dose or dose range can be confidently selected for the initial Phase 2 efficacy study in the target patient population. METHODS: This review was based on a literature search using both Google Scholar and PubMed, dated back to 1970, using search terms including "healthy volunteers", "Phase 1", and "normal volunteers", and also based on the authors' own experience conducting Phase 1 clinical trials. This paper reviews the history of Phase 1 studies of small molecules and their rapid evolution, focusing on the critical single and multiple dose studies, their designs, methodology, use of pharmacokinetic and pharmacodynamic modeling, application of potentially helpful biomarkers, study stopping criteria, and novel study designs. RESULTS: We advocate for determining the safe dose range of a new compound by conducting careful dose escalation in a well-staffed inpatient setting, defining the maximally tolerated dose (MTD) by reaching the minimally intolerated dose (MID). The dose immediately below the MID is then defined as the MTD. This is best accomplished by using appropriately screened patients for the target indication, as patients in many CNS indications often tolerate doses differently than healthy non-patients. Biomarkers for safety and pharmacodynamic measures can also assist in further defining a safe and potentially effective dose range for subsequent clinical trial phases. CONCLUSION: Phase 1 studies can yield critical insights into the pharmacology of a new compound in man and offer perhaps the only development period in which the dose range can be safely and thoroughly explored. Phase 1 studies often contain multiple endpoint objectives, the reconciliation of which can present a dilemma for drug developers and study investigators alike, but which can crucially determine whether a compound can survive to the next step in the drug development process.

Exploratory Biomarker Study of the Triple Reuptake Inhibitor SEP-432 Compared to the Dual Reuptake Inhibitor Duloxetine in Healthy Normal Subjects.

INTRODUCTION: SEP-432 is a triple monoamine reuptake inhibitor of norepinephrine (NE), serotonin (5-HT), and dopamine (DA), based on in vitro binding studies. We sought evidence that SEP-432 engages these monoamine systems by measuring concentrations of monoamines and/or their main metabolites in cerebrospinal fluid (CSF) and plasma and comparing results to duloxetine, a dual reuptake inhibitor of NE and 5-HT. METHODS: Eighteen healthy normal subjects received either SEP-432 (300 mg/day), duloxetine (60 mg/day), or placebo for 14 days in-clinic (double blind) with CSF and plasma collections at baseline (single lumbar puncture) and Day 14 (24-h CSF and plasma collection). Concentrations of monoamines and their metabolites, as well as pharmacokinetic concentrations of SEP-432 and metabolite, were quantified by liquid chromatography-tandem mass spectrometry. RESULTS: Compared to placebo in the Day 14 area under the curve 24-h (AUC0-24 h ) analysis, SEP-432 significantly (P < 0.05) decreased the NE metabolite dihydroxyphenylglycol (DHPG) in CSF and plasma, decreased 5-HT in plasma, and did not affect DA metabolites, while duloxetine had significant effects on DHPG and 5-HT. Time-matched baseline to Day 14 biomarker comparisons confirmed these findings. CONCLUSION: CSF monoamine biomarkers confirmed central NET activity for SEP-432 and duloxetine's dual reuptake inhibition.

Sex differences in the psychopharmacological treatment of depression.

Although a number of studies have observed that females respond better to serotonergic antidepressants than males and that postmenopausal females have a diminished response to antidepressants compared with younger females, there are also studies that conflict with both of these findings, making any generalizations regarding sex differences difficult to make. Sex variance in antidepressant efficacy and pharmacokinetics profiles have been attributed to sex-based physiological differences, behavioral differences, related disorders, and sex-specific conditions, including pregnancy and menopause. This paper will review the history and current research on sex effects of antidepressant treatment.

Aunque varios estudios han mostrado que las mujeres responden mejor a los antidepresivos serotoninérgicos que los hombres y que las mujeres postmenopáusicas tienen una respuesta disminuida a los antidepresivos en comparación con las mujeres más jóvenes, también hay estudios que cuestionan estos hallazgos, con lo que se hace difícil plantear algunas generalizaciones respecto a las diferencias por sexo. Las variaciones por sexo en cuanto a la eficacia antidepresiva y los perfiles farmacocinéticos han sido atribuidas a diferencias fisiológicas basadas en el sexo, diferencias conductuales, trastornos relacionados, y condiciones específicas del sexo incluyendo el embarazo y la menopausia. Este artículo revisará la historia y la investigación actual acerca de los efectos del sexo en el tratamiento antidepresivo.

De nombreuses études ont constaté une meilleure réponse aux antidépresseurs sérotoninergiques chez les femmes que chez les hommes et une réponse diminuée aux antidépresseurs chez les femmes ménopausées comparées aux femmes plus jeunes, . mais dD'autres études contredisent ces résultats, et il il est donc difficile de généraliser sur les différences selon le sexe. La variance bilité deselon le sexe de l'efficacité des antidépresseurs sive et dess profils pharmacocinétiques selon le sexe a été attribuée aux différences physiologiques, et comportementales selon liées aule sexe, aux troubles qui y sont liés et aux à des états spécifiques du sexe comme la grossesse et la ménopause. Nous analysons dans cet article l'historique et la recherche actuelle sur les effets du des traitements antidépresseurs selon le sexe.

The impact of gender on antidepressants.

There is a large body of literature debating whether and how gender affects the metabolism, side-effect profile, and efficacy of antidepressants. Gender differences in antidepressant pharmacokinetics and efficacy profiles have been attributed to not only anatomic and physiological differences between the sexes, but also behavioral factors, comorbid disorders, and gender-specific conditions, such as pregnancy and menopause. Despite the large body of research on this topic, few definitive conclusions regarding effects of gender on antidepressant treatment exist, and much of this research is incomplete, contradictory, or not fully used to optimize the administration of antidepressants and the response to treatment. This chapter will review the latest research on gender-specific effects of antidepressant treatment, focusing on the overall, gender-related differences in efficacy, metabolism, and side-effect profile of antidepressants, and how these differences can be used to better optimize treatment of depression in a clinical setting.

Galantamine hydrobromide: an agent for Alzheimer's disease.

The pharmacology, dosage, adverse effects, efficacy, and economics of galantamine hydrobromide are discussed. Galantamine hydrobromide is a tertiary alkaloid that has been extracted from plant sources and is now synthesized for use in the treatment of mild to moderate Alzheimer's disease (AD). Galantamine acts both as a reversible competitive inhibitor of acetylcholinesterase (AChE) and as an allosteric modulator of nicotinic acetylcholine receptors. The recommended starting dosage is 4 mg (as the hydrobromide) twice daily. The dosage should be increased in increments of 8 mg/day in two divided doses after four weeks at a given dosage until a maintenance dosage of 16-24 mg/day in two divided doses is reached. Adverse effects are primarily mild and cholinergic and include nausea, vomiting, diarrhea, and dizziness. Five large clinical trials demonstrated that galantamine is more effective than placebo in controlling the symptoms of mild to moderate AD. Optimal therapy appears to require early initiation of the drug and a dosage-adjustment period of eight weeks. In one study, galantamine delayed full-time care by 10% and reduced the overall cost of care by $528. Because galantamine has not yet been compared directly with other AChE inhibitors, cost should be the principal factor weighed during formulary evaluations. Galantamine provides the clinician with another choice of an AChE inhibitor for use in treating AD.

Generalised anxiety disorder: treatment options.

In recent years generalised anxiety disorder (GAD) has become a much better defined disorder, with specific criteria distinguishing it from the other anxiety disorders; however, it still lacks the same public and scientific interests as some of the other anxiety disorders such as panic and social phobia. Nevertheless, refinement in the treatment of GAD is becoming more evident through the conduct of clinical trials. Up until the mid-1980's, treatment consisted primarily of benzodiazepines. However, as a result of growing characterisation of their abuse potential, other therapeutic options were explored. Benzodiazepines became seen as an effective short-term therapy, and buspirone and some of the newer antidepressants have become the treatment of choice for patients with GAD requiring long-term treatment. Buspirone was the first available alternative to the benzodiazepines in the US; however, the initial excitement over this agent was somewhat dampened because of its mild efficacy combined with a slow onset of action. The antidepressants were seen as beneficial for the treatment of GAD because of the high comorbidity with depression, thus allowing a better outcome for these patients. The antidepressants that offer both a good adverse effect profile and efficacy are the selective serotonin reuptake inhibitors including paroxetine, and the serotonin-norepinephrine reuptake inhibitors such as venlafaxine. Clinicians should also consider the potential benefits of psychotherapy as an adjunct to medication. There are a number of potentially new pharmacotherapies being investigated, including newer serotonin 5-HT1A receptor agonists, cholecystokinin receptor antagonists, neurokinin receptor antagonists, gabapentin and its analogues, and gamma-aminobutyric acid (GABA)A receptor modulators. However, these compounds are all in the early stages of investigation, and there are no new therapies expected to be released in the near future. Nonetheless, in the search for the ideal anxiolytic, a more positive outlook is allowed by imminent future research for new treatment options in patients with GAD.

Risperidone in the treatment of Hispanic inpatients with schizophrenia: a pilot study.

A growing body of scientific evidence over the last two decades suggests that certain ethnic groups may require lower dosages of standard antipsychotics for the treatment of schizophrenia symptoms. Recent studies have implicated the role of genetic and environmental factors in the metabolism of these drugs as the basis for this differential response. In this pilot study, 10 Hispanic and 8 non-Hispanic patients with schizophrenia were enrolled in a double-blind, parallel-group, inpatient risperidone dosing (daily versus twice daily) trial with the novel antipsychotic risperidone. The result of repeated measures ANOVA reveals a significant interaction effect for race, indicative of a faster rate of symptom improvement (PANSS General) in Hispanic patients. The findings suggest that this novel agent may be preferable for certain ethnic groups. A trend toward more frequently occurring extrapyramidal symptoms among Hispanics was also found, which suggests that dosages lower than those typically recommended may be necessary in Hispanic schizophrenics.