Drug Development with Radiopharmaceuticals
Martin G. Pomper, Juri G. Gelovani, Benjamin Tsui, Kathleen Gabrielson, Richard Wahl, S. Sam Gambhir, Jeff Bulte, Raymond Gibson, William C. Eckelman in Molecular Imaging in Oncology, 2008
The CPI is a framework for a new approach to drug approvals. The FDA wanted to reduce the time it takes to approve new applications and stimulate the submission of new applications by encouraging the use of enabling technologies such as genomics, proteomics, bioinformatics, material science, and medical imaging. Out of this process came a reexamination of the IND process and the pathway for first-in-human studies. Under the original IND process, new chemical entities had to go through extensive toxicity testing, costing upward of $1 million, before initial human studies would be allowed. This process is inefficient as first-in-human studies are in the critical path and where many new drugs fail. In concert with the drug industry, the concept of microdosing was accepted as a means of early testing in humans. With minimal toxicity requirements, several compounds may be brought forward for microdosing studies in humans. This process was captured in guidance documentation by the FDA and became known as the “exploratory investigational new drug” application or phase 0 clinical trials (25). While this process was largely developed to evaluate multiple new drug compounds in humans, a section of the new guidance was devoted to requirements for radiotracer first-in-human studies. Like the drug entities, the toxicity data required for new radiotracers are significantly reduced compared with a full IND application. This lower barrier to initial human testing has already stimulated the evaluation of several new drugs (26) and radiotracers in humans.
Biomedical Accelerator Mass Spectrometry
Graham Lappin, Simon Temple in Radiotracers in Drug Development, 2006
There has been much debate about pharmacokinetic linearity of microdosing.33 Much of this debate, however, rather misses the point. In Chapter 1, it was explained that in vitro data are an aid to decision making, and that in vitro data are useful rather than precise. The same premise applies to human phase 0 studies. Precise linearity between the microdose and the therapeutic dose is not really required. It is true that if the microdose gave a wildly different set of pharmacokinetic parameters than the therapeutic dose, then the human phase 0 study might be misleading. However, this situation already exists with reliance on in vitro and animal models. The intention of the human phase 0 study is to provide the extra data that are required, when they are required, to aid in the decision-making process. If microdosing reduces the drug attrition rate in clinical trials by only a few percent, then this represents many millions of dollars (see Figure 1.1 in Chapter 1). Microdosing and human phase 0 studies have to be applied intelligently, and in this respect, they are no different than any other experiment that may be conducted in the drug development program.
Translating Promising Experimental Approaches to Clinical Trials
Michel M. J. Modo, Jeff W. M. Bulte in Molecular and Cellular MR Imaging, 2007
The European Medicines Agency (EMEA) issued a position paper in an attempt to ease the entry of compounds into man and introduced the microdosing concept.10 This position paper defines modified requirements for the nonclinical safety studies needed to support human clinical trials of a single microdose of a pharmacologically active compound (pre-phase I studies). A microdose is defined as less than 1/100 of the dose calculated to yield a pharmacologic effect based on pharmacodynamic data obtained in vitro and in vivo, with a maximum dose of ≤100 μg per individual. The nonclinical requirements are very much like those for a Group I drug as described in the FDA’s guidance document9; however, microdosing does not require prior clinical experience with the compound.
Modern approaches for the phenotyping of cytochrome P450 enzymes in children
Published in Expert Review of Clinical Pharmacology, 2020
In children, the administration of low- or microdosed probe drugs rather than therapeutic doses, in order to avoid any toxicity, may be considered for CYP450 phenotyping. Microdosing is generally defined as the administration of a dose substantially reduced (usually at least 100 times) compared to the therapeutic dose [8]. In order to replace the use of therapeutic doses of probe drugs with lower or microdoses, it is essential to first assess the linearity of the pharmacokinetic parameters between the two dosages [8]. For example, van Groen et al. showed recently that an intravenous [14 C]midazolam microdose (37.6 ng kg−1) can be an alternative to midazolam administered at therapeutic doses in children after having demonstrated linearity [9]. It is important to note that formulation of low- or microdosed probe drugs is often not available and may require specific and internal manufacturing or reconditioning unless a liquid formulation is already marketed for instance [8]. In addition, it requires a more sensitive quantification method than probe drugs used at therapeutic doses [8]. Despite these constraints, low-dose or microdosed probe drugs may offer a great opportunity to improve knowledge of CYP450 activity in children after clinical validation. However, even if it is technically feasible, it is still largely unexploited.
Psychedelic Microdosing: Prevalence and Subjective Effects
Published in Journal of Psychoactive Drugs, 2020
Lindsay P. Cameron, Angela Nazarian, David E. Olson
Of the various psychedelic compounds used for microdosing, LSD and psilocybin were the most common (48.58% and 26.18% respectively, NT = 317, Table 3). Individuals who selected “Other” (11.67%, n = 37, NT = 317) reported using marijuana, cocaine, or a combination of psychedelic compounds (i.e., LSD and psilocybin or LSD and ayahuasca). We did not collect information regarding dosing regimen because previous work has demonstrated that users largely estimate the dosage reported (Hutten et al. 2019; Winstock et al. 2018). Additionally, dosage can vary according to factors that cannot be controlled in survey studies, such as the compound used, the purity of the substance used, and the weight or body composition of the individual.
Psychedelic Microdosing: A Subreddit Analysis
Published in Journal of Psychoactive Drugs, 2020
Toby Lea, Nicole Amada, Henrik Jungaberle
We analyzed Reddit discussions about microdosing to better understand people’s motivations and experiences of microdosing psychedelics. Online discussion forums are a unique setting to analyze emerging trends in substance use and unconventional health practices as they occur, particularly for phenomena such as microdosing that have experienced a rapid increase in media attention and limited published research (Barratt, Allen, and Lenton 2014). We found that the subreddit posters were primarily motivated to microdose to improve mental health and wellbeing, and to enhance cognitive performance. Many posters reported that microdosing had met and often exceeded their expectations, particularly in providing relief from depression and anxiety, enhancing focus and productivity, and fostering improved health behaviors and habits. Some posters experienced minimal or no improvement in mental health or cognitive performance, with some reporting increased anxiety and adverse physical effects.
Related Knowledge Centers
- Hormesis
- Psychedelic Drug
- Serotonin
- Drug
- Phases of Clinical Research
- Microdispensing
- Psychedelic Microdosing
- Radioactive Tracer
- Pharmacology