Clinical and Translational Science
February 26, 2016
T Burt, K Yoshida, G Lappin et al.
91 citations
Phase 0 clinical trials, including microdosing, limit drug exposure in first-in-human studies to reduce risks, costs, and time in drug development. These exploratory trials, governed by ICH M3 guidelines, involve subtherapeutic doses—for small molecules, no greater than 100 μg or 1/100th of the NOAEL—and require sensitive analytical tools like LC-MS/MS. Evidence supports extrapolating pharmacokinetic and pharmacodynamic data from microdose to therapeutic doses, though validity depends on drug properties and modeling. Applications include studying metabolism, receptor binding, and local drug effects. Ethical advantages include reduced human and animal exposure. The term 'in humano' is proposed for such limited human testing. An increasing number of applications demonstrate the versatility of these approaches.
Clinical and Translational Science
September 11, 2022
Emma Eckernäs, Christopher Timmermann, Daniel Röshammar et al.
22 citations
The psychedelic compound DMT is cleared from the body at a very high rate—26 L/min—indicating its elimination is independent of blood flow. Plasma concentrations follow a two-compartment model, with DMT metabolized to indole 3-acetic acid. The intensity of the psychedelic experience is linked to DMT concentration at an effect site, with half-maximal effect at 95 nM. Simulated median intensity ratings after doses of 1, 4, 7, 14, and 20 mg were zero, 2, 4, 8, and 9 on a 0–10 scale. The model can help predict suitable doses for clinical studies based on desired subjective experience intensity.
Clinical and Translational Science
May 1, 2025
Katelijne V. van der Heijden, Rob G J A Zuiker, Marije E. Otto et al.
7 citations
Intravenous DMT administered as a 30-second bolus followed by a 6-hour infusion, reaching peak blood concentrations around 35 ng/mL, is safe in healthy volunteers. No serious adverse events occurred; all side effects were mild and self-limiting. Vital signs, electrocardiography, and measures of suicidality or psychopathology showed no significant abnormalities. Mild psychedelic effects were accompanied by temporary decreases in sustained attention, postural stability, and occipital alpha brain wave power at the highest dose. Moderate variability in drug levels between individuals was observed. These findings support further testing of prolonged DMT infusion as a potential treatment to promote neuroplasticity in stroke recovery.
Clinical and Translational Science
April 1, 2026
Matthijs W Van Hoogdalem, Dong-Jing Fu, Wayne C. Drevets et al.
Esketamine nasal spray is the first glutamate-modulating antidepressant approved as a monotherapy for adults with treatment-resistant depression. It acts rapidly by blocking NMDA receptors on inhibitory interneurons, which disinhibits glutamate release and alters synaptic plasticity. Administered at 56 mg or 84 mg, it reaches peak concentration in 20–40 minutes with about 50% bioavailability. This review covers its regulatory approval, mechanism of action, pharmacokinetics, and clinical trial data for efficacy and safety in treatment-resistant depression and major depressive disorder with acute suicidal ideation or behavior.
Clinical and Translational Science
January 8, 2022
Amr Alaarg, Rajeev Menon, David Rizzo et al.
A new method using a stable labeled intravenous microdose accurately measured the absolute bioavailability of venetoclax, a highly hydrophobic, poorly water-soluble drug. In a clinical study, female subjects received a single 100 mg oral dose of venetoclax followed by a 100 µg intravenous dose of 13C-venetoclax at the time of peak oral concentration. Plasma samples collected over 72 hours showed the absolute bioavailability of venetoclax under fasting conditions was 5.4%. The low extraction ratio of 0.06 indicates that transfer from enterocytes into the liver limits bioavailability. This approach avoids radioactive labeling and can be applied to similar compounds to guide formulation development.