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
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.