Evaluation of dose linearity in the systemic availability and pharmacokinetics of topically administered diclofenac: A 14C-microdosing study in healthy volunteers.
Severin Mairinger, Mihye Kwon, Martin Bauer, Jinho Song, Edith Lackner, Anselm Jorda, Felix Bergmann, Iris K Minichmayr, Ka Yeon Kim, Min Sun Choi, Jae Hoon Shim, Stephen R Dueker, Markus Zeitlinger, Oliver Langer
Drug Metabolism and Disposition July 1, 2025 DOI: 10.1016/j.dmd.2025.100091 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Crossover study Peer reviewed |
|---|---|
| Sample size | 8 |
| Population | Healthy participants (6 men and 2 women) |
| Intervention | Diclofenac |
| Dose | topical microdose 62 ± 6 μg; intravenous microdose 0.95 ± 0.03 μg; topical therapeutic dose 120 mg; intravenous therapeutic dose 75 mg |
| Duration | 24 h post-dosing |
| Topics | Microdosing |
| Keywords | Dose linearity Microdialysis Topical drugs |
| Key points | Systemic absorption after topical administration was not dose-linear; the fraction absorbed was higher for the microdose (0.48%) than for the therapeutic dose (0.13%). |
Abstract
An important safety consideration for topically administered drugs is the extent of systemic exposure they achieve. The aim of this study was to evaluate whether a topically administered microdose of the model drug diclofenac can predict the systemic availability, plasma, and tissue pharmacokinetics of a topical therapeutic dose. Eight healthy participants (6 men and 2 women) participated in a 4-period, crossover study. In period 1, a topical microdose (62 ± 6 μg) was administered; in period 2, a single intravenous microdose (0.95 ± 0.03 μg) was administered; in period 3, a topical therapeutic dose (120 mg) was administered; and in period 4, a single intravenous therapeutic dose (75 mg) of [14C]diclofenac was administered, with or without the addition of unlabeled diclofenac. Venous blood, urine, and microdialysis samples from subcutaneous adipose tissue beneath the dermal application site were collected for 24 h post-dosing. Total 14C-concentrations in plasma and microdialysates were quantified using accelerator mass spectrometry. The disposition of intravenously administered [14C]diclofenac was dose-linear. However, after topical administration, the fraction of total 14C absorbed (geometric mean and 95% confidence interval) was higher (P = .0019, 2-tailed, paired t test) for the microdose (0.48% and 0.34%-0.67%) compared with the therapeutic dose (0.13% and 0.07%-0.22%) (geometric mean ratio and 90% confidence interval: 3.79 and 2.41-5.98). Dose-normalized 14C-concentrations in microdialysates were low, variable, and did not differ between doses. Our study demonstrates the feasibility of quantifying 14C-concentrations in plasma and microdialysates following the topical administration of a microdose of [14C]diclofenac. The observed nonlinearity in systemic availability after topical dosing suggests that microdosing may not accurately predict the disposition of certain topical drugs at therapeutic doses. SIGNIFICANCE STATEMENT: We assessed whether a topically applied microdose of diclofenac could predict the systemic availability of a therapeutic dose. Results showed that systemic absorption was not dose-linear, indicating that microdosing may have limited use for predicting the pharmacokinetics of some topical drugs.
Comparable studies
Other randomized controlled trials on microdosing, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Use of microdosing to predict pharmacokinetics at the therapeutic dose: Experience with 5 drugs Volunteers | 2006 | Crossover study | |
| Self-blinding citizen science to explore psychedelic microdosing. Participants who microdose psychedelics | 2021 | Self-blinding citizen science initiative with placebo control | n = 191 |
| Microdosing with psilocybin mushrooms: a double-blind placebo-controlled study Individuals starting to microdose with psilocybin mushrooms (Psilocybe cubensis) | 2022 | Double-blind placebo-controlled experimental design | n = 34 |
| Preliminary Report on the Effects of a Low Dose of LSD on Resting-State Amygdala Functional Connectivity. Healthy young adults, 18 to 35 years old | 2019 | Randomized controlled trial | n = 20 |
| Acute Mood-Elevating Properties of Microdosed Lysergic Acid Diethylamide in Healthy Volunteers: A Home-Administered Randomized Controlled Trial. Healthy male volunteers | 2023 | Randomized controlled trial | n = 80 |
Citations in the library
Cites 3
- Use of microdosing to predict pharmacokinetics at the therapeutic dose: Experience with 5 drugs Clinical Pharmacology & Therapeutics September 1, 2006
- Phase 0/microdosing approaches: time for mainstream application in drug development? Nature Reviews Drug Discovery September 8, 2020
- Microdosing as a Potential Tool to Enhance Clinical Development of Novel Antibiotics: A Tissue and Plasma PK Feasibility Study with Ciprofloxacin Clinical Pharmacokinetics January 7, 2022