Microdosing of a Carbon-14 Labeled Protein in Healthy Volunteers Accurately Predicts Its Pharmacokinetics at Therapeutic Dosages.
Maria L H Vlaming, Esther van Duijn, M R Dillingh, R Brands, A D Windhorst, N H Hendrikse, Sieto Bosgra, J Burggraaf, M C De Koning, A Fidder, J A J Mocking, H Sandman, R A F De Ligt, B O Fabriek, W J Pasman, W Seinen, T Alves, M Carrondo, C Peixoto, P A M Peeters, Wouter Vaes
Clinical Pharmacology & Therapeutics August 2015 DOI: 10.1002/cpt.131 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Phase 0/phase 1 first-in-human trial Peer reviewed |
|---|---|
| Population | Healthy volunteers |
| Dose | microdose 53 μg [14C]-hRESCAP; therapeutic doses up to 5.3 mg |
| Topics | Microdosing |
| Key findings | Pharmacokinetic analysis showed dose linearity from a microdose of 53 μg [14C]-hRESCAP to therapeutic doses up to 5.3 mg in healthy volunteers. The authors argue that microdosing with ultrasensitive accelerator mass spectrometry in a very small cohort can provide human pharmacokinetic data early and accelerate clinical development of new biological entities. |
Abstract
Preclinical development of new biological entities (NBEs), such as human protein therapeutics, requires considerable expenditure of time and costs. Poor prediction of pharmacokinetics in humans further reduces net efficiency. In this study, we show for the first time that pharmacokinetic data of NBEs in humans can be successfully obtained early in the drug development process by the use of microdosing in a small group of healthy subjects combined with ultrasensitive accelerator mass spectrometry (AMS). After only minimal preclinical testing, we performed a first-in-human phase 0/phase 1 trial with a human recombinant therapeutic protein (RESCuing Alkaline Phosphatase, human recombinant placental alkaline phosphatase [hRESCAP]) to assess its safety and kinetics. Pharmacokinetic analysis showed dose linearity from microdose (53 μg) [(14) C]-hRESCAP to therapeutic doses (up to 5.3 mg) of the protein in healthy volunteers. This study demonstrates the value of a microdosing approach in a very small cohort for accelerating the clinical development of NBEs.
Comparable studies
Other non-randomized and open-label trials on microdosing, most cited first.
Citations in the library
Cited by 7
- Phase 0/microdosing approaches: time for mainstream application in drug development? Nature Reviews Drug Discovery September 8, 2020
- Microdosing and Other Phase 0 Clinical Trials: Facilitating Translation in Drug Development Clinical and Translational Science February 26, 2016
- Phase 0, Including Microdosing Approaches: Applying the Three Rs and Increasing the Efficiency of Human Drug Development Alternatives to Laboratory Animals December 1, 2018
- Intra‐Target Microdosing (ITM): A Novel Drug Development Approach Aimed at Enabling Safer and Earlier Translation of Biological Insights Into Human Testing Clinical and Translational Science April 18, 2017
- Microdosing of protein drugs Clinical Pharmacology & Therapeutics February 1, 2016
and 2 more 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
- Impact of microdosing clinical study — Why necessary and how useful? Advanced Drug Delivery Reviews October 14, 2010
- Human microdosing for the prediction of patient response Bioanalysis March 1, 2010