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Clinical Pharmacology & Therapeutics February 1, 2016 M Rowland
Poor pharmacokinetics (PK) can seriously limit clinical utility. Knowing early whether a new compound is likely to have the desired PK profile at therapeutic doses is therefore important. One approach, microdosing,has shown high success with small molecular weight compounds,despite early skepticism. Vlaminget al.report the first, and successful, clinical application of a microdose of a...
Clinical Pharmacokinetics January 2016 Sieto Bosgra, Maria L H Vlaming, Wouter Vaes
Microdosing studies allow clinical investigation of pharmacokinetics earlier in drug development, before all high-dose safety concerns have been sorted out. Furthermore, microdosing allows inclusion of target groups that are inadmissible in high-dose phase I trials. A potential concern when considering a microdosing study is that a particular drug candidate may display non-linear...
Journal of Nuclear Medicine November 2015 Tal Burt, Douglas C Rouse, Kihak Lee et al.
Intraarterial microdosing (IAM) is a novel drug development approach combining intraarterial drug delivery and microdosing. We aimed to demonstrate that IAM leads to target exposure similar to that of systemic full-dose administration but with minimal systemic exposure. IAM could enable the safe, inexpensive, and early study of novel drugs at the first-in-human stage and the study of...
Clinical Pharmacology in Drug Development November 1, 2015 Graham Lappin
AbstractThe concept of microdosing has been around for more than a decade. It consists of the subpharmacologic administration of an investigational drug (1% of the pharmacologic dose or 100 µg, whichever is lower) to human subjects to attain pre–phase 1 pharmacokinetics (PK) in humans. The major concern with microdosing has been the potential for nonlinear PK between doses, but methods are...
Cancer chemotherapy and pharmacology October 2015 Ken-ichi Fujita, Etsuko Yoshino, Kaori Kawara et al.
Whether microdosing studies can be used to evaluate the human pharmacokinetics of new anticancer drugs remains unclear. The disposition of docetaxel in cancer patients is linear in terms of dose proportionality. We examined whether the pharmacokinetics of docetaxel in a clinically relevant therapeutic dose could be predicted from the pharmacokinetics of a microdose of docetaxel in Japanese...
Clinical Pharmacology & Therapeutics September 1, 2015 M Roth‐Cline, RM Nelson
Microdosing studies in children are used to obtain pharmacokinetic information, to study the ontogeny of metabolic enzymes, or to study drug disposition.
Clinical Pharmacology & Therapeutics August 2015 Maria L H Vlaming, Esther van Duijn, M R Dillingh et al.
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...
Nuclear medicine and biology June 2015 Peter Johnström, Linda Bergman, Katarina Varnäs et al.
The myeloperoxidase inhibitor AZD3241 has been selected as a candidate drug currently being developed to delay progression in patients with neurodegenerative brain disorders. Part of the decision tree for translation of AZD3241 into clinical studies included the need for assessment of brain exposure in non-human primates by PET microdosing. For that purpose a rapid multistep method for...
International Journal of Cancer April 1, 2015 Gregory T. Wurz, Michael W. DeGregorio
As Phase 0 studies have proven to be reasonably predictive of therapeutic dose pharmacokinetics, the application of microdosing has expanded into metabolism, drug–drug interactions and now diagnostics. One potentially serious issue with this application of microdosing that has not been previously discussed is the possibility of activating cellular mechanisms of drug resistance. Here, we provide...
Journal of Clinical Oncology March 1, 2015 Helen Chow, Sisi Wang, Hongyong Zhang et al.
356 Background: DNA adduct formation and incorporation of gemcitabine into genomic DNA are critical steps in cancer cell response to platinum (Pt) and gemcitabine chemotherapy, respectively. We hypothesize that levels of Pt-DNA adducts and gemcitabine in genomic DNA below a threshold are predictive of chemoresistance. Accelerator mass spectrometry (AMS) is an ultrasensitive method for measuring...