Human microdosing Phase 0 studies are used to obtain key information in early drug development concerning a drug's pharmacokinetic and limited pharmacodynamic parameters. Developed as a method in the 2000s, microdosing has become part of the critical path of drug development. Microdosing studies can assist in drug candidate selection prior to going into expensive Phase I studies. This chapter...
Abstract: Gemcitabine is commonly given in combination with cisplatin or carboplatin (GC therapy) as the first-line chemotherapy regimen for several malignancies, including bladder cancer. Unfortunately, less than half of patients respond to the therapy, generating a critical need for a test that predicts tumor response to GC therapy. The goal of this project is to measure drug-DNA adducts...
Alzheimer s & DementiaMarch 1, 2014Peter J. Snyder, Yen Ying Lim, Rachel Schindler et al.
Abstract: Background: Abnormal β‐amyloid (Aβ) is associated with deleterious changes in central acetylcholinergic tone in the very early stages of Alzheimer's disease (AD), which may be unmasked by a cholinergic antagonist. We aimed to establish an optimal “microdose” of scopolamine for the development of a “cognitive stress test.” Methods: Healthy older adults (n = 26, aged 55–75 years) with...
Abstract: Purpose: DNA adduct formation is a critical step in platinum(Pt)–induced cell death. The goal of this project is to measure carboplatin-DNA adducts after a single non-toxic microdose of [14C]carboplatin, use this information to predict efficacy before cancer patients receive toxic chemotherapy and assess the underlying chemoresistance mechanisms, thus enhancing personalized therapy....
INTRODUCTION: Microdosing is an approach to early drug development where exploratory pharmacokinetic data are acquired in humans using inherently safe sub-pharmacologic doses of drug. The first publication of microdose data was 10 years ago and this review comprehensively explores the microdose concept from conception, over the past decade, up until the current date. AREAS COVERED: The authors...
Objective:Phase 0 studies can provide initial pharmacokinetics (PKs) data in humans and help to facilitate early drug development, but their predictive value for standard dosing is controversial. To evaluate the prediction of microdosing for active intracellular drug metabolites, we compared the PK profile of 2 antiretroviral drugs, zidovudine (ZDV) and tenofovir (TFV), in microdose and...
Ultrasensitive analytical methodologies have now made possible the ability to characterize the pharmacokinetics (PK) of compounds following administration to humans of a minute, subpharmacologic dose, a microdose. This has the potential to provide pre-IND information to help in early candidate selection, but only if such information is reasonably predictive of PK at pharmacologic doses. The...
Abstract: Low drug doses used in microdose or phase 0 studies present quantitation challenges to routine bioanalytical methods. Liquid chromatography‐mass spectrometry (LC‐MS), accelerator mass spectrometry (AMS), and positron emission tomography (PET) are bioanalytical techniques used for analysis of phase 0 samples. LC‐MS is most common and generally preferred if drug and metabolite...
ObjectiveThe aim of this crossover human male volunteer study was to investigate the utility of microdosing in the investigation of drug-drug interactions.MethodsA mixture of midazolam, tolbutamide, caffeine and fexofenadine were administered as a microdose (25 μg each) before and after administration of a combined pharmacological dose of ketoconazole (400 mg) and fluvoxamine (100 mg) to...
Clearance of atorvastatin occurs through hepatic uptake by organic anion transporting polypeptides (OATPs) and subsequent metabolism by cytochrome P450 (CYP) 3A4. To demonstrate the relative importance of OATPs and CYP3A4 in the hepatic elimination of atorvastatin in vivo, a clinical cassette microdose study was performed. A cocktail consisting of a microdose of atorvastatin along with probe...