Use of Microdosing and Accelerator Mass Spectrometry To Evaluate the Pharmacokinetic Linearity of a Novel Tricyclic GyrB/ParE Inhibitor in Rats

Abstract

Determining the pharmacokinetics (PKs) of drug candidates is essential for understanding their biological fate. The ability to obtain human PK information early in the drug development process can help determine if future development is warranted. Microdosing was developed to assess human PKs, at ultra-low doses, early in the drug development process. Microdosing has also been used in animals to confirm PK linearity across subpharmacological and pharmacological dose ranges. The current study assessed the PKs of a novel antimicrobial preclinical drug candidate (GP-4) in rats as a step toward human microdosing studies. Dose proportionality was determined at 3 proposed therapeutic doses (3, 10, and 30 mg/kg of body weight), and PK linearity between a microdose and a pharmacological dose was assessed in Sprague-Dawley rats. Plasma PKs over the 3 pharmacological doses were proportional. Over the 10-fold dose range, the maximum concentration in plasma and area under the curve (AUC) increased 9.5-and 15.8-fold, respectively. PKs from rats dosed with a 14 C-labeled microdose versus a 14 C-labeled pharmacological dose displayed dose linearity. In the animals receiving a microdose and the therapeutically dosed animals, the AUCs from time zero to infinity were 2.6 ng · h/ml and 1,336 ng · h/ml, respectively, and the terminal half-lives were 5.6 h and 1.4 h, respectively. When the AUC values were normalized to a dose of 1.0 mg/kg, the AUC values were 277.5 ng · h/ml for the microdose and 418.2 ng · h/ml for the pharmacological dose. This 1.5-fold difference in AUC following a 300-fold difference in dose is considered linear across the dose range. On the basis of the results, the PKs from the microdosed animals were considered to be predictive of the PKs from the therapeutically dosed animals.T he development of new drugs is a long and costly process, often taking more than 10 years and over $1 billion to get one drug to market (1). The huge cost of new drugs is a consequence of the high failure rate of potential candidates prior to approval. One of the factors contributing to the high attrition rate during development is poor pharmacokinetics (PKs). Poor PK parameters are responsible for up to 40% of drug candidates failing to make it past the first studies in humans (2, 3). The ability to predict complete biodistribution profiles, which include PKs, tissue distribution, and route of elimination, early in the drug development process would provide critical data for decisions about the continued development of a drug lead. These data are also useful for the optimization of dosage regimes, potentiation of therapeutic efficacy, tailoring of drug delivery systems, and evaluation of safety. Early evaluation of these factors in humans would determine if further development is warranted before the initiation of costlier clinical trials.Microdosing is a technique used to assess a compound's in vivo biological fate through the administration of subpharmacological doses of a 14 C-labeled drug candidate that produce virtually no adver...

The biodistribution and pharmacokinetics of the oxime acetylcholinesterase reactivator RS194B in guinea pigs

“…Furthermore, the inherent high sensitivity of the technique allows for studies where high specific activities of radiolabeled compounds are not possible. AMS has been utilized for both rodent and human studies including: nanoparticle dosimetry (Malfatti et al, 2012) and pharmacokinetic and metabolic evaluation of therapeutics and environmental contaminants (Henderson and Pan 2010; Wagner et al, 2011; Malfatti et al, 2014; Madeen et al, 2015). …”

Manipulation of the Gut Microbiome Alters Acetaminophen Biodisposition in Mice

“…plasma concentration over time. The concentration of acetaminophen in plasma was determined by quantifying the amount of 14 C equivalents in plasma, using AMS, at time points up to and including 2 h and constructing concentration vs. time curves 29 . A two-stage approach was used to independently fit the plasma concentration data from each mouse, and then determine the means ± standard errors.…”

Phase 0/microdosing approaches: time for mainstream application in drug development?

“…Both sources of non-linearity can be incorporated into pharmacokinetic prediction of therapeutic doses through physiologically based pharmacokinetic (PBPK) modelling and simulation, which has made considerable progress in recent years (see later, Fig. 3 and Supplementary information C) [37][38][39][40] . Since the different approaches (microdosing and PBPK modelling) use non-overlapping sources of data and theoretical constructs, they are often complementary and indeed synergistic when used together (box 2).…”

“…Results of validation efforts demonstrate prediction of therapeutic-level drug disposition following microdose administration in 68% or 94% of cases depending on whether the administration is enteral or parenteral, respectively 36 . In addition, greater insight into non-linear mechanisms, their impact on extrapolation of subtherapeutic to therapeutic-level exposures and their management through modelling further increased the reliability and validity of extrapolation 29,33,[37][38][39][40] (discussed further later). In parallel, academic and commercial entities continued research into methods and applications 18, (Supplementary information A) to expand the effectiveness of these approaches, and sponsors have increasingly used phase 0 approaches in developmental scenarios not effectively addressed by traditional approaches [9][10][11][12][13][14]16,35,37,38,41, (Table 3; Supplementary information A).…”