Human microdose evaluation of the novel EP1 receptor antagonist GSK269984A

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• The microdose administration of novel drug candidates to humans in early development is currently undergoing evaluation as a cost‐efficient approach to the early assessment of pharmacokinetics (PK) before the commitment of resources required to support formal phase 1 studies.• The microdose approach assumes that PK can be extrapolated linearly over the full range of exposures achieved with sub‐pharmacological doses up to the therapeutic dose range.• Few microdose studies have been undertaken in the context of pharmaceutical drug development and their precise role in the selection of candidates for further clinical evaluation at therapeutic doses has yet to be fully substantiated.WHAT THIS STUDY ADDS• The present study describes the elective application of a human microdose study with a novel EP1 receptor antagonist, GSK269984A, to address a critical development liability posed by uncertainty with respect to the predicted human PK profile.• Microdose data revealed a favourable PK profile, consistent with a clinically acceptable dosing regimen. These data support the value of undertaking a microdose study early in the drug discovery process to facilitate risk evaluation and to enable decision‐making.AIM The primary objective was to evaluate the pharmacokinetics (PK) of the novel EP1 antagonist GSK269984A in human volunteers after a single oral and intravenous (i.v.) microdose (100 µg).METHOD GSK269984A was administered to two groups of healthy human volunteers as a single oral (n= 5) or i.v. (n= 5) microdose (100 µg). Blood samples were collected for up to 24 h and the parent drug concentrations were measured in separated plasma using a validated high pressure liquid chromatography‐tandem mass spectrometry method following solid phase extraction.RESULTS Following the i.v. microdose, the geometric mean values for clearance (CL), steady‐state volume of distribution (Vss) and terminal elimination half‐life (t1/2) of GSK269984A were 9.8 l h−1, 62.8 l and 8.2 h. Cmax and AUC(0,∞) were 3.2 ng ml−1 and 10.2 ng ml−1 h, respectively; the corresponding oral parameters were 1.8 ng ml−1 and 9.8 ng ml−1 h, respectively. Absolute oral bioavailability was estimated to be 95%. These data were inconsistent with predictions of human PK based on allometric scaling of in vivo PK data from three pre‐clinical species (rat, dog and monkey).CONCLUSION For drug development programmes characterized by inconsistencies between pre‐clinical in vitro metabolic and in vivo PK data, and where uncertainty exists with respect to allometric predictions of the human PK profile, these data support the early application of a human microdose study to facilitate the selection of compounds for further clinical development.

Microdosing and drug development: past, present and future

“…The low doses administered obviously demand the use of highly sensitive analytical techniques in order to measure the plasma drug concentrations over sufficient time. The majority of human microdose studies reported in the literature have been conducted using 14 C-labelled drug and analysis conducted using the ultrasensitive isotope-ratio technique of AMS although studies have also been performed using non-labelled drug and sensitive LC-MS [35,36] and the relative merits of both techniques have been previously discussed [16]. The choice of analytical technique is largely driven by the expected plasma-drug concentrations and the limit of quantification of the analytical method.…”

“…In addition, for drugs in development, microdose studies can be performed before the drug might be administered at therapeutic doses and so it can be some time before the therapeutic data are published. There are therefore a number of accounts of microdosing in the literature where a therapeutic dose of drug has not yet been given [35,44,45]. A comprehensive summary of the peer-reviewed literature comparing human microdose with therapeutic dose pharmacokinetics is shown in Table 1 .…”

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

“…Conflicting data from in vivo and/or in vitro experiments and inability to validate extrapolation methods Modelling and simulation produce results inconsistent with in vivo and/or in vitro data or with existing human data from related compounds given in therapeutic doses Inconsistent pharmacokinetic profiles 13,35,101,102,[104][105][106][107][108]119 Challenging allometric scaling due to high plasma protein binding 102 Demonstrated tumour penetration in contrast to preclinical data 109 Poor animal models of Alzheimer disease 9,10,100,117,126 Assessment of linearity across the microdose to therapeutic dose range in animals to enhance the validity of extrapolation 37,38 Toxicity/safety concerns Preclinical data suggest high toxicity potential (for example, binding to non-therapeutic targets)…”

Prostaglandin E2 induces Skin Aging via E-prostanoid 1 in Normal Human Dermal Fibroblasts

“…5 shows how PGE2 induces intracellular signaling of EP1. Studies have reported EP1 agonists, such as ONO-8103, ONO-8359, GSK269984A, and GSK345931A, as EP1 inhibitors [35][36][37][38]. Each inhibitor alleviates bladder pain [35] or suppresses acid-derived heartburn symptoms [36] and inflammatory pain [38].…”