A human microdose study of the antimalarial drug GSK3191607 in healthy volunteers

Abstract

The information generated by this study provides a basis for predicting the expected oral PK profiles of GSK3191607 in man and supports decisions on the future clinical development of the compound.

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)…”

“…It is obviously of value to obtain, as soon as possible, data in the stage most likely to lead to termination of development. Other methodological advantages over phase I approaches discussed later are the ability to test multiple candidates simultaneously in the same individuals (cassette microdosing), the ability to test enteric drugs by administering them parenterally and the use of methods such as ITM 11,13,16,28 .…”

“…As noted earlier, study of drug parameters after intravenous microdose administration is attractive because it has been associated with very high probability of success in extrapolating from a microdose to the therapeutic dose (94% of cases are within a twofold range) 30,36 . This may be an especially useful prospect when preclinical oral administration raises concerns about linearity of extrapolation due to first-pass effects of transporters or metabolism 13,30,36 . Parenteral administration is possible in a microdose for almost all drug candidates even if their intended therapeutic route of administration is enteral.…”

“…Phase 0 approaches also have the potential to provide data that is not readily available with traditional approaches. These include first-in-human testing in patients, simultaneous testing of multiple drug candidates (known as cassette microdosing), intravenous administration of oral drugs and intratarget microdosing (ITM; the administration of microdoses locally to generate momentarily therapeutic level exposures in targets of interest) [9][10][11][12][13][14][15][16][17][18] . These advantages allow triaging of preclinical candidates for entry into clinical Adoption of phase 0/microdosing approaches by drug developers has been limited by uncertainty about the impact of non-linearity on extrapolation from subtherapeutic to therapeutic-level exposures, the perception that only pharmacokinetic data can be obtained with these approaches and the concern that application of phase 0 approaches will lead to delays in developmental timelines 26,27 .…”

“…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).…”