Case studies addressing human pharmacokinetic uncertainty using a combination of pharmacokinetic simulation and alternative first in human paradigms

Abstract

PF-184298 ((S)-2,3-dichloro-N-isobutyl-N-pyrrolidin-3-ylbenzamide) and PF-4776548 ((3-(4-fluoro-2-methoxy-benzyl)-7-hydroxy-8,9-dihydro-3H,7H-pyrrolo[2,3-c][1,7]naphthyridin-6-one)) are novel compounds which were selected to progress to human studies. Discordant human pharmacokinetic predictions arose from pre-clinical in vivo studies in rat and dog, and from human in vitro studies, resulting in a clearance prediction range of 3 to >20 mL min⁻¹ kg⁻¹ for PF-184298, and 5 to >20 mL min⁻¹ kg⁻¹ for PF-4776548. A package of work to investigate the discordance for PF-184298 is described. Although ultimately complementary to the human pharmacokinetic data in characterising the disposition of PF-184298 in humans, these data did not provide any further confidence in pharmacokinetic prediction. A fit for purpose human pharmacokinetic study was conducted for each compound, with an oral pharmacologically active dose for PF-184298, and an intravenous and oral microdose for PF-4776548. This provided a relatively low cost, clear decision making approach, resulting in the termination of PF-4776548 and further progression of PF-184298. A retrospective analysis of the data showed that, if the tools had been available at the time, the pharmacokinetics of PF-184298 in human could have been predicted from a population based simulation tool in combination with physicochemical properties and in vitro human intrinsic clearance.

Microdosing and drug development: past, present and future

“…By incorporating an intravenous microdose study into pharmacokinetic simulations, reliable values for drug clearance in humans could be included, thereby generating much better overall predictions. In a case study, a development compound, PF-4776548, was quickly terminated based on a combination of microdose and physiologically based pharmacokinetic studies [73]. Another compound, PF-184298, was selected for development, mitigating risks due to oral exposure and metabolism by CYP2D6.…”

Human microdose evaluation of the novel EP1 receptor antagonist GSK269984A

“…single microdoses) was used to advance the compound with the most favourable profile. More recently, microdosing data were used to support the decision to terminate progression of the HIV integrase inhibitor PF-4776548 [24]. Here, we have shown how the incorporation of a microdose study into the planned clinical development of a novel EP1 receptor antagonist GSK269984A, through the administration of a sub-pharmacological dose to a small number of subjects, provided an opportunity to address a critical developmental risk posed by allometric predictions of a sub-optimal human PK profile.…”

“…Following the successful microdose readout, there was then a requirement for additional compound synthesis and toxicology resource to backfill studies in support of a conventional phase 1 programme, such that the overall time to achieve phase II completion would have been longer than for a default plan. On the other hand, for an unsuccessful outcome, a cost-saving can be realized since the decision to terminate further compound development based on microdose data can be achieved at an earlier time point with fewer resources as described by Harrison et al [24]. Nevertheless, the question of whether the inclusion of a microdose study might present a universally cost-efficient approach for a given drug development programme irrespective of the outcome remains a complex one.…”

“…and related enabling activities [20][21][22][23][24].They have been the subject of recent regulatory guidance documents [25,26] and enable the administration of a human dose that does not exceed 1/100th of that calculated to produce a pharmacological effect, with a maximum dose of 100 mg. Here we report on the PK evaluation of GSK269984A quantified in plasma using a highly sensitive high pressure liquid chromatography/tandem mass spectrometry (HPLC/MS/ MS) method following oral and i.v.…”

“…In our view, the decision will be a function of the risk analysis, the cost, the availability and timing of resource allocation, as well as the development strategy and the desired outcomes for enabling compound progression. In terms of timing, Harrison and colleagues make a compelling argument, based on their case studies of PF-184298 and PF-4776548, for the early acceptance of PK prediction uncertainty (where it exists) and the immediate diversion of resources into an exploratory human PK study [24]. Such an approach, it is argued, may be preferable to the pursuit of costly and lengthy preclinical investigations in an attempt to gain further understanding of discordance in PK predictions, and where the impact of such activities on the success of additional drug optimization is likely to remain uncertain.…”