Microdose Pharmacokinetics of IDX899 and IDX989, Candidate HIV‐1 Non‐Nucleoside Reverse Transcriptase Inhibitors, Following Oral and Intravenous Administration in Healthy Male Subjects

Abstract

IDX899 and IDX989 are new non-nucleoside reverse-transcriptase inhibitors (NNRTIs) that exhibit potent inhibition of HIV-1 replication, including NNRTI-resistant mutants. This microdose study investigates the pharmacokinetics and determined oral bioavailability. For each compound, 4 healthy male subjects are randomized to receive via a crossover design a single 100-microg oral and intravenous dose together with 100 nCi of [(14)C]-labeled drug. Plasma and urine samples are obtained over a period of 168 hours postdose and analyzed for total, unchanged drug and major metabolites using an accelerator mass spectrometry method. Based on total radioactivity, oral absorption is near complete. For the parent drug, mean absolute bioavailability is 61% and 65% for IDX899 and IDX989, respectively. Both compounds are extensively metabolized especially after oral dosing. Observed terminal phase half-lives after oral and intravenous doses range from 4 to 10 hours and are comparable for the 2 compounds. Urine excretion of radioactivity for both compounds is less than 10%. These data show for the first time that IDX899 and IDX989 possess favorable pharmacokinetic properties in humans, including high mean absolute bioavailability and long half-life. IDX899 has been selected based on these initial pharmacokinetic assessments and other criteria as the candidate for further clinical development.

Microdosing and drug development: past, present and future

“…This means, therefore, that a 14 C drug synthesis is likely to be necessary for the microdose study, which adds cost and time. On the other hand, inclusion of 14 C in the drug can have advantages in terms of determining the metabolic profile of the drug, albeit at a low dose [38] and this is discussed further below (Section 4.2.5).…”

Prediction of Nonlinear Intestinal Absorption of CYP3A4 and P-Glycoprotein Substrates from their In Vitro Km Values

“…We termed the dose/Km the linearity index (LIN). The use of microdose clinical studies in the development of new drugs has attracted attention recently (14)(15)(16)(17), and microdose clinical studies have been performed to select candidates for clinical development (18)(19)(20). To maximize the value of microdose clinical studies, the ability to predict the nonlinear pharmacokinetics between the microdose and therapeutic dose is important.…”

Applications of Accelerator Mass Spectrometry (AMS)

“…Whole blood, urine, and fecal samples were collected over 7 days to obtain mass balance, plasma pharmacokinetic, and metabolite profi ling information. It is noteworthy that, although AMS was capable of analyzing radioactivity levels far below the detection limits of liquid scintillation counting, in this study maximal plasma total 14 C concentrations (i.e., 1.6 -2.9 dpm/mL, analyzing applied to pharmacokinetics and oral bioavailability assessment is not , Vuong et al, 2007and Zhou et al, 2009 ).…”