Investigation of Clinical Absorption, Distribution, Metabolism, and Excretion and Pharmacokinetics of the HIV-1 Maturation Inhibitor GSK3640254 Using an Intravenous Microtracer Combined with EnteroTracker for Biliary Sampling.

GSK3640254 is a next-generation maturation inhibitor in development for HIV-1 treatment, with pharmacokinetics (PK) supporting once-daily oral dosing in human. This open-label, nonrandomized, two-period clinical mass balance and excretion study was used to investigate the excretion balance, PK, and metabolism of GSK3640254. Five healthy men received a single intravenous microtracer of 100 g [C]GSK3640254 with a concomitant oral nonradiolabeled 200-mg tablet followed by an oral 85-mg dose of [C]GSK3640254 14 days later.

Meeting report: oligonucleotide ADME workshop.

The current regulatory landscape for the development of oligonucleotide drugs may lead companies to perform a variety of small molecule-focussed absorption, distribution, metabolism and elimination (ADME) studies in support of filing packages. Asking the question, if the current activities are suitable for these modalities and should science-driven decisions on development of such molecules be implemented more in the industry.Challenges and opportunities within oligonucleotide ADME were presented and discussed at the online oligonucleotide ADME workshop (17th and 18th of November 2021).

Pharmacokinetics and ADME Characterization of Intravenous and Oral [C]-Linerixibat in Healthy Male Volunteers.

Linerixibat, an oral small-molecule ileal bile acid transporter inhibitor under development for cholestatic pruritus in primary biliary cholangitis, was designed for minimal absorption from the intestine (site of pharmacological action). This study characterized the pharmacokinetics, absorption, metabolism, and excretion of [C]-linerixibat in humans after an intravenous microtracer concomitant with unlabeled oral tablets and [C]-linerixibat oral solution. Linerixibat exhibited absorption-limited flip-flop kinetics: longer oral versus intravenous half-life (6-7 hours vs.

An Innovative Approach to Characterize Clinical ADME and Pharmacokinetics of the Inhaled Drug Nemiralisib Using an Intravenous Microtracer Combined with an Inhaled Dose and an Oral Radiolabel Dose in Healthy Male Subjects.

An innovative open-label, crossover clinical study was used to investigate the excretion balance, pharmacokinetics, and metabolism of nemiralisib-an inhaled phosphoinositide 3-kinase delta inhibitor being developed for respiratory diseases. Six healthy men received a single intravenous microtracer of 10 g [C]nemiralisib with a concomitant inhaled nonradiolabeled 1000 g dose followed by an oral 800 g dose of [C]nemiralisib 14 days later. Complementary methods including accelerator mass spectrometry allowed characterization of a range of parameters including oral absorption (F), proportion of nemiralisib escaping gut wall metabolism (F), hepatic extraction (E), fraction of dose absorbed from inhaled dose (F), and renal clearance.

Radical curative efficacy of tafenoquine combination regimens in Plasmodium cynomolgi-infected Rhesus monkeys (Macaca mulatta).

Background: Tafenoquine is an 8-aminoquinoline being developed for radical cure (blood and liver stage elimination) of Plasmodium vivax. During monotherapy treatment, the compound exhibits slow parasite and fever clearance times, and toxicity in glucose-6-phosphate dehydrogenase (G6PD) deficiency is a concern. Combination with other antimalarials may mitigate these concerns.