Absorption, metabolism and excretion of pictilisib, a potent pan-class I phosphatidylinositol-3-Kinase (PI3K) inhibitor, in rats, dogs, and humans.

The absorption, metabolism and excretion of pictilisib, a selective small molecule inhibitor of class 1 A phosphoinositide 3-kinase (PI3K), was characterized following a single oral administration of [14C]pictilisib in rats, dogs and humans at the target doses of 30 mg/kg, 5 mg/kg and 60 mg, respectively.Pictilisib was rapidly absorbed with Tmax less than 2 h across species. In systemic circulation, pictilisib represented the predominant total radioactivity greater than 86.6% in all species.Total pictilisib and related radioactivity was recovered from urine and faeces in rats, dogs, and human at 98%, 80% and 95%, respectively, with less than 2% excreted in urine and the rest excreted into faeces.In rat and dog, more than 40% of drug-related radioactivity was excreted into the bile suggesting biliary excretion was the major route of excretion. Unchanged pictilisib was a minor component in rat and dog bile. The major metabolite in bile was O-glucuronide of oxidation on indazole moiety (M20, 21% of the dose) in rats and an oxidative piperazinyl ring-opened metabolite M7 (10.8% of the dose) in dogs.Oxidative glutathione (GSH) conjugates (M18, M19) were novel metabolites detected in rat bile, suggesting the potential generation of reactive intermediates from pictilisib. The structure of M18 was further confirmed by NMR to be a N-hydroxylated and GSH conjugated metabolite on the moiety of the indazole ring.

Investigation of the absolute bioavailability and human mass balance of navoximod, a novel IDO1 inhibitor.

AIMS: Navoximod (GDC-0919, NLG-919) is a small molecule inhibitor of indoleamine-2,3-dioxygenase 1 (IDO1), developed to treat the acquired immune tolerance associated with cancer. The primary objectives of this study were to assess navoximod's absolute bioavailability (aBA), determine the mass balance and routes of elimination of [14 C]-navoximod, and characterize navoximod's metabolite profile. METHODS: A phase 1, open-label, two-part study was conducted in healthy volunteers. In Part 1 (aBA), subjects (n = 16) were randomized to receive oral (200 mg tablet) or intravenous (5 mg solution) navoximod in a crossover design with a 5-day washout. In Part 2 (mass balance), subjects (n = 8) were administered [14 C]-navoximod (200 mg/600 µCi) as an oral solution. RESULTS: The aBA of navoximod was estimated to be 55.5%, with a geometric mean (%CV) plasma clearance and volume of distribution of 62.0 L/h (21.0%) and 1120 L (28.4%), respectively. Mean recovery of total radioactivity was 87.8%, with 80.4% detected in urine and the remainder (7.4%) in faeces. Navoximod was extensively metabolized, with unchanged navoximod representing 5.45% of the dose recovered in the urine and faeces. Glucuronidation was identified as the primary route of metabolism, with the major glucuronide metabolite, M28, accounting for 57.5% of the total drug-derived exposure and 59.7% of the administered dose recovered in urine. CONCLUSIONS: Navoximod was well tolerated, quickly absorbed and showed moderate bioavailability, with minimal recovery of the dose as unchanged parent in the urine and faeces. Metabolism was identified as the primary route of clearance and navoximod glucuronide (M28) was the most abundant metabolite in circulation with all other metabolites accounting for <10% of drug-related exposure.

A better method of quality control for 99mTc-tetrofosmin.

UNLABELLED: The method of quality control (QC) described on the package insert for (99m)Tc-tetrofosmin requires meticulous attention to technique for accurate radiochemical purity results. About 30 min are needed. Other proposed methods have been validated only with pertechnetate. We developed a convenient new method using silica cartridges. METHODS: A silica cartridge with 70:30 methanol:water was determined to be acceptable. The method was validated against sodium pertechnetate ((99m)TcO(4)), (99m)Tc-glucoheptonate, (99m)Tc-sulfur colloid, and low-purity (99m)Tc-tetrofosmin. The validations were made by using a small volume of concentrated (99m)TcO(4) with expired kits. Instant thin-layer chromatography (ITLC) showed 6 impurities after an hour or two. The effects of sample size and flow rate were determined. The precision of repeated tests was determined by comparison with the results of 8 replications on the same batch. The 2 methods were compared at a hospital and at 2 commercial nuclear pharmacies, for a total of 134 replications, with 21 preparations being of <90% radiochemical purity. RESULTS: Volumes between 25 and 100 micro L did not affect the silica-cartridge method but did affect the ITLC method. Flow rate is critical and must be < or =5 mL/min with the silica cartridges. The SD and variance by ITLC were 7 and 51 times larger, respectively. Using the package insert technique as the gold standard, all batches of <90% radiochemical purity were rejected and those of >90% radiochemical purity were accepted. Linear regression gave the following equation: ITLC = 1.0051 x silica cartridge (R = 0.99). One- and 2-binned chi(2) analyses gave P values > 0.999999. A 2 x 2 contingency table showed 100% sensitivity, accuracy, and specificity, with a Fisher's exact test P value of 5.7 x 10(-25). Correlation was nearly perfect. CONCLUSION: According to the published rating criteria for alternate radiochemical purity tests (American Pharmacists' Association), the silica-cartridge method has a score of 90.2, versus 65.8 for ITLC. On the basis of published criteria for alternate radiochemical purity testing methods, the new method is clearly seen to be superior. Furthermore, alternate methods were validated only with free (99m)TcO(4) and colloidal impurities. We showed that these are not the significant radiochemical impurities with (99m)Tc-tetrofosmin and that those methods are not valid. This new method is fast, convenient, accurate, safe, and economical, but careful control of flow rate is required.