Total Radioactivity Research Articles

Metabolic disposition of [14 C]-abivertinib, an epidermal growth factor receptor tyrosine kinase inhibitor: Role of glutathione conjugation.

To determine the absorption, distribution, metabolism and excretion of abivertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced non-small cell lung cancer (NSCLC). Seven patients with advanced NSCLC were given a single 200 mg/83 μCi oral suspension of [14 C]-abivertinib. Blood, urine and faeces were collected. Mass balance of radioactivity, the pharmacokinetics of abivertinib, and the total radioactivity were determined. Metabolite profiling and characterisation were performed. The mean recovery was 82.16%, with 2.38 and 79.78% of the radioactive dose excreted in urine and faeces, respectively. The unchanged abivertinib was the major radioactive component detected in plasma within the first 24 hours after dosing, accounting for 59.17% of the total drug-related radioactivity. Abivertinib in urine accounted for only 0.96% of the administered dose, whereas in faeces it accounted for 33.36%. Eight metabolites were detected and characterised in plasma, among which MII-7, a product of cysteine glycine conjugate, was the only circulating metabolite, accounting for approximate 10.6% of the total drug-related exposure. MII-2 (an abivertinib cysteine-glycine adduct) and M7 (a reduced product of abivertinib) were the 2 major metabolites in the excreta, accounting for 20.0 and 12.4%, respectively, of the drug-related radioactivity in faeces. Following a single oral administration, the unchanged abivertinib was the predominant drug-related material in plasma, urine and faeces. The drug-related materials were primarily eliminated via the faecal route. Direct glutathione conjugation of abivertinib played a significant role in the metabolic clearance and metabolite exposure of abivertinib.

Distinction between Radiocesium (RCs)-bearing Microparticles and RCs-sorbing Minerals Derived from the Fukushima Nuclear Accident Using Acid Treatment

Radiocesium (RCs)-carrying materials derived from the Fukushima nuclear accident consist of RCs-sorbing minerals (CsSMs) and RCs-bearing silicate-glass microparticles (CsMPs). We reveal that while acid treatment has little effect on CsMPs, it significantly decreases the radioactivity of CsSMs due to dissolution. Using this difference, we propose a novel approach to estimating the contributions of CsMPs and CsSMs to total radioactivity of contaminated materials using autoradiography or γ-ray spectroscopy. Distribution of CsMPs in samples can also be elucidated without time-consuming microscopic analysis.

Prospective Study of Systemic Yttrium-90 Elution during Radioembolization of Hepatic Metastases

PurposeTo evaluate total blood radioactivity (BR) after SIR-Spheres yttrium-90 (90Y) radioembolization and differences in BR based on delivery method. Materials and MethodsTwenty participants with hepatic metastases undergoing first radioembolization were prospectively enrolled from December 2017 to June 2018. Blood samples were drawn at baseline and 0, 10, 20, 60, and 120 minutes after 90Y administration. BR was measured with a γ-counter and scaled by estimated blood volume. Percentage of instilled radioactivity in the bloodstream was calculated as area under the fitted curve, and differences between delivery methods were examined with nonparametric statistical tests. ResultsIn 10 participants, resin microspheres were instilled with 50% Isovue 300 diluted in saline solution in the D line, and 10 others were treated with dextrose 5% in water (D5W) in the D line. Median administered activities were 944 MBq (range, 746–1,993 MBq) and 1,213 MBq (range, 519–2,066 MBq), respectively. Fraction of 90Y in blood was significantly higher with dilute contrast agent than with D5W (median, 0.5% of injected activity vs 0.2%; P = .001). Among all participants, the maximum activity delivered was 2,066 MBq, and a maximum of 1% of administered radioactivity was measured as free 90Y in blood. Assuming these highest-case values and complete decay of all free 90Y in bone, a dose to red marrow of 132.3 mGy was calculated by Organ Level INternal Dose Assessment/EXponential Modeling. ConclusionsBlood sampling after radioembolization allowed for estimation of the time–activity curve and BR. Delivery with 50% contrast agent in saline solution resulted in a significant increase in BR vs D5W, even though the total BR for both groups was nominal.

Metabolite V, an epoxide species is a minor circulating metabolite in humans following a single oral dose of deflazacort.

Deflazacort (Emflaza) was approved in the United States in 2017 for the treatment of the Duchenne muscular dystrophy in patients aged 2 years and older. Several deflazacort metabolites were isolated and identified from rats, dogs, monkeys, and humans. Among them, 1ß,2ß‐epoxy‐3ß‐hydroxy‐21‐desacetyl deflazacort, referred to as Metabolite V, was reported to be one of the major circulating metabolites in humans. However, its quantitative distribution in plasma was not fully characterized. The objective of this study was to determine deflazacort plasma pharmacokinetics, metabolite profiles and their quantitative exposures in humans following a single oral dose. Six healthy male subjects were each administered a single oral dose of 60 mg [14C]‐deflazacort. Plasma and urine were collected and deflazacort metabolites in plasma were quantified by high performance liquid chromatography radio‐profiling followed by liquid chromatography‐mass spectrometry characterization. Metabolite V was isolated from urine and its structure was further confirmed by nuclear magnetic resonance analysis. These analyses demonstrated that deflazacort was not detectable in plasma; of the eight circulating deflazacort metabolites identified or characterized, the pharmacologically active metabolite 21‐desacetyl deflazacort and inactive metabolite 6ß‐hydroxy‐21‐desacetyl deflazacort accounted for 25.0% and 32.9% of the 0‐24 hours plasma total radioactivity, respectively, while Metabolite V, an epoxide species, was a minor circulating metabolite, representing only about 4.7% of the total plasma radioactivity.

Efficacy of systemic administration of riboflavin on a rabbit model of corneal alkali burn

Changes in the barrier mechanisms in the eye should determine the rational route for the administration and dosage of each drug in the treatment of traumatic injuries and other pathologies. The aim of this study was to examine the efficacy of intra-arterial delivery of 14C-riboflavin (as an “indicator”) and compare it with intravenous and intramuscular administration in an animal model of chemical eye burn. 14C-riboflavin (14C-I) was administered by intra-arterial (carotid artery), intravenous (femoral vein) and intramuscular (femoral muscle) routes. The total radioactivity was determined over 2 h in the plasma and structures of the rabbit’s eyes using a scintillation counter. The results of the study show that intravascular administration of 14C-I gives significantly higher concentrations of total radioactivity in the blood and is accompanied by a significant increase in the permeability of the blood-barrier and barrier in eyes suffering from burns. The highest concentration in the plasma and aqueous humour of the anterior chamber of the eye was observed during the first hour with the intra-arterial route of administration of 14C-I in either burnt and unburnt eyes. The distribution of total radioactivity in the structures of the eye over the 2 h of the experiment showed a higher level of the drug under intra-arterial administered in the uveal regions, namely: the iris, ciliary body, choroid, retina and also the sclera and cornea. This experimental model shows that intra-arterial administration can increase the bioavailability of a drug to the structures of the eye within a short period of time.

Metabolism and disposition in rats, dogs, and humans of erdafitinib, an orally administered potent pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor

This article describes in vivo biotransformation and disposition of erdafitinib following single oral dose of 3H-erdafitinib and 14C-erdafitinib to intact and bile duct-cannulated (BC) rats (4 mg/kg), 3H-erdafitinib to intact dogs (0.25 mg/kg), and 14C-erdafitinib to humans (12 mg; NCT02692677). Peak plasma concentrations of total radioactivity were achieved rapidly (T max: animals, 1 h; humans, 2–3 h). Recovery of drug-derived radioactivity was significantly slower in humans (87%, 384 h) versus animals (rats: 91–98%, 48 h; dogs: 81%, 72 h). Faeces was the primary route of elimination in intact rats (95%), dogs (76%), and humans (69%); and bile in BC rats (48%). Renal elimination of radioactivity was relatively low in animals (2–12%) versus humans (19%). Unchanged erdafitinib was major component in human excreta (faeces, 17%; urine, 11%) relative to animals. M6 (O-desmethyl) was the major faecal metabolite in humans (24%) and rats (intact, 46%; BC, 11%), and M2 (O-glucuronide of M6) was the prevalent biliary metabolite in rats (14%). In dogs, besides M6, majority of radioactive dose in faeces was composed of multiple minor metabolites. In humans, unchanged erdafitinib was the major circulating entity. O-demethylation of erdafitinib was the major metabolic pathway in humans and animals.

Abstract CT170: Phase 1 study to characterize the pharmacokinetics and safety of tazemetostat in b-cell lymphomas or advanced solid tumors

Abstract Tazemetostat (TAZ), a selective inhibitor of EZH2, was administered intravenously and orally (unlabeled and [14C]-labeled) to patients (pts) with B-Cell lymphomas (BCL) or advanced solid tumors (AdvST) to characterize its pharmacokinetic (PK) (oral TAZ only) and safety profile in an open-label, 2-part phase 1 study (NCT03010982). In Part A, pts received oral TAZ (800 mg twice daily) for ≥14 days plus 1 dose of [14C]-labeled TAZ (12 μg TAZ containing 500 nCi of [14C]-TAZ) as an IV bolus on Day 15. Serial blood samples were collected for 24 hours after the Day 15 oral dose. In part B, pts received oral TAZ solution (800 mg twice daily) containing ~400 μCi (14.8 MBq) of [14C]-TAZ on Day 16. Blood, plasma, urine, and fecal samples were collected for up to 120 hours after administration. Pts could continue receiving oral TAZ until disease progression/unacceptable toxicity. Part A primary endpoints included PK parameters for oral TAZ, metabolite EPZ-6930, and IV [14C]-TAZ. Part B primary endpoints included total and relative radioactivity excretion. Secondary endpoints included safety (both parts), TAZ bioavailability (Part A), and additional PK parameters (Part B). As of May 7, 2019, 3 lymphoma pts were enrolled and received study treatment as planned. The pts were of >50 years of age and had received ≥3 prior lines of systemic therapy. The half-life of TAZ and its metabolite EPZ-6930 was 3-4 hours regardless of the route of administration. Cumulatively, 93.25%-94.7% of the administered TAZ dose was excreted through urine and feces. Two pts discontinued TAZ due to disease progression and the remaining pt entered a rollover study. All pts experienced ≥1 treatment-related (TR) treatment-emergent adverse events (TEAEs); 2 experienced ≥1 Grade 3/4 TR TEAEs. No TEAE resulted in dose reduction/interruption. All pts experienced ≥1 serious TEAEs; 2 experienced serious TR TEAEs. PK and safety in this small sample size are consistent with those previously reported. TAZEPZ-6930[14C]-TAZPK Parameter (Unit)Day 15 (oral TAZ: tablets) (n=3)Day 16 (oral TAZ: solution) (n=3)Day 15 (oral TAZ: tablets) (n=3)Day 16 (oral TAZ: solution) (n=3)Day 16 (TAZ IV bolus) (n=3Cmax (ng/mL)a1110 (37.5)1780 (51.5)1670 (25)2190 (25.3)0.702 (0.0154)tmax (h)b1.05 (1.02-2.92)0.917 (0.583-0.967)1.05 (1.02-4.92)1.97 (0.917-1.98)0.0167 (0.0167-0.0333)AUC0-last (h•ng/mL)a4390 (74.1)6950 (65.7)9750 (54.5)13200 (46.8)210 (27.6)AUC0-∞ (h•ng/mL)a5110 (69.2)7620 (64.9)12000 (46.9)14900 (50.4)218 (26.4)AUC0-12 (h•ng/mL)a4620 (69.5)6950 (65.6)10400 (47.9)13200 (46.7)206 (21.8)t½ (h)a3.52 (12.4)3.66 (20.5)3.91 (15.7)3.53 (8.99)3.39 (23.8)λza0.197 (12.6)0.189 (18.5)0.177 (14.5)0.196 (9.18)0.204 (22.4)CL/F (L/h)aNDNDNDND55.0 (23.2)Vz/F (L)aNDNDNDND269 (12.5)MPRaNANA2.36 (0.193)2.00 (0.166)NANote: Day 15 included oral administration of 800 mg TAZ and Day 16 included oral administration of 800 mg TAZ containing 400 μCi of [14C]-TAZ.aData reported as geometric mean (CV%).bData reported as median (minimum-maximum). λz = apparent first-order terminal elimination rate constant; AUC0-∞ = area under the concentration-time curve from time 0 extrapolated to infinity time; AUC0-12 = area under the concentration-time curve from time 0 to 12 hours; AUC0-last = area under the concentration-time curve from time 0 to last; CL/F = apparent clearance; Cmax = maximum plasma concentration; CV% = percent coefficient of variation; IV = intravenous; MPR = metabolite-to-parent ratio; NA = not applicable; ND = not determined; PK = pharmacokinetic; t½ = half-life; TAZ = tazemetostat; tmax = time to maximum plasma concentration; Vz/F = apparent volume of distribution. Citation Format: Evren Kocabas Argon, Felicia Nguyen, Anand Rajarethinam, Vikram Kansra, Andrew Pettitt. Phase 1 study to characterize the pharmacokinetics and safety of tazemetostat in b-cell lymphomas or advanced solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT170.

Вміст радіонуклідів у фітопланктоні на різних ділянках Запорізького водосховища

The radionuclides, which have occurred in the aquatic ecosystem are quickly redistributed there. Most of them come through the water phase to the benthal deposit, while the other part of them accumulates in suspensions and hydrobionts. Even low concentrations of radionuclides in water contributes to its radioactive contamination that poses risks to the environment. The radionuclide contamination of freshwater ecosystems is particularly pressing issue, since water with low mineralization enhances the radionuclides activity in the sediments compared to the water by a factor of 10 or even more, and in the animals by hundreds and thousands of times. Phytoplankton is the fundamental autotrophic link of aquatic ecosystems. Due to a large total sorption surface, it is able to absorb, retain and transmit radionuclides along the food chains, leading to a deterioration of the environmental position of the reservoir. Phytoplankton was sampled in the summer of 2019 at 5 sites along the course of the Zaporizke reservoir, which differ in hydrological and hydrochemical conditions: Samara Bay, Festivalnyi pier, Monastyrsky island, creek of the Mokra Sura river and the lower section of the reservoir (near Viyskove village). The specific radioactivity of phytoplankton samples was determined using generally accepted radiochemical methods and gamma spectrometry. The specific radioactivity of radionuclides is given in bequerels per kilogram (Bq/kg) of fresh, natural weight. Statistical processing of research results was carried out using generally accepted methods of variation statistics for a small sample using the Excel 2010 software package. Purpose of the work. To determine the content of natural ( 232 Th, 226 Ra and 40 K) and artificial ( 137 Cs and 90 Sr) radionuclides in phytoplankton at different sites of the Zaporizke reservoir. The content of artificial radionuclides in the phytoplankton of the Zaporizke reservoir averaged as follows: 137 Cs – 7.61±0.501 Bq/kg; 90 Sr – 1.13±0.242 Bq/kg. The maximum values of the content of artificial radionuclides in phytoplankton were recorded in the area of the Festivalnyi pier and the minimum values were recorded near Viyskove village ( 137 Cs) and Samara bay ( 90 Sr). In total, phytoplankton has a relatively low content of artificial radionuclides, which is explained by its low content in water. Hydrobionts receive the main portion of radiation exposure from natural sources of radiation. About 300 natural radionuclides have been identified in the environment; among them 226 Ra, 232 Th and 40 K make a significant contribution to the total natural radioactivity. The specific activity of natural radionuclides in the water area of the Zaporizke reservoir on average was following: 226 Ra – 95.45±7,010 Bq/kg; 232 Th – 85.66±4,013 Bq/kg; 40 K – 185.26±23.74 Bq/kg. The lowest content of natural radionuclides was observed in the phytoplankton of the Samara bay. The maximum recorded specific activity of 226 Ra and 40 K was observed in the creek of the Mokra Sura river, which may indicate an increased content of radionuclides in the water of this river, because the river is polluted throughout its length by industrial, agricultural and municipal wastewater. It has been found that the specific activity of natural radionuclides 226 Ra, 232 Th and 40 K was 80-320 times higher than that of the artificial ones ( 90 Sr and 137 Cs). The distribution of radionuclides in the elements of the freshwater ecosystem is characterized by accumulation coefficients. According to the accumulation coefficients with respect to water, the sequence of accumulation of radionuclides in the phytoplankton of the Zaporizke reservoir has been arranged in descending order: 137 Cs> 232 Th> 226 Ra> 40 K> 90 Sr. The accumulation coefficients of 40 K and 90 Sr are 11-22 times less than those of 137 Cs and 232 Th, which is quite appropriately, because freshwater algae are more able to accumulate 137 Cs. For most of the radionuclides studied, the maximum values of accumulation coefficients have been recorded in phytoplankton in the area of the Festivalnyi pier ( 137 Cs, 90 Sr, 232 Th) and the creek of the Mokra Sura river ( 226 Ra, 40 K). The latter is associated with both the hydrochemical and hydrological conditions of these sites, and with increased anthropogenic impact, especially in the area of the river creek. The data obtained indicate that there is a potential threat of accumulation of radionuclides in phytoplankton and their transfer further along food chains. With reference to the above mentioned, it is important to monitor the content of radionuclides in phytoplankton in order to minimize their transmission through the food chain and preserve the biodiversity of aquatic ecosystems.

Excretion balance and pharmacokinetics following a single oral dose of [14C]-fedratinib in healthy subjects.

Fedratinib is an oral and selective kinase inhibitor with activity against wild type and mutationally activated Janus kinase 2 and FMS-like tyrosine kinase 3, for the treatment of adult patients with intermediate-2 or high-risk primary or secondary myelofibrosis. This open-label mass balance study in healthy subjects investigated the excretion balance and systemic exposure of radioactivity after oral administration of [14C]-fedratinib; and the pharmacokinetics of fedratinib and its contribution to overall exposure of radioactivity. Six healthy males received a single oral dose of 200mg [14C]-fedratinib base (2.775MBq, 75μCi) as a solution. Blood, urine and feces samples were collected for up to 35day postdose. Urine and feces samples were collected until the 24-h excretion of radioactivity fell below 0.5% of administered dose (at least 14day postdose). Expired air was collected up to 8-h postdose. Total radioactivity (blood, plasma, urine, feces, and expired air) and fedratinib concentrations (plasma) were measured. Approximately 77% (23% unchanged) of fedratinib derived radioactivity was excreted in feces and 5% (3% unchanged) was excreted in urine. Excretion via expired air was negligible. The time to maximum concentration for both total radioactivity and parent drug was similar, with unchanged drug representing the majority of the circulating radioactivity. The ratio of blood to plasma concentration of radioactivity ranged from 0.615 to 0.753 indicating limited distribution of fedratinib and/or its metabolites into red blood cells. Fedratinib derived radioactivity was primarily excreted in feces following a single oral dose of radiolabeled fedratinib to healthy subjects.

Disposition and metabolism of antibacterial agent, triclocarban, in rodents; a species and route comparison

Triclocarban is a residue-producing antibacterial agent used in a variety of consumer products. These studies investigated the disposition and metabolism of [14C]triclocarban. In male rats following a single gavage administration of 50, 150, and 500 mg/kg, excretion was primarily via feces (feces, 85–86%; urine, 3–6%) with no apparent dose-related effect. In male rats, 29% of the administered dose was excreted in bile suggesting some of the fecal excretion is from the absorbed dose which was excreted to the intestine via bile. The tissue retention of radioactivity was low in male rats (24 h, 3.9%; 72 h, 0.1%). Disposition pattern following gavage administration of 50 mg/kg in female rats and male and female mice were similar to male rats. Plasma elimination half-life of triclocarban in rats following gavage administration was shorter (∼2 h) compared to that based on total radioactivity (≥9 h) which included all products of triclocarban. Absorption following a single dermal application of 1.5 or 3% was low (≤3%) in rodents. Hydroxylated and conjugated metabolites of triclocarban predominated in bile. In hepatocytes, clearance of triclocarban in mouse and human was similar and was faster than in rat.

Disposition and metabolism of 2,2′-dimorpholinodiethyl ether in sprague dawley rats and B6C3F1/N mice after oral, intravenous administration, and dermal application

The specialty amine catalyst 2,2′-dimorpholinodiethyl ether (DMDEE) is a high-production volume chemical used in the production of flexible foam, high-resilient molded foam, and in coatings and adhesives. The disposition and metabolism of [14C]DMDEE (20 or 200 mg/kg) were determined in male ane female rats and mice after oral and intravenous administration and dermal application. In male and female rats, following a single oral administration, [14C]DMDEE was well-absorbed and excreted rapidly and extensively via urine (75–93%) and some in feces (∼4–8%). The total radioactivity in tissues at 24 h and 72 h (males only) following oral administration was 8–10% and ∼4%, respectively, suggesting considerable tissue distribution. A moderate amount of the total tissue radioactivity in kidney and liver were unextractable suggesting covalent binding of [14C]DMDEE-derived products in tissue macromolecules. Absorption following a single dermal application in rats was significant (∼64%) with a similar disposition pattern to oral. The oral and dermal disposition of [14C]DMDEE in male and female mice was similar to rats. Urinary products of DMDEE identified were oxidative metabolism of the morpholine ring. Coadministration of DMDEE with nitrite in rats didn’t produce the rodent carcinogen, N-nitrosomorpholine.

940-P: 14C-Tirzepatide ADME Studies in Rat and Monkey

Novel dual GIP and GLP-1 receptor agonist, tirzepatide (TZP), is being developed as a potential weekly treatment for type 2 diabetes (T2DM), weight management and nonalcoholic steatohepatitis. The absorption, metabolism and excretion of a single subcutaneous (SC) dose of 14C-tirzepatide was investigated in Sprague Dawley rat and cynomolgus monkey. In addition, tissue distribution of 14C-tirzepatide was assessed in quantitative whole-body autoradiography (QWBA) study in pigmented Long Evans rat following a single SC dose. 14C-Tirzepatide was prepared by incorporating four 14C’s in the mini-PEG linker between the peptide backbone and the di-acid chain to provide a specific activity of ∼ 40 µCi/mg. Following a single SC dose of 14C-tirzepatide in rat (3 mg/kg) and monkey (0.5 mg/kg), total radioactivity recovery was > 97% over the course of study (336 hours for rat and 672 hours for monkey). The dosed radioactivity was similarly excreted via urine and feces in rats and monkeys. Metabolism of 14C-tirzepatide was characterized in plasma and excreta. Parent drug was the major component in circulation accounting for approximately 87% of total radioactivity in rat and 84% in monkey. Tirzepatide was primarily metabolized via catabolism of the peptide backbone and β-oxidation of the di-acid chain. Following a single SC dose of 14C-tirzepatide in rats (3 mg/kg), radioactivity was distributed to tissues as early as the first collection time point at 1-hour post dose. The tissues with the highest radioactivity concentrations were observed in the dose site, kidney, cecum, urinary bladder, intervertebral ligaments, arterial wall, lungs, and liver, generally at 12 to 48 hours post dose. Disclosure J. Martin: Employee; Self; Eli Lilly and Company. K. Cassidy: Employee; Self; Eli Lilly and Company. B. Czeskis: None. J. Alberts: Employee; Self; Eli Lilly and Company. Y. Lao: Employee; Spouse/Partner; Eli Lilly and Company. J. Gluff: None. A.M. Niedenthal: None.

Accumulation of 137Cs in insects – herpetobiont integuments

Abstract . The study of the radioactivity of insects - herpetobiont elytra that belong to different trophic groups shown the presence of incorporated 137 Cs, there were concentrated about 20% of total animal radioactivity. The comparison of the radionuclide comparison was done in both dried and fresh samples. Radioactive contamination of integument comes mainly from the terminal phase of metamorphosis (at the ninth phase).

Metabolism and Pharmacokinetic Drug-Drug Interaction Profile of Vericiguat, A Soluble Guanylate Cyclase Stimulator: Results From Preclinical and Phase I Healthy Volunteer Studies.

BackgroundVericiguat is a stimulator of soluble guanylate cyclase currently under investigation as a first-in-class therapy for worsening chronic heart failure (NCT02861534). Patients with heart failure often require polypharmacy because of comorbidities. Hence, understanding the clearance mechanisms, elimination, and potential for pharmacokinetic drug–drug interactions of vericiguat is important for dose recommendations in this patient population.MethodsBiotransformation and perpetrator properties of vericiguat were characterized in vitro using human hepatocytes, liver microsomes, and recombinant enzymes. This was complemented by a human mass balance study and ten drug–drug interaction studies in healthy volunteers wherein vericiguat was co-administered orally with omeprazole, magnesium/aluminum hydroxide, ketoconazole, rifampicin, mefenamic acid, midazolam, warfarin, digoxin, sacubitril/valsartan, aspirin, or sildenafil.ResultsIn the human mass balance study, mean total radioactivity recovered was 98.3% of the dose administered (53.1% and 45.2% excreted via urine and feces, respectively). The main metabolic pathway of vericiguat is glucuronidation via uridine diphosphate-glucuronosyltransferase 1A9 and 1A1. In vitro studies revealed a low risk of vericiguat acting as a perpetrator by inhibiting cytochrome P450s, uridine diphosphate-glucuronosyltransferase isoforms, or major transport proteins, or by inducing cytochrome P450s. These observations were supported by phase I drug–drug interaction studies. Phase I studies that assessed the propensity of vericiguat as a victim drug showed changes in the range that did not warrant recommendations for dose adjustment in phase III.ConclusionsA low pharmacokinetic interaction potential of vericiguat was estimated from in vitro data and confirmed in vivo. Thus, vericiguat is suitable for a patient population with multiple comorbidities requiring polypharmacy.Electronic supplementary materialThe online version of this article (10.1007/s40262-020-00895-x) contains supplementary material, which is available to authorized users.

Metabolism, Excretion, and Pharmacokinetics of Lorlatinib (PF-06463922) and Evaluation of the Impact of Radiolabel Position and Other Factors on Comparability of Data Across 2 ADME Studies.

While an initial clinical absorption, distribution, metabolism, and excretion (ADME) study (Study 1; N = 6) with 100 mg/100 µCi [14 C]lorlatinib, radiolabeled on the carbonyl carbon, confirmed that the primary metabolic pathways for lorlatinib are oxidation (N-demethylation, N-oxidation) and N-glucuronidation, it also revealed an unanticipated, intramolecular cleavage metabolic pathway of lorlatinib, yielding a major circulating benzoic acid metabolite (M8), and an unlabeled pyrido-pyrazole substructure. Concerns regarding the fate of unknown metabolites associated with this intramolecular cleavage pathway led to conduct of a second ADME study (Study 2; N = 6) of identical design but with the radiolabel positioned on the pyrazole ring. Results were similar with respect to the overall mass balance, lorlatinib plasma exposures, and metabolic profiles in excreta for the metabolites that retained the radiolabel in both studies. Differences were observed in plasma total radioactivity exposures (2-fold area under the plasma concentration-time curve from time 0 to infinity difference) and relative ratios of the percentage of dose recovered in urine vs feces (48% vs 41% in Study 1; 28% vs 64% in Study 2). In addition, an approximately 3-fold difference in the mean molar exposure ratio of M8 to lorlatinib was observed for values derived from metabolic profiling data relative to those derived from specific bioanalytical methods (0.5 vs 1.4 for Studies 1 and 2, respectively). These interstudy differences were attributed to a combination of factors, including alteration of radiolabel position, orthogonal analytical methodologies, and intersubject variability, and illustrate that results from clinical ADME studies are not unambiguous and should be interpreted within the context of the specific study design considerations.

OR23-05 Human Absorption, Metabolism, Excretion, and Absolute Oral Bioavailability of 14C-CRN00808, an Orally Bioavailable, Nonpeptide, Selective, Somatostatin Receptor 2 (sST2) Biased Agonist for the Treatment of Acromegaly

Injected depot formulations of somatostatin peptide analogs are routinely used to treat acromegaly and neuroendocrine tumors (NETs). CRN00808, a small molecule nonpeptide selective somatostatin receptor 2 (sst2) agonist, is being evaluated for efficacy and safety in patients with acromegaly. The current Phase 1 study was conducted in two Parts: In Part A, the absorption, metabolism, excretion, and mass balance of a single oral dose of 20 mg [14C]-CRN00808 (3.0 MBq) oral solution was characterized in six healthy male subjects. Plasma, blood, urine, and feces were collected for up to 432 hours, and were analyzed for total radioactivity and CRN00808 concentrations (plasma only). Metabolite profiling was conducted on the plasma, urine, and feces samples. In Part B, the absolute bioavailability of CRN00808 was determined by administering a single oral dose of 20 mg CRN00808 compared with a single micro-tracer intravenous (IV) bolus injection of 50 µg [14C]-CRN00808 (0.0185 MBq) in five healthy male subjects. The IV dose was administered approximately 90 minutes after the oral dose. Plasma samples were collected for up to 144 hours and were analyzed for total radioactivity and CRN00808 concentrations (plasma only).Key data from Part A and Part B will be presented. Available data from Part A of the study show that >90% of radioactivity was recovered within 7 days of dosing. The primary route of excretion was the feces (>90%) with minimal excretion in the urine (<10%). Absorption of total [14C]-CRN00808-derived radioactivity in plasma was rapid (median Tmax=1 hour), and the mean Cmax, AUC0-∞, and t1/2 were determined to be 194 ng-equivalents/mL, 3340 ng-equivalents.hr/mL, and 31 hours, respectively. The pharmacokinetic parameters of unchanged CRN00808 in plasma were similar, suggesting that majority of the circulating drug-derived radioactivity is accounted for by unchanged CRN00808 and there are no abundant circulating metabolites. Treatment emergent adverse events associated with CRN00808 were generally mild and transient, and consistent with those reported with other somatostatin agonists. In conclusion, results from this clinical trial in healthy volunteers confirm that CRN00808 has excellent drug-like properties for chronic once-daily oral treatment of patients with acromegaly.

The Effects of an Albumin Binding Moiety on the Targeting and Pharmacokinetics of an Integrin αvβ6-Selective Peptide Labeled with Aluminum [18F]Fluoride.

The αvβ6-BP peptide selectively targets the integrin αvβ6, a cell surface receptor recognized as a prognostic indicator for several challenging malignancies. Given that the 4-[18F]fluorobenzoyl (FBA)-labeled peptide is a promising PET imaging agent, radiolabeling via aluminum [18F]fluoride chelation and introduction of an albumin binding moiety (ABM) have the potential to considerably simplify radiochemistry and improve the pharmacokinetics by increasing biological half-life. The peptides NOTA-αvβ6-BP (1) and NOTA-K(ABM)-αvβ6-BP (2) were synthesized on solid phase, radiolabeled with aluminum [18F]fluoride, and evaluated in vitro (integrin ELISA, albumin binding, cell studies) and in vivo in mouse models bearing paired DX3puroβ6 [αvβ6(+)]/DX3puro [αvβ6(-)], and for [18F]AlF 2, BxPC-3 [αvβ6(+)] cell xenografts (PET imaging, biodistribution). The peptides were radiolabeled in 23.0 ± 5.7% and 22.1 ± 4.4% decay-corrected radiochemical yield, respectively, for [18F]AlF 1 and [18F]AlF 2. Both demonstrated excellent affinity and selectivity for integrin αvβ6 by ELISA (IC50(αvβ6) = 3-7nM vs IC50(αvβ3) > 10μM) and in cell binding studies (51.0 ± 0.7% and 47.2 ± 0.7% of total radioactivity bound to DX3puroβ6 cells at 1h, respectively, vs. ≤ 1.2% to DX3puro for both compounds). The radiotracer [18F]AlF 1 bound to human serum at 16.3 ± 1.9%, compared to 67.5 ± 1.0% for the ABM-containing [18F]AlF 2. In vivo studies confirmed the effect of the ABM on blood circulation (≤ 0.1% ID/g remaining in blood for [18F]AlF 1 as soon as 1h p.i. vs. > 2% ID/g for [18F]AlF 2 at 6h p.i.) and higher αvβ6(+) tumor uptake (4h: DX3puroβ6; [18F]AlF 1: 3.0 ± 0.7% ID/g, [18F]AlF 2: 7.2 ± 0.7% ID/g; BxPC-3; [18F]AlF 2: 10.2 ± 0.1% ID/g). Both compounds were prepared using standard chemistries; affinity and selectivity for integrin αvβ6 in vitro remained unaffected by the albumin binding moiety. In vivo, the albumin binding moiety resulted in prolonged circulation and higher αvβ6-targeted uptake.

The dependence of natural radioactivity levels and its radiological hazards on the texture of agricultural soil in Upper Egypt

To control outdoor exposure to natural radiation, assessment of activity concentrations of the radionuclides in soils is substantial. In this paper, the activity concentration of natural radionuclides (226Ra, 232Th, 40K) was estimated for 174 agriculture soil samples using a sodium iodide detector (NaI) of (3” × 3”). Soil samples were collected from seven regions (56 locations) in EL-Minya governorate, Upper Egypt. The variability of natural activity concentration with soil’s textures was checked. The texture types of soil samples were silt clay loam, clay loam, sandy clay loam, and sandy silt loam. The obtained results indicate that the mean values of specific activity ranged from 11.3 ± 0.5 (sandy silt loam) to 21 ± 1(silt clay loam), 6.8 ± 0.3 (sandy silt loam) to 13.7 ± 0.7 (sandy clay loam), and 112 ± 5 (sandy silt loam) to 272 ± 13.6 (sandy clay loam) Bq kg−1 for 226Ra, 232Th, and 40 K, respectively. The obtained results were compared with the global average and tolerable limits as recommended in UNSCEAR 2008. On the other side, the radiological hazard resulting from the total natural radioactivity in the studied soil samples was estimated by different approaches. The obtained values were within the recommended safety limit and do not pose significant radiation hazards.

Tissue distribution of sprifermin (recombinant human fibroblast growth factor 18) in the rat following intravenous and intra-articular injection

Fibroblast growth factor 18 (FGF18) is involved in chondrogenesis and articular cartilage repair. We investigated tissue distribution and pharmacokinetics of radioactive [3H]sprifermin, a recombinant human FGF18, in rats after a single intravenous (i.v.) or intra-articular (i.a.) injection. In two studies (48-96-h [n=23] and 28-day [n=12]), 35 male albino (Sprague Dawley) rats received single i.v. or i.a. dose [3H]sprifermin (0.24mg/kg). Radioactivity was measured in blood, serum, and (in animals receiving i.a. administration) in the knee joint by liquid scintillation counting. Radioactivity in organs, tissues, and distribution in the whole body were measured with whole-body autoradiography. After i.v. injection, radioactivity peaked in serum and whole blood after 4 and 24h, respectively, with greater total radioactivity in serum. After i.a. injection, radioactivity peaked in serum and whole blood after 24 and 48h, respectively; intact [3H]sprifermin was not detected in vena caval serum and systemic exposure was low, approximately 20% of that with i.v. injection. Following i.v. injection, radioactivity was mainly found in the liver, adrenal glands, kidney, and spleen; following i.a. injection, radioactivity was preferentially concentrated in articular cartilage after initial distribution in the joint capsule, and still evident in the joint after 28 days. After i.a. injection of [3H]sprifermin in rats, radioactivity was concentrated in the knee joint, particularly articular cartilage, with low levels in other investigated tissues. Systemic exposure to sprifermin was greater with i.v. than i.a. injection. Subsequent clinical investigation in patients with osteoarthritis has reported consistent results.

Absorption, distribution, metabolism and excretion of molidustat in healthy participants.

The absorption, distribution, metabolism and excretion of molidustat were investigated in healthy male participants. In study 1, a mass balance study, radiolabelled molidustat 25 mg (3.57 MBq) was administered as an oral solution (n = 4). Following rapid absorption, molidustat‐related radioactivity was predominantly distributed in plasma rather than in red blood cells. The total recovery of the administered radioactivity was 97.0%, which was mainly excreted renally (90.7%). Metabolite M‐1, produced by N‐glucuronidation, was the dominant component in plasma (80.2% of the area under the concentration‐time curve for total radioactivity) and was primarily excreted via urine (~85% of dose). Only minor amounts of unchanged molidustat were excreted in urine (~4%) and faeces (~6%). Study 2 investigated the absolute bioavailability and pharmacodynamics of molidustat (part 1, n = 12; part 2, n = 16). Orally administered molidustat immediate release tablets had an absolute bioavailability of 59%. Following intravenous administration (1, 5 and 25 mg), total body clearance of molidustat was 28.7‐34.5 L/h and volume of distribution at steady state was 39.3‐50.0 L. All doses of molidustat transiently elevated endogenous erythropoietin levels, irrespective of the route of administration. Molidustat was considered safe and well tolerated at the administered doses.