Quantitative intravitreal pharmacokinetics in mouse as a step towards inter-species translation.

Although mouse models are widely used in retinal drug development, pharmacokinetics in mouse eye is poorly understood. In this study, we applied non-invasive in vivo fluorophotometry to study pharmacokinetics of intravitreal fluorescein sodium (molecular weight 0.38 kDa) and fluorescein isothiocyanate-dextran (FD-150; molecular weight 150 kDa) in mice. Intravitreal half-lives of fluorescein and FD-150 in mouse eyes were 0.53 ± 0.06 h and 2.61 ± 0.86 h, respectively. These values are 8-230 times shorter than the elimination half-lives of similar compounds in the human vitreous. The apparent volumes of distribution in the mouse vitreous were close to the anatomical volume of the mouse vitreous (FD-150, 5.1 µl; fluorescein, 9.6 µl). Dose scaling factors were calculated from mouse to rat, rabbit, monkey and human translation. Based on pharmacokinetic modelling and compound concentrations in the vitreous and anterior chamber, fluorescein is mainly eliminated posteriorly across blood-retina barrier, but FD-150 is cleared via aqueous humour outflow. The results of this study improve the knowledge of intravitreal pharmacokinetics in mouse and facilitate inter-species scaling in ocular drug development.

Kinetics of Excretion of the Perfluoroalkyl Surfactant cC6O4 in Humans.

cC6O4 is a new-generation perfluoroalkyl surfactant used in the chemical industry for the synthesis of perfluoroalkyl polymers. It was introduced as a less biopersistent substitute of traditional perfluoroalkyl surfactants such as PFOA, but its kinetics in humans was never investigated. This work is aimed to investigate the kinetics of elimination of cC6O4 in exposed workers. Eighteen male individuals occupationally exposed to cC6O4 in the production of fluoropolymers volunteered for the study. Blood and urine samples were collected from the end of a work-shift for the following 5 days off work. Serum and urinary cC6O4 were measured by LC-MS/MS. Seventy-two samples with serum cC6O4 ranging from 0.38 to 11.29 µg/L were obtained; mean levels were 3.07, 2.82, 2.67 and 2.01 µg/L at times 0, 18, 42 and 114 h. Two hundred and fifty-four urine samples with cC6O4 ranging from 0.19 to 5.92 µg/L were obtained. A random-intercept multiple regression model was applied to serum data and a half-life of 184 (95% CI 162-213) h for a first-order kinetics elimination was calculated; a mean distribution volume of 80 mL/kg was also estimated. Pearson's correlation between ln-transformed serum and daily urine concentrations was good, with r ranging from 0.802 to 0.838. The amount of cC6O4 excreted daily in urine was about 20% of the amount present in serum. The study allowed calculating a half-life for cC6O4 in blood of about 8 days in humans, supporting its much shorter biopersistence in comparison with legacy PFAS. The good correlation between urine and serum cC6O4 suggests urine as a possible non-invasive matrix for biomonitoring. The amount of cC6O4 excreted daily in urine suggests urine as the sole elimination route.

Elucidating the fate of perfluorooctanoate sulfonate using a rainbow trout (Oncorhynchus mykiss) physiologically-based toxicokinetic model.

Per- and poly-fluorinated substances (PFAS) are widely found in freshwater ecosystems because of their resistance to degradation. Among them, several long-chain perfluoroalkyl acids bioaccumulate in aquatic vertebrates, but our understanding of the mechanisms of absorption, distribution and elimination is still limited in fish. For this purpose, we developed a 10-compartment physiologically-based toxicokinetic (PBTK) model to elucidate perfluorooctane sulfonate (PFOS) kinetics in adult rainbow trout. This PBTK model included various physiological characteristics: blood perfusion to each organ, plasmatic fraction, PFOS free fraction, and growth of individuals. The parameters were optimized using Bayesian inferences. First, only PFOS absorption by diet was considered in the model as well as its elimination by urine, bile and feces. Then two mechanistic hypotheses, assumed to govern PFOS toxicokinetics in fish, namely the enterohepatic cycle and the absorption and elimination though gills, were tested. Improvement of the model's fit to the data was studied in each organ by comparing predictions with observed data using relative error. The experimental data set was obtained from an exposure experiment, where adult rainbow trout were fed with a PFOS-spiked diet for 42 days, followed by a 35-day depuration period. In all cases, PFOS concentrations were accurately predicted in organs and feces by the model. The results of this PBTK model demonstrated that feces represented the major elimination route for PFOS while urine was a minor route. Also, PFOS branchial uptake can be substantial despite low concentrations of the compound in water, and elimination through gills should not be neglected. Finally, the enterohepatic cycle is likely to play a minor role in PFOS toxicokinetics. Overall, this PBTK model accurately described PFOS distribution in rainbow trout and provides information on the relative contribution of absorption and elimination pathways.

Pimasertib, a selective oral MEK1/2 inhibitor: absolute bioavailability, mass balance, elimination route, and metabolite profile in cancer patients.

AIM: This trial (NCT: 01713036) investigated the absolute bioavailability, mass balance and metabolite profile of pimasertib in a new design combining these investigations in a single group of patients. METHODS: Six male patients with pathologically confirmed, locally advanced or metastatic solid tumours were enrolled. Exclusion criteria included Eastern Cooperative Oncology Group performance status >1. In Part A of the trial, patients received a 60 mg oral dose of unlabelled pimasertib followed by an intravenous (i.v.) tracer dose of [14 C]pimasertib 2 µg (equalling 9 kBq) as a bolus injection, one hour after the oral dose, on Day 1. On Day 8, all patients received 60 mg pimasertib capsules spiked with 2.6 MBq of [14 C]pimasertib. Patients received 60 mg oral unlabelled pimasertib twice daily from Day 3 to Day 21 of Part A and in subsequent 21-day cycles in Part B. RESULTS: Following i.v. administration, [14 C]pimasertib exhibited a geometric mean total body clearance of 45.7 l h-1 (geometric coefficient of variation [geometric CV]: 47.2%) and a volume of distribution of 229 l (geometric CV: 42.0%). Absolute bioavailability was 73%. The majority of the oral [14 C] dose (85.1%) was recovered in excreta. Total radioactivity was mainly excreted into urine (52.8%) and faeces (30.7%) with 78.9% of the [14 C] dose recovered as metabolites. Two major circulating metabolites were identified in plasma: a carboxylic acid (M445) and a phosphoethanolamine conjugate (M554). The safety profile was in line with the published pimasertib trials. CONCLUSION: Pimasertib showed a favourable pharmacokinetic profile with high absolute bioavailability and a unique metabolic pathway (conjugation with phosphoethanolamine).