Mass Balance and Metabolic Pathways of Eliapixant, a P2X3 Receptor Antagonist, in Healthy Male Volunteers.

BACKGROUND: Overactive adenosine triphosphate signaling via P2X3 homotrimeric receptors is implicated in multiple conditions. To fully understand the metabolism and elimination pathways of eliapixant, a study was conducted to assess the pharmacokinetics, mass balance, and routes of excretion of a single oral dose of the selective P2X3 receptor antagonist eliapixant, in addition to an in vitro characterization. METHODS: In this single-center open-label non-randomized non-placebo-controlled phase I study, healthy male subjects (n = 6) received a single dose of 50 mg eliapixant blended with 3.7 MBq [14C]eliapixant as a PEG 400-based oral solution. Total radioactivity and metabolites excreted in urine and feces, and pharmacokinetics of total radioactivity, eliapixant, and metabolites in plasma were assessed via liquid scintillation counting and high-performance liquid chromatography-based methods coupled to radiometric and mass spectrometric detection. Metabolite profiles of eliapixant in human in vitro systems and metabolizing enzymes were also investigated. RESULTS: After administration as an oral solution, eliapixant was rapidly absorbed, reaching maximum plasma concentrations within 2 h. Eliapixant was eliminated from plasma with a mean terminal half-life of 48.3 h. Unchanged eliapixant was the predominant component in plasma (72.6% of total radioactivity area under the curve). The remaining percentage of drug-related components in plasma probably represented the sum of many metabolites, detected in trace amounts. Mean recovery of total radioactivity was 97.9% of the administered dose (94.3-99.4%) within 14 days, with 86.3% (84.8-88.1%) excreted via feces and 11.6% (9.5-13.1%) via urine. Excretion of parent drug was minimal in feces (0.7% of dose) and urine (≈ 0.5%). In feces, metabolites formed by oxidation represented > 90% of excreted total radioactivity. The metabolites detected in the in vitro experiments were similar to those identified in vivo. CONCLUSION: Complete recovery of administered eliapixant-related radioactivity was observed in healthy male subjects with predominant excretion via feces. Eliapixant was almost exclusively cleared by oxidative biotransformation (> 90% of dose), with major involvement of cytochrome P450 3A4. Excretion of parent drug was of minor importance (~ 1% of dose). CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT04487431 (registered 27 July 2020)/EudraCT number: 2020-000519-54 (registered 3 February 2020), NCT02817100 (registered 26 June 2016), NCT03310645 (registered 16 October 2017).

Eliapixant is a drug that acts on structures in the body called P2X3 receptors that are involved in several conditions, including chronic cough, overactive bladder, and endometriosis-related pain. When evaluating a new drug, it is important to know how it is being removed from the body by natural mechanisms. We performed a study in which six healthy male volunteers took a single dose of eliapixant, and we investigated what happened to the drug after it was taken. We measured the amount of eliapixant in the volunteers' blood, urine, and feces, and also measured the compounds formed when eliapixant was broken down naturally by the body ("metabolites"). We also used human cells in the laboratory to investigate how the different metabolites of eliapixant are formed. Almost three-quarters of eliapixant in the blood had not been broken down at all, while the remaining one-quarter had been converted into many different metabolites. A total of 2 weeks after taking eliapixant, almost all of it had been converted to metabolites and eliminated from the body (mostly in feces, but also a small amount in urine). The most important organ for breaking down eliapixant is the liver. The information from this study will help doctors determine whether eliapixant is likely to interfere with other drugs taken simultaneously, and whether patients with liver or kidney problems might take longer than healthy people to remove it from their bodies.

Novel aldo-keto reductase 1C3 inhibitor affects androgen metabolism but not ovarian function in healthy women: a phase 1 study.

OBJECTIVE: Aldo-keto reductase 1C3 (AKR1C3) has been postulated to be involved in androgen, progesterone, and estrogen metabolism. Aldo-keto reductase 1C3 inhibition has been proposed for treatment of endometriosis and polycystic ovary syndrome. Clinical biomarkers of target engagement, which can greatly facilitate drug development, have not yet been described for AKR1C3 inhibitors. Here, we analyzed pharmacodynamic data from a phase 1 study with a new selective AKR1C3 inhibitor, BAY1128688, to identify response biomarkers and assess effects on ovarian function. DESIGN: In a multiple-ascending-dose placebo-controlled study, 33 postmenopausal women received BAY1128688 (3, 30, or 90 mg once daily or 60 mg twice daily) or placebo for 14 days. Eighteen premenopausal women received 60 mg BAY1128688 once or twice daily for 28 days. METHODS: We measured 17 serum steroids by liquid chromatography-tandem mass spectrometry, alongside analysis of pharmacokinetics, menstrual cyclicity, and safety parameters. RESULTS: In both study populations, we observed substantial, dose-dependent increases in circulating concentrations of the inactive androgen metabolite androsterone and minor increases in circulating etiocholanolone and dihydrotestosterone concentrations. In premenopausal women, androsterone concentrations increased 2.95-fold on average (95% confidence interval: 0.35-3.55) during once- or twice-daily treatment. Note, no concomitant changes in serum 17ß-estradiol and progesterone were observed, and menstrual cyclicity and ovarian function were not altered by the treatment. CONCLUSIONS: Serum androsterone was identified as a robust response biomarker for AKR1C3 inhibitor treatment in women. Aldo-keto reductase 1C3 inhibitor administration for 4 weeks did not affect ovarian function.ClinicalTrials.gov Identifier: NCT02434640; EudraCT Number: 2014-005298-36.

Pharmacokinetics of intravenous pan-class I phosphatidylinositol 3-kinase (PI3K) inhibitor [14C]copanlisib (BAY 80-6946) in a mass balance study in healthy male volunteers.

PURPOSE: To determine the pharmacokinetics of radiolabeled copanlisib (BAY 80-6946) in healthy male volunteers and to investigate the disposition and biotransformation of copanlisib. METHODS: A single dose of 12 mg copanlisib containing 2.76 MBq [14C]copanlisib was administered as a 1-h intravenous infusion to 6 volunteers with subsequent sampling up to 34 days. Blood, plasma, urine and feces were collected to monitor total radioactivity, parent compound and metabolites. RESULTS: Copanlisib treatment was well tolerated. Copanlisib was rapidly distributed throughout the body with a volume distribution of 1870 L and an elimination half-life of 52.1-h (range 40.4-67.5-h). Copanlisib was the predominant component in human plasma (84% of total radioactivity AUC) and the morpholinone metabolite M1 was the only circulating metabolite (about 5%). Excretion of drug-derived radioactivity based on all 6 subjects was 86% of the dose within a collection interval of 20-34 days with 64% excreted into feces as major route of elimination and 22% into urine. Unchanged copanlisib was the main component excreted into urine (15% of dose) and feces (30% of dose). Excreted metabolites (41% of dose) of copanlisib resulted from oxidative biotransformation. CONCLUSIONS: Copanlisib was eliminated predominantly in the feces compared to urine as well as by hepatic biotransformation, suggesting that the clearance of copanlisib would more likely be affected by hepatic impairment than by renal dysfunction. The dual mode of elimination via unchanged excretion of copanlisib and oxidative metabolism decreases the risk of clinically relevant PK-related drug-drug interactions.

From adults to children: simulation-based choice of an appropriate sparse-sampling schedule.

BACKGROUND: According to the International Conference on Harmonisation guideline E11, pharmacokinetic (PK) bridging studies can be applied to support pediatric drug development. However, for PK studies in infants and children the sampling schedule needs to be optimized to minimize the number of blood samples per individual. OBJECTIVE: The aim of this study was to describe how clinical trial simulations (CTS) based on adult data were used to select an appropriate sparse-sampling schedule for a future pediatric population PK (popPK) study. METHODS: A popPK model for gadobutrol (Gadovist®) was developed using data from a phase I study in adults. This model was used for CTS to select the most appropriate sparse-sampling schedule that met predefined acceptance criteria. This sampling schedule was applied in a pediatric clinical phase I/III study. Non-linear mixed-effects modeling was used for PK modeling and simulations. RESULTS: An appropriate sampling schedule requiring only three blood samples per patient was selected and successfully applied in a pediatric study with a gadobutrol standard dose of 0.1 mmol/kg bodyweight. A popPK analysis was performed to determine individual PK parameters in the pediatric study population. CONCLUSIONS: A priori evaluation of selected sampling schedules by simulation from adult data provides a useful tool for efficient planning of pediatric studies.

Population pharmacokinetics of the BEACOPP polychemotherapy regimen in Hodgkin's lymphoma and its effect on myelotoxicity.

BACKGROUND AND OBJECTIVE: The BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone) chemotherapy regimen for the treatment of advanced Hodgkin's lymphoma has a superior outcome, but its toxicity (mainly haematotoxicity) is pronounced and highly variable. The present study was conducted to address the role of pharmacokinetics in individual toxicity. STUDY DESIGN: Three plasma samples and a 24-hour urine collection for day 1 of the first three cycles of chemotherapy were analysed in 30 patients, and the pharmacokinetic parameters of the respective drugs were estimated by population pharmacokinetic methods (nonlinear mixed-effects model [NONMEM] software). Demographic data, doses and durations of infusion were also recorded. The effect of these parameters on platelet counts was estimated by analysis of covariance using a general linear model. RESULTS: The pharmacokinetic parameters and respective covariates were similar to the published data. The body surface area, peak concentrations of etoposide, urinary recovery of dechloroethylcyclophosphamide (formed by cytochrome P450 [CYP] 3A4) relative to the cyclophosphamide dose and number of cycles had a significant effect on toxicity. These factors explained 37% of the interindividual variability in the change in platelet counts from day 1 to day 8 of each cycle. CONCLUSION: The results show that the individual pharmacokinetics of BEACOPP drugs are an important link between dosage and toxicity. Accordingly, individualisation of treatment based on pharmacokinetics may result in more uniform toxicity. Individualisation may also allow escalation of the mean dose, which is probably related to better efficacy. As a consequence of the present study, infusion rates should be standardised, and the potential of a dose reduction in the first cycle and of CYP3A4 phenotyping should be addressed in clinical studies.

Effect of grapefruit juice intake on etoposide bioavailability.

PURPOSE: Oral administration of etoposide is limited by the high degree of unpredictable variation in systemic availability. This pilot study was conducted to evaluate the potential of pretreatment with grapefruit juice for improving the use of oral etoposide. METHODS: In a randomized crossover study, six patients were sequentially treated with 50 mg IV etoposide over 1 h, 50 mg orally, or 50 mg orally post grapefruit juice on day 1, day 4, and day 8. Blood samples were drawn up to 24 h after the end of infusion and oral drug administration. Plasma etoposide concentrations were determined by reversed-phase HPLC with UV detection. A two-compartment model was used for pharmacokinetic parameter estimation. Pharmacokinetic parameters were evaluated using descriptive statistics. RESULTS: Pretreatment with grapefruit juice resulted in an unexpected decrease of 26.2% in the AUC after oral treatment. Median absolute bioavailability with and without pretreatment with grapefruit juice was 52.4% and 73.2%, respectively. Interindividual variability was large in all treatment arms. CONCLUSION: Grapefruit juice seems to reduce rather than increase oral bioavailability of etoposide. Moreover, we did not observe a reduction in interpatient variability of bioavailability.