Minor Elimination Research Articles

Metabolism and Excretion of [14C]Mobocertinib, a Selective Covalent Inhibitor of Epidermal Growth Factor Receptor (EGFR) Exon 20 Insertion Mutations, in Healthy Male Subjects.

Mobocertinib (formerly known as TAK-788) is a targeted covalent tyrosine kinase inhibitor of epidermal growth factor receptor with exon 20 insertion mutations. This article describes the metabolism and excretion of mobocertinib in healthy male subjects after a single oral administration of [14C]mobocertinib. Mobocertinib-related materials were highly covalently bound to plasma proteins such as human serum albumin. The mean extraction recovery of total radioactivity was only 3.9% for six individual Hamilton pooled plasma samples. After extraction, mobocertinib was the most abundant component accounting for 7.7% of total extracted circulating radioactivity (TECRA) in the supernatant. Each of identified metabolites accounted for <10% of TECRA. Mobocertinib underwent extensive first-pass metabolism with the fraction of the dose absorbed estimated to be approximately 91.7%. Fecal excretion of mobocertinib metabolites was the major elimination route. Mobocertinib was mainly eliminated via oxidative metabolism with a fraction of approximately 88% metabolized by CYP3A4/5. The other minor elimination pathways included cysteine conjugation, metabolism by other cytochrome P450s, and renal excretion of unchanged mobocertinib. SIGNIFICANCE STATEMENT: This article describes the metabolism and excretion of a targeted covalent inhibitor mobocertinib in humans after a single oral administration of [14C]mobocertinib. Mobocertinib was highly covalently bound to human plasma proteins. No metabolite accounted for >10% of total extracted circulating radioactivity in human plasma. Mobocertinib was mainly eliminated via CYP3A4/5 mediated oxidative metabolism followed by fecal excretion after approximately 91.7% of the dose was absorbed.

Leveraging the mechanism of action (MOA) of xevinapant, an IAP inhibitor, for phase 3 dosing (RP3D) strategies in combination with radiation (RT) and chemoradiotherapy (CRT) in patients with locally advanced squamous cell carcinoma of the head and neck (LA SCCHN).

e18001 Background: Xevinapant is a first-in-class, oral IAP (inhibitor of apoptosis protein) inhibitor designed to restore cancer cell sensitivity to apoptosis, thereby enhancing the efficacy of RT and CRT. Xevinapant 200 mg/d (d1-14, Q3W) + CRT showed clinical benefit vs placebo + CRT in a phase (ph) 2 study of patients (pts) with LA SCCHN (NCT02022098). Exposure-response (E-R) relationships for efficacy and the composite safety endpoint of “mucositis and/or dysphagia” (AE_MD, a known RT-associated toxicity) were also identified. Two ph 3 studies of 200 mg/d xevinapant (d1-14, Q3W) + RT (XRay Vision; NCT05386550) or CRT (TrilynX; NCT04459715) followed by xevinapant monotherapy (MT) in pts with LA SCCHN are ongoing. We leverage the MOA of xevinapant to confirm RP3D strategy. Methods: Results from clinical and preclinical studies and quantitative pharmacology modeling were integrated. Results: Updated analyses of NCT02022098 data show an association between complete response (CR) and AE_MD in both treatment arms; AE_MD was the only AE with identified E-R relationship out of 13 AEs tested. In the xevinapant arm, the CR+AE_MD+ group had the highest median AUC but it overlapped with other groups (CR-AE_MD+, CR+AE_MD-, CR-AE_MD-) which all had similar AUCs. These data suggest that AE_MD is related to the RT-enhancing MOA of xevinapant and that decoupling efficacy from AE_MD incidence by exposure modulation is not feasible. Intermittent dosing for xevinapant was designed for recovery from epithelial toxicities considering the turnover of mucosal cells. In a human breast cancer mouse model, cIAP1 degradation with the intermittent regimen (100 mg/kg Q3D) at the end of the dosing interval was ~50% compared with the continuous one (30 mg/kg QD) expected to maintain maximal (max) cIAP1 degradation, but showed similar efficacy. This suggests continuous max cIAP1 degradation may not be required for efficacy, consistent with RT-enhancing MOA. Based on population PKPD modeling, at the RP3D for xevinapant max cIAP1 degradation was achieved during the dosing period; 91% of pts had at least 50% suppression at the end of the cycle. Xevinapant MT cycles are supported by enhanced anti-tumor activity with extended MT dosing following xevinapant/ RT cycles in MC38 syngeneic mouse model. Food-agnostic dosing is supported by similar AUCs observed in fed and fasted conditions. A human ADME study showed that urinary excretion is a minor elimination pathway, supporting no dose adjustment for pts with moderate renal impairment. Conclusions: Integrated assessment of all available clinical and nonclinical data supports the proposed RP3D strategy for xevinapant combined with RT or CRT, selected to maximize efficacy while minimizing potential adverse events and cumulative toxicity. Clinical trial information: NCT02022098 .

AZD5634, an inhaled ENaC inhibitor, in healthy subjects and patients with cystic fibrosis

BackgroundEpithelial sodium channel (ENaC) inhibitors may offer clinical benefit in cystic fibrosis (CF); however, data are limited. We report the outcomes of a Phase I (NCT02679729) and a Phase Ib (NCT02950805) study of AZD5634, a novel inhaled ENaC inhibitor. MethodsA Phase I, first-in-human, single-blind, placebo-controlled, single ascending dose, sequential dose group study assessed the safety, tolerability, and pharmacokinetics of AZD5634 in healthy subjects (n=53) in part A following inhaled doses up to 1700 µg, and, in part B, following administration of single inhaled (1700 µg) and intravenous (65 µg) doses. A Phase Ib, randomized, double-blind, placebo-controlled, single-dose, 2-way cross-over study assessed the effects of a single dose (600 µg) of inhaled AZD5634 on mucociliary clearance (MCC), pharmacokinetics and safety and tolerability in patients with CF (n=11). Nasal potential difference (NPD) was assessed as an in situ target engagement exploratory biomarker. ResultsAbsolute bioavailability of AZD5634 after inhalation was approximately 3%, indicating minimal distribution into the systemic circulation. Urinary excretion was a minor elimination pathway. Administration of inhaled AZD5634 did not improve MCC in CF patients, but AZD5634 inhibited ENaC in the nasal epithelium, as measured by NPD. AZD5634 was safe and well tolerated in both studies. ConclusionsAZD5634 showed favorable pharmacokinetics and safety in healthy subjects and patients with CF. However, despite achieving target engagement, proof of mechanism was not achieved after a single dose in patients with CF. Further evaluation into multiple dose studies is warranted to explore its therapeutic potential.

Combating antimicrobial resistance with cefiderocol for complicated infections involving the urinary tract.

Cefiderocol is a unique siderophore cephalosporin antimicrobial agent that has shown promise in treating complicated urinary tract infections (cUTI). Urinary tract infections are commonly diagnosed infections with risk increasing with age and prevalence more common in women. cUTI poses a risk of recurrence and is more likely to be associated with antibiotic-resistant bacteria. The Food and Drug Administration approved cefiderocol for use as a last-line option in the treatment of cUTI including pyelonephritis. Cefiderocol has activity against all forms of carbapenemases due to its ability to overcome the mechanisms of carbapenemase resistance. Because of this, resistance to cefiderocol is unlikely to occur. Studies show cefiderocol is well tolerated among younger patients and patients greater than 65 years of age, the latter making up most of the study population. Renal dose adjustments are recommended. Dose adjustment in the presence of hepatic impairment is not recommended, as hepatic clearance represents a minor elimination pathway for cefiderocol. The ability of cefiderocol to overcome multiple resistance mechanisms makes it a novel choice in combating multidrug-resistant bacteria in the treatment of cUTI.

Effectiveness of Minor Overhaul Elimination on Decreasing Cost of Production in Hydroelectric Power Plant

The projection of the renewable energy target in 2025 is 23%. The high production cost makes it difficult to compete with fossil plants. The strategy chosen to reduce the risk is to eliminate minor overhauls in power plants to increase production. To prove its effectiveness, hydropower was chosen by using markov chain method. It took samples for 26 months and divided plant into 3 states based on the operating performance. The test was between implementation of overhauls on schedule and eliminating minor overhauls when the status was good. The results of data processing obtained that the best decision is not to do minor overhaul elimination because of the potential to reduce 29.77% good conditions, 30.69% improvement in moderate conditions. Comparison between the 2017-2019 data show there’s no production cost reduction even though potential production increase. Calculation can be implemented into a web form using the PHP on the Laravel Framework

DPP-4 Inhibitors: Renoprotective Potential and Pharmacokinetics in Type 2 Diabetes Mellitus Patients with Renal Impairment.

The continuously increasing incidence of diabetes worldwide has attracted the attention of the scientific community and driven the development of a novel class of antidiabetic drugs that can be safely and effectively used in diabetic patients. Of particular interest in this context are complications associated with diabetes, such as renal impairment, which is the main cause of high cardiovascular morbidity and mortality in diabetic patients. Intensive control of glucose levels and other risk factors associated with diabetes and metabolic syndrome provides the foundations for both preventing and treating diabetic nephropathy. Dipeptidyl peptidase-4 (DPP-4) inhibitors represent a highly promising novel class of oral agents used in the treatment of type 2 diabetes mellitus that may be successfully combined with currently available antidiabetic therapeutics in order to achieve blood glucose goals. Beyond glycemic control, emerging evidence suggests that DPP-4 inhibitors may have desirable off-target effects, including renoprotection. All type 2 diabetes mellitus patients with impaired renal function require dose adjustment of any DPP-4 inhibitor administered except for linagliptin, for which renal excretion is a minor elimination pathway. Thus, linagliptin is the drug most frequently chosen to treat type 2 diabetes mellitus patients with renal failure.

Dose calculation of radioactive nanoparticles: first considerations for the Design of Theranostic Agents.

The use of radioactive nanoparticles as imaging and therapeutic agents is increasing globally. Indeed, the use of these nanoparticles as perfect theranostic agent is highly anticipated in the pharmaceutical market. Among the radioactive nanoparticles, liposomes, solid lipid nanoparticles and polymeric nanoparticles are the most studied. However little information among adverse reactions, absorbed dose and correct dose to achieve the theranostic goal in a translational application is available. We developed a radioactive polymeric nanoparticle and calculated the absorbed dose in animal model (Wistar rats) using the OLINDA/EXM program. The results showed that some nanoparticle were uptake in five organs and minor elimination through the gastrointestinal and urinary pathways. The data corroborates the safe use in terms of blood-brain barrier and did not show high uptake by liver. The dosimetry data support the safe use of radioactive nanoparticles as theranostic agent. Graphical abstract ᅟ.

Read-across of 90-day rat oral repeated-dose toxicity: A case study for selected n-alkanols

n-Alkanols provide an excellent example where a category-approach to read-across may be used to estimate the repeated-dose endpoint for a number of untested derivatives (target chemicals) using experimental data for tested derivatives (source chemicals). n-Alkanols are non-reactive and exhibit the unspecific, reversible simple anaesthesia or non-polar narcosis mode of toxic action in that the metabolic products of the parent alcohols do not contribute to the toxic endpoint evaluated. In this case study, the chemical category is limited to the readily bioavailable (C5–C13) analogues. The toxicokinetic premise includes rapid absorption via the gastrointestinal tract, distribution in the circulatory system, and first-pass metabolism in the liver resulting in metabolism via oxidation to CO2 and with minor elimination of oxidative intermediate as glucuronides. Two analogues have experimental 90-day oral repeated-dose toxicity data which exhibit qualitative and quantitative consistency. Typical findings include decreased body weight, slightly increased liver weight which, in some cases, is accompanied by clinical chemical and haematological changes but generally without concurrent histopathological effects at the Lowest Observed Effect Level (LOEL). Chemical similarity between the analogues is readily defined by a variety of structure-related properties; data uncertainty associated with toxicokinetic and toxicodynamic similarities is low. Uncertainty associated with mechanistic relevance and completeness of the read-across is reduced by the concordance of in vivo and in vitro results, as well as high throughput and in silico methods data. As shown in detail, the 90-day oral repeated-dose toxicity No Observed Effect Level (NOEL) value of 1000mg/kgbw/d for 1-pentanol and 1-hexanol based on a LOEL of very low systemic toxicity can be read across to fill the data gaps of the untested analogues in this category with acceptable uncertainty.

Multidimensional Reaction Dynamics Reveal How the Enzyme TcTS Suppresses Competing Side Reactions and Their Side Products

The suppression of competing reactions that lead to side products is one of the key mechanistic actions defining enzyme catalysis. The transfer of sialic acid (SA) in a water solution is susceptible to two competing side reactions, but a single product is the outcome in the glycosylation and deglycosylation steps of the trans-sialidase (TS) in the Trypanosoma cruzi (T. cruzi) parasite, generally known as TcTS. We use multidimensional QM/MM free energy computations to reveal a competition between a minor elimination reaction and the dominant displacement reaction present in both steps. The simultaneous monitoring of the progression of the competing reactions reveals lower barriers in the free energy profiles, a greater sampling of favorable reactant stereoelectronic alignments, and a greater number of possible transition paths leading to successful crossing reaction trajectories for the dominant displacement reactions in comparison with those of the elimination reactions.

Preclinical Pharmacokinetics Study of R- and S-Enantiomers of the Histone Deacetylase Inhibitor, AR-42 (NSC 731438), in Rodents.

AR-42, a new orally bioavailable, potent, hydroxamate-tethered phenylbutyrate class I/IIB histone deacetylase inhibitor currently is under evaluation in phase 1 and 2 clinical trials and has demonstrated activity in both hematologic and solid tumor malignancies. This report focuses on the preclinical characterization of the pharmacokinetics of AR-42 in mice and rats. A high-performance liquid chromatography-tandem mass spectrometry assay has been developed and applied to the pharmacokinetic study of the more active stereoisomer, S-AR-42, when administered via intravenous and oral routes in rodents, including plasma, bone marrow, and spleen pharmacokinetics (PK) in CD2F1 mice and plasma PK in F344 rats. Oral bioavailability was estimated to be 26 and 100% in mice and rats, respectively. R-AR-42 was also evaluated intravenously in rats and was shown to display different pharmacokinetics with a much shorter terminal half-life compared to that of S-AR-42. Renal clearance was a minor elimination pathway for parental S-AR-42. Oral administration of S-AR-42 to tumor-bearing mice demonstrated high uptake and exposure of the parent drug in the lymphoid tissues, spleen, and bone marrow. This is the first report of the pharmacokinetics of this novel agent, which is now in early phase clinical trials.

Comment on: “Enzalutamide: A Step Towards Pharmacokinetic-Based Dosing in Men with Metastatic Castration-Resistant Prostate Cancer”

Dear Editors, We thank Dr. Paul Hutson for his thorough commentary [1] on our recent article entitled ‘Enzalutamide: a step towards pharmacokinetic-based dosing in men with metastatic castration-resistant prostate cancer’ [2]. We would like to provide an important correction to Dr. Hutson’s commentary, regarding the following statements: Gibbons et al. do not report the renal clearance or the effect of renal failure on the clearance of enzalutamide or its active N-desmethyl metabolite, and to date no other reports of enzalutamide renal clearance are available to guide dosing. The mass-balance studies in the present study demonstrate that approximately 60 % of the dose was recovered in the urine, suggesting that dosing of the drug may need to be reduced in patients with kidney dysfunction. While not emphasized, the article does describe renal clearance on page 1050 (paragraph 2): The major route of excretion of 14C-radioactivity was urine (71.0 % of dose), primarily as metabolites. The remainder of the radioactivity was excreted in feces (13.6 % of dose). Based on LC–MS/MS analysis, the main component in urine was the carboxylic acid metabolite, which accounted for 62.7 % of the dose. A trace amount of unchanged parent enzalutamide was excreted in urine. N-Desmethyl enzalutamide was too low to quantitate in urine by LC–MS/MS. Based on this information, renal excretion is a minor elimination pathway for unchanged parent enzalutamide and N-desmethyl enzalutamide. As indicated in this excerpt, 62.7 % of the dose was recovered in urine as the inactive carboxylic acid metabolite, and the remainder was additional minor metabolites; enzalutamide and N-desmethyl enzalutamide (active metabolite) were present in urine at only trace amounts. These data indicate that renal excretion is a minor elimination pathway for unchanged parent enzalutamide and N-desmethyl enzalutamide. Further details are captured in the US prescribing information for XTANDI® (enzalutamide) capsules (product label), which states the following: A dedicated renal impairment trial for XTANDI has not been conducted. Based on the population pharmacokinetic analysis using data from clinical trials in patients with metastatic CRPC and healthy volunteers, no significant difference in enzalutamide clearance was observed in patients with pre-existing mild to moderate renal impairment [30 mL/min ≤ creatinine clearance (CrCL) ≤ 89 mL/min] compared to patients and volunteers with baseline normal renal function (CrCL ≥90 mL/min). No initial dosage adjustment is necessary for patients with mild to moderate renal impairment. Severe renal impairment (CrCL <30 mL/min) and end-stage renal disease have not been assessed [see Clinical Pharmacology (12.3)]. In summary, data presented in our original research article [2], as well as results in the XTANDI® product label, indicate that starting dose reductions are not required in patients with mild to moderate renal impairment. There are no data to assess the effects of severe renal impairment (CrCL <30 mL/min). As Dr. Hutson’s commentary misstates dosing recommendations for XTANDI®, we request that you kindly publish a supplementary response to Dr. Hutson’s commentary in Clinical Pharmacokinetics.

Ageing and thermal stability studies on quasi-solid composite electrolytes for Grätzel-type solar cells

Loss of volatile components from two types of quasi-solid gel electrolytes to be used in Gratzel (or dye-sensitized, DSSC)-type alternative solar cells are checked time to time by thermogravimetry (TG) to follow the stability or changes of composites during storage at ambient. One of the gel samples, labeled as P2000 and based on UreaSil 2000, a 3D-cage precursor compound, has been found quite stable, while the related P230 sample based on UreaSil 230 seems to have a bit higher deviation in heterogeneity and some tendencies losing gradually from its volatile content, time to time. In addition, two online coupled evolved gas analytical tools (TG–EGA–FTIR and TG/DTA–EGA–MS) are applied to check the gel electrolytes for thermal vaporization, degradation, and decomposition processes as a function of temperature during dynamic heating in air. Initial minor elimination of ethyl acetate has been detected by both in situ coupled mass spectroscopy and FTIR spectroscopic gas cell. According to both evolved gas analytical systems, the other liquid ingredients, acetic acid (AcOH) and sulfolane are also released in the order of their volatility. Above 300 °C, an oxidative thermal degradation of UreaSil-type host matrices is indicated by the occurrence of, among others, formaldehyde or ammonia for electrolyte samples P2000 and P230, respectively. Evolution of various alkyl iodides with short chain length has only been detected by the mass spectroscopic evolved gas analysis method only.

Metabolism and Disposition of Betrixaban and Its Lack of Interaction with Major CYP Enzymes.

Abstract 2266Betrixaban is a once daily oral Factor Xa inhibitor being investigated in a Phase 3 clinical trial to prevent venous thromboembolism in acute medically ill patients (APEX Study). Mass balance, metabolite profile and interaction with major CYP enzymes were evaluated in this study.Portola study 06–005 was an open-label, single-dose, mass-balance and metabolic profiling study using 14C-labeled betrixaban in 5 healthy male volunteers. Each subject received a single oral solution containing 40 mg of betrixaban labeled with 100 μCi of 14C. Blood samples were taken serially over a 168-hour interval. Urine samples and fecal samples were collected during the 7–14 day confinement period. Subjects were discharged from the unit when at least one of the following criteria were met: 90% of the radioactivity was recovered in urine and feces, daily excreted radioactivity was 1% or less of administered dose on two consecutive days, or subject reached 336 hours (14 days) post dose. The plasma concentration equivalents of total radioactivity increased rapidly following dosing with a mean peak of 31.69 ng eq/mL occurring at 3.5 hours post-dose. AUC and half-life could not be calculated as radioactivity in plasma could only be detected up to 6 hours post dose. Terminal elimination half life determined in other clinical pharmacology studies was 37 hours. Total radioactivity recovered from urine and feces was approximately 96% (range 92% to 99%), with the majority of 14C recovery in feces (82% to 89% of the dose). The 14C dose recovered in urine, composed of betrixaban and inactive metabolites, ranged from 6% to 13%.The metabolic profile of betrixaban was determined in plasma, urine and feces. Unchanged betrixaban was the predominant component found in human plasma and excreta, accounting for 85.3% of the dose excreted in urine and feces. The major biotransformation pathway for betrixaban was hydrolysis to form PRT062802 and PRT062803, a non-14C labeled metabolite (Figure 1). PRT062803 can be demethylated to form PRT062799 or hydroxylated to form PRT062982. PRT062982 is further conjugated with sulfate to form PRT063069. Both PRT062802 and PRT063069 were major circulating metabolites in human plasma with AUC of 34% and 24% that of betrixaban, respectively. PRT062802 was the only prominent metabolite detected in human urine and feces. In addition to hydrolysis metabolites, two CYP-mediated metabolites, O-desmethyl betrixaban (PRT058326) and N-desmethyl betrixaban (PRT054156), were observed in plasma at trace levels (AUC of each was <1% that of betrixaban). Trace levels of PRT058326 was also observed in urine and feces. Both PRT062802 and PRT063069 were inactive (IC50 for fXa inhibition >10 μM). PRT058326 and PRT054156 have an IC50 for fXa inhibition of approximately 5 nM compared to betrixaban Ki of 0.117 pM.Interaction of betrixaban with CYP enzymes was studied in vitro. CYP inhibition potential was evaluated in human liver microsomes with or without 30 minute pre-incubation of betrixaban. Selective probe substrates were used to monitor CYP activities, i.e. phenacetin for 1A2, tolbutamide for 2C9, S-mephenytoin for 2C19, dextromethorphan for 2D6, and testosterone and midazolam for 3A4. Betrixaban had IC50 > 80 μM for CYP1A2, 2C9, 2D6 and 3A4 for both competitive and time-dependent inhibition. IC50 for 2C19 were 43 and 88 μM for competitive and time-dependent inhibition, respectively. The CYP inhibition IC50’s are much higher than the betrixaban therapeutic concentration of 50 nM.CYP induction by betrixaban was also studied using cryopreserved human hepatocytes (n=3). Betrixaban at 1, 10 and 25 μM were incubated in hepatocyte preparation for 48 hours. The activities for CYP1A2, CYP2C9, CYP2C19, and CYP3A4 were determined by measuring the formation of metabolites of the probe substrates similar to those used in the CYP inhibition study. CYP2C19 activities were not quantifiable in all three donors; therefore, induction for this CYP isoform could not be assessed. Betrixaban did not induce the activities of CYP1A2, CYP2C9, and CYP3A4.These results demonstrated that betrixaban was mainly excreted as the unchanged drug most likely via biliary secretion. Renal excretion and metabolism were minor elimination pathways. Betrixaban is unlikely to have drug-drug interactions with CYP-substrate, inducer, or inhibitor drugs. [Display omitted] Disclosures:Hutchaleelaha:Portola pharmaceuticals: Employment. Ye:Portola Pharmaceuticals: Employment. Song:Portola Pharmaceuticals: Employment. Lorenz:Portola Pharmaceuticals: Employment. Gretler:Portola Pharmaceuticals: Equity Ownership. Lambing:Portola Pharmaceuticals: Employment.

Absorption, Metabolism, and Excretion of Quizartinib (AC220), a FLT3 Tyrosine Kinase Inhibitor for Treatment of Acute Myeloid Leukemia, in Healthy Male Volunteers

AbstractAbstract 4327Quizartinib (AC220) is an oral tyrosine kinase inhibitor that has shown promising activity in refractory/relapsed acute myeloid leukemia patients in a Phase 1 and a Phase 2 study. The absorption, metabolism, and excretion of quizartinib were characterized in healthy volunteers in a Phase 1 mass balance study. Six healthy males (mean ± SD age 29 ± 8.4 years) received a single oral dose of 60 mg quizartinib as a solution; approximately 1.6% of the total dose was labeled with 14C (approximately 100 μCi). Blood, plasma, urine, and feces were collected for 14 days (336 h) after dosing.Maximum mean ± SD blood radioactivity concentrations, reached 4 h after dosing, were 296 ± 67.4 ng equivalents/g. Maximum blood radioactivity concentrations in individual subjects occurred 4 h after dosing and ranged from 228 to 397 ng equivalents/g.Excretion of radioactivity was relatively consistent throughout the study. The maximum mean ± SD urinary concentration of radioactivity was 112 ± 52.3 ng equivalents/g at 8 to 24 hours after dosing, and the maximum mean ± SD fecal concentration of radioactivity was 51,100 ± 21,300 ng equivalents/g at 24 to 48 h after dosing. A mean ± SD of 1.64 ± 0.482% of the dose was recovered in urine, and 76.3 ± 6.23% was recovered in feces. The overall mean ± SD recovery of radioactivity in urine and feces was 78.0 ± 6.24% over the course of the study, with recovery from individual subjects ranging from 72.4% to 88.3%. Excretion of radioactivity was still ongoing at study completion (336 h). Recovery of <90% was not unexpected given the long half-life (approximately 3.5 days) of quizartinib.The major radiolabeled components of plasma were unchanged quizartinib and the oxidative metabolite AC886. Five additional metabolites in plasma were identified by LC-MS but could not be identified by measurement of radioactivity, because of low levels. Eighteen radioactive peaks in urine were detected, representing less than 0.09% of the administered dose, but their putative structures could not be identified because of low levels.Quizartinib was extensively metabolized, with the metabolites excreted primarily in feces, suggesting hepatobiliary excretion of radioactivity, non-biliary excretion into the gastrointestinal tract, or metabolism within the gastrointestinal tract. Forty-two radioactive peaks were detected in fecal extracts, of which unchanged quizartinib was a significant radioactive component (mean of 4.0% of the administered radioactive dose), and 15 metabolites, each representing a mean of 1.0% to 3.5% of the administered radioactive dose, were identified.Quizartinib was predominantly metabolized by phase I biotransformations, as was evident by the absence of any conjugates of quizartinib or of oxidative metabolites under the analytical conditions used to profile plasma, urine, and feces. Quizartinib was metabolized by multiple biotransformation pathways, including oxidation, reduction, dealkylation, deamination, and hydrolysis, and by combinations of these pathways.Quizartinib was well tolerated as a single 60 mg dose in this study. There were no clinically significant changes in vital signs, ECGs, or laboratory test results. Two subjects experienced adverse events. Grade 1 dry skin in 1 subject was considered to be unrelated to study treatment, and Grade 1 diarrhea in 1 subject was considered to be possibly related to treatment.The results of this study indicated that, in humans, quizartinib was orally available and predominantly eliminated in feces, with renal clearance as a minor elimination route, and that AC886 was the only major metabolite in the circulation. Disclosures:Li:Ambit Biosciences: Employment. Bresnahan:Ambit Biosciences: Employment. Gammon:Ambit Biosciences: Employment. Sanga:Covance Laboratories, Inc.: Employment. Hale:Covance, Inc.: Employment. Hashimoto:Astellas Pharma, Inc.: Employment. Gill:Astellas Pharma, Inc.: Employment. James:Ambit Biosciences: Employment.

Deletion ofAbcg2Has Differential Effects on Excretion and Pharmacokinetics of Probe Substrates in Rats

This study was designed to characterize breast cancer resistance protein (Bcrp) knockout Abcg2(-/-) rats and assess the effect of ATP-binding cassette subfamily G member 2 (Abcg2) deletion on the excretion and pharmacokinetic properties of probe substrates. Deletion of the target gene in the Abcg2(-/-) rats was confirmed, whereas gene expression was unaffected for most of the other transporters and metabolizing enzymes. Biliary excretion of nitrofurantoin, sulfasalazine, and compound A [2-(5-methoxy-2-((2-methyl-1,3-benzothiazol-6-yl)amino)-4-pyridinyl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one] accounted for 1.5, 48, and 48% of the dose in the Abcg2(+/+) rats, respectively, whereas it was decreased by 70 to 90% in the Abcg2(-/-) rats. Urinary excretion of nitrofurantoin, a significant elimination pathway, was unaffected in the Abcg2(-/-) rats, whereas renal clearance of sulfasalazine, a minor elimination pathway, was reduced by >90%. Urinary excretion of compound A was minimal. Systemic clearance in the Abcg2(-/-) rats decreased 22, 43 (p<0.05), and 57%, respectively, for nitrofurantoin, sulfasalazine, and compound A administered at 1 mg/kg and 27% for compound A administered at 5 mg/kg. Oral absorption of nitrofurantoin, a compound with high aqueous solubility and good permeability, was not limited by Bcrp. In contrast, the absence of Bcrp led to a 33- and 11-fold increase in oral exposure of sulfasalazine and compound A, respectively. These data show that Bcrp plays a crucial role in biliary excretion of these probe substrates and has differential effects on systemic clearance and oral absorption in rats depending on clearance mechanisms and compound properties. The Abcg2(-/-) rat is a useful model for understanding the role of Bcrp in elimination and oral absorption.

Apixaban Metabolism and Pharmacokinetics after Oral Administration to Humans

The metabolism and disposition of [(14)C]apixaban, an orally bioavailable, highly selective, and direct acting/reversible factor Xa inhibitor, was investigated in 10 healthy male subjects without (group 1, n=6) and with bile collection (group 2, n=4) after a single 20-mg oral dose. Urine, blood, and feces samples were collected from all subjects. Bile samples were also collected for 3 to 8 h after dosing from group 2 subjects. There were no serious adverse events or discontinuations due to adverse effects. In plasma, apixaban was the major circulating component and O-demethyl apixaban sulfate, a stable and water-soluble metabolite, was the significant metabolite. The exposure of apixaban (C(max) and area under the plasma concentration versus time curve) in subjects with bile collection was generally similar to that in subjects without bile collection. The administered dose was recovered in feces (group 1, 56.0%; group 2, 46.7%) and urine (group 1, 24.5%; group 2, 28.8%), with the parent drug representing approximately half of the recovered dose. Biliary excretion represented a minor elimination pathway (2.44% of the administered dose) from group 2 subjects within the limited collection period. Metabolic pathways identified for apixaban included O-demethylation, hydroxylation, and sulfation of hydroxylated O-demethyl apixaban. Thus, apixaban is an orally bioavailable inhibitor of factor Xa with elimination pathways that include metabolism and renal excretion.

Population Pharmacokinetic/Pharmacodynamic Modelling of the Analgesic Effects of Tramadol in Pediatrics

The efficacy of tramadol (T) in children is not clearly understood because it is still unknown the ability of that population to form the active metabolite O-demethyltramadol (M1) and, whether or not the parent compound has a contribution to the efficacy. The aim was to develop a population pharmacokinetic/pharmacodynamic model for T in pediatrics, identifying the main active components. One hundred four children, mean age (4.55 years) received intravenously 1 mg/kg dose of T over 2.5 min at the end of surgery. If pain relief was inadequate, then an additional 0.33 mg/kg dose was given at 15, 30 and/or 45 min. Plasma samples and analgesic responses such as crying and movement were measured during a 6-h period. The estimates of the apparent volumes of distribution of the central compartment and at steady state and total plasma clearance of T were 8 l, 46.2 l, and 15.2 l/h, respectively. M1 formation clearance represented only a minor elimination pathway of T. Effect site concentrations of T and M1 were found to be the best predictors of the movement and crying responses, respectively. Steady-state plasma concentration levels of T and M1 of 100 and 15 ng/ml were associated with a 95% probability of adequate pain relief. Children have the ability to produce enough M1 to achieve proper pain relief. The response variables investigated give further evidence that not only the opioid effects of the metabolite are relevant, also the non-opiod effects of tramadol seem to give a significant contribution in its clinical use.

Pharmacokinetics and metabolism of TR-14035, a novel antagonist of α4β1/α4β7 integrin mediated cell adhesion, in rat and dog

The pharmacokinetics and disposition of N-(2,6-dichlorobenzoyl)-4-(2,6-dimethoxyphenyl)-L-phenylalanine (TR-14035), a novel α4β1/α4β7 antagonist, were investigated in the rat and dog. Results indicate extensive clearance of TR-14035 and low oral bioavailability, 17% and 13% in the rat and dog, respectively, at an oral dose of 10 mg/kg. At least 63% of the oral dose was absorbed from the gastrointestinal tract in the rat, and about one-third of the intravenous dose was excreted into bile as unchanged drug in the rat and dog. These data indicate that the oral bioavailability of TR-14035 was limited due to significant first-pass metabolism and biliary excretion in the liver. A species-dependent difference in metabolism was observed. The principal metabolite, O-desmethyl TR-14035, observed in rat, dog and probably human, was further conjugated with sulfate in the rat, but never in dog and human, based on in vitro metabolism and in vivo metabolite profile studies. Urinary excretion was a minor elimination route, but an interesting species difference was recognized. TR-14035 was reabsorbed from the rat renal proximal tubules, and by contrast, secreted into the tubules in the dog, probably via active transport systems.

Nuclear waste burner for minor actinides elimination

The report contains a suggestion to unite efforts of the leading International and Russian scientific research centers for resolving a major problem of nuclear power - utilization of long-lived radioactive wastes. Proposals for launching an international project for the creation of the world's first ADS Nuclear Waste Burner (NWB) in Russia and semi-industrial demonstration of the technology for safe transmutation of MA and other high-level radwastes have been formulated.

Comparison of pharmacokinetics and tissue disposition of an antisense phosphorothioate oligonucleotide targeting human Ha‐ras mRNA in mouse and monkey

The plasma pharmacokinetics and tissue disposition of ISIS 2503 were studied in mice following single and multiple bolus intravenous (iv) injections of 1–50 mg/kg, and in monkeys following single and multiple 2‐h iv infusions of 1–10 mg/kg and bolus iv injections of 1 mg/kg of ISIS 2503. ISIS 2503 and its metabolites were measured in plasma, urine, and tissues using solid‐phase extraction followed by capillary gel electrophoresis (CGE). In both species, the plasma clearance of ISIS 2503 was characterized by rapid distribution to tissues, and to a lesser extent, metabolism. The plasma clearance in mice was at least two‐fold more rapid than in monkeys at equivalent doses. The plasma disposition (t1/2) increased with dose. The highest concentrations of oligonucleotide were consistently observed in the kidney and liver in both species. At equivalent doses, tissue concentrations in monkeys were much higher than tissue concentrations in mice. Urinary excretion of total oligonucleotide was a minor elimination pathway in both species at doses < 10 mg/kg. However, urinary excretion of total oligonucleotide in mice was increased to 12–29% as dose increased from 20 to 50 mg/kg. © 2001 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:182–193, 2001