Estimated Elimination Half-life Research Articles

Safety, tolerability, pharmacokinetics, and immunological activity of dual-combinations and triple-combinations of anti-HIV monoclonal antibodies PGT121, PGDM1400, 10-1074, and VRC07-523LS administered intravenously to HIV-uninfected adults: a phase 1 randomised trial

Preclinical and clinical studies suggest that combinations of broadly neutralising antibodies (bnAbs) targeting different HIV envelope epitopes might be required for sufficient prevention of infection. We aimed to evaluate the dual and triple anti-HIV bnAb combinations of PGDM1400 (V2 Apex), PGT121 (V3 glycan), 10-1074 (V3 glycan), and VRC07-523LS (CD4 binding site). In this phase 1 trial (HVTN 130/HPTN 089), adults without HIV were randomly assigned (1:1:1) to three dual-bnAb treatment groups simultaneously, or the triple-bnAb group, receiving 20 mg/kg of each antibody administered intravenously at four centres in the USA. Participants received a single dose of PGT121 + VRC07-523LS (treatment one; n=6), PGDM1400 + VRC07-523LS (treatment two; n=6), or 10-1074 + VRC07-523LS (treatment three; n=6), and two doses of PGDM1400 + PGT121 + VRC07-523LS (treatment four; n=9). Primary outcomes were safety, pharmacokinetics, and neutralising activity. Safety was determined by monitoring for 60 min after infusions and throughout the study by collecting laboratory assessments (ie, blood count, chemistry, urinalysis, and HIV), and solicited and unsolicited adverse events (via case report forms and participant diaries). Serum concentrations of each bnAb were measured by binding antibody assays on days 0, 3, 6, 14, 28, 56, 112, 168, 224, 280, and 336, and by serum neutralisation titres against Env-pseudotyped viruses on days 0, 3, 28, 56, and 112. Pharmacokinetic parameters were estimated by use of two-compartment population pharmacokinetic models; combination bnAb neutralisation titres were directly measured and assessed with different interaction models. This trial is registered with ClinicalTrials.gov, NCT03928821, and has been completed. 27 participants were enrolled from July 31, to Dec 20, 2019. The median age was 26 years (range 19-50), 16 (58%) of 27 participants were assigned female sex at birth, and 24 (89%) participants were non-Hispanic White. Infusions were safe and well tolerated. There were no statistically significant differences in pharmacokinetic patterns between the dual and triple combinations of PGT121, PGDM1400, and VRC07-523LS. The median estimated elimination half-lives of PGT121, PGDM1400, 10-1074, and VRC07-523LS were 32·2, 25·4, 27·5, and 52·9 days, respectively. Neutralisation coverage against a panel of 12 viruses was greater in the triple-bnAb versus dual-bnAb groups: area under the magnitude-breadth curve at day 28 was 3·1, 2·9, 3·0, and 3·4 for treatments one to four, respectively. The Bliss-Hill multiplicative interaction model, which assumes complementary neutralisation with no antagonism or synergism among the bnAbs, best described combination bnAb titres in the dual-bnAb and triple-bnAb groups. No pharmacokinetic interactions among the bnAbs and no loss of complementary neutralisation were observed in the dual and triple combinations. This study lays the foundation for designing future combination bnAb HIV prevention efficacy trials. US National Institute of Allergy and Infectious Diseases, US National Institute on Drug Abuse, US National Institute of Mental Health, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

Acute sodium oxybate intoxication: a case report and review of the literature.

Despite a better safety profile than illicit γ-hydroxybutyric acid (GHB) and other GHB-analogs, sodium oxybate continues to raise serious concerns regarding clinical safety. In this study, the authors report the case of near-fatal intoxication involving sodium oxybate-alcohol combination in a 40-year-old woman. In addition, a review of the literature on published cases of intoxication involving this pharmaceutical form of GHB was conducted. A 40-year-old woman was admitted to the intensive care unit in a coma following voluntary ingestion of 18 g of sodium oxybate and alcohol. The GHB plasma concentration was quantified to be 146 mg/L using liquid chromatography coupled with tandem mass spectrometry. An English literature search was performed using PubMed without any limiting period to identify all available scientific publications involving cases of sodium oxybate intoxication; six cases were identified. Five cases involved fatal intoxication, with GHB post-mortem blood concentrations ranging from 11.5 to 3500 mg/L. One involved a non-fatal intoxication case with a GHB serum concentration of 569 mg/L 7 h post-ingestion. In the present case, the estimated elimination half-life was 154 min. The risk of acute poisoning appears to be high considering the pharmacokinetic properties of sodium oxybate. Physicians and toxicologists must take such properties into account.

The Disposition and Metabolism of Bempedoic Acid, A Potent Inhibitor of ATP Citrate Lyase, In Healthy Human Subjects.

The disposition and metabolism of bempedoic acid, a selective inhibitor of ATP citrate lyase, were examined in healthy male subjects. After a single administration of [14C] bempedoic acid (240 mg, 113 μCi) oral solution, mean concentrations of total radioactivity in plasma as a function of time indicated absorption was rapid with peak concentrations achieved at 1 hour after dose administration. Radioactivity was decreased in a multiexponential fashion with an estimated elimination half-life of 26.0 hours. Radiolabeled dose was predominantly recovered in urine (62.1% of dose) and a smaller amount in feces (25.4% of dose). Bempedoic acid was extensively metabolized with 1.6% to 3.7% of dose excreted unchanged in urine and feces combined. Overall, the major clearance route of bempedoic acid is metabolism by uridine 5'‑diphosphate glucuronosyltransferases. Metabolism in hepatocyte cultures of human and nonclinical species were generally in agreement with clinical metabolite profiles. Pooled plasma samples were characterized by the presence of bempedoic acid, which accounted for 59.3% of total plasma radioactivity, ESP15228 (a reversible keto metabolite of bempedoic acid), and their respective glucuronide conjugates. The acyl glucuronide of bempedoic acid represented 23% to 36% of radioactivity in plasma and accounted for approximately 37% of dose excreted in urine. In feces, the majority of radioactivity was associated with a co-eluting mixture of a carboxylic acid metabolite of bempedoic acid, a taurine conjugate of bempedoic acid and hydroxymethyl-ESP15228, which collectively accounted for 3.1% to 22.9% of bempedoic acid dose across subjects. Significance Statement This study characterizes the disposition and metabolism of bempedoic acid, an inhibitor of ATP citrate lyase for hypercholesterolemia. This work provides further understanding of bempedoic acid clinical pharmacokinetics and clearance pathways in adult subjects.

Analysis of bisaminotetrazole cobinamide, a next-generation antidote for cyanide, hydrogen sulfide and methanethiol poisoning, in swine plasma by liquid chromatography-tandem mass spectrometry

Cyanide, hydrogen sulfide, and methanethiol are common toxic inhalation agents that inhibit mitochondrial cytochrome c oxidase and result in cellular hypoxia, cytotoxic anoxia, apnea, respiratory failure, cardiovascular collapse, seizure and potentially death. While all are occupational gas exposure hazards that have the potential to cause mass casualties from industrial accidents or acts of terrorism, only cyanide has approved antidotes, and each of these has major limitations, including difficult administration in mass-casualty settings. While bisaminotetrazole cobinamide (Cbi(AT)2) has recently gained attention because of its efficacy in treating these metabolic poisons, there is no method available for the analysis of Cbi(AT)2 in any biological matrix. Hence, in this study, a simple and rapid liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the analysis of Cbi(AT)2 in swine plasma. The method is extremely simple, consisting of protein precipitation, separation and drying of the supernatant, reconstitution in an aqueous solvent, and LC-MS/MS analysis. The method produced an LOD of 0.3 μM with a wide dynamic range (2 – 500 μM). Inter- and intraassay accuracies (100 ± 12 % and 100 ± 19 %, respectively) were acceptable and the precision (<12 % and < 9 % relative standard deviation, respectively) was good. The developed method was used to analyze Cbi(AT)2 from treated swine and the preliminary pharmacokinetic parameters showed impressive antidotal behavior, most notably a long estimated elimination half-life (t1/2 = 37.5 h). This simple and rapid method can be used to facilitate the development of Cbi(AT)2 as a therapeutic against toxic cyanide, hydrogen sulfide and methanethiol exposure.

Fipronil and fipronil sulfone in chicken: From in vitro experiments to in vivo PBK model predictions

In 2017 a large-scale fipronil contamination in eggs occurred in several European countries. Fipronil and its metabolites have the potential to be transferred into the eggs of laying hens, thereby entering the human food chain. Here, first the metabolism of fipronil was measured in vitro using chicken liver S9. The results show that fipronil is mainly metabolised into fipronil sulfone and the clearance obtained in vitro was extrapolated to in vivo liver clearance. In a second step a physiologically based kinetic model was developed with a focus on fipronil and its major sulfone metabolite and the model outcome was compared to available in vivo data in eggs from the literature. The experimentally obtained clearance was used as model input to evaluate whether such an in vitro-based model can be used in an early phase of a contamination incident to predict the time-concentration curves. Overall, all model predictions were within a 10-fold difference and the estimated elimination half-life for fipronil equivalents was 14 days. In vitro experiments are definitely recommended compared to in vivo studies, since they provide a fast first insight into the behaviour of a chemical in an organism.

Autoimmune Hemolytic Anemia and Hemolytic Transfusion Reactions in Two Patients with Waldenström Macroglobulinemia Treated with Combination BTK Inhibitor and PD-1 Inhibitor

IntroductionBruton's tyrosine kinase (BTK) inhibitors have recently been shown to be safe and highly active as monotherapy in Waldenström macroglobulinemia (WM). Immune checkpoint inhibitors are being actively investigated in many lymphoid malignancies, and the expression of programmed cell death protein 1 (PD-1) and its ligands on malignant B cells in WM provides a rationale for the use of PD-1 inhibitors.Two patients with relapsed WM were treated with a novel anti-PD-1 antibody (BGB-A317) in combination with BGB-3111, a BTK inhibitor, as part of a Phase 1b study (NCT02795182). Both developed a newly identified syndrome of severe direct antiglobulin test (DAT) negative hemolysis and reticulocytopenia associated with transfusions, requiring cessation of the anti-PD-1 antibody and initiation of additional therapies.Case descriptionsPatient 1 is a 62-year-old female with WM who had previously received rituximab, cyclophosphamide and dexamethasone, and later rituximab and bendamustine (BR). After her most recent relapse she was treated with BGB-3111 followed 7 days later by BGB-A317. Four weeks after administration of the anti-PD-1 agent she developed hemoglobinuria, flank pain and fever during a red cell transfusion, with biochemical markers of hemolysis. DAT was negative and no red cell antibodies were identified. BGB-A317 was ceased, however hemolysis persisted and she required 26 further red cell transfusions. She was profoundly reticulocytopenic throughout this time. Prednisolone at 1mg/kg was initiated with a rapid resolution of hemolysis. The steroids were weaned and ceased over 7 weeks and she remains 4 months transfusion independent. Her WM is responding to single agent BGB-3111.Patient 2 is a 67-year-old female initially managed for WM with fludarabine, cyclophosphamide and rituximab. First relapse was treated with BR followed by autologous transplant. After a 3-year remission, a further relapse led to initiation of BGB-3111 then BGB-A317. Fourteen days after infusion of BGB-A317 she developed a hemolytic transfusion reaction with hemoglobinuria and elevation of biochemical markers of hemolysis. The blood film was unremarkable, DAT was negative and no antibodies could be identified. Reticulocytopenia was notable and worsened with progressing hemolysis. Ongoing hemolysis of transfused and native red cells was refractory to high dose prednisolone and intravenous immunoglobulin. Life-threatening anemia (nadir hemoglobin 4.4 g/dL, peak LDH 1544 U/L) prompted therapy with cyclophosphamide and pulse methylprednisone. BGB-3111, briefly withheld due to thrombocytopenia, was reinitiated. These measures were effective and the hemolytic anemia resolved over 3 weeks. Prednisone was weaned and the patient remains 4 months transfusion independent. Notably, a brief cessation of BGB-3111 at a later stage resulted in a transient recrudescence of hemolysis.DiscussionImmune related adverse events are well described with immune checkpoint inhibitors, including a few reported cases of autoimmune hemolytic anemia. In our patients, there was a clear temporal relationship between the BGB-A317 and hemolysis, which started 28 and 14 days after the first dose. Subsequent resolution of the syndrome took 80 and 55 days from the final dose of BGB-A317, equivalent to 5 times the estimated elimination half-life of 11 to 17 days. The response to glucocorticoids and cyclophosphamide support an immune mechanism initiated by checkpoint inhibition. The profound reticulocytopenia and marked erythroid hypoplasia suggest that erythroid precursors may have been a predominant target of the immune attack.No other cancer patients treated with BGB-A317 have developed a similar reaction to the two patients, who were the first worldwide with WM to receive the agent. These observations suggest a pathophysiological role of WM, which is known to be associated with immune dysregulation and autoimmune phenomena. We hypothesize that control of the underlying lymphoma by BGB-3111 contributed to resolution of the hemolysis.Lymphoproliferative disorders such as WM involve complex aberrations of immune function and inhibition not limited to the malignant clone. The introduction of therapeutic agents harnessing the immune system in this patient population should be approached with caution, as demonstrated by the unexpected and severe adverse events suffered by these two patients. [Display omitted] DisclosuresTam:Roche: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Janssen Cilag: Honoraria, Research Funding. Huang:BeiGene: Employment. Lin:BeiGene: Employment. Hilger:BeiGene: Employment. Trotman:Roche: Membership on an entity's Board of Directors or advisory committees, Other: All positions non-remunerated, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Funding facilitating research paid to third parties. All positions non-remunerated; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Position non-remunerated; Janssen Cilag: Membership on an entity's Board of Directors or advisory committees, Other: Funding facilitating research paid to third parties. All positions non-remunerated, Speakers Bureau.

Detection of Systemic AL Amyloidosis and Differentiation of AL from Attr Using 124I-p5+14 PET Imaging

Background: Systemic immunoglobulin light chain-associated amyloidosis (AL) is a rare disorder associated with the production of monoclonal free light chain proteins. The aggregation of misfolded light chains leads to the extracellular deposition of amyloid fibrils associated with proteoglycans and other serum-derived proteins. Amyloid deposits accumulate in abdominothoracic organs, notably the heart, liver, spleen, kidneys, as well as peripheral nerves. This process results in cytotoxicity and ultimately to organ dysfunction. Presently, there are no radiotracers approved in the US for the quantitative detection and measurement of systemic AL amyloidosis. We have developed a synthetic peptide radiotracer, designated 124I-p5+14 that has been shown, in preclinical assays, to bind many forms of amyloid including AL, ATTR, and ALECT2 (Wall, J.S. et al. (2015) Molecules, 20, 7657). In 2018, a Phase 1, first-in-human PET imaging study began using 124I-p5+14 in patients with a biopsy-confirmed diagnosis of AL amyloidosis. In addition, patients with other forms of systemic amyloidosis are also being recruited into this ongoing clinical study (NCT 03678259). To date, 30 patients have completed the PET/CT imaging study including 15 subjects with AL amyloidosis. The primary endpoint includes safety and dosimetry estimation with a secondary endpoint of patient- and organ-specific sensitivity of 124I-p5+14. Patients receive follow up contact by study staff on days 9 and 28 for safety and symptom assessment. Here we provide an update on the detection and quantitation of AL amyloid in patients, using 124I-p5+14 PET imaging. Additionally, we present a method, using PET imaging of the radiotracer, for differentiating patients with AL from those with transthyretin-associated (ATTR) amyloidosis. Methods: Patients &amp;gt;18 years of age with biopsy-proven amyloidosis with adequate renal function (Cr &amp;lt; 1.5 x ULN) and not requiring heparin therapy are eligible. Subjects received &amp;lt;2 mg of 124I-p5+14 (&amp;lt;2 mCi) administered as a single IV bolus. PET/CT images for the first three AL patients were acquired at 25 min, 50 min, 2 h, 3 h, 6h, 24 h and 48 h post injection. The second cohort of patients are imaged at both 6 h and 24 h post injection. PET image data are acquired using either a Biograph 16 or mCT PET/CT scanner using a low dose CT with 5 min bed positions for PET imaging to cover the full CT field of view. Images were analyzed using a region of interest method and the radioactivity in each organ measured (Bq/cc). The standard uptake value ratio for each organ was calculated using thoracic aorta blood pool as the reference tissue. Results: Blood pool clearance of the 124I-p5+14 was analyzed using a two-phase exponential equation which yielded an excellent fit to the data (R2 &amp;gt; 0.99 for all data), with estimated elimination half-life values of between 667.8 min and 746.7 min. Analysis of PET images indicated retention of 124I-p5+14 in the heart, kidneys, liver, spleen, pancreas, bone marrow, lung, and adrenal gland of AL patients. Cardiac uptake of the radiotracer was observed in 70% of AL patients, with a mean myocardium:blood pool ratio of 2.2 ± 0.5 in positive images. Additionally, liver, spleen and kidney retention of 124I-p5+14 was observed in 38%, 61%, and 69% of AL patients, respectively. The patient-based sensitivity for AL patients is 93% (14/15). Using an ROC analysis of SUVR organ ratios it was possible to differentiate AL from ATTR patients with p = 0.002 and an AUC of 0.96. A cutoff value of 1.40 yielded a 100% sensitivity and 75% specificity for diagnosing ATTR relative to AL from the image data. Conclusion: PET/CT imaging of amyloidosis using 124I-p5+14 provides quantitative detection of systemic AL amyloidosis in multiple organ systems. In addition to detecting and monitoring amyloid burden, this technique can be used to differentiate the two major forms of systemic amyloidosis, ATTR and AL. Acknowledgments: This study was supported in part by the National Heart Lung and Blood Institute, National Institutes of Health, through the Science Moving TowArds Research Translation and Therapy (SMARTT) program via the following contract(s) HHSN268201600011C, HHSN268201600012C, and HHSN268201600014C, as well as by contributions from Gerdau to the ACTP Gift Fund at the UTGSM and support from UHS. In addition, we thank Carmella Moody, PhD and Derry Ridgway, MD and the many patients for their support. Disclosures Guthrie: Attralus Bio: Current Employment.

Baclofen self-poisoning: Is renal replacement therapy efficient in patient with normal kidney function?

AimsWe aimed at assessing the effectiveness of renal replacement therapy in patients severely self-poisoned with baclofen and with normal kidney function. MethodsA population pharmacokinetic model was built using analytical data extracted from 26 baclofen poisoning cases reported to a French Poison Centre: 8 patients underwent renal replacement therapy (RRT), 18 did not. In the RRT group, 2 patients suffered from kidney failure. Mechanical ventilation was required for 20 patients with normal kidney function; 15 were not treated by RRT and 5 were. Pharmacokinetic profiles of baclofen were measured in 28 patients and further modelled by a non-parametric approach (PMetrics®). The total data set was divided into a building data set (26 patients, 57 observations) and a validation set (2 external patients, 6 observations). Then, the estimated elimination half-life of baclofen and the duration of intubation were compared in patients with or without RRT using Wilcoxon–Mann–Whitney test. ResultsA model using three parameters plus a lag time and bioavailability was necessary to determine the pharmacokinetics of baclofen. Estimated elimination half-life in the ‘RRT’ group and the ‘no RRT’ group were respectively 3.1 [2.2−4.8] h (n = 6 patients) and 3.4 [1.4−5.5] h (n = 19 patients, p = 0.53). The median duration of intubation was not significantly different between groups (72 [48−72] h and 72 [24−96] h, respectively; p = 0.38). ConclusionRenal replacement therapy did not appear to significantly increase baclofen clearance in patients without kidney failure.

Abstract CT019: Population pharmacokinetics of an aurora kinase A inhibitor, LY3295668 erbumine (AK-01), in patients with locally advanced or metastatic solid tumors

Abstract Background: The aurora kinase family plays a vital regulatory role in mitotic and meiotic events, with aurora kinase A (AurA) critical to centrosome maturation, mitotic spindle formation and checkpoint activation. LY3295668 erbumine (AK-01) is an inhibitor of AurA with 1000-fold selectivity for inhibition of AurA over aurora kinase B (AurB). Pharmacokinetic-pharmacodynamic (PK-PD) nonclinical models have shown that 90% inhibition of AurA phosphorylation (pAurA) over an extended period (≥ 16 hours per day) was required to yield efficacy in H446 (small cell lung cancer) xenograft models. Nonclinical plasma LY3295668 concentrations associated with 90% pAurA inhibition (IC90) were estimated previously using a direct sigmoidal relationship between PK and pAurA. In this first-in-man study, PK of LY3295668 in patients with advanced/metastatic cancer were evaluated. Human PK profiles were simulated subsequently and compared to pAurA IC90 to estimate a human efficacious dose range. Methods: LY3295668 erbumine was administered to 13 patients with locally advanced or metastatic solid tumors over a dose range of 25 to 75 mg given twice daily (BID). In the first cycle, serial plasma PK samples were collected up to 8 hours on Day 1 and Day 15. Additional trough samples were obtained prior to dosing on Day 2, on Day 8 and at discontinuation if applicable. PK parameter estimations were performed using non-linear mixed effects models in NONMEM v7.3. Results: The population PK model was developed using 146 plasma concentrations collected from 13 patients. A 2-compartment PK model with first order absorption best described the disposition of LY3295668. Following oral administration, LY3295668 was rapidly absorbed with peak concentrations occurring within 1 to 2 hours. The estimated elimination half-life was approximately 21 hours; therefore, steady state was attained within 4 to 5 days of dosing. Simulations of plasma concentration-time profiles showed that at the maximum tolerated dose (MTD) of 25 mg BID, 90% of patients are expected to achieve steady-state plasma concentrations greater than the pAurA IC90 for the entire day. Patients with dose limiting toxicities (DLTs) had the highest model-predicted exposures amongst the 13 patients. Conclusion: At the MTD of 25 mg BID, steady state LY3295668 plasma concentrations are maintained above the pAurA IC90 for the entire dosing interval, exceeding the minimum requirements for efficacy associated with non-clinical xenograft models. Trial Registration: NCT03092934 Citation Format: Eunice Yuen, Yu-Hua Hui, Amparo de la Peña, Sonya C. Tate, John R. Stille, Andrew Lithio, Patricia S. Smith, Quincy Chu, Gerald Batist, Nathaniel Bouganim, Caroline Fortier, Sara Zaknoen, Jill Kremer. Population pharmacokinetics of an aurora kinase A inhibitor, LY3295668 erbumine (AK-01), in patients with locally advanced or metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT019.

Pharmacokinetics of 38% topical silver diamine fluoride in healthy adult volunteers

BackgroundSilver diamine fluoride (SDF) is used topically to prevent or arrest caries. The authors' aim was to characterize the kinetics of silver and fluoride after topical application of SDF. MethodsSixteen adults participated in a pharmacokinetics study after the application of 38% SDF to 5 teeth (approximately 50 microliters, estimated 4-11 milligrams per participant). Serum and urine samples were collected over 24 hours after application and were analyzed for silver and fluoride. ResultsSilver serum peak was 0.67 (standard deviation [SD], 0.49) nanograms per milliliter; median time to peak was 3 hours. The estimated elimination half-life of silver was 46 (SD, 26) hours. No silver was recovered in urine. Baseline fluoride serum levels ranged from less than 10 through 50 ng/mL (< 0.01-0.05 parts per million) and fluctuated around baseline after SDF. The 24-hour urinary fluoride was 1.29 (SD, 0.81) mg. ConclusionsSDF was well tolerated in this study, and no adverse events related to SDF were reported. Practical ImplicationsThis clinical study confirmed that topical application of 38% SDF, in growing use in the United States, is safe and well tolerated in healthy adults.

Dried blood spot testing for estimation of renal function and analysis of metformin and sitagliptin concentrations in diabetic patients: a cross-sectional study.

Dried blot spot (DBS) analysis of drugs or clinical parameters offers many advantages. We investigated the feasibility of using DBS for analysis of anti-diabetic drugs concomitantly with the estimated creatinine clearance (Clcrea). The cross-sectional study involved physicians in an enabling analysis with 70 diabetic patients and community pharmacists in a field investigation with 84 participants. All 154 DBS samples were analyzed for creatinine, metformin, and sitagliptin. The diabetic patients revealed of a wide range of age (32-88years), BMI values (19.8-54.7kg/m2), and extent of polypharmacotherapy (1-21 drugs). A correlation factor to convert capillary blood creatinine from DBS into plasma concentrations was determined. Patients' Clcrea ranged from 21.6-155.9mL/min. The results indicated statistically significant correlations (p< 0.05) between the use of two or three particular drug classes (diuretics, NSAIDs, renin-angiotensin system blockers) and a decreased renal function. DBS concentrations of metformin ranged between 0.23-4.99μg/mL. The estimated elimination half-life (t ½) of metformin was 11.9h in patients with a ClCrea higher than 60mL/min and 18.5h for diabetics with lower ClCrea. Sitagliptin capillary blood concentrations ranged between 11.12-995.6ng/mL. Calculated t ½ of sitagliptin were 8.4h and 13.0h in patients with a ClCrea above and below 60mL/min, respectively. DBS allow for the analysis of concentrations of predominantly renally eliminated drugs and community pharmacists can provide a valuable contribution to DBS sampling.

Abstract CT132: Safety and dose selection for LYC-55716, a first-in-class RORγ agonist to treat solid tumors: Phase I results from an open-label, multicenter Phase I/IIa trial

Abstract Background: LYC-55716, a first-in-class, oral, small-molecule agonist of the retinoic acid receptor-related orphan receptor γ (RORγ), is under development as a novel immuno-oncology agent for solid tumors. Preclinical data show that LYC-55716 modulates gene expression to reprogram immune cells for improved anti-tumor effector function as well as decreased immunosuppressive mechanisms, resulting in slower tumor growth and enhanced survival. An ongoing, open-label, Phase I/IIa trial is evaluating the safety and tolerability of the investigational agent LYC-55716 in patients with advanced solid tumors. Methods: The Phase I portion of the trial (NCT02929862) enrolled adults with locally advanced or metastatic solid tumors (no specific exclusions) who had progressed on standard therapy. Patients received 28-day treatment cycles of LYC-55716 in which dose and dosing regimen were determined according to PK profile and safety. Primary endpoints were safety (monitoring of adverse events [AEs], physical examination, lab results) and incidence of dose-limiting (Grade 3-4) toxicities during the first treatment cycle. Secondary endpoints included pharmacokinetics (PK) and response assessment. Pharmacodynamic markers of RORγ activation were also evaluated. Results: Data to date: Thirty-two patients were enrolled (23-79 y; 63% female); 27 completed ≥1 (28-day) treatment cycle. Treatment-related AEs occurring in ≥3 patients included diarrhea (n=7 [22%]); fatigue (n=5 [16%]); and anemia, poor appetite, and dry mouth (n=3 [9%] each). No dose-limiting toxicities were observed during Phase 1. The majority of treatment-related AEs were Grade 1-2; Grade 3 treatment-related AEs were reported only for anemia, elevated gamma-glutamine transferase, and hypophosphatemia; no Grade 4 treatment-related AEs occurred. None of the 5 deaths or 14 serious AEs (in 11 patients) were considered treatment-related, and no subjects withdrew due to AEs. LYC-55716 demonstrated an estimated elimination half-life of ~12 h. Twice daily dosing resulted in minimum plasma concentrations that were consistently higher than QD dosing and the highest BID dose resulted in a median minimum plasma concentration that exceeded by ~24-fold the 50% effective concentration that preclinical studies had indicated was required for target gene regulation. Pharmacodynamic data indicated target engagement, consistent with PK evidence of exposure levels in the predicted efficacious range. Updated data, including details of Phase II dose selection and response assessment, will be presented. Conclusion: Phase I data support the safety of LYC-55716 and selection of a BID dosing regimen for the ongoing Phase 2a phase of the trial in patients with non-small cell lung, head and neck, gastroesophageal, renal cell, urothelial, and ovarian cancers. Citation Format: Devalingam Mahalingam, Judy S. Wang, Erika P. Hamilton, Garry Weems, Marshall Schreeder, H. Jeffrey Wilkins. Safety and dose selection for LYC-55716, a first-in-class RORγ agonist to treat solid tumors: Phase I results from an open-label, multicenter Phase I/IIa trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT132.

Elimination profile of triamcinolone in urine following oral administration.

Triamcinolone (T) is a glucocorticoid commonly used to relieve inflammation and treat arthritis, severe allergies, and asthma; however, it is banned by the World Anti-Doping Agency in competition for athletes when administered orally, intravenously, intramuscularly, or rectally. The minimum required performance limit (MRPL) for urinary T is 30ng/mL. However, the data about the urinary excretion of T after oral administration is limited. We investigate the elimination profile and determine whether single-dose administration of T would cause a positive doping result. Twelve healthy volunteers received a single-dose of 4-mg T rally, and urine samples were collected for 24hours. A validated liquid chromatography-tandem mass spectrometry method was used to determine urinary T levels. Non-compartmental modeling was used to estimate the pharmacokinetic parameters. All the urinary T concentrations were much higher than the MRPL. The peak urinary T concentration was 3211.4 ± 860.3ng/mL (mean ± SD), time to peak concentration was 1.7 ± 0.9hours, and the estimated elimination half-life was 4.4 ± 2.8hours. About 27.76% of the consumed dose was eliminated via urine within 24hours of intake. After a single-dose oral administration, urinary T concentrations still exceeded the MRPL after 24hours. This information could be useful for limiting the misuse of T. Athletes should be aware when using T in competition and acquire approval for a therapeutic use exemption prior to use. Moreover, the elimination profile of orally administered T may be crucial information for distinguishing different dosage routes.

Mistaking 2C-P for 2C-B: What a Difference a Letter Makes

2,5-Dimethoxy-4(n)-propylphenethylamine (2C-P) is a synthetic phenethylamine derivative belonging to the large family of the so-called 2C drugs. These compounds can differ significantly in receptor affinity, potency and duration of action, and an important structural difference is the ligand in the 4 position of the phenyl ring, such as propyl in 2C-P or bromine in 2,5-dimethoxy-4-bromophenethylamine (2C-B). The 2C drugs are known for their hallucinogenic properties. We present a case of a 19-year-old male admitted to the emergency department with severe hallucinations, mydriasis, tachycardia, agitation and confusion following the use of a substance sold as 2C-B. By using liquid chromatography-mass spectrometry, the more potent substance 2C-P was detected and quantified. On the basis of two blood sample concentrations, the estimated elimination half-life was 19 h. This case report illustrates and discusses the differences in potency and duration of action of 2C drugs.

Antimalarial activity of artefenomel (OZ439), a novel synthetic antimalarial endoperoxide, in patients with Plasmodium falciparum and Plasmodium vivax malaria: an open-label phase 2 trial

SummaryBackgroundArtefenomel (OZ439) is a novel synthetic trioxolane with improved pharmacokinetic properties compared with other antimalarial drugs with the artemisinin pharmacophore. Artefenomel has been generally well tolerated in volunteers at doses up to 1600 mg and is being developed as a partner drug in an antimalarial combination treatment. We investigated the efficacy, tolerability, and pharmacokinetics of artefenomel at different doses in patients with Plasmodium falciparum or Plasmodium vivax malaria.MethodsThis phase 2a exploratory, open-label trial was done at the Hospital for Tropical Diseases, Bangkok, and the Shoklo Malaria Research Unit in Thailand. Adult patients with acute, uncomplicated P falciparum or P vivax malaria received artefenomel in a single oral dose (200 mg, 400 mg, 800 mg, or 1200 mg). The first cohort received 800 mg. Testing of a new dose of artefenomel in a patient cohort was decided on after safety and efficacy assessment of the preceding cohort. The primary endpoint was the natural log parasite reduction per 24 h. Definitive oral treatment was given at 36 h. This trial is registered with ClinicalTrials.gov, number NCT01213966.FindingsBetween Oct 24, 2010, and May 25, 2012, 82 patients were enrolled (20 in each of the 200 mg, 400 mg, and 800 mg cohorts, and 21 in the 1200 mg cohort). One patient withdrew consent (before the administration of artefenomel) but there were no further dropouts. The parasite reduction rates per 24 h ranged from 0·90 to 1·88 for P falciparum, and 2·09 to 2·53 for P vivax. All doses were equally effective in both P falciparum and P vivax malaria, with median parasite clearance half-lives of 4·1 h (range 1·3–6·7) to 5·6 h (2·0–8·5) for P falciparum and 2·3 h (1·2–3·9) to 3·2 h (0·9–15·0) for P vivax. Maximum plasma concentrations, dose-proportional to 800 mg, occurred at 4 h (median). The estimated elimination half-life was 46–62 h. No serious drug-related adverse effects were reported; other adverse effects were generally mild and reversible, with the highest number in the 1200 mg cohort (17 [81%] patients with at least one adverse event). The most frequently reported adverse effect was an asymptomatic increase in plasma creatine phosphokinase concentration (200 mg, n=5; 400 mg, n=3; 800 mg, n=1; 1200 mg, n=3).InterpretationArtefenomel is a new synthetic antimalarial peroxide with a good safety profile that clears parasitaemia rapidly in both P falciparum and P vivax malaria. Its long half-life suggests a possible use in a single-dose treatment in combination with other drugs.FundingBill & Melinda Gates Foundation, Wellcome Trust, and UK Department for International Development.

What do We Know about the Risk Arising from Perfluorinated Compounds

Many studies have shown the adverse effects of perfluorinated compounds (PFCs) on living organisms. PFCs include groups of perfluorinated sulfonic acids, perfluorinated carboxylic acids, fluorotelomer alcohols, high-molecular weight fluoropolymers and low-molecular weight perfluoroalkanamides. These compounds are chemically very stable and are highly resistant to biological degradation. Currently, humans are at increased risk as PFCs are resistant to hydrolysis, photolysis, microbial degradation, or metabolism, and their estimated elimination half-life is about 3.8 years. Therefore, the scale of the bioaccumulation of PFCs in humans is not fully known. Our review provides basic information regarding the chemical nature of PFCs, their production, and use, as well as the current European Union legislation. A special focus was put on the sources of food contamination by PFCs, toxicological studies, estimation of human exposure to PFCs, and tolerable daily intake. At present, there is no legislation for perfluorinated compounds in food of plant and animal origin within the European Union.

Determination of 5-hydroxythiabendazole in human urine as a biomarker of exposure to thiabendazole using LC/MS/MS.

Thiabendazole (TBZ) is widely used as a pre-planting and post-harvest agricultural fungicide and as an anthelminthic in humans and animals. TBZ is of toxicological concern, since adverse effects including nephrogenic, hepatogenic, teratogenic and neurological effects have been reported in mammals. Occupational exposure can occur among agricultural workers and the general public may be environmentally exposed to TBZ through the diet. The metabolite 5-hydroxythiabendazole (5-OH-TBZ) was chosen as biomarker of exposure to TBZ and a LC/MS/MS method for the quantification of 5-OH-TBZ in human urine was developed. The method includes enzyme hydrolysis, as 5-OH-TBZ is conjugated to glucuronide and sulphate in urine. Sample through put was optimised using 96-well plates for sample handling as well as for solid phase extraction (SPE). The method has excellent, within-run, between-run and between-batch precision between 4 and 9%. The limit of detection (LOD) of 0.05 and a limit of quantification (LOQ) of 0.13ng 5-OH-TBZ/mL urine enable detection in environmentally exposed populations. When applying the method in a general Swedish population, 52% had levels above LOD. The method was also applied in one oral and one dermal human experimental exposure study in two individuals. After oral exposure, the excretion of 5-OH-TBZ in urine was described by a two-compartment model and both the first rapid and the second slower elimination phase followed first-order kinetics, with estimated elimination half-life of 2h and 9-12h. The recoveries in urine were between 21 and 24% of the dose. Dermal exposure was described by a one compartment model and followed first order kinetics, with estimated elimination half-life of 9-18h. The recovery in urine was 1% of the administrated dose of TBZ. Although these studies are limited to two individuals, the data provide new basic information regarding the toxicokinetics of TBZ after oral and dermal exposure.

Inhalation and oral toxicokinetics of 6:2 FTOH and its metabolites in mammals

The toxicokinetics of 6:2 fluorotelomer alcohol (6:2 FTOH) and its terminal perfluorinated and polyfluorinated metabolites (PFBA, PFHxA, PFHpA and 5:3 Acid) have been calculated from laboratory studies of rats and from a biomonitoring study of humans. In vitro studies with mouse, rat and human hepatocytes indicate qualitatively similar metabolic pathways of 6:2 FTOH. In a one-day inhalation study of 6:2 FTOH in rats, PFBA, PFHxA, PFHpA and 5:3 Acid were determined to be the major metabolites in plasma with calculated elimination half-lives of 1.3–15.4h and metabolic yields up to 2.7mol%. In five-day and 23-day inhalation studies and a 90-day oral study of 6:2 FTOH, the plasma or serum concentration profile of 5:3 Acid was several-fold higher than concentrations observed in the single day study, resulting in an estimated elimination half-life of 20–30d. In contrast, the concentrations of PFBA, PFHxA and PFHpA showed little or no concentration increase with repeated exposure. Elimination half-lives of PFHxA, PFHpA and 5:3 Acid in humans were estimated from a study of professional ski wax technicians who were occupationally exposed to aerosolized and volatilized components of fluorinated glide wax. The resulting human elimination half-life values of PFHxA, PFHpA and 5:3 Acid were 32, 70 and 43d, respectively. Based on a one compartment toxicokinetic model, current environmental air concentrations of 6:2 FTOH are estimated to result in plasma concentrations of PFHxA, PFHpA and 5:3 Acid that are less than or equal to typical LOQ values, in agreement with extant biomonitoring results.

Tissue specific uptake and elimination of perfluoroalkyl acids (PFAAs) in adult rainbow trout (Oncorhynchus mykiss) after dietary exposure

Tissue specific uptake and elimination of perfluoroalkyl acids (PFAAs) were studied in rainbow trout (Oncorhynchus mykiss). Adult trout were exposed to perfluorobutane sulfonic acid (PFBS), perfluorohexane sulfonic acid (PFHxS), perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA) and perfluorononanoic acid (PFNA) via food over a time period of 28d. In the following 28-d depuration period the fish were fed PFAA-free food. At defined sampling times four animals were removed from the experimental tank, euthanized and dissected. Muscle, liver, kidneys, gills, blood, skin and carcass were examined individually. At the end of the accumulation phase between 0.63% (PFOA) and 15.5% (PFOS) of the absolute, applied quantity of PFAAs was recovered in the whole fish. The main target organ was the liver with recovery rates between 0.11% (PFBS) and 4.01% (PFOS) of the total amount of ingested PFAAs. Perfluoroalkyl sulfonic acids were taken up more readily and had longer estimated elimination half-lives than perfluoroalkyl carboxylic acids of the same chain length. The longest estimated elimination half-lives were found to be for PFOS between 8.4d in muscle tissue and 20.4d in the liver and for PFNA between 8.2d in the blood and 11.6d in the liver.

Chapter Four - Dasatinib

Dasatinib (Sprycel®), a second-generation TKI, has been shown to be effective as an anticancer drug in the treatment of patients with chronic myeloid leukemia or Philadelphia chromosome-positive acute lymphoblastic leukemia who are resistant or intolerant to imatinib. Several methods of gefitinib synthesis are included in this review. UV spectroscopy of dasatinib showed a λmax of approximately 320-330nm, and IR spectroscopy principal peaks were observed at 3418 (NH), 3200 (OH), 1620 (CO), 1582 (CC and CN), 1513 (CHCH) cm(-1). Characteristic NH peaks were observed in nuclear magnetic resonance (NMR) spectroscopy at 11.47 and 9.88ppm. The molecular mass was observed at m/z=487.3((35)Cl) and 488.9((37)Cl) (molecular weight=487.15) and the fragmentation pattern was studied using ion trap mass spectrometry. In addition, different analytical methods for determination of dasatinib are also described in this review. Pharmacokinetically, dasatinib is rapidly absorbed after oral administration where the solubility is dependent on pH. Dasatinib extensively binds to human plasma proteins by approximately 96%. In leukemic patient, the calculated apparent volume of distribution for dasatinib was 2502L and the estimated elimination half-life was approximately 3-5h. Dasatinib is metabolized in humans markedly by CYP3A4 to active metabolites and by phase II drug-metabolizing enzymes, such as UDP glucuronosyltransferase. Dasatinib is mainly eliminated via the feces (85%), of which relatively small amount of dasatinib is excreted unchanged as intact drug (19%). Most of the adverse effects associated with dasatinib therapy are mild to moderate in severity and are usually reversible and manageable with appropriate intervention, such as cardiac failure, hypertension, and coronary artery disease.