Serum Elimination Half-life Research Articles

Effects of Perfluorohexane Sulfonate Exposure on Immune Cell Populations in Naive Mice.

Perfluorohexane sulfonate (PFHxS) is a member of the per- and polyfluoroalkyls (PFAS) superfamily of molecules, characterized by their fluorinated carbon chains and use in a wide range of industrial applications. PFHxS and perfluorooctane sulfonate are able to accumulate in the environment and in humans with the approximated serum elimination half-life in the range of several years. More recently, some PFAS compounds have also been suggested as potential immunosuppressants. In this study, we analyze immune cell numbers in mice following 28-d repeated oral exposure to potassium PFHxS at 12, 120, 1,200, and 12,000 ng/kg/d, with resulting serum levels ranging up to ∼1,600 ng/ml, approximating ranges found in the general population and at higher levels in PFAS workers. The immunosuppressant cyclophosphamide was analyzed as a positive control. B cells, T cells, and granulocytes from the bone marrow, liver, spleen, lymph nodes, and thymus were evaluated. We found that at these exposures, there was no effect of PFHxS on major T or B cell populations, macrophages, dendritic cells, basophils, mast cells, eosinophils, neutrophils, or circulating Ab isotypes. By contrast, mice exposed to cyclophosphamide exhibited depletion of several granulocyte and T and B cell populations in the thymus, bone marrow, and spleen, as well as reductions in IgG1, IgG2b, IgG2c, IgG3, IgE, and IgM. These data indicate that exposures of up to 12,000 ng/kg of PFHxS for 28 d do not affect immune cell numbers in naive mice, which provides valuable information for assessing the risks and health influences of exposures to this compound.

An investigation of 3M Cordova, IL production worker's per- and polyfluoroalkyl substances biomonitoring results and mortality experience

Per- and polyfluoroalkyl substances (PFAS) are a wide-ranging group of chemicals that have been used in a variety of polymer and surfactant applications. While 3M Cordova, Illinois was not one of 3M's primary manufacturing facilities for the legacy long-chain PFAS (PFOS, PFOA, PFHxS), it has been a major manufacturing site for short-chain PFAS (compounds that are or may degrade to PFBS or PFBA). The purpose of this research focused on: 1) an analysis of biomonitoring data of employees and retirees, and 2) an analysis of the cohort mortality of workers from 1970 to 2018. Employees had higher PFBS and PFBA serum concentrations than the retirees, while retirees had higher concentrations for PFOS, PFOA, and PFHxS. Compared to the 2017–2018 NHANES data, employees’ PFOS and PFHxS concentrations in 2022 were two-fold higher, with PFOA levels comparable. These NHANES data did not include serum PFBS or PFBA. Cross-sectional trends of PFOS and PFOA levels from 1997 to 2022 showed PFOS declined from 151 ng/mL to 10.4 ng/mL. Similarly, PFOA decreased from 100 ng/mL to 1.5 ng/mL. A longitudinal analysis of 48 participants with measurements in both 2006 and 2022 showed concentrations decreased by 74% for PFOS and 90% for PFOA. In the mortality study, 1707 employees who worked 1 day or longer were followed for an average of 25.6 years and had 143 (8%) deaths. There were no significantly elevated risks for any specific cause of death, regardless of latency period (0 or 15 years). While no specific PFAS exposures were examined, worker mortality experience (1970–2018) was analyzed by major departments representing primary work areas. Employees and retirees at the Cordova facility continue to have elevated PFOS and PFHxS serum concentrations compared to the general population, however, their legacy PFAS concentrations have declined over time, consistent with the estimated serum elimination half-lives of these PFAS in humans assuming nominal ambient exposures. For PFBS and PFBA, the results indicated no long-term accumulation in the blood likely due to their short serum elimination half-lives. After nearly 50 years of follow-up, this Cordova workforce showed no increased risk of mortality from cancer or any other specific cause of death.

Exposure Trends and Half-lives of Per- and Polyfluoroalkyl Substances (PFAS) in Australian Firefighters

BACKGROUND AND AIM: Per- and polyfluoroalkyl substances (PFASs) are persistent manmade compounds used in aqueous film forming foam (AFFF). The extensive use of AFFF has led to widespread environmental PFAS contamination and exposures to firefighters. The aim of this study is to determine PFAS blood serum concentration trends and apparent serum elimination half-lives in firefighters after the replacement of AFFF. METHODS: Current and former employees of an Australian corporation providing aviation firefighting services, where AFFF had been used in the past, were recruited to participate in this study. Special focus was placed on re-recruiting participants who had provided blood samples five years prior. Participants were asked to provide a blood sample and complete a questionnaire. Serum samples were analysed for 40 different PFASs using HP LC-MS/MS. RESULTS: A total of 799 participants provided blood samples. Of these, 130 previously provided blood serum five years prior. Mean serum concentrations of perfluorooctane sulfonate (PFOS, 27 ng/mL), perfluoroheptane sulfonate (PFHpS, 1.7 ng/mL) and perfluorohexane sulfonate (PFHxS, 14 ng/mL) were significantly higher than the levels in the general Australian population. Serum concentrations were associated with the use of PFOS/PFHxS based AFFF. Participants who commenced service after the replacement of this foam had serum concentrations similar to those in the general Australian population. Average individual apparent half-lives were estimated to be 5.0 years (perfluorooctanoic acid (PFOA)), 7.8 years (PFHxS), 7.4 years (PFHpS) and 6.5 years (PFOS). CONCLUSIONS: This study shows how workplace interventions such as replacement of AFFF, can benefit employees at risk of occupational exposure. KEYWORDS: Biological Monitoring Occupational Exposure Firefighters Follow-Up Studies Half-Life

Perfluoroalkyl Carboxylic Acids Interact with the Human Bile Acid Transporter NTCP.

Na+/taurocholate cotransporting polypeptide (NTCP) is important for the enterohepatic circulation of bile acids, which has been suggested to contribute to the long serum elimination half-lives of perfluoroalkyl substances in humans. We demonstrated that some perfluoroalkyl sulfonates are transported by NTCP; however, little was known about carboxylates. The purpose of this study was to determine if perfluoroalkyl carboxylates would interact with NTCP and potentially act as substrates. Sodium-dependent transport of [3H]-taurocholate was measured in human embryonic kidney cells (HEK293) stably expressing NTCP in the absence or presence of perfluoroalkyl carboxylates with varying chain lengths. PFCAs with 8 (PFOA), 9 (PFNA), and 10 (PFDA) carbons were the strongest inhibitors. Inhibition kinetics demonstrated competitive inhibition and indicated that PFNA was the strongest inhibitor followed by PFDA and PFOA. All three compounds are transported by NTCP, and kinetics experiments revealed that PFOA had the highest affinity for NTCP with a Km value of 1.8 ± 0.4 mM. The Km value PFNA was estimated to be 5.3 ± 3.5 mM and the value for PFDA could not be determined due to limited solubility. In conclusion, our results suggest that, in addition to sulfonates, perfluorinated carboxylates are substrates of NTCP and have the potential to interact with NTCP-mediated transport.

Formulation And In-Vitro Evaluation Of Cocrystals Of Pantoprazole Sodium For Immediate Release

Pantoprazole is extensively metabolized in the liver and has a total serum clearance of 0.1 l/h/kg, a serum elimination half-life of about 1.1 h, and an apparent volume of distribution of 0.15 L/kg. 98% of pantoprazole is bound to serum proteins. Elimination half-life, clearance, and volume of distribution are independent of the dose. Almost 80% of an oral or intravenous dose is excreted as metabolites in urine; the remainder is found in feces and originates from biliary secretion. The clearance of pantoprazole is only slightly affected by age, with its half-life being approximately 1.25 h in the elderly. Pantoprazole is an acid labile drug that requires protection from degradation in acidic media. Hence, co-crystallization of pantoprazole sodium with appropriate co-formers will inhibit its degradation in acidic medium ensuring fast release in the stomach. The acid-labile drugs for oral administration may also be protected from gastric acidity by inhibiting its degradation upon entering into acidic environment. So, the current approach includes co-crystallization of the provided drug with appropriate co-former which prevents degradation of drug by quick absorption and protects the drug from low pH. Apart from that, the formulations also modulate or control the drug release for an immediate action.
 Keywords: Pantoprazole sodium, Co-crystal, solvent drop method, Co-former.

Pharmacokinetics of Bisphenol A in Humans Following Dermal Administration

Background Human exposures to bisphenol A (BPA) are widespread. Sources include food packaging and cash register receipts. Assessments of human health risk from BPA exposure rely on pharmacokinetic data for estimation of internal dose following human exposure. We addressed uncertainties regarding human pharmacokinetics of BPA following dermal exposure through an examination of absorption, distribution, metabolism and excretion in humans following dermal administration. Methods We dermally administered deuterated BPA (d6-BPA) to 10 subjects (6 men, 4 women) at a dose of 100 µg/kg over a 12-hour period and collected blood and urine samples over a follow-up period of three or six days. Using total and unconjugated (“free”) d6-BPA concentrations in serum, we calculated the elimination half-life and area under the curve. Results Detectable serum levels of total d6-BPA and unconjugated BPA were observed at 1.4 hours and 2.8 hours, respectively, after start of dermal administration, with maximum serum concentrations (Cmax) of 3.26 nM and 0.272 nM, respectively. Beginning at approximately seven hours and continuing to 12 hours, the rate of increase in free and total serum d6-BPA slowed. The elimination half-lives of total d6-BPA and free d6-BPA were 17.9 ± 4.88 h and 14.8 ± 4.06 h, respectively. Unconjugated d6-BPA was a greater percentage of the area under the curve of total serum BPA (8.95%) compared to 0.56% in our previously published oral study. Recovery of total administered d6-BPA in urine was ~1% of the applied dose after three days. Analysis of the area under the curve for dermal and oral administration revealed 2.3% of the dermal dose became systemically available. Conclusions These data confirm predictions that pharmacokinetics of BPA differ following oral and dermal exposure. Dermal exposure resulted in a longer apparent serum elimination half-life and higher free:total d6-BPA ratio compared to oral. This abstract does not represent EPA policy.

Comparative Pharmacokinetics and bioavailability of marbofloxacin in geese (Anser Anser domesticus) after two sites of intramuscular administrations.

The pharmacokinetics of marbofloxacin (MAR) was compared in geese (Anser Anser domesticus) after single intravenous (IV) and intramuscular (IM) (thigh and pectoral muscles) administrations of 5mg/kg. Serum concentrations of MAR were determined with high-performance liquid chromatography (HPLC) method. Serum MAR concentrations versus time were analyzed by a noncompartmental method. After IV administration, MAR showed high volume of distribution at steady state (Vdss ) of 5.24±1.08L/kg. The serum body clearance (Cl) and elimination half-life (T1/2 λz) of MAR were 0.79±0.07 Lhr-1 kg-1 and 6.94±1.12hr, respectively. The peak of MAR serum concentrations Cmax achieved at one and 0.50hr after thigh and pectoral IM sites of injections, respectively, were 1.20 and 0.91μg/ml. Significant differences were found in the mean absorption time (MAT), the systemic bioavailability (F%), and elimination parameters of MAR between two sites of injections, indicating that the absorption was fairly slow and complete after thigh IM injection. The pharmacokinetics of MAR in geese diverged according to the site of IM injection following a parallel study design. We recommend the thigh muscle as IM site of injection to obtain maximum concentrations of the administered drug in geese.

Serum elimination half-lives adjusted for ongoing exposure of tri-to hexabrominated diphenyl ethers: Determined in persons moving from North America to Australia

The objective of the study was to determine the human serum elimination half-life of polybrominated diphenyl ethers (PBDEs) adjusted for ongoing exposure in subjects moving from a higher exposure region (North America) to a lower exposure region (Australia).The study population was comprised of exchange students and long-term visitors from North America moving to Brisbane, Australia (N = 27) and local residents (N = 23) who were followed by repeated serum sampling every other month. The local residents were sampled to adjust for ongoing exposure in Australia. Only one visitor remained in Australia for a period of time similar to the elimination half-life and had a sufficiently high initial concentration of PBDEs to derive a half-life. This visitor arrived in Australia in March of 2011 and remained in the country for 1.5 years. Since the magnitude of PBDE exposure is lower in Australia than in North America we observed an apparent 1st order elimination curve over time from which we have estimated the serum elimination half-lives for BDE28, BDE47, BDE99, BDE100, and BDE153 to be 0.942, 1.19, 1.03, 2.16, and 4.12 years, respectively. Uncertainty in the estimates were estimated using a Monte Carlo simulation. The human serum elimination half-life adjusted for ongoing exposure can allow us to assess the effectiveness and reduction in exposure in the general population following phase out of commercial penta- and octaBDE in 2004 in the United States.

Abstract B111: Characterization of APVO436, a bispecific anti-CD123 x anti-CD3 ADAPTIR™ molecule for redirected T-cell cytotoxicity, in preclinical models of AML and nonhuman primates

Abstract Introduction: CD123 has emerged as a promising target for T-cell directed immunotherapy in acute myeloid leukemia due to its high level of expression on leukemic blasts and stem cells and low frequency of expression on normal cell types. CD123 is expressed by rare normal leukocyte populations, including basophils and plasmacytoid dendritic cells in circulation and hematopoietic progenitor cells in the bone marrow. We have developed APVO436, a bispecific anti-CD123 x anti-CD3 ADAPTIR molecule for redirecting T-cell cytotoxicity to CD123-expressing tumor cells. Results are presented that examine the in vitro and in vivo activity of APVO436 in preclinical models of AML, as well as pharmacokinetics and tolerability in nonhuman primates. Methods: CHO-produced APVO436 protein was used for in vitro functional studies with CD123+ AML tumor cell lines and primary human T-cell populations. Cytotoxic activity was determined using chromium release assays. On-cell binding, T-cell activation and proliferation were assessed using multicolor flow cytometry. Cytokine levels were measured using multiplex assay kits. In vivo studies to examine tumor growth inhibition activity were performed using NSG mice with established AML tumors followed by treatment with APVO436 coadministered with T cells. Tumor growth was assessed by bioluminescent imaging. In vivo studies to determine pharmacokinetics of APVO436 following single intravenous injections were performed in healthy BALB/c mice and cynomolgus monkeys. Results: APVO436 bound to CD123 and CD3 expressing cells with high affinity. APVO436 induced concentration-dependent lysis of CD123+ AML cell lines with primary human T cells at low effector-to-target ratios, accompanied by T-cell activation and proliferation. These activities were dependent on the expression of CD123 by the tumor target cells. Treatment of established disseminated tumors in mice with APVO436 resulted in a significant reduction in tumor burden. A single 10 mg/kg IV injection of APVO436 in normal BALB/c mice demonstrated an extended elimination serum half-life of approximately 300 hours. Single IV injections of APVO436 ranging from 0.25 mg/kg to 1 mg/kg were well tolerated in cynomolgus monkeys. The observed elimination half-life in cynomolgus serum was up to 84 hours with normal clearance and volume distribution. Conclusions: These data demonstrate APVO436 has potent in vitro activity against a number of CD123-expressing tumor cell lines and in vivo significantly reduces established tumor burden in xenograft models. APVO436 demonstrates an extended serum half-life in normal mice and cynomolgus monkeys. These data are supportive of further investigation of APVO436 as a potential treatment option for AML and other hematologic malignancies. Citation Format: Michael R. Comeau, Robert E. Miller, Jeannette Bannink, Starrla Johnson, Robert Bader, Rebecca Gottschalk, Lynda Misher, Danielle Mitchell, Lara Parr, Melissa DeFrancesco, David Bienvenue, Catherine J. McMahan, Gabriela H. Hoyos, Jane A. Gross. Characterization of APVO436, a bispecific anti-CD123 x anti-CD3 ADAPTIR™ molecule for redirected T-cell cytotoxicity, in preclinical models of AML and nonhuman primates [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B111.

Abstract 597: Bispecific anti-CD123 x anti-CD3 ADAPTIR™ molecules for redirected T-cell cytotoxicity in hematological malignancies

Abstract Introduction: CD123 is a component of the IL-3 receptor expressed in several hematological malignancies including AML, ALL, HCL, and MDS. CD123 is a compelling target in AML due to its overexpression on AML blasts as well as leukemic stem cells, which are thought to be resistant to chemotherapy and may be responsible for relapse of disease following treatment. While CD123 is expressed by some normal leukocyte populations in circulation and hematopoietic progenitor cells in the bone marrow, the low frequency of expression on normal cell types provides a therapeutic window for targeting CD123 in tumor settings with the potential for durable response and reversible side effects. We have developed bispecific anti-CD123 x anti-CD3 ADAPTIR molecules APVO436 and APVO437 for redirecting T-cell cytotoxicity to CD123-expressing tumor cells. Results are presented that examine the in vitro and in vivo activity of these molecules in preclinical models of AML. Methods: APVO436 and APVO437 proteins were expressed in CHO cells. Affinity SPR studies were performed using recombinant CD123-ectodomain. In vitro functional studies were conducted with CD123+ AML tumor cell lines and primary human and cynomolgus macaque T-cell populations. Cytotoxic activity was determined using chromium release assays. On-cell binding, T-cell activation and proliferation were assessed using multi-color flow cytometry. Pharmacokinetic parameters were determined in BALB/c mice using a single IV dose of approximately 10 mg/kg. In vivo studies to examine tumor growth inhibition activity were performed with NOD/SCID mice co-implanted subcutaneously with AML tumor cells and human T-cells followed by treatment with APVO436 or APVO437. Tumor growth was assessed by measuring tumor volume and Bioluminescent Imaging. Results: APVO436 and APVO437 bound human CD123 protein with high affinity and binding to CD123 and CD3 expressing cell lines was confirmed by flow cytometry. Both APVO436 and APVO437 induced concentration-dependent lysis of CD123+ AML cell lines with primary human effector T-cells, accompanied by T-cell activation and proliferation. Comparable redirected T-cell cytotoxicity function was observed using primary cynomolgus macaque T cells. These activities were dependent on the expression of CD123 by the tumor target cells. APVO436 and APVO437 demonstrated an extended elimination half-life in mouse serum, typical of molecules capable of binding the neo-natal Fc receptor. In vivo, growth of AML tumor cells was inhibited by treatment with low doses of APVO436 and APVO437, significantly improving host survival. Conclusion: Taken together these data demonstrate potent in vitro and in vivo activity of APVO436 and APVO437 against CD123 expressing tumor cells and are supportive of further investigation of this approach as a potential treatment option for AML and other hematological malignancies. Citation Format: Michael R. Comeau, Danielle Mitchell, Rebecca Gottschalk, Lynda Misher, Mollie Daugherty, Lara Parr, Peter Pavlik, Brian Woodruff, Hang Fang, Megan Aguilar, Jeannette Bannink, Starrla Johnson, Gary Li, Robert E. Miller, Robert Bader, Nicole Zhang, Toddy Sewell, Maria Dasovich, Gabriela H. Hoyos, John W. Blankenship, Catherine McMahan, David Bienvenue, Jane A. Gross. Bispecific anti-CD123 x anti-CD3 ADAPTIR™ molecules for redirected T-cell cytotoxicity in hematological malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 597. doi:10.1158/1538-7445.AM2017-597

Organic Anion Transporting Polypeptides Contribute to the Disposition of Perfluoroalkyl Acids in Humans and Rats.

Perfluoroalkyl sulfonates (PFSAs) such as perfluorohexane sulfonate (PFHxS) and perfluorooctane sulfonate (PFOS) have very long serum elimination half-lives in humans, and preferentially distribute to serum and liver. The enterohepatic circulation of PFHxS and PFOS likely contributes to their extended elimination half-lives. We previously demonstrated that perfluorobutane sulfonate (PFBS), PFHxS, and PFOS are transported into hepatocytes both in a sodium-dependent and a sodium-independent manner. We identified Na+/taurocholate cotransporting polypeptide (NTCP) as the responsible sodium-dependent transporter. Furthermore, we demonstrated that the human apical sodium-dependent bile salt transporter (ASBT) contributes to the intestinal reabsorption of PFOS. However, so far no sodium-independent uptake transporters for PFSAs have been identified in human hepatocytes or enterocytes. In addition, perfluoroalkyl carboxylates (PFCAs) with 8 and 9 carbons were shown to preferentially distribute to the liver of rodents; however, no rat or human liver uptake transporters are known to transport these PFCAs. Therefore, we tested whether PFBS, PFHxS, PFOS, and PFCAs with 7-10 carbons are substrates of organic anion transporting polypeptides (OATPs). We used CHO and HEK293 cells to demonstrate that human OATP1B1, OATP1B3, and OATP2B1 can transport PFBS, PFHxS, PFOS, and the 2 PFCAs (C8 and C9). In addition, we show that rat OATP1A1, OATP1A5, OATP1B2, and OATP2B1 transport all 3 PFSAs. In conclusion, our results suggest that besides NTCP and ASBT, OATPs also are capable of contributing to the enterohepatic circulation and extended human serum elimination half-lives of the tested perfluoroalkyl acids.

MOR209/ES414, a Novel Bispecific Antibody Targeting PSMA for the Treatment of Metastatic Castration-Resistant Prostate Cancer.

Treatment of metastatic, castration-resistant prostate cancer (mCRPC) remains a highly unmet medical need and current therapies ultimately result in disease progression. Immunotherapy is a rapidly growing approach for treatment of cancer but has shown limited success to date in the treatment of mCRPC. We have developed a novel humanized bispecific antibody, MOR209/ES414, built on the ADAPTIR (modular protein technology) platform, to redirect T-cell cytotoxicity toward prostate cancer cells by specifically targeting T cells through CD3ε to prostate cancer cells expressing PSMA (prostate-specific membrane antigen). In vitro cross-linking of T cells with PSMA-expressing tumor cells by MOR209/ES414 triggered potent target-dependent tumor lysis and induction of target-dependent T-cell activation and proliferation. This activity occurred at low picomolar concentrations of MOR209/ES414 and was effective at low T-effector to tumor target cell ratios. In addition, cytotoxic activity was equivalent over a wide range of PSMA expression on target cells, suggesting that as few as 3,700 PSMA receptors per cell are sufficient for tumor lysis. In addition to high sensitivity and in vitro activity, MOR209/ES414 induced limited production of cytokines compared with other bispecific antibody formats. Pharmacokinetic analysis of MOR209/ES414 demonstrated a serum elimination half-life in NOD/SCID γ (NSG) mice of 4 days. Administration of MOR209/ES414 in murine xenograft models of human prostate cancer significantly inhibited tumor growth, prolonged survival, and decreased serum prostate-specific antigen levels only in the presence of adoptively transferred human T cells. On the basis of these preclinical findings, MOR209/ES414 warrants further investigation as a potential therapeutic for the treatment of CRPC. Mol Cancer Ther; 15(9); 2155-65. ©2016 AACR.

Disposition of the anti-ulcer medications ranitidine, cimetidine, and omeprazole following administration of multiple doses to exercised Thoroughbred horses.

The use of anti-ulcer medications, such as cimetidine, ranitidine, and omeprazole, is common in performance horses. The use of these drugs is regulated in performance horses, and as such a withdrawal time is necessary prior to competition to avoid a medication violation. To the authors' knowledge, there are no reports in the literature describing repeated oral administrations of these drugs in the horse to determine a regulatory threshold and related withdrawal time recommendations. Therefore, the objective of the current study was to describe the disposition and elimination pharmacokinetics of these anti-ulcer medications following oral administration to provide data upon which appropriate regulatory recommendations can be established. Nine exercised Thoroughbred horses were administered 20mg/kg BID of cimetidine or 8mg/kg BID of ranitidine, both for seven doses or 2.28g of omeprazole SID for four doses. Blood samples were collected, serum drug concentrations were determined, and elimination pharmacokinetic parameters were calculated. The serum elimination half-life was 7.05±1.02, 7.43±0.851 and 3.94±1.04h for cimetidine, ranitidine, and omeprazole, respectively. Serum cimetidine and ranitidine concentrations were above the LOQ and omeprazole and omeprazole sulfide below the LOQ in all horses studied upon termination of sample collection.

Elimination of cetirizine following administration of multiple doses toexercised thoroughbred horses.

Cetirizine is an antihistamine used in performance horses for the treatment of hypersensitivity reactions and as such a withdrawal time is necessary prior to competition. The objective of the current study was to describe the disposition and elimination of cetirizine following oral administration in order to provide additional serum concentration data upon which appropriate regulatory recommendations can be established. Nine exercised thoroughbred horses were administered 0.4mg/kg of cetirizine orally BID for a total of five doses. Blood samples were collected immediately prior to drug administration and at various times postadministration. Serum cetirizine concentrations were determined and selected pharmacokinetic parameters determined. The serum elimination half-life was 5.83±0.841h. Average serum cetirizine concentrations were still above the LOQ of the assay (0.05ng/mL) at 48h (final sample collected) postadministration of the final dose.

Pharmacokinetics of guaifenesin following administration of multiple doses to exercised Thoroughbred horses.

Guaifenesin is an expectorant commonly used in performance horses to aid in the clearance of mucus from the airways. Guaifenesin is also a centrally acting skeletal muscle relaxant and as such is a prohibited drug with withdrawal necessary prior to competition. To the authors' knowledge, there are no reports in the literature describing single or multiple oral administrations of guaifenesin in the horse to determine a regulatory threshold and related withdrawal time. Therefore, the objective of the current study was to describe the pharmacokinetics of guaifenesin following oral administration in order to provide data upon which appropriate regulatory recommendations can be established. Nine exercised Thoroughbred horses were administered 2g of guaifenesin orally BID for a total of five doses. Blood samples were collected immediately prior to drug administration and at various times postadministration. Serum guaifenesin concentrations were determined and pharmacokinetic parameters calculated. Guaifenesin was rapidly absorbed (Tmax of 15min) following oral administration. The Cmax was 681.3±323.8ng/mL and 1080±732.8 following the first and last dose, respectively. The serum elimination half-life was 2.62±1.24h. Average serum guaifenesin concentrations remained above the LOQ of the assay (0.5ng/mL) by 48h postadministration of the final dose in 3 of 9 horses.

Milk and serum concentration of ceftiofur following intramammary infusion in goats.

Five dairy goats were used to determine the milk and serum concentrations along with elimination characteristics of ceftiofur following intramammary administration. One udder half of each goat was infused twice with 125mg ceftiofur with a 24-h interval between infusions. Milk samples were collected at 1, 2, 8, and 12h after the last infusion and then every 12h for a total of 7days. Blood was collected from each animal at 3, 8, 12, and 24h after infusion and then every 24h for 6days. Following a washout period of 1week, the experiment was repeated using the opposite udder half. The elimination half-life of ceftiofur from the mammary gland was 4.7h. The concentration of ceftiofur was greater than published MIC90 values for Staphylococcus spp. bacteria for 24h. Ceftiofur was absorbed into systemic circulation from the mammary gland. The maximum concentration was 552ng/mL at 3h after infusion, and the serum elimination half-life was 10h. Intramammary infusion of 125mg ceftiofur every 24h can be expected to maintain drug concentration in milk above published MIC90 for Staphylococcus spp.

Use of in vitro vancomycin testing results to predict susceptibility to oritavancin, a new long-acting lipoglycopeptide.

Oritavancin is a recently approved lipoglycopeptide antimicrobial agent with activity against Gram-positive pathogens. Its extended serum elimination half-life and concentration-dependent killing enable single-dose treatment of acute bacterial skin and skin structure infections. At the time of regulatory approval, new agents, including oritavancin, are not offered in the most widely used susceptibility testing devices and therefore may require application of surrogate testing using a related antimicrobial to infer susceptibility. To evaluate vancomycin as a predictive susceptibility marker for oritavancin, 26,993 recent Gram-positive organisms from U.S. and European hospitals were tested using reference MIC methods. Organisms included Staphylococcus aureus, coagulase-negative staphylococci (CoNS), beta-hemolytic streptococci (BHS), viridans group streptococci (VGS), and enterococci (ENT). These five major pathogen groups were analyzed by comparing results with FDA-approved susceptible breakpoints for both drugs, as well as those suggested by epidemiological cutoff values and supported by pharmacokinetic/pharmacodynamic analyses. Vancomycin susceptibility was highly accurate (98.1 to 100.0%) as a surrogate for oritavancin susceptibility among the indicated pathogen species. Furthermore, direct MIC comparisons showed high oritavancin potencies, with vancomycin/oritavancin MIC90 results of 1/0.06, 2/0.06, 0.5/0.12,1/0.06, and >16/0.06 μg/ml for S. aureus, CoNS, BHS, VGS, and ENT, respectively. In conclusion, vancomycin demonstrated acceptable accuracy as a surrogate marker for predicting oritavancin susceptibility when tested against the indicated pathogens. In contrast, 93.3% of vancomycin-nonsusceptible enterococci had oritavancin MIC values of ≤0.12 μg/ml, indicating a poor predictive value of vancomycin for oritavancin resistance against these organisms. Until commercial oritavancin susceptibility testing devices are readily available, isolates that when tested show vancomycin susceptibility can be inferred to be susceptible to oritavancin by using FDA-approved breakpoints.

Perinatal exposure to perfluorooctane sulfonate affects glucose metabolism in adult offspring.

Perfluoroalkyl acids (PFAAs) are globally present in the environment and are widely distributed in human populations and wildlife. The chemicals are ubiquitous in human body fluids and have a long serum elimination half-life. The notorious member of PFAAs, perfluorooctane sulfonate (PFOS) is prioritized as a global concerning chemical at the Stockholm Convention in 2009, due to its harmful effects in mammals and aquatic organisms. PFOS is known to affect lipid metabolism in adults and was found to be able to cross human placenta. However the effects of in utero exposure to the susceptibility of metabolic disorders in offspring have not yet been elucidated. In this study, pregnant CD-1 mice (F0) were fed with 0, 0.3 or 3 mg PFOS/kg body weight/day in corn oil by oral gavage daily throughout gestational and lactation periods. We investigated the immediate effects of perinatal exposure to PFOS on glucose metabolism in both maternal and offspring after weaning (PND 21). To determine if the perinatal exposure predisposes the risk for metabolic disorder to the offspring, weaned animals without further PFOS exposure, were fed with either standard or high-fat diet until PND 63. Fasting glucose and insulin levels were measured while HOMA-IR index and glucose AUCs were reported. Our data illustrated the first time the effects of the environmental equivalent dose of PFOS exposure on the disturbance of glucose metabolism in F1 pups and F1 adults at PND 21 and 63, respectively. Although the biological effects of PFOS on the elevated levels of fasting serum glucose and insulin levels were observed in both pups and adults of F1, the phenotypes of insulin resistance and glucose intolerance were only evident in the F1 adults. The effects were exacerbated under HFD, highlighting the synergistic action at postnatal growth on the development of metabolic disorders.

Comprehensive update of dalbavancin activity when tested against uncommonly isolated streptococci, Corynebacterium spp., Listeria monocytogenes, and Micrococcus spp. (1357 strains)

Dalbavancin is an investigational lipoglycopeptide having an extended serum elimination half-life allowing once-weekly dosing. Data from testing 1357 strains of uncommonly isolated species expand the dalbavancin spectrum details as follows (MIC50/90): β-haemolytic streptococcal serogroups C, F, and G (≤0.03/≤0.03 μg/mL), 7 viridans group of streptococci (≤0.03/≤0.03–0.06 μg/mL), 5 Corynebacterium spp. (0.06/0.12 μg/mL), Listeria monocytogenes (0.06/0.12 μg/mL), and Micrococcus spp. (≤0.03/≤0.03 μg/mL). Among all reported isolates, 99.8% of tested strains were inhibited at dalbavancin MIC values at ≤0.12 μg/mL. Dalbavancin remains very potent against rarer Gram-positive pathogens, using in vitro test experience with organisms cultured through 2011.

Evidence for rituximab (R) underdosing in subpopulations of elderly patients with DLBC: Results of the RICOVER-60 study of the DSHNHL.

8024 Background: Gender and weight independently influence R clearance and R serum elimination half life (Mueller et al., Blood 2012). To investigate whether the differences in R pharmacokinetics translate into different outcomes, we analyzed elderly patients (pts) with different R pharmacokinetics treated in the RICOVER-60 study. Methods: 1222 elderly pts. (61-80 y) were randomized to receive 6 or 8 cycles of CHOP-14 with or without R given on days 1, 15, 29, 43, 57, 71, 85, and 99. For this study, subgroup analyses were performed for pts with faster R clearance: elderly male (vs. female) pts and elderly weighty (upper quartile: >77kg) vs. slim (lower quartile: ≤60 kg) female pts. Results: Elderly females had a slower R clearance (8.21 ml/h vs. 12.68 ml/h; p=0.003) and a prolonged R half life compared to men (t1/2ß=30.7 vs. t1/2ß=24.7 d; p=0.003). Female pts had a higher 3-year PFS (68% vs. 61%; p=0.062) and OS (74% vs. 68% p=0.086). The differences in outcome were due to a greater outcome improvement by the addition of R in females: the difference in 3-year PFS between female and male pts was 5.1% (p=0.448) in pts. receiving CHOP-14 only and 7.7% (p=0.053) when R was added. In a multivariate analysis the relative risk for progression in male compared to female patients was not significantly elevated after CHOP-14 (1.1; p=0.348), but was significantly higher after R-CHOP-14 (1.6; p=0.004). With respect to weight, addition of R resulted in a significantly improved 3-year PFS (74% vs. 49%; p=0.006) in female pts with a body weight within the lower quartile (≤60 kg) who have an R serum half life of >38.1 days, while there was no improvement by the addition of R (72% vs. 71%; p=0.816) in female pts. with a body weight within the upper quartile (>77kg), who have a serum half life of <29.3 days. Conclusions: The reduced benefit of adding R to CHOP in elderly DLBCL pts. with a shorter rituximab serum half life (and hence lower serum levels) suggests that the respective subpopulations (males and weighty females) are underdosed when R is dosed based on body surface area at 375 mg/m2. Ongoing studies of the DSHNHL investigate whether higher R doses for pts with a shorter R serum half life can improve the outcome of the respective pts.