Average Steady-state Concentration Research Articles

Abstract B188: Pharmacokinetic assessment of drug-drug interaction potential when rosiglitazone or combined oral contraceptive is coadministered with vismodegib in patients with locally advanced or metastatic solid tumors.

Abstract Vismodegib is a first-in-class small molecule Hedgehog pathway inhibitor that is being developed for the treatment of advanced basal cell carcinoma. In a previous phase I study for patients with advanced malignancies, vismodegib was well tolerated and tumor regressions were seen in patients with advanced basal cell carcinoma and medulloblastoma. In vitro, vismodegib inhibits CYP2C8 with a Ki of 6.0 μM, which was the most potent relative to other CYP isoforms. With the average steady-state plasma concentration of total vismodegib being approximately 20 μM, inhibition of CYP2C8 by vismodegib may be important when patients are taking drugs known to be metabolized by CYP2C8. Furthermore, while vismodegib was not shown to induce CYP enzymes in vitro, it is a known teratogen. A DDI assessment with combined oral contraceptive (OC) was therefore conducted to ensure efficacious levels of OC would be maintained in patients taking vismodegib and OC in combination. This single-arm study consisted of two cohorts; 24 patients took 4 mg rosiglitazone (a known CYP2C8 substrate) and 27 patients took OC (norethindrone 1 mg/ethinyl estradiol 35 mcg, Ortho-Novum 1/35®). On Day 1 patients took rosiglitazone or OC followed by extensive PK sampling for 24 hrs. From Day 2 to Day 7 patients took 150 mg vismodegib once per day. On Day 8 patients took either vismodegib and rosiglitazone or vismodegib and OC followed by extensive PK sampling for 24 hrs. From Day 9 onward patients took vismodegib until disease progression or lack of benefit. The primary objective of this study was to evaluate the relative effect of vismodegib on AUC and Cmax for rosiglitazone and OC (ethinyl estradiol and norethindrone). The average steady state plasma concentration of total vismodegib (N=51) was 20.6 μM (range, 7.93 − 62.4 μM). There was no clinically meaningful difference in rosiglitazone PK parameters between Day 1 (without vismodegib) and Day 8 (with vismodegib) with a less than 10% difference in AUCinf and Cmax, on average. The geometric mean ratios (GMRs) for rosiglitazone AUC0−inf and Cmax were 93.1 and 93.4 with corresponding 90% confidence intervals (CIs) of (85.0, 102) and (89.4, 97.6), respectively. Concomitant administration of vismodegib with OC did not strongly impact the plasma concentrations of ethinyl estradiol or norethindrone, as evidenced by a less than 20% change in AUCinf and Cmax, on average, for both components. The GMRs for ethinyl estradiol AUC0−inf and Cmax were 99.3 and 106 with corresponding 90% CIs of (91.9, 107) and (94.8, 117), respectively while the GMRs for norethindrone AUC0−inf and Cmax were 124 and 112 with corresponding 90% CIs of (116, 132) and (101, 124), respectively. In the current study, the steady state plasma concentration of total vismodegib was above the in vitro Ki for CYP2C8. In addition, daily dosing of 150 mg vismodegib for 7 days should have been adequate to result in enzyme induction, if applicable. Overall, results from this study indicate that there was no clinically meaningful difference in AUC0−inf and Cmax for rosiglitazone, ethinyl estradiol, or norethindrone when co-administered with vismodegib. Taken together these results suggest that vismodegib can be co-administered with CYP substrates and combined oral contraceptive without the risk of a pharmacokinetic DDI. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B188.

Electrochemical Impedance Spectroscopy of Liquid Tin Anode Solid Oxide Fuel Cell

Solid oxide fuel cells (SOFCs) can convert the chemical energy stored in hydrocarbon fuels directly into electricity bypassing the many energy transfers that normally occur, (chemical→ heat (steam boiler)→ mechanical (turbine)→ electrical (generator)), when hydrocarbon fuels are combusted to produce electricity. CellTech Power has developed a liquid tin anode (LTA) SOFC that is not damaged by fuels that contain sulfur. This paper develops an analytical electrochemical impedance spectroscopy model from first principals for the the LTA-SOFC anode half cell. The model is in conjunction with experimental data to determine; the average Ohmic resistance, 8.81mΩ, average steady state concentration of tin oxide in liquid tin, 1.09E-9 mol/cm3, effective diffusion coefficient of tin oxide through liquid tin, 0.198 cm2/s, and the pre-exponential factor for the butler volmer equation 2.92E5 C*cm/mol/s.

Essential Requirement for PP2A Inhibition by the Oncogenic Receptor c-KIT Suggests PP2A Reactivation as a Strategy to Treat c-KIT+ Cancers — Letter

In the article by Roberts and colleagues (1), the authors demonstrated that inhibition of protein phosphatase 2A (PP2A) was required for survival of myeloid cells expressing mutant KIT. Restoration of PP2A activity by FTY720 (fingolimod; Novartis) was cytotoxic to these cells. The U.S. Food and Drug Administration (FDA) has just approved fingolimod as treatment for relapsing forms of multiple sclerosis (MS) at 0.5 mg daily dose based on the results of 2 phase 3 clinical trials (2, 3). In view of the FDA approval and the work by Roberts and colleagues, there is clear potential for FTY720 as a therapeutic agent for KIT-expressing tumors.Our group focuses on preclinical and clinical development of new therapeutic approaches for patients with gastrointestinal stromal tumor (GIST), a sarcoma driven by KIT gain-of-function mutations. The standard-of-care for patients with advanced GIST is imatinib mesylate but most patients develop resistance after about 2 years (4). As such, we believe that dephosphorylation and inactivation of KIT induced by PP2A activation offers an attractive therapeutic strategy for patients with GIST. However, we are cautiously optimistic about the clinical applicability of FTY720 as proposed by Roberts and colleagues. Specifically, the IC50 of FTY720 for murine FDC-P1 cells expressing the imatinib-resistant D816V mutant KIT was found to be 2.4 μmol/L (737.9 ng/mL). Similarly, the IC50 ranged between 3.4 and 4.9 μmol/L in human leukemia cell lines expressing mutant KIT. Although effective in vitro, these concentrations exceed that obtained in clinical trials and would require higher oral dosing than has been reported. In a pooled pharmacokinetic analysis of the phase III studies for MS the average steady-state plasma concentrations of FTY720 at doses of 0.5 and 1.25 mg were 2 to 3 and 5 to 6 ng/mL, respectively (2, 3).This prompted us to evaluate FTY720 in a panel of previously-described GIST cells (Table 1) harboring imatinib-sensitive and -resistant KIT mutations (5). Although FTY720 was significantly cytotoxic, achieving 80% to 95% inhibition in all GIST cell lines, the concentration required for antitumor efficacy was 10 μmol/L. The IC50 of FTY720 at 72 hours ranged between 2.9 and 3.9 μmol/L in GIST cells.In summary, we feel that PP2A-reactivation is a promising approach in GIST but will require higher doses of FTY720 than that observed in patients with MS. Although we hope that this agent will prove active in the treatment of patients with GIST, we also hope that these issues are considered in the design of clinical trials for patients with GIST.See the Response, p. 2404GIST-T1 cells were kindly provided by Drs. Andrew Godwin and Takahiro Taguchi, GIST882 by Dr. Jonathan Fletcher, and GIST48IM and GIST430IM by Dr. Anette Duensing.

Pharmacokinetic and Pharmacodynamic Interaction Between Allopurinol and Probenecid in Patients with Gout

To investigate the pharmacokinetic and pharmacodynamic interaction between probenecid and oxypurinol (the active metabolite of allopurinol) in patients with gout. This was an open-label observational clinical study. Blood and urine samples were collected to measure oxypurinol and urate concentrations. We examined the effects of adding probenecid to allopurinol therapy upon plasma concentrations and renal clearances of urate and oxypurinol. Twenty patients taking allopurinol 100-400 mg daily completed the study. Maximum coadministered doses of probenecid were 250 mg/day (n = 1), 500 mg/day (n = 19), 1000 mg/day (n = 7), 1500 mg/day (n = 3), and 2000 mg/day (n = 1). All doses except the 250 mg daily dose were divided and dosing was twice daily. Estimated creatinine clearances ranged from 28 to 113 ml/min. Addition of probenecid 500 mg/day to allopurinol therapy decreased plasma urate concentrations by 25%, from mean 0.37 mmol/l (95% CI 0.33-0.41) to mean 0.28 mmol/l (95% CI 0.24-0.32) (p < 0.001); and increased renal urate clearance by 62%, from mean 6.0 ml/min (95% CI 4.5-7.5) to mean 9.6 ml/min (95% CI 6.9-12.3) (p < 0.001). Average steady-state plasma oxypurinol concentrations decreased by 26%, from mean 11.1 mg/l (95% CI 5.0-17.3) to mean 8.2 mg/l (95% CI 4.0-12.4) (p < 0.001); and renal oxypurinol clearance increased by 24%, from mean 12.7 ml/min (95% CI 9.6-15.8) to mean 16.1 ml/min (95% CI 12.0-20.2) (p < 0.05). The additional hypouricemic effect of probenecid 500 mg/day appeared to be lower in patients with renal impairment. Coadministration of allopurinol with probenecid had a significantly greater hypouricemic effect than allopurinol alone despite an associated reduction of plasma oxypurinol concentrations. Australian Clinical Trials Registry ACTRN012606000276550.

Technical Note: An Algorithm for the Detection of Steady-State Measurements of Gas Emissions From Compost

High concentrations of carbon monoxide (CO) have been observed in the enclosed composting facility at the Edmonton Waste Management Centre in Alberta, Canada. An elevated concentration of CO in the facility is a potential health threat to workers. Research was conducted to assess the temporal and spatial variability of CO emissions from the composting bays, using Fourier Transform Infrared spectroscopy. Repeated gas measurements of CO, CO2, and CH4 were taken above and inside the compost bed using a metal gas probe. The probe was connected to the FTIR gas analyzer, which continuously collected gas concentration data. The data collected using the FTIR resulted in a continuous time series of gas measurements, where the peaks in the data signal corresponded to gas measurements taken inside the compost, and valleys represented the gas measurements taken above the compost bed. This article describes the algorithm that was devised to determine the gas concentrations at each sampling location using the MATLAB® programming environment. The algorithm was able to successfully identify the sampling locations from the continuous gas measurement data, and determine the average steady-state gas concentration above and inside of the composting bays for CO, CO2, and CH4.

Assessment of Bisphenol a Exposure in Korean Pregnant Women by Physiologically Based Pharmacokinetic Modeling

The objective of this study was to predict the exposure to bisphenol A (BPA) after oral intake in human blood and tissues using physiologically based pharmacokinetic (PBPK) modeling. A refined PBPK model was developed taking into account of glucuronidation, biliary excretion, and slow absorption of BPA in order to describe the second peak of BPA observed following oral intake. This developed model adequately described the second peak and BPA concentrations in blood and various tissues in rats after oral administration. A prospective validation study in rats additionally supported the proposed model. For extrapolation to humans, a daily oral BPA dose of 0.237 mg/70 kg/d or 0.0034 mg/kg/d was predicted to achieve an average steady-state blood concentration of 0.0055 ng/ml (median blood BPA concentration in Korean pregnant women). This dose was lower than the reference dose (RfD, 0.016 mg/kg/d) and the tolerable daily intake established by the European Commission (10 μg/kg/d). Data indicate that enterohepatic recirculation may be toxicologically important as this pathway may increase exposure and terminal half-life of BPA in humans.

A population pharmacokinetic evaluation of the influence of CYP2D6 genotype on risperidone metabolism in patients with acute episode of schizophrenia

The objective of this prospective study was to characterize the metabolism of risperidone to (+)− and (−)−9-hydroxyrisperidone in vivo and to evaluate the influence of CYP2D6 genotype. A population pharmacokinetic modeling approach was used to estimate the interindividual variability of the pharmacokinetic parameters in 50 hospitalized patients with acute episode of schizophrenia. CYP2D6 genotype remarkably influenced the formation clearances of the risperidone metabolites, while creatinine clearance was related to the plasma clearance of 9-hydroxyrisperidone. CYP2D6 genotype was also associated with the average plasma concentration of risperidone active moiety (a sum of all three active compounds). In comparison to the patients with CYP2D6*1/*1 genotype, average steady-state plasma concentration of risperidone active moiety was 3.3- and 1.6-fold higher in poor metabolizers (both alleles nonfunctional; CYP2D6*3 or *4) and intermediate metabolizers (one nonfunctional allele and one allele for diminished enzyme activity; CYP2D6*10 or *41), respectively. Additionally, average plasma concentration of risperidone active moiety was higher in the patients with dystonia ( p = 0.0066) and parkinsonism ( p = 0.046). The results of this study imply the potential role of CYP2D6 genotyping in personalizing risperidone therapy in patients with schizophrenia to reduce the incidence of adverse extrapyramidal symptoms.

Rate and Extent of Drug Accumulation after Multiple Dosing Revisited

For drugs that have a narrow therapeutic margin in their concentration-effect profile, blood concentration measurements can be an invaluable guide to the individualization of dosage regimens. For clinicians involved in therapeutic drug monitoring, background knowledge of basic pharmacokinetics related to drug behaviour with repeated dose regimens is crucial, especially recognition of the factors affecting the rate and extent of drug accumulation, which ultimately determine the steady-state drug concentrations in the blood. Much of the available literature describing accumulation focuses on average steady-state concentrations or its related parameter, the area under the blood/plasma concentration-time curve. However, in practice, for most drugs, it is the individual concentrations at different times within each dosing interval at steady state that can be more predictive of the effectiveness and/or toxicity of the drug. Furthermore, most reference textbooks describe accumulation in terms of drugs that follow a one-compartment model with bolus administration, whereas the mode of dose administration can have an impact on measures of accumulation in a manner that differs from intravascular bolus dosing. Additionally, the accumulation kinetics in the plasma are profoundly influenced by multicompartment or nonlinear pharmacokinetics. Another consideration in accumulation kinetics is how tissue concentrations might be influenced by repeated doses - which, as shown in this review, can have clinical ramifications. In this article, drug accumulation is reviewed in a comprehensive manner, and the influences of the route of administration, nonlinear elimination and tissue concentrations are discussed.

Pharmacokinetics of penicillin antibiotics: intravenous-to-oral switch therapy

Farmakokinetika Penicilinskih Antibiotikov: Preklop iz Intravenske na Peroralno Terapijo Penicilinski antibiotiki delujejo baktericidno in spadajo med časovno odvisne antibiotike. Za večino penicilinov je značilna kratka razpolovna doba eliminacije. Benzilpenicilini se po peroralni aplikaciji ne absorbirajo, ampicilin in kloksacilin se sicer absorbirata, vendar slabo, medtem ko se amoksicilin skoraj v celoti absorbira. Pri slednjem je smotrno z intravenske terapije preklopiti na peroralno, če lahko s peroralno aplikacijo dosežemo plazemske koncentracije penicilina, primerljive s tistimi po intravenski aplikaciji, t. j. enako povprečno plazemsko koncentracijo penicilina v stacionarnem stanju. Posledično lahko pričakujemo enako učinkovitost obeh aplikacij. Smiselnost preklopne terapije je treba proučiti predvsem s stališča bolnika, saj ni primerna za bolnike, ki so v kritičnem stanju in imajo močno zvišano telesno temperaturo ali malabsorbcijski sindrom. Prednost preklopne terapije pa je v tem, da zmanjša pojavnost flebitisa in seps. V članku sta obravnavana dva primera preklopne terapije. Na osnovi farmakokinetičnih simulacij in indeksov učinkovitosti protibakterijskega zdravljenja je pokazana primerljivost intravenske terapije z ampicilinom in peroralne terapije z amoksicilinom, medtem ko preklopna terapija pri zdravljenju osteomielitisa s kloksacilinom ostaja nedorečena. Na podlagi predstavljenih primerov članek ilustrativno prikazuje, da ustrezna razlaga farmakokinetičnih parametrov bistveno pripomore k pravočasnemu preklopu z intravenske na peroralno terapijo s penicilinom. Takšna terapija je bolniku bolj prijazna, poleg tega pa prispeva k zniževanju stroškov za zdravljenje z zdravili v bolnišnicah ob še vedno varni in učinkoviti farmakoterapiji bakterijskih okužb.

Pharmacokinetics of Acyclovir and Its Metabolites in Cerebrospinal Fluid and Systemic Circulation after Administration of High-Dose Valacyclovir in Subjects with Normal and Impaired Renal Function

Valacyclovir, the L-valyl ester prodrug of acyclovir (ACV), is widely prescribed to treat infections caused by varicella-zoster virus or herpes simplex virus. Rarely, treatment is complicated by reversible neuropsychiatric symptoms. By mechanisms not fully understood, this occurs more frequently in the setting of renal impairment. We characterized the steady-state pharmacokinetics of ACV and its metabolites 9-[(carboxymethoxy)methyl]guanine (CMMG) and 8-hydroxy-acyclovir (8-OH-ACV) in cerebrospinal fluid (CSF) and the systemic circulation. We administered multiple doses of high-dose valacyclovir to 6 subjects with normal renal function and 3 subjects with chronic renal impairment (creatinine clearance [CrCl], approximately 15 to 30 ml/min). Dosages were 2,000 mg every 6 h and 1,500 mg every 12 h, respectively. Indwelling intrathecal catheters allowed serial CSF sampling throughout the dosing interval. The average steady-state concentrations of acyclovir, CMMG, and 8-OH-ACV were greater in both the systemic circulation and the CSF among subjects with impaired renal function than among subjects with normal renal function. However, the CSF penetration of each analyte, reflected by the CSF-to-plasma area under the concentration-time curve over the 6- or 12-h dosing interval (AUC(tau)) ratio, did not differ based on renal function. Renal impairment does not alter the propensity for ACV or its metabolites to distribute to the CSF, but the higher concentrations in the systemic circulation, as a result of reduced elimination, are associated with proportionally higher concentrations in CSF.

Physiologically Based Pharmacokinetics of Zearalenone

The objectives of this study were to (1) develop physiologically based pharmacokinetic (PBPK) models for zearalenone following intravenous (iv) and oral (po) dosing in rats and (2) predict concentrations in humans via interspecies scaling. The model for iv dosing consisted of vein, artery, lung, liver, spleen, kidneys, heart, testes, brain, muscle, adipose tissue, stomach, and small intestine. To describe the secondary peak phenomenon observed after po administration, the absorption model was constructed to reflect glucuronidation, biliary excretion, enterohepatic recirculation, and fast and slow absorption processes from the lumenal compartment. The developed models adequately described observed concentration–time data in rats after iv or po administration. Upon model validation in rats, steady-state zearalenone concentrations in blood and tissues were simulated for rats after once daily po exposures (0.1 mg/kg/d). The average steady-state blood zearalenone concentration predicted in rat was 0.014 ng/ml. Subsequently, a daily human po dose needed to achieve the same steady-state blood concentration found in rats (0.014 ng/ml) was determined to be 0.0312 mg/kg/d or 2.18 mg/70 kg/d. The steady-state zearalenone concentration–time profiles in blood and tissues were also simulated for human after multiple po administrations (dose 0.0312 mg/kg/d). The developed PBPK models adequately described the pharmacokinetics in rats and may be useful in predicting human blood and tissue concentrations for zearalenone under different po exposure conditions.

Carboplatin and Paclitaxel in Combination With Oral Enzastaurin in Advanced Ovarian or Primary Peritoneal Cancer: Results From a Safety Lead-in Study

This safety lead-in study examined the pharmacokinetic and adverse event profile of combining enzastaurin with paclitaxel plus carboplatin as first-line therapy for the treatment of advanced-stage ovarian cancer and primary peritoneal carcinoma. The specific objectives of this study were to assess safety and tolerability after 2 cycles of treatment, to determine if enzastaurin alters paclitaxel and carboplatin pharmacokinetics, and to determine if enzastaurin pharmacokinetics is affected by paclitaxel and carboplatin. After debulking surgery, patients with previously untreated epithelial ovarian or primary peritoneal carcinoma received sequential paclitaxel (175 mg/m) and carboplatin (area under the curve, 5 mg x min/mL) on day 1 every 3 weeks for 6 cycles. Patients ingested an oral loading dose of 1125 mg enzastaurin on day 4 of cycle 1, followed by oral 500-mg enzastaurin daily until the end of therapy. Adverse events were graded according to the Common Terminology Criteria for Adverse Events v3.0. There were 5 serious adverse events in 4 of 11 patients: soft tissue injury, wound infection, intestinal fistula, clostridial infection, and anemia. Coadministration with enzastaurin did not significantly alter paclitaxel and carboplatin pharmacokinetics (area under the curve ratio of treatment comparison asymptotically equal to 1.05 and 1.06, respectively). Enzastaurin exposures were unchanged (Cav,ss ratio of treatment comparison asymptotically equal to 0.95 for average steady-state total analyte concentrations of enzastaurin and its metabolite). Adding enzastaurin to paclitaxel plus carboplatin chemotherapy is feasible for advanced ovarian cancer after radical cytoreduction. Enzastaurin did not alter paclitaxel or carboplatin pharmacokinetics, and enzastaurin exposures were not significantly changed by carboplatin and paclitaxel.

Phase Ib safety and pharmacokinetic evaluation of daily and twice daily oral enzastaurin in combination with pemetrexed in advanced/metastatic cancer

BackgroundThis phase Ib study evaluated the safety, pharmacokinetics, and activity of enzastaurin either 500 mg once daily (QD) or 250 mg twice daily (b.i.d.) in combination with pemetrexed. Patients and methodsPemetrexed 500 mg/m2 with folic acid and vitamin B12 was given on day 1 every 21 days with enzastaurin 500 mg orally QD starting on day 5 of cycle 1 after a loading dose of 400 mg thrice daily on day 4. To evaluate whether a b.i.d. regimen results in higher enzastaurin exposures, the study was amended. After amendment, in cycle 1, patients received 500 mg enzastaurin QD on days 1–15 without initial loading dose and 250 mg b.i.d. on days 16–30; in subsequent cycles, patients received pemetrexed on day 1 every 21 days with enzastaurin b.i.d. ResultsSixty-eight patients (42 preamendment and 26 postamendment) were assessed. Pemetrexed toxicity and pharmacokinetics did not appear to be altered by enzastaurin. Enzastaurin average steady-state plasma concentration (Cav,ss) decreased by ∼25% in the presence of pemetrexed. Enzastaurin Cav,ss were ∼40% higher in the b.i.d. versus QD regimen. Three patients (4.4%) with thyroid cancer of follicular/papillary type had partial response as defined by RECIST. ConclusionsPemetrexed plus enzastaurin is well tolerated with preliminary evidence of anticancer activity, particularly in thyroid cancer.

Investigation of the Influence ofCYP1A2andCYP2C19Genetic Polymorphism on 2-Cyano-3-hydroxy-N-[4-(trifluoromethyl)phenyl]-2-butenamide (A77 1726) Pharmacokinetics in Leflunomide-Treated Patients with Rheumatoid Arthritis

Leflunomide is a disease-modifying antirheumatic drug used for the treatment of rheumatoid arthritis (RA). Cytochromes P450, mainly CYP1A2 and CYP2C19, may be involved in the transformation of leflunomide to leflunomide metabolite (A77 1726, 2-cyano-3-hydroxy-N-[4-(trifluoromethyl)phenyl]-2-butenamide). The aim of this study was to investigate whether genetic polymorphisms in CYP1A2 and CYP2C19 influence leflunomide pharmacokinetics, treatment response, and the occurrence of adverse drug reactions (ADRs). The study included 67 patients with RA and 4 patients with polyarthritis resembling RA and psoriasis treated with leflunomide. A77 1726 steady-state plasma concentrations were determined by validated high-performance liquid chromatography with UV detection. A population pharmacokinetic model was developed to estimate the oral clearance (CL/F) and volume of distribution (V/F). A genotyping approach was used to determine C-163A, C-729T, and T-739G in the CYP1A2 gene as well as single nucleotide polymorphisms that characterize CYP2C19*2, *3, *4, and *17 alleles. A large interindividual variability in trough A77 1726 steady-state plasma concentrations was observed (from 1.9 to 156.9 mg/l). A77 1726 CL/F was 71% higher in carriers of the CYP2C19*2 allele compared with noncarriers. The A77 1726 average steady-state plasma concentration was associated with the treatment response. Patients with a greater decrease in C-reactive protein (CRP) had higher average steady-state plasma A77 1726 concentrations: 49.7 +/- 39.0 mg/l in patients with DeltaCRP of more than 8.5 mg/l compared with 24.8 +/- 13.7 mg/l in patients with DeltaCRP of <or=8.5 mg/l (p = 0.015). No association of A77 1726 steady-state plasma concentrations with the occurrence of ADRs was observed. Our results suggest that genetic variability in leflunomide-metabolizing enzymes influences leflunomide metabolite concentrations that are associated with the treatment response but not with leflunomide-induced toxicity.

A phase I study of enzastaurin (Enz) combined with pemetrexed (Pem) in advanced non-small cell lung cancer (NSCLC)

2572 Background: Enz is an oral serine-threonine kinase inhibitor that is designed to suppress tumor growth through PKC and PI-3 kinase/AKT. Pre-clinical data shows Enz's synergistic activity with Pem in many cancer cell lines including NSCLC. This phase 1 study is to evaluate the safety, pharmacokinetics (PK), and clinical activity of two schedules of Enz combined with Pem in patients (pts) with previously treated advanced NSCLC. Methods: An oral daily dose of 500 mg Enz was given once daily (QD) in cohort 1 or twice daily (BID) in cohort 2 in combination with 500 mg/m2 Pem on day 1 in repeated 21-day cycles. Cycle 1 started with a 7-day Enz lead-in treatment that preceded Pem administration: a loading dose of 1125 mg on day 1 followed by 500 mg total daily dose on days 2–7. Blood samples for PK evaluation were collected on day 2 of cycle 1 (following loading dose) and day 1 of cycle 2 (steady- state). Samples were analyzed for Enz, Pem, and its active metabolites. Results: 12 pts (8 males, 4 females; ECOG PS 0–1) with median age of 62 (49 - 74) were enrolled into this study and completed safety evaluation for cycle 1: 8 pts with adenocarcinoma, 3 pts with squamous cell carcinoma, and one with other. All pts had received prior platinum-based chemotherapy. Total analyte concentrations (sum of Enz and its metabolites) reached steady-state by day 8 of dosing. Total analyte mean steady-state average concentrations (%CV) following QD and BID dosing were 2850 nmol/L (53.5%) and 3420 nmol/L (39.5%), respectively. Exposures following loading dose were within the range of concentrations seen at steady-state. Enz dosing regimen (QD or BID) did not alter Pem PK. One dose-limiting toxicity (Grade 3 QTc prolongation) occurred 1 day after the Enz loading dose in cohort 1. Grade 3/4 toxicities occurring in 6 pts included leukocytopenia, neutropenia (3 pts each), increased ALT, and increased AST (2 pts each). To date, 1 pt achieved PR and 6 pts achieved SD. 5 pts received more than 10 cycles of treatment without disease progression; 4 of these pts are still on therapy. Conclusions: Both schedules of Enz in combination with Pem are well tolerated and clinically active in pts with advanced NSCLC. [Table: see text]

Major Depressive Disorder and Patient Satisfaction in Relation to Methadone Pharmacokinetics and Pharmacodynamics in Stabilized Methadone Maintenance Patients

Many patients enrolled in methadone maintenance treatment experience significant interdose opioid withdrawal. Mood states have been related to patient satisfaction with treatment and may influence how methadone patients experience opioid withdrawal. The objective of this study was to investigate the influence of major depressive disorder on response to methadone in patients on methadone maintenance treatment. Seventeen methadone patients (7 depressed and 10 not depressed) had pharmacokinetic and pharmacodynamic assessments (opioid withdrawal, drug effects, and mood) over one 24-hour dosing interval. Subjects were also divided based on their satisfaction with methadone treatment: 12 holders and 5 nonholders. Depressed subjects experienced more dysphoric opioid effects as measured by the Addiction Research Centre Inventory (area under the effect versus time curve, 14 +/- 32 vs -31 +/- 47, P < 0.04) and had higher scores on the Subjective Opioid Withdrawal Scale (area under the effect versus time curve, 33 +/- 97 vs -74 +/- 67, P < 0.02) over the dosage interval. Hamilton Depression scores significantly correlated with trough subjective opioid withdrawal scale scores (r = 0.7, P < 0.004). Nonholders had significantly higher exposure to unbound (S)-methadone compared with holders, specifically: trough concentration (6.1 +/- 2.7 ng/mL vs 2.7 +/- 1.7 ng/mL, P < 0.01), average steady-state concentration (7.6 +/- 4.0 ng/mL vs 4.1 +/- 2.5 ng/mL, P < 0.05), maximum concentration (14.6 +/- 7.1 ng/mL vs 7.5 +/- 4.2 ng/mL, P < 0.04), and area under the curve (183 +/- 95 h*ng/mL vs 99 +/- 61 h*ng/mL, P < 0.05). Study findings suggest that (S)-methadone may relate to patients' dissatisfaction with methadone treatment. Depressed methadone patients may be more sensitive to negative opioid effects and opioid withdrawal.

Effect of PEG6000 on the In Vitro and In Vivo Transdermal Permeation of Ondansetron Hydrochloride from EVA1802 Membranes

The objective was to evaluate ethylene vinyl acetate (EVA) copolymer membranes with vinyl acetate content of 18% w/w (EVA1802) for transdermal delivery of ondansetron hydrochloride. The EVA1802 membranes containing selected concentrations (0, 5, 10 and 15% w/w) of PEG6000 were prepared, and subjected to in vitro permeation studies from a nerodilol-based drug reservoir. Flux of ondansetron from EVA1802 membranes without PEG6000 was 64.1 ± 0.6 μg/cm2·h, and with 10%w/w of PEG6000 (EVA1802-PEG6000-10) it increased to 194.9 ± 4.6 μg/cm2·h. However, with 15%w/w of PEG6000, EVA1802 membranes produced a burst release of drug which in turn decreased drug flux. The EVA1802-PEG6000-10 membrane was coated with an adhesive emulsion, applied to rat epidermis and subjected to in vitro permeation studies against controls. Flux of ondansetron from transdermal patch across rat epidermis was 111.7 ± 1.3 μg/cm2·h, which is about 1.3 times the required flux. A TTS was fabricated using adhesive-coated EVA1802-PEG6000-10 membrane and other TTS components, and subjected to in vivo delivery in human volunteers against a control. It was concluded from the comparative pharmacokinetic study that TTS of ondansetron, prepared with EVA1802-PEG6000-10 membrane, provided average steady-state plasma concentration on par with multiple-dosed oral tablets, but with a low percent of peak-to-trough fluctuation.

Predicting Plasma Concentrations of Bisphenol A in Children Younger Than 2 Years of Age after Typical Feeding Schedules, using a Physiologically Based Toxicokinetic Model

BackgroundConcerns have recently been raised regarding the safety of potential human exposure to bisphenol A (BPA), an industrial chemical found in some polycarbonate plastics and epoxy resins. Of particular interest is the exposure of young children to BPA via food stored in BPA-containing packaging.ObjectivesIn this study we assessed the age dependence of the toxicokinetics of BPA and its glucuronidated metabolite, BPA-Glu, using a coupled BPA–BPA-Glu physiologically based toxicokinetic (PBTK) model.MethodsUsing information gathered from toxicokinetic studies in adults, we built a PBTK model. We then scaled the model to children < 2 years of age based on the age dependence of physiologic parameters relevant for absorption, distribution, metabolism, and excretion.ResultsWe estimated the average steady-state BPA plasma concentration in newborns to be 11 times greater than that in adults when given the same weight-normalized dose. Because of the rapid development of the glucuronidation process, this ratio dropped to 2 by 3 months of age. Simulation of typical feeding exposures, as estimated by regulatory authorities, showed a 5-fold greater steady-state BPA plasma concentration in 3- and 6-month-olds compared with adults, reflecting both a reduced capacity for BPA metabolism and a greater weight-normalized BPA exposure. Because of uncertainty in defining the hepatic BPA intrinsic clearance in adults, these values represent preliminary estimates.ConclusionsSimulations of the differential BPA dosimetry between adults and young children point to the need for more sensitive analytical methods for BPA to define, with greater certainty, the adult hepatic BPA intrinsic clearance, as well as a need for external exposure data in young children.

Anticholinergic Activity of 107 Medications Commonly Used by Older Adults

The objective of this study was to measure the anticholinergic activity (AA) of medications commonly used by older adults. A radioreceptor assay was used to investigate the AA of 107 medications. Six clinically relevant concentrations were assessed for each medication. Rodent forebrain and striatum homogenate was used with tritiated quinuclidinyl benzilate. Drug-free serum was added to medication and atropine standard-curve samples. For medications that showed detectable AA, average steady-state peak plasma and serum concentrations (C(max)) in older adults were used to estimate relationships between in vitro dose and AA. All results are reported in pmol/mL of atropine equivalents. At typical doses administered to older adults, amitriptyline, atropine, clozapine, dicyclomine, doxepin, L-hyoscyamine, thioridazine, and tolterodine demonstrated AA exceeding 15 pmol/mL. Chlorpromazine, diphenhydramine, nortriptyline, olanzapine, oxybutynin, and paroxetine had AA values of 5 to 15 pmol/mL. Citalopram, escitalopram, fluoxetine, lithium, mirtazapine, quetiapine, ranitidine, and temazepam had values less than 5 pmol/mL. Amoxicillin, celecoxib, cephalexin, diazepam, digoxin, diphenoxylate, donepezil, duloxetine, fentanyl, furosemide, hydrocodone, lansoprazole, levofloxacin, metformin, phenytoin, propoxyphene, and topiramate demonstrated AA only at the highest concentrations tested (patients with above-average C(max) values, who receive higher doses, or are frail may show AA). The remainder of the medications investigated did not demonstrate any AA at the concentrations examined. Psychotropic medications were particularly likely to demonstrate AA. Each of the drug classifications investigated (e.g., antipsychotic, cardiovascular) had at least one medication that demonstrated AA at therapeutic doses. Clinicians can use this information when choosing between equally efficacious medications, as well as in assessing overall anticholinergic burden.

A phase I study of XL647, an EGFR, HER2, VEGFR2 inhibitor, administered orally daily to patients (pts) with advanced solid malignancies (ASM)

3528 Background: XL647 is an orally bioavailable small molecule inhibitor of multiple receptor tyrosine kinases involved in tumorigenesis and angiogenesis, including EGFR/ErbB1, HER2/ErbB2 and VEGFR2/KDR. The purpose of the present study is to determine the MTD of daily XL647 dosing, and to evaluate pharmacokinetics and pharmacodynamics in pts with ASM. Methods: Cohorts of ASM pts received escalating dose levels of XL647 daily for repeated 28 day cycles. PK sampling was conducted at each dose level. Plasma markers reflecting effects of XL647 on angiogenesis are being analyzed. Eyebrow hair bulbs from a subset of pts are being evaluated as a potential surrogate for the effects of XL647. DCE-MRI studies are being conducted in pts enrolled in the MTD cohort. Response was assessed by RECIST. Results: Enrollment has been completed with 31 pts enrolled (range 26–79 yrs; 20M/11F). Dose levels of 75 mg (n=3), 150 mg (n=3), 200 mg (n=3), 300 mg (n=18) and 350 mg (n=4) were studied. A DLT of Grade (G) 3 pneumonitis occurred in 1/6 pts at 300 mg. At 350 mg 2/4 pts developed a DLT of clinically asymptomatic G3 QTc prolongation (by machine, G2 by manual re-read): 300 mg was declared the MTD. Twelve pts have been enrolled in the expanded MTD cohort. Nine pts remain on study with the majority discontinued due to PD. Two pts withdrew consent and 2 discontinued due to AEs (G3 pneumonitis and G3/4 transaminitis). To date, twelve pts had SD for > 3mo. The most common AEs include G1/2 rash, diarrhea, fatigue, dysgeusia, and clinically asymptomatic QTc prolongation. Preliminary PK analysis indicates rapid absorption (median tmax = 4 hours) with steady state concentrations reached by Day 15. Average steady state concentrations were about 3.4-fold higher compared to Day 1. XL647 caused a significant reduction in phosphorylation of the downstream signaling kinases AKT and ERK in eyebrow hair bulbs at a dose of 150 mg; analysis continues. Levels of pharmacodynamic plasma markers were not consistently changed after XL647 and no PK/pharmacodynamic relationships have been identified to date. Conclusions: The MTD of XL647 is 300 mg when administered daily. XL647 is generally well-tolerated at doses up to 300 mg. Phase 2 studies are ongoing in NSCLC pts at this dose level. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Exelixis, Inc. Exelixis, Inc. Exelixis, Inc. Exelixis, Inc. Exelixis, Inc.