Post-dose Time Research Articles

STANDARD OR INDIVIDUALISED GENTAMICIN DOSING FOR NEONATES?

Aim NICE guidance for treatment of suspected early on-set sepsis (EOS) in neonates recommends 5 mg/kg of gentamicin every 36 hours for all, and measurement of a pre-dose trough concentration with dosing adjusted accordingly.1 At our hospital individualised pharmacokinetics are used to calculate dose and dosing frequency.2 The study aims to establish if 5 mg/kg of gentamicin every 36 hours is appropriate for all. Method All babies receiving gentamicin for EOS from birth to 72 hours were included. Patient details including date of birth, gestational age, weight, dose given, administration time, two post-dose blood concentrations and sample time were collated and used to calculate individualised elimination rate constant, half-life and distribution volume. Peak concentrations, 1-hour post-dose and pre-dose troughs were predicted using these pharmacokinetic parameters for both the individualised dosing regime and the standard regime of 5 mg/kg every 36 hours. These were compared with the target concentration: 1 hour post dose peak 8 to 12 mg/L; pre-dose trough less than 1 mg/L. All data were entered into Microsoft® Excel®. Results Ninety-one neonates were studied. Gestational age ranged (mean±standard deviation) 23 to 42 weeks (33±4weeks). Weight ranged 0.67 to 4.68 kg (2.44±1 kg). 5 mg/kg under-dosed 28 neonates (30%):5.9–7.9 mg/L, 7.1 mg/L±0.6 mg/L. In such cases a dose of 6 mg/kg would be more appropriate. Four babies (4.4%) were overdosed: 12.1–14.1 mg/L, 12.7 mg/L±0.9 mg/L. In such cases 4 mg/kg would be more appropriate. A loading dose of 5 mg/kg was therefore not appropriate in a third of neonates. Monitoring a pre-dose trough concentration will not identify if babies are given too low or too high a dose. There is no established method to predict which patients require a dose of 4 or 6 mg/kg. An individualised approach allows dosing to be fine-tuned from the start of a treatment course, according to each neonate9s unique pharmacokinetic parameters. In seven neonates (7.7%), dosing every 36 hours would give a trough concentration greater than 2 mg/L. In 32 neonates (35%), dosing every 36 hours would give a trough concentration greater than 1 mg/L. In such cases an extended dosing interval would be required, unless the trough was high because the initial dose was too much. Giving gentamicin every 36 hours will achieve a trough less than 2 mg/L as per NICE guidelines in most babies. However if treatment exceeds 3 doses, only 65% of patients would achieve a target gentamicin concentration under 1 mg/L. Longer dosing intervals, or perhaps smaller doses, would thus be needed. Limitations of the study include the small volume of drug administered to neonates less than 1 kg, with possible administration error which influences reported concentration, and impacts on subsequent pharmacokinetic calculations. Other limitations relate to clinical acuity such as renal function and hydration levels, which were not recorded. Conclusion Sixty-five percent of neonates treated with 5 mg/kg of gentamicin every 36 hours achieve a 1 hour post dose peak concentration of 8 to 12 mg/L and pre-dose trough of less than 1 mg/L. Thirty-five percent do not. Dosing individualisation is still necessary. The study reports results from an individualised dosing process based on two-timed gentamicin concentrations.

An evaluation of Retaine™ ophthalmic emulsion in the management of tear film stability and ocular surface staining in patients diagnosed with dry eye.

A single-center, open-label study consisting of two visits over the course of approximately 2 weeks was conducted to evaluate the efficacy of Retaine™ ophthalmic emulsion in improving the signs and symptoms of dry eye. Forty-two subjects were enrolled and received 1–2 drops twice daily of Retaine™ beginning at the first visit (day 1) and ending at the second visit. Subjects were instructed to complete a symptomatology diary twice daily prior to drop instillation through the morning of the second visit. Ocular sign and symptom assessments, visual acuity procedures, and comfort assessments were conducted during both visits. A statistically significant reduction was observed in mean breakup area on the second visit between the predose time and the postdose time (P=0.026). On the second visit, subjects had significantly less corneal fluorescein staining in the superior (P=0.002), central (P=0.017), corneal sum (P=0.011), and all ocular regions combined (P=0.038) than on the first visit. On the second visit, statistically significant reductions in dryness (P<0.001), grittiness (P=0.0217), ocular discomfort (P=0.0017), and all symptoms (P<0.001) were also seen as measured by the Ora Calibra™ Ocular Discomfort and 4-Symptom Questionnaire (0–5 scale). Subjects reported a statistically significant improvement in their abilities to work with a computer at night (P=0.044). Mean drop comfort scores ranged from 1.29–1.81 on the Ora Calibra™ 0–10 Drop Comfort Scale, on which 0 is very comfortable and 10 is very uncomfortable. Retaine™ demonstrates promising results as a novel artificial tear option for individuals suffering from dry eye. The unique mechanism of action of Retaine™ provides enhanced comfort and improves the quality of life of dry eye subjects while reducing the ocular signs of dry eye.

A thorough QT/QTc study of the effect of fasiglifam, a GPR40 agonist, on cardiac repolarization in healthy adults.

This double-blind, randomized, placebo- and active-controlled, parallel group trial evaluated the potential for multiple-dose fasiglifam to prolong the QT/QTc interval in healthy adults. A total of 280 men and women aged 18-50 years were randomized to receive 14 days of fasiglifam 50 mg (n = 69), fasiglifam 400 mg (n = 70), or placebo (n = 70), or 13 days of placebo followed by single-dose moxifloxacin 400 mg (positive control; n = 71). The primary endpoint was the least square mean difference between fasiglifam and placebo in time-matched change from baseline to last dosing day in QT interval corrected using the Fridericia method (QTcF, calculated as QT/RR(0) (.333) ). For both fasiglifam doses, differences from placebo in QTcF were between -4.9 and 3.0 milliseconds at all postdose time points; maximum upper bounds of the one-sided 95% confidence interval for the difference were 5.7 milliseconds for fasiglifam 50 mg and 2.3 milliseconds for fasiglifam 400 mg, meeting predefined criteria for absence of prolongation. Alternate correction methods (Bazett and Individual) showed similar results. Fasiglifam was well tolerated; no subject withdrew due to an adverse event after receiving fasiglifam. In summary, multiple-dose fasiglifam did not affect cardiac repolarization at therapeutic and supratherapeutic doses and was well tolerated in healthy subjects.

A Double-Blind, Placebo-Controlled Trial to Evaluate the Safety, Tolerability, and Pharmacokinetics of Single, Escalating Oral Doses of JDTic.

Animal studies suggest that kappa opioid receptor antagonists (KORAn) potentially could treat a wide variety of addictive and depressive disorders. We assessed the KORAn JDTic for safety, tolerability, and pharmacokinetics in a double-blind, placebo-controlled, randomized trial evaluating single oral doses in healthy adult males. Predose and postdose safety assessments included orthostatic vital signs; 6-lead continuous telemetry monitoring (approximately 16 h predose to 24 h postdose); 12-lead electrocardiograms (ECGs); clinical chemistry, hematology, coagulation, and urinalysis; psychomotor functioning (using the Wayne Saccadic Fixator (WSF)); and adverse events. As a potential indicator of JDTic effects on affect, the POMS Standard instrument was administered predose and daily postdose Days 1–6. At 1 mg, 2 of the 6 JDTic (and 0/6 placebo) subjects experienced a single, asymptomatic event of multiple beats of nonsustained ventricular tachycardia (NSVT). Their events were temporally similar with respect to time postdose (and the postdose timing of an NSVT event in a monkey). These events triggered a study stopping rule. No differences were observed between the placebo and JDTic subjects with respect to clinical chemistry, hematology, coagulation, urinalysis, orthostatic vital signs, WSF, or 12-lead ECG parameters. Plasma JDTic levels were below the lower limit of quantitation (0.1 nM) in all subjects. There were no significant differences in POMS scores between the placebo and JDTic groups. Although the evidence is circumstantial, it suggests that NSVT is a potential JDTic toxicity in humans. Given the therapeutic potential of KORAn, further investigation is needed to determine whether a significant JDTic human cardiac effect indeed exists, and if so, whether it is specific to JDTic or represents a KORAn class effect.

Dose-dependent pharmacokinetics and brain penetration of rufinamide following intravenous and oral administration to rats

Rufinamide is a third-generation antiepileptic drug, approved recently as an orphan drug for the treatment of Lennox–Gastaut syndrome. Although extensive research was conducted, its pharmacokinetics in rats was not described. This work addresses that area by describing in a rapid pharmacokinetic study the main pharmacokinetic properties of rufinamide at three different doses of 1mg/kg body weight (bw), 5mg/kgbw, and 20mg/kgbw. Furthermore, total brain concentrations of the drug were determined in order to characterize its brain-to-plasma partition coefficient. Adult Wistar male rats, weighing 200–450g, were administered rufinamide by intravenous and oral routes. Rufinamide concentrations from plasma samples and brain tissue homogenate were determined using a liquid chromatography–mass spectrometric method and pharmacokinetic parameters were calculated. The mean half-life was between 7 and 13h, depending on route of administration – intravenously administered drug was eliminated faster than orally administered drug. Mean (S.E.M.) total plasma clearance was 84.01±3.80ml/h/kg for intravenous administration, while the apparent plasma clearance for oral administration was 95.52±39.45ml/h/kg. The mean (S.E.M.) maximum plasma concentration reached after oral administration of 1mg/kgbw and 5mg/kgbw was 0.89±0.09μg/ml and 3.188±0.71μg/ml, respectively. The median (range) time to reach maximum plasma concentration (tmax) was 4 (2–8)h. Mean (S.E.M.) brain-to-plasma concentration ratio of rufinamide was 0.514±0.036, consistent with the brain-to-plasma ratio calculated from the area under curves (AUC0−t) of 0.441±0.047. No influence of dose, route of administration, or post-dosing time was observed on brain-to-plasma ratio.

Controlling on-demand gastric acidity in obese subjects: a randomized, controlled trial comparing a single dose of 20 mg rabeprazole and 20 mg omeprazole.

BackgroundObesity is associated with a risk of gastroesophageal reflux disease. The pharmacodynamic efficacy of proton pump inhibitors has not been specifically evaluated in obese subjects. The aim of this study was to compare the antisecretory response to a single oral dose of 20 mg rabeprazole, 20 mg omeprazole and placebo in obese subjects.MethodsGastric pH was monitored for 24 hours on three separate occasions in eighteen H. pylori-negative, asymptomatic obese subjects. Subjects were given omeprazole, rabeprazole or placebo in a randomized order and in a double-blind fashion. The main analysis criterion was 24-h percent of time post dose with intragastric pH above 3; secondary criteria were percentage of time above pH 4, median pH, [H+] concentrations and nocturnal acid breakthrough (NAB). Results were analyzed using linear mixed models and Wilks test comparing variances.Results24-h median [IQ] percentages of time with gastric pH above 3 and 4 were higher with rabeprazole than omeprazole (46 [37–55] vs. 30 [15–55] %, 9 [5-11] % for placebo) but the differences did not reach statistical significance (p = 0.11 and 0.24, respectively). Median acid concentrations were significantly lower with rabeprazole than with omeprazole and placebo (22 [14–53] vs. 54 [19–130] and 95 [73–170] mmoles/l, p < 0.01) for all periods. The number of NAB was significantly lower with rabeprazole than with omeprazole (median 1 [1,2] vs. 2 [1-3], p = 0.04). Variances of 24-h data (pH above 3 and 4, median pH, [H+] concentrations) were significantly lower with rabeprazole than with omeprazole (p < 0.0001).ConclusionsIn asymptomatic obese subjects the gastric antisecretory response to a single dose of rabeprazole and omeprazole was strong and not significantly different between drugs despite a significantly more homogeneous response with rabeprazole.Trial registrationClinicalTrial.gov: NCT01136317

Single therapeutic and supratherapeutic doses of anacetrapib, a cholesteryl ester transfer protein inhibitor, do not prolong the QTcF interval in healthy volunteers

Anacetrapib is a cholesteryl ester transfer protein inhibitor in Phase III development. This double-blind, double-dummy, randomized, placebo- and active-comparator-controlled, 4-period, balanced crossover study evaluated the effects of anacetrapib (100 mg and 800 mg) on QTcF interval in healthy subjects. QTcF measurements were made up to 24 h following administration of single doses of anacetrapib 100 or 800 mg, moxifloxacin 400 mg, or placebo in the fed state. The primary hypothesis was supported if the 90% CI for the least squares (LS) mean differences between anacetrapib 800 mg and placebo in QTcF interval change from baseline were entirely <10 msec at every post-dose time point (1, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 h). The upper bounds of the 90% CIs for LS mean differences from placebo in changes from baseline in QTcF intervals for anacetrapib 100 and 800 mg were <5 msec at every time point. In conclusion, single doses of anacetrapib 100 and 800 mg do not prolong the QTcF interval to a clinically meaningful degree relative to placebo and are generally well tolerated in healthy subjects.

A randomized, placebo-controlled, four-period crossover, definitive QT study of the effects of APF530 exposure, high-dose intravenous granisetron, and moxifloxacin on QTc prolongation.

BackgroundRegulatory concern about potential QT-interval prolongation by serotonin-receptor antagonist antiemetics prompted product-label changes. The first-generation serotonin-receptor antagonist granisetron is available in oral (PO), intravenous (IV), and transdermal formulations. APF530 is a formulation that provides sustained release of granisetron when administered as a single subcutaneous (SC) injection. The Phase I study reported here evaluated effects of APF530 on electrocardiographic intervals.MethodsThis single-site, double-blind, placebo-controlled, four-period crossover trial randomized healthy men and women to receive varying sequences of APF530 1 g SC, granisetron 50 μg/kg IV, moxifloxacin 400 mg PO, and placebo. Subjects were assessed for 49 hours after each treatment. The primary objective was to evaluate differences between baseline-adjusted, heart rate-corrected QT-interval change using the Fridericia rate correction (dQTcF) for APF530 1 g SC and placebo. Electrocardiograms were performed at various times throughout the assessment period. Pharmacokinetics and safety were evaluated.ResultsThe upper one-sided 95% confidence interval (CI) for mean baseline-adjusted dQTcF at each post-dose time point between APF530 and placebo excluded 10 ms, indicating that APF530 1 g SC had no clinically significant effect on QTcF. Maximum observed QTcF change was 4.15 ms (90% CI, 0.94 to 7.36) at Hour 3. No clinically significant changes in other electrocardiogram intervals were observed. APF530 SC pharmacokinetics were as expected, with slow absorption (maximum plasma concentration 35.8 ng/mL, median time to maximum plasma concentration 11.1 hours) and slow elimination (mean half-life 18.6 hours; systemic clearance 20.2 L/hour) of granisetron versus the expected early peak concentration and elimination of granisetron IV. APF530 SC was well tolerated. Adverse events, most commonly constipation and SC injection-site reactions, were generally mild and quickly resolved.ConclusionAPF530 1 g SC did not induce clinically significant QTcF interval prolongation or changes in the other electrocardiogram intervals, and was well tolerated at twice the recommended dose.

Loxapine delivered as a thermally generated aerosol does not prolong QTc in a thorough QT/QTc study in healthy subjects

The objective of this study was to establish effects of inhaled loxapine on the QTc interval in this randomized, placebo-controlled, double-blind crossover study. Forty-eight healthy volunteers received a single inhaled placebo or 10 mg loxapine. Plasma concentrations of loxapine increased with a median Tmax of 1 minute and a mean Cmax of 312 ng/mL. After an initial rapid distribution phase, plasma concentrations of loxapine declined with a terminal half-life of 8 hours. Exposure to the active metabolite 7-OH-loxapine was 15% of the parent compound based on mean AUCinf and its terminal half-life was 12 hours. Inhaled loxapine did not increase QT intervals, as demonstrated by the upper bound of the 1-sided 95% CIs placed on the point estimate of the placebo-subtracted change of QTcI (ΔΔQTcI) being less than 10 milliseconds at all 11 post-dose times. The maximum ΔΔQTcI occurred at 1 hour post-dose (LSmean 5.42 milliseconds, upper confidence bound 7.75 milliseconds). The study outcome was validated by the demonstrated assay sensitivity using the positive control moxifloxacin maximum ΔΔQTcI occurred at 3 hour post-dose (LSmean 8.36 milliseconds, lower confidence bound 5.82 milliseconds). The analyses of QTc outliers, and the lack of emergent diagnostic findings for QTcI, QTcB, and QTcF; and simple mean placebo-subtracted changes of QTcI and QTcF supported the primary QT analysis conclusion that this is a negative finding and there is no apparent QT prolongation associated with the therapeutic dose of inhaled loxapine.

Randomized comparative trial of efficacy of paracetamol, ibuprofen and paracetamol-ibuprofen combination for treatment of febrile children

Objective:Paracetamol and ibuprofen are widely used for fever in children as monotherapy and as combined therapy. None of the treatments is proven clearly superior to others. Hence, the study was planned to compare the efficacy of paracetamol, ibuprofen and paracetamol-ibuprofen combination for treatment of febrile children.Materials and Methods:This was an investigator blind, randomized, comparative, parallel clinical trial conducted in 99 febrile children, 6 months to 12 years of age, allocated to three groups. First group received paracetamol 15 mg/kg, second group received ibuprofen 10 mg/kg and third group received both paracetamol and ibuprofen, all as a single dose by the oral route. Patients were followed-up at intervals of 1, 2, 3 and 4 h post dose by tympanic thermometry.Results:Mean tympanic temperature after 4 h of drug administration was significantly lower in the combination group compared with paracetamol group (P < 0.05); however, the difference was not clinically significant (<1°C). The rate of fall of temperature was highest in the combination group. Number of afebrile children any time post dose until 4 h was highest in the combination group. Difference between combination and paracetamol was significant for the 1st h (P = 0.04). Highest fall of temperature was noted in the 1st h of drug administration in all the groups. No serious adverse events were observed in any of the groups.Conclusion:Paracetamol and ibuprofen combination caused quicker temperature reduction than either paracetamol or ibuprofen alone. If quicker reduction of body temperature is the desired goal of therapy, the use of combination of paracetamol + ibuprofen may be advocated.

A Randomized, Rater-Blinded, Crossover Study of the Effects of Oxymorphone Extended Release, Fed versus Fasting, on Cognitive Performance as Tested with CANTAB in Opioid-Tolerant Subjects

The maximum plasma concentration (Cmax ) of oxymorphone extended release (ER) 20 mg and 40 mg is approximately 50% higher in fed than in fasted subjects, with most of the difference in area-under-the-curve (AUC) occurring in the first 4 hours post-dose. Hence, the US FDA recommends in the approved labeling that oxymorphone ER is taken at least 1 hour before or 2 hours after eating. In order to determine the potential impact on cognitive performance of the increased absorption of oxymorphone ER, fed versus fasting, we conducted a randomized, rater-blinded, crossover study in 30 opioid-tolerant subjects, using tests from the Cambridge Neuropsychological Test Automated Battery (CANTAB). The subjects randomly received 40 mg oxymorphone ER after a high-fat meal of approximately 1,010 kCal or after fasting for 8-12 hours, and were tested 1 hour and 3 hours post-dose. The CANTAB tests, Spatial Recognition Memory (SRM) and Spatial Working Memory (SWM), showed no statistically significant differences between the fed and fasting conditions. However, sustained attention, as measured by the Rapid Visual Information Processing (RVP) CANTAB test, showed a statistically significant interaction of fed versus fasting and post-dose time of testing (F[1,28] = 6.88, P = 0.01), suggesting that 40 mg oxymorphone ER after a high-fat meal versus fasting mitigates the learning effect in this particular cognition domain from 1 hour to 3 hours post-dose. Oxymorphone 40 mg ER affected cognitive performance similarly within 3 hours post-dose, whether given on an empty stomach or after a high-fat meal, suggesting that the effect of food on plasma concentration may not be relevant in the medication's impact on cognition.

High-Performance Liquid Chromatographic Determination of Memantine in Human Urine Following Solid-Phase Extraction and Precolumn Derivatization

A validated HPLC-UV method is presented for the quantification of urinary memantine hydrochloride, a novel medication approved to treat moderate and advanced cases of Alzheimer's disease. The drug and amantadine hydrochloride, the internal standard, were extracted from human urine using SPE. The extract was then buffered and derivatized at room temperature using o-phthalaldehyde in the presence of N-acetyl-L-cyteine. Chromatographic separation of the formed derivatives was achieved on a C18 column using methanol-water mobile phase adjusted to pH 7 and pumped isocratically at 1 mL/min. The UV detector was set at 340 nm. The chromatographic run time did not exceed 10 min. The LOD and LOQ were 8 and 20 ng/mL, respectively. The RSDs for intraday and interday precisions did not exceed 5.5%. The method was used to monitor memantine hydrochloride in human urine in order to determine an appropriate sampling interval for future noninvasive therapeutic drug monitoring. The assay could also be applied to the determination of amantadine. The described assay showed that a postdosing time interval of 25-75 h seems adequate for sampling and monitoring memantine in urine.

Pharmacokinetics of Indomethacin in Chronic Migraine Patients after Withdrawal from the Overused Combination of Indomethacin, Prochlorperazine and Caffeine

Indomethacin, in combination with prochlorperazine and caffeine (IPC), is often overused by migraine patients who develop medication-overuse headache. Indomethacin clearance is slower in chronic migraine patients overusing IPC combination than in migraine patients only occasionally taking it. The objective of this study was to verify if indomethacin reduced clearance reverted to normal values after withdrawal of the overused IPC combination. Therefore, we repeated the study of indomethacin pharmacokinetics in 9 female chronic migraine patients after 3 months from inpatient withdrawal treatment from IPC combination overuse. The IPC combination (indomethacin 50 mg, prochlorperazine 8 mg, caffeine 150 mg) habitually taken was administered by rectal route to each patient. Blood samples were drawn before dosing and at the following post-dose times: 0.5, 1, 2, 3, 4, and 6 h. Indomethacin concentrations were measured by HPLC method. We found that 4 of 9 patients (group A) who were still overusing the combination and suffering from daily headache had still high indomethacin concentrations after 6 hours, therefore showing a slow elimination of the drug. Instead, in the 5 patients (group B) who had discontinued overuse of IPC combination after withdrawal treatment, indomethacin concentrations after 6 hours were significantly lower than those measured before withdrawal (P < 0.05, Student’s t-test for paired data), and also than those observed in group A (P < 0.05, ANOVA and Newman-Keuls’test). Hence, by suspending IPC abuse indomethacin clearance reverts to normal values and this is associated with an improvement of migraine. Instead, the higher plasma levels of indomethacin in patients who continue IPC abuse do not solve migraine and might support medication-overuse headache.

Losmapimod concentration–QT relationship in healthy volunteers: meta-analysis of data from six clinical trials

The objective of this work was to describe the losmapimod concentration-QT relationship using meta-analysis of data from clinical trials with healthy volunteers and to evaluate the covariates that have significant impact on the QT prolongation. Losmapimod plasma concentration and QT interval data were collected from six early clinical studies with healthy volunteers. The electrocardiograms (ECGs) were collected at baseline and at a number of post-dose time points (losmapimod or placebo). The population pharmacokinetic/pharmacodynamic (PK/PD) modelling approach was applied to investigate the relationship between losmapimod concentration and QT prolongation. The dataset for analysis comprised 190 healthy adults who took at least one dose of losmapimod or placebo. Of the 2,494 QT observations collected, 1,532 observations had matched QT and losmapimod plasma concentration data. Population PK/PD analyses indicated that the model with the individual heart rate correction factor (α) fitted the data better than those using fixed α (0.33 for Fridericia's correction or 0.5 for Bazett's correction) and that there was no relationship between losmapimod concentration and QT interval. Female volunteers had about a 3 % higher QT interval at baseline than the male volunteers. No other covariates had a significant effect on the QT interval. It is appropriate to apply population PK/PD analysis to investigate the effect of drug concentration on QT prolongation. Our meta-analysis of healthy volunteer data indicated no relationship between systemic losmapimod concentration and QT interval in healthy volunteers.

Randomised, Multicentre, Placebo-controlled, Double-blind Crossover Study Investigating the Effect of Solifenacin and Oxybutynin in Elderly People with Mild Cognitive Impairment: The SENIOR Study

BackgroundCompared with younger people, the elderly are more likely to suffer from overactive bladder (OAB) and to have other chronic conditions that affect physical or cognitive function. Despite this, there are few data on the cognitive safety of antimuscarinic agents in older patients and none that examine the effect of these agents on those with mild cognitive impairment (MCI). ObjectiveTo evaluate cognitive effects during chronic stable dosing with solifenacin and oxybutynin versus placebo in older (≥75 yr) subjects with MCI. Design, setting, and participantsA randomised, double-blind, triple-crossover trial in 26 elderly volunteers with MCI. Cognitive function was assessed using Cognitive Drug Research (CDR) computerised testing. InterventionThree treatment periods of 21 d each with solifenacin 5mg once daily, oxybutynin 5mg twice daily, or placebo, separated by 21-d washout periods. Outcome measurements and statistical analysisThe primary end point was change from baseline in cognitive function with solifenacin at 6h postdose and oxybutynin at 2h postdose (time points close to their predicted time to peak concentration). Secondary end points included change in cognitive function at additional time points, and safety and tolerability assessments. Results and limitationsNeither agent was associated with significant changes from baseline in any of the five standard, composite outcomes of cognitive function (power of attention, continuity of attention, quality of working memory, quality of episodic memory, and speed of memory). In a secondary analysis, oxybutynin was associated with significant decreases in power and continuity of attention versus placebo at 1–2h postdose. Both agents were well tolerated, with the most frequently reported adverse event being mild or moderate dry mouth. ConclusionsSolifenacin had no detectable effect on cognition in this group of elderly people with MCI.

Onset of Bronchodilation with Fluticasone/Formoterol Combination Versus Fluticasone/Salmeterol in an Open-Label, Randomized Study

The inhaled corticosteroid, fluticasone propionate (fluticasone), and the long-acting beta(2)-agonist, formoterol fumarate (formoterol), have been combined in a single aerosol inhaler (fluticasone/formoterol). In a randomized, open-label study, fluticasone/formoterol showed similar efficacy to fluticasone/salmeterol after 12 weeks of treatment. This post-hoc analysis compared the onset of bronchodilation with the two treatments. Adults with mild-to-moderate-severe persistent asthma were randomized to fluticasone/formoterol (100/10 or 250/10 μg twice daily [b.i.d.]) or fluticasone/salmeterol (100/50 or 250/50 μg b.i.d.) for 12 weeks. The onset of bronchodilation (the first post-dose time point at which the forced expiratory volume in 1 second [FEV(1)] was ≥12% greater than the pre-dose value), responder rates (the proportion of patients achieving bronchodilation), and changes in FEV(1) were assessed at days 0 (baseline) and 84. Fluticasone/formoterol (n = 101) provided more rapid onset of bronchodilation than fluticasone/salmeterol (n = 101) over the first 120 min post-dose on days 0 (hazard ratio [HR] = 1.47 [95% CI 1.05-2.05]) and 84 (HR = 1.77 [95% CI 1.14-2.73]). The odds of a patient achieving bronchodilation within 5 min of dosing were almost four-times higher with fluticasone/formoterol than with fluticasone/salmeterol on day 0 (odds ratio [OR] = 3.97 [95% CI 1.96-8.03]) and almost 10-times higher on day 84 (OR = 9.58 [95% CI 2.14-42.90]); the odds of achieving bronchodilation within 120 min post-dose were approximately twofold higher with fluticasone/formoterol on both days. The overall percentage increase in least-squares (LS) mean FEV1 during the 120-min post-dose period was significantly greater with fluticasone/formoterol than fluticasone/salmeterol on days 0 (LS mean treatment difference: 4.70% [95% CI 1.57-7.83]; P = 0.003) and 84 (2.79% [95% CI 0.65-4.93]; P = 0.011). These analyses showed that fluticasone/formoterol provided a faster onset of bronchodilation than fluticasone/salmeterol, which was maintained over 12 weeks of treatment. This benefit may facilitate treatment adherence among patients with asthma.

A Phase 1 dose-escalation study of the safety and pharmacokinetics of once-daily oral foretinib, a multi-kinase inhibitor, in patients with solid tumors

Foretinib is an oral multi-kinase inhibitor targeting MET, vascular endothelial growth factor receptor (VEGFR)-2, RON, KIT, and AXL kinases. In this Phase 1, open-label, non-randomized study, foretinib was administered once daily at doses of 60 mg, 80 mg, 100 mg, or 120 mg for 28 days. The primary objectives were to determine the maximum tolerated dose (MTD) and assess the safety and tolerability of the daily oral administration schedule. Secondary objectives included pharmacokinetics, pharmacodynamics, and assessment of tumor response. Patients had histologically confirmed metastatic or unresectable solid tumors for which no standard treatments existed and all received oral foretinib once daily. Dose escalation was planned as a conventional "3+3" design with an expansion at the MTD for collection of additional safety and pharmacokinetic information. Thirty-seven patients were treated across four dose levels. The MTD was established as 80 mg foretinib. Dose-limiting toxicities were hypertension, dehydration, and diarrhea. The most common adverse events included fatigue, hypertension, nausea, and diarrhea. Twenty-three of 31 patients (74 %) had a best response of stable disease. No patient had a confirmed partial or complete response. At the MTD, steady state was achieved by approximately 2 weeks, with average post-dose time to maximum concentration, peak concentration, and trough concentration of 4 h, 46 ng/mL, and 24 ng/mL, respectively. In patients treated at the MTD, soluble MET and VEGF-A plasma levels significantly increased (P<0.003) and soluble VEGFR2 plasma levels significantly decreased from baseline (P<0.03). The MTD of foretinib bisphosphate salt was determined to be 80 mg once daily.

Embryo-fetal distribution of a biopharmaceutical IgG2 during rat organogenesis

Embryo-fetal biodistribution of a maternally administered humanized IgG2 in rats was evaluated by enzyme-linked immunosorbent assay in dose response and time course studies. Fetal and maternal plasma IgG2 levels increased with dose from 10 to 300mg/kg but fetal:maternal ratio decreased with increasing dose. Plasma IgG2 levels decreased in fetal rat with increasing time post-dose but more slowly than maternal levels. This difference in post-dose kinetics resulted in an increased fetal:maternal ratio with increasing days since last dose. Lastly, IgG2 in embryo-fetal tissue was detected at very low levels on gestation day (GD) 10–12 and levels increased over 100-fold by GD 17. The profile of increasing IgG2 levels as gestation progressed continued in extra-embryonic fluid (GD 12–19) until the end of gestation in fetal plasma (GD 19–21). Based on the current study, there is a potential for direct effects on rat embryo-fetal development following maternal administration of a biopharmaceutical IgG2.

A new class of prolylcarboxypeptidase inhibitors, Part 1: Discovery and evaluation

A new structural class of potent prolylcarboxypeptidase (PrCP) inhibitors was discovered by high-throughput screening. The series possesses a tractable SAR profile with sub-nanomolar in vitro IC50 values. Compared to prior inhibitors, the new series demonstrated minimal activity shifts in pure plasma and complete ex vivo plasma target engagement in mouse plasma at the 20h post-dose time point (po). In addition, the in vivo level of CNS and non-CNS drug exposure was measured.

Analysis of the pharmacodynamic activity of the mTOR inhibitor ridaforolimus (AP23573, MK-8669) in a phase 1 clinical trial

As part of a phase 1 dose-escalation trial, the pharmacodynamic activity of the mammalian target of rapamycin (mTOR) inhibitor ridaforolimus was assessed in multiple tissues by measuring levels of phosphorylated 4E binding protein-1 (p-4E-BP1) or S6, two downstream markers of mTOR activity. 32 patients (pts) were dosed intravenously with ridaforolimus once daily for 5 consecutive days (QD × 5) every 2 weeks. The pharmacodynamic activity of ridaforolimus was assessed in peripheral blood mononuclear cells (PBMCs; 32 pts), skin (28 pts), and tumor specimens (3 pts) collected before and after dosing by measuring levels of p-4E-BP1 by immunoblot analysis or pS6 by immunohistochemistry. Levels of these markers were assessed in up to 19, 5, and 2 pre- and post-dose time points in PBMC, skin, and tumor specimens, respectively. In preclinical models, ridaforolimus induced a dose-dependent inhibition of p-4E-BP1 in PBMCs that was associated with antitumor activity. Rapid and potent inhibition of mTOR was observed in PBMCs from all 32 pts dosed, with a median level of inhibition of 96% observed within 1 h after the first dose. Inhibition of mTOR (>90%) was sustained during the entire QD × 5 dosing period, and substantial inhibition was still observed after the 9-day holiday between dosing courses. Evidence of mTOR inhibition was also obtained in skin in pts from all dose cohorts, although it did not persist through the break between courses. After two to three doses of ridaforolimus, inhibition of mTOR was detected in the tumor from one of three pts analyzed. Ridaforolimus was shown to inhibit its intended target, mTOR, in PBMCs, skin, and tumors. In PBMCs and skin, inhibition was observed at all dose levels tested, thus supporting but not driving the selection of a recommended phase 2 dose.