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Background and Objective Sepsis and continuous renal replacement therapy (CRRT) can both significantly affect antifungal pharmacokinetics. This study aimed to describe the pharmacokinetics of caspofungin in critically ill patients during different CRRT modes. Methods Patients receiving caspofungin and undergoing continuous veno-venous haemofiltration (CVVH) or haemodiafiltration (CVVHDF) were eligible to take part in the study. Blood samples were collected at seven sampling times during a dosing interval. Demographics and clinical data were recorded. Population pharmacokinetic analysis and Monte-Carlo simulation were undertaken using Pmetrics. Results Twelve pharmacokinetic profiles from nine patients were analysed. The caspofungin CRRT clearance (CL) was 0.048 ± 0.12 L/h for CVVH and 0.042 ± 0.042 L/h for CVVHDF. A two-compartment linear model best described the data. Patient weight was the only covariate affecting drug CL and central volume. The mean (standard deviation) parameter estimates were 0.64 ± 0.12 L/h for CL, 9.35 ± 3.56 L for central volume, 0.25 ± 0.19 per h for the rate constant for drug distribution from central to peripheral compartments and 0.19 ± 0.10 per h from peripheral to central compartments. Based on simulation results, a caspofungin 100 mg loading dose followed by a 50 mg maintenance dose for patients with a total body weight of ≤80 kg best achieved the pharmacokinetic/PD targets whilst a 70 mg maintenance dose was required for patients with a weight of >80 kg. Conclusion No caspofungin dosing adjustment is necessary for patients undergoing either form of CRRT. However, higher than recommended loading doses of caspofungin are required to achieve pharmacokinetic/pharmacodynamic targets in critically ill patients. Registration: ClinicalTrials.gov Identifier NCT01403220

Hereditary angio-oedema is a recurrent, oedematous disorder caused by deficiency of functional C1 inhibitor. Infusions of plasma-derived C1 esterase inhibitor deter attacks of hereditary angio-oedema, but the prophylactic effect of recombinant human C1 esterase inhibitor has not been rigorously studied. We aimed to assess the efficacy of recombinant human C1 esterase inhibitor for prophylaxis of hereditary angio-oedema. We conducted this phase 2, multicentre, randomised, double-blind, placebo-controlled crossover trial at ten centres in Canada, the Czech Republic, Israel, Italy, Macedonia, Romania, Serbia, and the USA. We enrolled patients aged 13 years or older with functional C1-inhibitor concentrations of less than 50% of normal and a history of four or more attacks of hereditary angio-oedema per month for at least 3 months before study initiation. Patients were randomly assigned centrally (1:1:1:1:1:1), via an interactive response technology system with fixed allocation, to receive one of six treatment sequences. During each sequence, patients received intravenous recombinant human C1 esterase inhibitor (50 IU/kg; maximum 4200 IU) twice weekly, recombinant human C1 esterase inhibitor once weekly and placebo once weekly, and placebo twice weekly, each for 4 weeks with a 1 week washout period between crossover. All patients, investigators, and study personnel who participated in patient care were masked to group allocation during the study. The primary efficacy endpoint was the number of attacks of hereditary angio-oedema observed in each 4 week treatment period. Attack symptoms were recorded daily. The primary efficacy analysis was done in the intention-to-treat population. Safety was assessed in all patients who received at least one injection of study medication. This study is registered with ClinicalTrials.gov, number NCT02247739. Between Dec 29, 2014, and May 3, 2016, we enrolled 35 patients, of whom 32 (91%) underwent randomisation (intention-to-treat population) and 26 (81%) completed the study. The mean number of attacks of hereditary angio-oedema over 4 weeks was significantly reduced with recombinant human C1 esterase inhibitor twice weekly (2·7 attacks [SD 2·4]) and once weekly (4·4 attacks [3·2]) versus placebo (7·2 attacks [3·6]), with mean differences of −4·4 attacks (p<0·0001) and −2·8 attacks (p=0·0004), respectively. We recorded adverse events in ten (34%) of 29 patients given twice-weekly recombinant human C1 esterase inhibitor, 13 (45%) of 29 patients given the once-weekly regimen, and eight (29%) of 28 patients given placebo. Headache (twice-weekly treatment) and nasopharyngitis (once-weekly treatment) were the most common adverse events. Two (7%) adverse events (fatigue and headache) were deemed possibly related to treatment with recombinant human C1 esterase inhibitor, but both resolved without additional treatment. No thrombotic or thromboembolic events, systemic allergic reactions (including anaphylaxis), or neutralising antibodies were reported. Prophylaxis with recombinant human C1 esterase inhibitor provided clinically relevant reductions in frequency of hereditary angio-oedema attacks and was well tolerated. In view of the pharmacokinetic profile of recombinant human C1 esterase inhibitor, our results suggest that efficacy of C1-inhibitor replacement therapy might not be a direct function of plasma trough concentrations of C1 inhibitor. Pharming Technologies.

Rationale Two biomarkers: concentration ratio of O -desmethylvenlafaxine/venlafaxine and concentration sum of venlafaxine +  O -desmethylvenlafaxine were adopted to indicate venlafaxine responses, but neither is validated. Objectives To evaluate the ability of two biomarkers in reflecting venlafaxine pharmacokinetic variations, and to further examine their relationship with venlafaxine treatment outcomes. Methods Two well-defined influencing factors: CYP2D6 genotypes and drug interactions were enriched into a three-period crossover study to produce venlafaxine pharmacokinetic variations: In each period, healthy CYP2D6 extensive metabolizers (EM group; n  = 12) and CYP2D6*10/*10 intermediate metabolizers (IM group; n  = 12) were pretreated with clarithromycin (CYP3A4 inhibitor), or nothing (control), or clarithromycin + paroxetine (CYP3A4 + CYP2D6 inhibitors), before administration of a single-dose of 75 mg venlafaxine. Both biomarkers were evaluated (1) for their relationship with the influencing factors in healthy volunteers and (2) for their relationships with the venlafaxine responses/adverse events reported in two patient studies. Results Significant venlafaxine pharmacokinetic variations were observed between the EM and IM groups (geometric mean ratio [95 % CI] of area under the curve, 3.0 [1.8–5.1] in the control period), and between the control and clarithromycin + paroxetine periods (4.1 [3.5–4.7] and 2.0 [1.7–2.4] in the EM and IM group, respectively). O -Desmethylvenlafaxine/venlafaxine was superior to venlafaxine +  O -desmethylvenlafaxine to reflect the influencing factors. In the patient studies, O -desmethylvenlafaxine/venlafaxine > 4 showed high precision in predicting venlafaxine responders/partial-responders (92 %) and patients without venlafaxine-related adverse events (88 %); the O -desmethylvenlafaxine/venlafaxine < 4 and venlafaxine +  O -desmethylvenlafaxine > 400 ng/ml combination showed higher precision (100 %) than O -desmethylvenlafaxine/venlafaxine < 4 alone (65 %) in predicting venlafaxine non-responders. Conclusion We propose using O -desmethylvenlafaxine/venlafaxine for CYP2D6 phenotyping, and O -desmethylvenlafaxine/venlafaxine with venlafaxine +  O -desmethylvenlafaxine for predicting venlafaxine treatment outcomes in future prospective studies.

Purpose We recently developed prostaglandin E₁ (PGE₁)-encapsulated nanoparticles, prepared with a poly(lactide) homopolymer (PLA, Mw = 17,500) and monomethoxy poly(ethyleneglycol)-PLA block copolymer (PEG-PLA) (NP-L20). In this study, we tested whether the accelerated blood clearance (ABC) phenomenon is observed with NP-L20 and other PEG-modified PLA-nanoparticles in rats. Methods The plasma levels of PGE₁ and anti-PEG IgM antibody were determined by EIA and ELISA, respectively. Results Second injections of NP-L20 were cleared much more rapidly from the circulation than first injections, showing that the ABC phenomenon was induced. This ABC phenomenon, and the accompanying induction of anti-PEG IgM antibody production, was optimal at a time interval of 7 days between the first and second injections. Compared to NP-L20, NP-L33s that were prepared with PLA (Mw = 28,100) and have a smaller particle size induced production of anti-PEG IgM antibody to a lesser extent. NP-L20 but not NP-L33s gave rise to the ABC phenomenon with a time interval of 14 days. NP-L33s showed a better sustained-release profile of PGE₁ than NP-L20. Conclusions This study revealed that the ABC phenomenon is induced by PEG-modified PLA-nanoparticles. We consider that NP-L33s may be useful clinically for the sustained-release and targeted delivery of PGE₁.

Objectives To investigate the pharmacokinetic and pharmacodynamic profile of dabigatran in healthy elderly subjects; to assess the intra- and interindividual variability of dabigatran pharmacokinetics in order to assess possible gender differences; and to assess the effect of pantoprazole coadministration on the bioavailability of dabigatran. Study design and setting Open-label, parallel-group, single-centre study, consisting of a baseline screening visit, 7-day treatment period and post-study examination visit. Subjects and intervention 36 healthy elderly subjects (aged ≥65 years) with a body mass index of 18.5–29.9 kg/m 2 . Subjects were randomized to receive dabigatran etexilate either with or without coadministration of pantoprazole. Dabigatran etexilate was administered as capsules at 150 mg twice daily over 6 days and once on the morning of day 7. Pantoprazole was administered at 40 mg twice daily, starting 2 days prior to dabigatran etexilate administration and ending on the morning of day 7. Main outcome measures The primary pharmacokinetic measurements included the area under the plasma concentration-time curve at steady state (AUC ss ), maximum (Cmax,ss) and minimum (Cmin,ss) plasma concentrations at steady state, terminal half-life (t½), time to reach Cmax,ss and renal clearance of dabigatran. The secondary pharmacokinetic parameters included the mean residence time, total oral clearance and volume of distribution. The pharmacodynamic parameters measured were the blood coagulation parameters ecarin clotting time (ECT) and activated partial thromboplastin time (aPTT). Results With twice-daily administration of dabigatran etexilate, plasma concentrations of dabigatran reached steady state within 2–3 days, which is consistent with a t½ of 12–14 hours. The mean (SD) peak plasma concentrations on day 4 of treatment in male and female elderly subjects were 256 ng/mL (21.8) and 255 ng/mL (84.0), respectively. The peak plasma concentrations were reached after a median of 3 hours (range 2.0–4.0 hours). Coadministration with pantoprazole decreased the average bioavailability of dabigatran (the AUCss) by 24% (day 4; 90% CI 7.4, 37.8) and 20% (day 7; 90% CI 5.2, 33.3). Intra- and interindividual pharmacokinetic variability in the overall population was low (<30% coefficient of variation), indicating that dabigatran has a predictable pharmacokinetic profile. Prolongation of the ECT and aPTT correlated with, and paralleled, the plasma concentration-time profile of dabigatran, which demonstrates a rapid onset of action without a time delay, and also illustrates the direct mode of action of the drug on thrombin in plasma. The ECT increased in direct proportion to the plasma concentration, and the aPTT displayed a linear relationship with the square root of the plasma concentration. The mean AUCss was 3–19% higher in female subjects than in male subjects, which was likely due to gender differences in creatinine clearance. The safety profile of dabigatran was good, with and without pantoprazole coadministration. Conclusions Dabigatran demonstrated reproducible and predictable pharmacokinetic and pharmacodynamic characteristics, together with a good safety profile, when administered to healthy elderly subjects. Minor gender differences were not considered clinically relevant. The effects of pantoprazole coadministration on the bioavailability of dabigatran were considered acceptable, and dose adjustment is not considered necessary.

Abstract Context Glucagon-like peptide-1 (GLP-1) agonists control postprandial glucose and lipid excursion in type 2 diabetes; however, the mechanisms are unclear. Objective To determine the mechanisms of postprandial lipid and glucose control with lixisenatide (GLP-1 analog) in type 2 diabetes. Design Randomized, double-blind, cross-over study. Setting Centre for Diabetes, Endocrinology, and Research, Royal Surrey County Hospital, Guildford, United Kingdom. Patients Eight obese men with type 2 diabetes [age, 57.3 ± 1.9 years; body mass index, 30.3 ± 1.0 kg/m2; glycosylated hemoglobin, 66.5 ± 2.6 mmol/mol (8.2% ± 0.3%)]. Interventions Two metabolic studies, 4 weeks after lixisenatide or placebo, with cross-over and repetition of studies. Main Outcome Measures Study one: very-low-density lipoprotein (VLDL) and chylomicron (CM) triacylglycerol (TAG) kinetics were measured with an IV bolus of [2H5]glycerol in a 12-hour study, with hourly feeding. Oral [13C]triolein, in a single meal, labeled enterally derived TAG. Study two: glucose kinetics were measured with [U-13C]glucose in a mixed-meal (plus acetaminophen to measure gastric emptying) and variable IV [6,6-2H2]glucose infusion. Results Study one: CM-TAG (but not VLDL-TAG) pool-size was lower with lixisenatide (P = 0.046). Lixisenatide reduced CM [13C]oleate area under the curve (AUC)60–480min concentration (P = 0.048) and increased CM-TAG clearance, with no effect on CM-TAG production rate. Study two: postprandial glucose and insulin AUC0–240min were reduced with lixisenatide (P = 0.0051; P < 0.05). Total glucose production (P = 0.015), rate of glucose appearance from the meal (P = 0.0098), and acetaminophen AUC0–360min (P = 0.006) were lower with lixisenatide than with placebo. Conclusions Lixisenatide reduced [13C]oleate concentrations, derived from a single meal in CM-TAG and glucose rate of appearance from the meal through delayed gastric emptying. However, day-long CM production, measured with repeated meal feeding, was not reduced by lixisenatide and decreased CM-TAG concentration resulted from increased CM-TAG clearance. Using stable isotopes, lixisenatide acutely slowed gastric emptying, lowering postprandial TAG levels. A more prolonged effect of reduced chylomicron TAG was from increased clearance.

Objective Allopurinol dosing has frequently been limited based on creatinine clearance (CrCL), resulting in failure to achieve target serum urate (SU). The aim of this analysis was to determine how many milligrams of allopurinol above the recommended CrCL-based dose (R+) are required to achieve target SU and to investigate the factors that influence R+. Methods We analysed data from participants in a 24-month open, randomized, controlled, parallel-group, comparative clinical trial. Data obtained during the 12-month dose escalation (DE) phase of the study (year 1 for DE/DE and year 2 for control/DE) were combined. R+ dose was defined as the number of milligrams of allopurinol above the CrCL-based dose at the final visit. Results Of the 132 participants, R+ allopurinol dose at the final visit was ≤ 100 mg/day in 38 (28.8%), 101–200 mg/day in 46 (34.8%) and > 200 mg/day in 48 participants (37.1%). There was no significant difference between the R+ groups in the number of participants achieving target SU. There was an increase in plasma oxypurinol and a larger percentage and absolute change in SU as R+ increased. Multivariate analysis revealed CrCL, weight, baseline SU and allopurinol dose, were significantly positively associated with allopurinol dose at 12 months. There were no significant differences across R+ groups in renal or liver function adverse events, although there were numerically more serious adverse events in the higher R+ groups. Conclusion A wide range of R+ doses are required to achieve target SU. Four easily obtained clinical variables (baseline SU, CrCL, weight, and allopurinol dose) may be helpful to predict allopurinol dose. Trial registration ANZCTR, ACTRN12611000845932 . Registered on 10 August 2011.

Phosphodiesterase 10A (PDE10A) is selectively expressed in the striatal regions in the brain and may play a role in modulating dopaminergic and glutamatergic second messenger pathways. PDE10A inhibitors are expected to be useful in treating neuropsychiatric disorders such as schizophrenia and Huntington’s disease. In this study, the brain kinetics of [11C]T-773 in the human brain and test-retest reproducibility of the outcome measures were evaluated. Subsequently, the occupancy of a novel PDE10A inhibitor, TAK-063, was measured using [11C]T-773. Dynamic PET measurements were conducted three times for 12 healthy male subjects after intravenous bolus injection of [11C]T-773: two baseline PETs and one postdose PET (3hours) after oral administration of TAK-063 for four subjects, and one baseline PET and two postdose PET (3hours and 23hours) for eight subjects. Kinetic model analysis was performed with arterial input functions. PDE10A occupancy was calculated as the percent change of the binding specific to PDE10A (Vs) total distribution volume (VT), which was calculated as the VT of the putamen minus the VT of the cerebellum. Regional brain uptake was highest in the putamen. Time-activity curves of the brain regions were described with two tissue-compartment (2TC) models. The mean VT was 5.5±0.7 in the putamen and 2.3±0.5 in the cerebellum in the baseline PET. Absolute VT variability between the two baseline scans was less than 7%. Reproducibility of VT was excellent. PDE10A occupancy in the putamen ranged from 2.8% to 72.1% at 3hours after a single administration of 3 to 1000mg of TAK-063, and increased in a dose- and plasma concentration-dependent manner. At 23hours postdose, PDE10A occupancy in the putamen was 0 to 42.8% following administration of 3 to 100mg of TAK-063. In conclusion, [11C]T-773 showed good characteristics as a PET radioligand for PDE10A in the human brain.

Introduction Edoxaban is a novel factor Xa inhibitor. This study characterizes the population pharmacokinetics of edoxaban in patients with non-valvular atrial fibrillation (NVAF) included in the phase III ENGAGE AF-TIMI 48 study, evaluates covariates for the dose–exposure relationship in this population, and assesses the impact of protocol-specified dose reductions on exposure using simulations. Methods Model development was performed using NONMEM ® and based on sparse data from the ENGAGE AF-TIMI 48 study augmented with dense data from 13 phase I studies to inform and stabilize the model. The influence of body weight (WT), creatinine clearance (CL CR ), concomitant P-glycoprotein (P-gp) inhibitors, age, sex, race, and NVAF on pharmacokinetic parameters was evaluated based on statistical significance and clinical relevance. Results A two-compartment model with first-order elimination and first-order absorption after an absorption lag-time best described the data. Apparent volume and clearance terms increased with increasing WT. Apparent renal clearance increased with increasing CL CR . Apparent non-renal, renal, and inter-compartmental clearance terms differed between phase I volunteers and NVAF patients. Asian patients were found to have increased apparent central volume of distribution, bioavailability, and total apparent clearance. Concomitant P-gp inhibitors increased the bioavailability statistically significantly, but this did not reach clinical relevance. Conclusion Edoxaban disposition and the variability in this disposition, including influence of covariates, after oral administration were adequately characterized in patients with NVAF. The 50 % dose reduction in patients with low WT (≤60 kg), moderate renal impairment (CL CR ≤50 mL/min), or concomitant P-gp inhibitors led to 30 % lower exposure than in the other patients.

Amfepramone (AFP) is an appetite-suppressant drug used in the treatment of obesity. Nonetheless, studies on interindividual pharmacokinetic variability and its association with genetic variants are limited. We employed a pharmacokinetic and pharmacogenetic approach to determine possible metabolic phenotypes of AFP and identify genetic markers that could affect the pharmacokinetic variability in a Mexican population. A controlled, randomized, crossover, single-blind, two-treatment, two-period, and two sequence clinical study of AFP (a single 75 mg dose) was conducted in 36 healthy Mexican volunteers who fulfilled the study requirements. Amfepramone plasma levels were measured using high-performance liquid chromatography mass spectrometry. Genotyping was performed using real-time PCR with TaqMan probes. Four AFP metabolizer phenotypes were found in our population: slow, normal, intermediate, and fast. Additionally, two gene polymorphisms, ABCB1 -rs1045642 and CYP3A4 -rs2242480, had a significant effect on AFP pharmacokinetics ( P  < 0.05) and were the predictor factors in a log-linear regression model. The ABCB1 and CYP3A4 gene polymorphisms were associated with a fast metabolizer phenotype. These results suggest that metabolism of AFP in the Mexican population is variable. In addition, the genetic variants ABCB1 -rs1045642 and CYP3A4 -rs2242480 may partially explain the AFP pharmacokinetic variability.