Stable Plasma Concentrations Research Articles

Olanzapine depot exposure in male rats: Dose-dependent lipogenic effects without concomitant weight gain

Treatment with second-generation antipsychotic agents such as olanzapine frequently results in metabolic adverse effects, e.g. hyperphagia, weight gain and dyslipidaemia in patients of both genders. The molecular mechanisms underlying metabolic adverse effects are still largely unknown, and studies in rodents represent an important approach in their exploration. However, the validity of the rodent model is hampered by the fact that antipsychotics induce weight gain in female, but not male, rats. When administered orally, the short half-life of olanzapine in rats prevents stable plasma concentrations of the drug. We recently showed that a single intramuscular injection of long-acting olanzapine formulation yields clinically relevant plasma concentrations accompanied by several dysmetabolic features in the female rat. In the current study, we show that depot injections of 100–250mg/kg olanzapine yielded clinically relevant plasma olanzapine concentrations also in male rats. In spite of transient hyperphagia, however, olanzapine resulted in weight loss rather than weight gain. The resultant negative feed efficiency was accompanied by a slight elevation of thermogenesis markers in brown adipose tissue for the highest olanzapine dose, but the olanzapine-related reduction in weight gain remains to be explained. In spite of the absence of weight gain, an olanzapine dose of 200mg/kg or above induced significantly elevated plasma cholesterol levels and pronounced activation of lipogenic gene expression in the liver. These results confirm that olanzapine stimulates lipogenic effects, independent of weight gain, and raise the possibility that endocrine factors may influence gender specificity of metabolic effects of antipsychotics in the rat.

Antithrombotic Management of Patients with Nonvalvular Atrial Fibrillation and Ischemic Stroke or Transient Ischemic Attack: Executive Summary of the Korean Clinical Practice Guidelines for Stroke.

Cardioembolic stroke related to nonvalvular atrial fibrillation is associated with a high recurrence rate and high mortality and morbidity. In this population, therefore, optimal anticoagulant therapy is required to prevent the occurrence of second stroke. Oral anticoagulant, warfarin has been traditionally used, but it is greatly limited by its narrow efficacy window, complex pharmacokinetics, and multiple drug interactions, thus requiring frequent blood monitoring. Recently, oral anticoagulants targeted for a specific coagulation component have been newly developed and tested in large clinical trials. Dabigatran, direct thrombin inhibitor, and rivaroxaban, apixaban, and edoxaban, inhibitors of factor Xa harbor great merits of rapid action time, short half-life, stable plasma concentration, and little drug interaction. Recently, large randomized clinical trials and meta-analyses have been published to show the efficacy and safety of the new oral anticoagulants compared with warfarin. Based on the results from recent clinical trials, we revised recommendations to apply optimal anticoagulant therapy in patients with nonvalvular atrial fibrillation and ischemic stroke or transient ischemic attack.

Effect of anagrelide on cardiac repolarization in healthy volunteers: a randomized, double‐blind, placebo‐ and positive‐controlled, thorough QT study

AbstractThe aim of this study was to assess the effect of low and high therapeutic doses of anagrelide (0.5 and 2.5 mg) on cardiac repolarization, measured by the QTcNi (individual correction) and QTcF (Fridericia's correction), compared with placebo and moxifloxacin 400 mg (positive control) in healthy subjects. In this randomized, double‐blind, crossover trial, 60 healthy volunteers were enrolled and randomized. Anagrelide 0.5 and 2.5 mg rapidly increased mean heart rate (HR) by 7.8 and 29.1 bpm respectively. For anagrelide 2.5 mg, the maximum time‐matched change (one‐sided 95% upper confidence bound) in mean QTcNi and QTcF was 13.0 msec (15.7 msec) and 10.0 msec (12.7 msec), respectively, at 1 h post dose. However, time‐matched changes in QTcNi and QTcF quickly decreased to <6 msec by 2 h post dose, despite high stable HR and high plasma concentrations of anagrelide and its active metabolite at these times. For anagrelide 0.5 mg, the maximum time‐matched change in mean QTcNi and QTcF was 7.0 msec (9.8 msec) and 5.0 msec (8.0 msec) respectively. No new safety concerns were reported. The increase in QTc interval met the definition for a positive thorough QT/QTc study only when HR was increasing rapidly, suggesting that the increased QTc may be related to the rapidly increasing HR rather than a direct effect of anagrelide plasma concentrations. However, the direct causal relationship of anagrelide on cardiac repolarization cannot be completely excluded, and caution is advised when treating patients with known risk factors for QT interval prolongation.

Development of Recombinant Human Growth Hormone (rhGH) sustained-release microspheres by a low temperature aqueous phase/aqueous phase emulsion method

A novel method has been developed to protect Recombinant Human Growth Hormone (rhGH) in poly (lactic-co-glycolic acid) (PLGA) microspheres using an aqueous phase/aqueous phase emulsion and S/O/W multi-emulsion method. This method develops a novel rhGH sustained-release system, which is based on the combination of rhGH-loaded dextran microparticles and PLGA microspheres. The process to fabricate rhGH-loaded dextran microparticles involves an aqueous phase/aqueous phase emulsion system formed at the reduced temperature. RhGH was first dissolved in water together with dextran and polyethylene glycol, followed by stirring at the speed of 2000rpm for 20–30s at 0°C, and then a freezing process could enable the dextran phase to separate from the continuous PEG phase and rhGH could preferentially be loaded with dextran. The sample after freezing and phase separation was then lyophilized to powder and washed with dichloromethane to remove the PEG. Once loaded in the dextran microparticles (1–4μm in diameter), rhGH gained resistance to interface tensions and was encapsulated into PLGA microspheres without aggregation thereafter. RhGH released from PLGA microspheres was in a sustained manner with minimal burst and maximally reduced incomplete release in vitro. Single subcutaneous injection of rhGH-loaded PLGA microspheres to rats resulted in a stable plasma concentration for 30days avoiding the drug concentration fluctuations after multiple injections of protein solutions. In a hypophysectomized rat model, the IGF-1 and bodyweight results showed that there were higher than the levels obtained for the sustained release formulation by W/O/W for 40days. These results suggest that the microsphere delivery system had the potential to be an injectable depot for sustained-release of the biocompatible protein of rhGH.

Pharmacokinetics, Safety and Tolerability of Rotigotine Transdermal Patch in Healthy Japanese and Caucasian Subjects

Background and ObjectivesRotigotine is a dopamine receptor agonist with activity across the D1 through to D5 receptors as well as select serotonergic and adrenergic sites; continuous transdermal delivery of rotigotine with replacement of the patch once daily maintains stable plasma concentrations over 24 h. Rotigotine is indicated for the treatment of early and advanced-stage Parkinson’s disease and moderate-to-severe idiopathic restless legs syndrome. The pharmacokinetics and pharmacodynamics of a drug may vary between subjects of different ethnic origin. This study evaluated the pharmacokinetics, safety, and tolerability of single-dose treatment with rotigotine transdermal patch in Japanese and Caucasian subjects.MethodsIn this open-label, parallel-group study, healthy male and female subjects of Japanese or Caucasian ethnic origin were matched by sex, body mass index, and age. A single transdermal patch delivering 2 mg/24 h rotigotine (patch content 4.5 mg) was applied to the ventral/lateral abdomen for 24 h. The main outcome measures were the plasma concentrations of unconjugated and total rotigotine and its desalkyl metabolites and derived pharmacokinetic parameters (area under the concentration–time curve from time zero to last quantifiable concentration [AUClast], maximum plasma concentration [C max], and body weight- and dose-normalized values).ResultsThe pharmacokinetic analysis included 48 subjects (24 Japanese, 24 Caucasian). The mean apparent dose of rotigotine was 2.0 ± 0.5 mg for Japanese subjects and 2.08 ± 0.58 mg for Caucasians. Plasma concentration–time profiles of unconjugated rotigotine and of the main metabolites were similar for both ethnic groups. Parameters of model-independent pharmacokinetics, C max, time to C max (t max), and AUClast, for unconjugated rotigotine showed no statistically significant differences between Japanese and Caucasian subjects. Values of concentration-dependent pharmacokinetic parameters were higher in female subjects; this difference was minimized after correction for body weight. A statistically significant difference between ethnic groups was observed for total rotigotine concentrations (total rotigotine = unconjugated rotigotine + conjugated rotigotine), with slightly lower values in Caucasians after correction for body weight and apparent dose. No relevant differences were observed between males and females. Inter-individual variability was high. The terminal half-life for unconjugated rotigotine was 5.3 h in Japanese subjects and 5.7 h in Caucasians; corresponding values for total rotigotine were 8.6 h and 9.6 h. Less than 0.1 % of the apparent dose was renally excreted as the parent compound. Renal elimination of total rotigotine covers 11.7 % of absorbed dose in Japanese subjects and 10.8 % of the absorbed dose in Caucasians, whereas the renal elimination via total despropyl rotigotine was 8.2 and 7.1 %, respectively. The corresponding values for total desthienylethyl rotigotine were 3.5 % in Japanese subjects and 4.2 % Caucasians. Most adverse events were mild in intensity and typical for dopamine agonists or for transdermal therapeutics.ConclusionAdministration of a single patch delivering 2 mg/24 h rotigotine resulted in comparable pharmacokinetic profiles in Japanese and Caucasian subjects. The rotigotine transdermal patch was generally well-tolerated. Our findings suggest similar dose requirements for Japanese and Caucasian populations.

Basal insulin analogs: From pathophysiology to therapy. What we see, know, and try to comprehend?

During the past 10years, several new basal insulin analogs have been developed. There has been for 3years controversy on the potential increased risk for cancer with insulin glargine, which ceased with the publication of the ORIGIN trial in 2012. In insulin-treated persons with type 2 diabetes, it is usual to recommend that plasma insulin concentrations remain within a 50–200pmol/L range in order to avoid overinsulinization, a potential causative factor for increased mitogenicity. Such concentrations are achieved when daily doses of insulin glargine or NPH insulin approximate 0.4 units/kg. However, the total plasma insulin concentrations are much greater in persons treated with insulin detemir and especially insulin degludec. These insulins derive their protracted action from the insertion of a long chain fatty acid moiety to the insulin molecule thereby increasing albumin binding. As a consequence, in persons with type 2 diabetes, stable total plasma concentrations as high as either 1600 or 6000pmol/L are observed for insulin detemir or degludec, respectively. At present, the free to bound ratio of plasma insulin concentrations remains unknown for these two compounds. A first requirement is to understand how these insulins are eliminated or degraded and secondly to quantify the respective contributions of the free and bound fractions. Therefore, prior to early phase 2 or 3 randomized clinical trials, a better comprehension of the metabolism of all the new insulins would be invaluable.

Reply

The exact etiology of nocturnal enuresis (NE) is unknown. But there are some suspected situations, such as developmental delay of antidiuretic hormone production at night, developmental delay of appropriate arousal thresholds, and nocturnal detrusor over-activity. 1 Rasmussen P.V. Kirk J. Borup K. et al. Enuresis nocturna can be provoked in normal healthy children by increasing the nocturnal urine output. Scand J Urol Nephrol. 1996; 30: 57-61 Crossref PubMed Scopus (20) Google Scholar , 2 Rittig S. Knudsen U.B. Norgaard J.P. et al. Abnormal diurnal rhythm of plasma vasopressin and urinary output in patients with enuresis. Am J Physiol. 1989; 256: F664-F671 PubMed Google Scholar , 3 Wolfish N.M. Pivik R.T. Busby K.A. Elevated sleep arousal thresholds in enuretic boys: clinical implications. Acta Paediatr. 1997; 86: 381-384 Crossref PubMed Scopus (152) Google Scholar , 4 Yeung C.K. Chiu H.N. Sit F.K. Bladder dysfunction in children with refractory monosymptomatic primary nocturnal enuresis. J Urol. 1999; 162 (discussion 1054-5): 1049-1054 PubMed Scopus (167) Google Scholar Underlying factors may change from one patient to another. This causes the treatment choice to differ, especially in the first evaluation of the patient. We value the editorial comments and would like to emphasize that the primary purpose of our report was to evaluate copeptin's role in the etiology of NE. Copeptin is more stable than arginine vasopressin (AVP) and reflects more stable plasma concentrations. We observed that copeptin levels decrease more significantly with increasing severity of the disease and a positive family history. Hence, in this group of patients, AVP deficiency at night may be the primary cause for NE, and these patients may benefit from desmopressin therapy much more than other patients. We agree with the editor that our study has some limitations. But this is a preliminary study, and by taking this study as a basis, further studies can be carried out with a greater number of patients and by measuring copeptin and AVP levels in the mornings and at nights and comparing desmopressin treatment outcomes according to copeptin levels thereby proving the marker's efficacy in clinical use. Editorial CommentUrologyVol. 82Issue 5PreviewWe know that primary monosymptomatic nocturnal enuresis (MNE) is a symptom of a multifactorial disease – insufficient arousal mechanism, smaller than expected bladder capacity, or nocturnal polyuria, or a combination of these, are some etiologies identified to date.1-3 Full-Text PDF

Effective long-term immunosuppression in rats by subcutaneously implanted sustained-release tacrolimus pellet: Effect on spinally grafted human neural precursor survival

Achievement of effective, safe and long-term immunosuppression represents one of the challenges in experimental allogeneic and xenogeneic cell and organ transplantation. The goal of the present study was to develop a reliable, long-term immunosuppression protocol in Sprague–Dawley (SD) rats by: 1) comparing the pharmacokinetics of four different subcutaneously delivered/implanted tacrolimus (TAC) formulations, including: i) caster oil/saline solution, ii) unilamellar or multilamellar liposomes, iii) biodegradable microspheres, and iv) biodegradable 3-month lasting pellets; and 2) defining the survival and immune response in animals receiving spinal injections of human neural precursors at 6weeks to 3months after cell grafting. In animals implanted with TAC pellets (3.4mg/kg/day), a stable 3-month lasting plasma concentration of TAC averaging 19.1±4.9ng/ml was measured. Analysis of grafted cell survival in SOD+ or spinal trauma-injured SD rats immunosuppressed with 3-month lasting TAC pellets (3.4–5.1mg/kg/day) showed the consistent presence of implanted human neurons with minimal or no local T-cell infiltration. These data demonstrate that the use of TAC pellets can represent an effective, long-lasting immunosuppressive drug delivery system that is safe, simple to implement and is associated with a long-term human neural precursor survival after grafting into the spinal cord of SOD+ or spinal trauma-injured SD rats.

Pharmacokinetics, Pharmacodynamics and Clinical Use of Valganciclovir in Newborns with Symptomatic Congenital Cytomegalovirus Infection

Congenital cytomegalovirus infection is the most common cause of nonhereditary sensorineural hearing loss and an important cause of psychomotor retardation. Newborns suffering from symptomatic congenital cytomegalovirus infection have been typically treated with i.v. ganciclovir (GCV). Nowadays valganciclovir (V-GCV), a mono-valyl ester pro-drug of GCV, is available as an oral syrup. The existing literature demonstrated that V-GCV is well absorbed from the gastrointestinal tract and is rapidly converted into GCV in the intestinal wall and liver. The mechanism of antiviral action is the same that has been described for GCV. All these characteristics make this formulation particularly suitable for the symptomatic congenitally infected newborns. In neonates, V-GCV oral formulation proved stable and constant GVC plasma concentrations, in the suggested therapeutic range. The syrup demonstrated to be clinically effective and well tolerated and to be appropriate for a prolonged post-discharge therapy avoiding the discomfort of hospitalization, reducing the risk for nosocomial infections and decreasing the cost for the National Health Service. This article reviews all the available literature about V-GCV syrup in the treatment of newborns and infants with congenital CMV infection with the regard to pharmacokinetics, pharmacodynamic properties and clinical use, focussing on new data and on our experience.

Pharmacokinetics, Pharmacodynamics and Clinical Use of Valganciclovir in Newborns with Symptomatic Congenital Cytomegalovirus Infection

Congenital cytomegalovirus infection is the most common cause of nonhereditary sensorineural hearing loss and an important cause of psychomotor retardation. Newborns suffering from symptomatic congenital cytomegalovirus infection have been typically treated with i.v. ganciclovir (GCV). Nowadays valganciclovir (V-GCV), a mono-valyl ester pro-drug of GCV, is available as an oral syrup. The existing literature demonstrated that V-GCV is well absorbed from the gastrointestinal tract and is rapidly converted into GCV in the intestinal wall and liver. The mechanism of antiviral action is the same that has been described for GCV. All these characteristics make this formulation particularly suitable for the symptomatic congenitally infected newborns. In neonates, V-GCV oral formulation proved stable and constant GVC plasma concentrations, in the suggested therapeutic range. The syrup demonstrated to be clinically effective and well tolerated and to be appropriate for a prolonged post-discharge therapy avoiding the discomfort of hospitalization, reducing the risk for nosocomial infections and decreasing the cost for the National Health Service. This article reviews all the available literature about V-GCV syrup in the treatment of newborns and infants with congenital CMV infection with the regard to pharmacokinetics, pharmacodynamic properties and clinical use, focussing on new data and on our experience.

An open label trial of the effects and safety profile of extended-release tramadol in the management of chronic pain

ObjectivesTramadol is a synthetic centrally-acting opioid analgesic. The newly developed extended-release formulation of tramadol offers a more stable plasma concentration and could improve patients' compliance. The purpose of this study was to evaluate the efficacy, safety, and adverse events of extended release tramadol in Taiwanese patients with moderate to severe chronic noncancer pain. MethodsSixty-six patients with moderate to severe chronic noncancer pain previously treated with conventional tramadol but unsatisfied with its efficacy were enrolled from four medical centers. The patients received the extended-release tramadol once daily for a week. ResultsThe usage of extended-release tramadol was more efficacious as the patients' visual analog scale score dropped significantly (−16 ± 14.1). In this study, the reported adverse events were similar to those of previous studies. Thirty patients reported adverse events and one patient reported a serious adverse event but was justified unrelated to the study drug. The most common adverse event was dizziness, followed by vomiting, nausea, somnolence, and constipation in sequence. In this study, patients with dizziness were observed to have a lower initial pain score (p = 0.032). Furthermore, the rate of premature termination and dizziness was closely correlated (p = 0.027). ConclusionPatients with chronic pain could obtain significantly better pain relief after the switch to larger doses of extended-release tramadol with safety and without severe adverse effects in a short period of time. Less severe adverse effects (no life-threatening event) was the leading cause of premature termination.

Carvedilol suppresses ventricular arrhythmia in a pressure over-load rabbit model through relieving transmural dispersion of repolarization with long-term administration

ObjectiveTo investigate the effects of carvedilol (CVD) on transmural dispersion of repolarization (TDR) and arrhythmia in pressure over-load rabbits. MethodsLeft ventricular hypertrophied (LVH) rabbit models were established by pressure over-load; All animal models were assigned into CVD group or LVH group randomly. The action potentials of endocardium, epicardium and transmural ECG of arterially perfused left ventricular preparations were recorded concurrently. Action potential duration (APD), TDR, ventricular arrhythmia and ultrasonic parameters, ratio of LVM to body weight (LVMI) were compared correspondingly. The stable plasma concentration of carvedilol in CVD group was detected by HPLC. APD, TDR and arrhythmia of LVH models were compared just pre- or post-perfusion with stable concentration of CVD. ResultsIn Contrast with values in LVH group, LVEF of CVD group were significantly elevated while the LVMI was remarkably reduced, TDRs were significantly shortened, and ratio of ventricular arrhythmia was lowered remarkably. No significant difference of APD, TDR and ratio of arrhythmia was found preor post-perfusion at stable plasma concentration of CVD. ConclusionCVD can ameliorate the structure and function of pressure over-load ventricles; CVD contributes to the improvement of ventricular arrhythmia associated with its long-term effect on APD, TDR shortening, whereas has nothing to do with its transient function on ionic channel blockade.

Steady-State Plasma Concentration Profile of Transdermal Rotigotine: An Integrated Analysis of Three, Open-Label, Randomized, Phase I Multiple Dose Studies

BackgroundThe dopamine agonist rotigotine is formulated in a transdermal delivery system (patch) for once-daily application. It has been reported as efficacious in the treatment of idiopathic Parkinson's disease (PD) and restless legs syndrome. ObjectiveThis article summarizes the results of 3 clinical studies conducted to characterize the 24-hour pharmacokinetic profile of rotigotine in steady state and the effect of different patch application sites on this profile. In addition, the relative bioavailability of a single, large patch versus 2 smaller patches was assessed. MethodsOne Phase I study (SP871) assessed the steady-state pharmacokinetic properties at different application sites at a rotigotine maintenance dose of 3 mg/24 hours in healthy participants. Due to tolerability issues, the steady-state pharmacokinetic properties of rotigotine at higher doses (8 mg/24 hours) was assessed in 2 Phase I studies (SP630, SP651) in early-stage PD patients. Relative rotigotine bioavailability from a 40 cm2 patch versus 2 × 20 cm2 patches (SP651) and from a 15 cm2 patch versus 1 × 5 cm2 + 1 × 10 cm2 patches (SP871) was also evaluated. Rotigotine concentrations in plasma were analyzed using a validated LC-MS/MS method. The pharmacokinetic variables were calculated using standard noncompartmental analysis. ResultsRelease of rotigotine to the skin was 31% to 62% of total drug content in the patch. Variability of rotigotine exposure was low within participants (15%) compared with the variability observed between participants (54%). Rotigotine exposure increased proportionally in the therapeutic dose range of 2 mg/24 hours to 8 mg/24 hours. Plasma concentrations at steady state were stable over the 24-hour patch-on period. Delivery via a single, large patch compared with a combination of smaller patches did not appear to influence exposure to rotigotine. Bioavailability showed some variability depending on patch application site (hip, shoulder, abdomen, flank, thigh, upper arm); the respective mean ratios for AUC ranged between 0.87 (abdomen vs flank) and 1.46 (shoulder vs thigh). ConclusionsContinuous rotigotine delivery via a once-daily transdermal patch generated stable mean steady-state 24-hour plasma concentrations in healthy participants as well as patients with early-stage PD. Doses were achieved either by application of 1 large patch or a combination of smaller patches, resulting in the same total surface area.

Abstract 2329: A Randomized Double Blind, Placebo controlled Phase 1a Clinical Trial of THR-18, a PAI-1 Derived peptide, in Normal Volunteers

Background: THR-18 is an 18-mer peptide derived from the sequence of human plasminogen activator inhibitor 1 (PAI-1) that has the ability to bind at the docking site of tissue plasminogen activator (tPA) and not to its catalytic site, thereby uncoupling the beneficial clot-dissolving properties of tPA from its deleterious non-fibrinolytic effects. THR-18 is being developed as an adjunct to tPA in the treatment of acute ischemic stroke and aims to address some of the limiting properties of tPA such as limited response rate, relatively high re-occlusion rate, limited safety profile and short therapeutic window. Methods: this was a phase 1a randomized double blind, placebo controlled study aiming to asses the safety of THR-18 in healthy volunteers. Subjects were treated in five different dose and dose regimen tiers of THR-18 or placebo and were carefully monitored for the occurrence of any side effects. The pharmacokinetics profile of THR-18 in serum was also studied. Results: Pharmcokinetic studies for bolus administration of THR-18 showed a linear Cmax with a half-life of 3-7 minutes. Administration of THR-18 as a 10% bolus followed by continuous drip of the remaining 90% over 60 minutes resulted in stable plasma concentrations over 60 minutes. THR-18 was well tolerated with no severe or serious adverse events at doses of 0.25-1 mg/kg. At the dose of 0.5mg/kg and 1mg/kg, a slight and transient drop in blood pressure with orthostatic hypotension was noted. Discussion: THR-18 appears to be safe and well tolerated in healthy volunteers at doses up to 1 mg/kg. Following the encouraging safety results of THR-18 a phase 1b/2a study assessing the safety of THR-18 in stroke patients is currently ongoing.

Role and clinical utility of pramipexole extended release in the treatment of early Parkinson's disease

The aim of this article is to provide a short review of the most relevant pharmacological and clinical data on pramipexole extended release (ER) as well as to address the clinical utility and potential advantages of a once-daily formulation especially in the treatment of early Parkinson’s disease (PD). Pramipexole is widely established as a symptomatic treatment in early as well as advanced PD. The development of an ER formulation, with stable pramipexole plasma concentration over 24 hours, now offers a bioequivalent once-daily alternative. Double-blind randomized controlled trials in early and advanced PD, have established noninferiority of pramipexole ER compared with immediate release as well as superiority of both formulations over placebo. The overnight switch from the standard to the once-daily formulation was shown to be successful in >80% of patients without requiring any dose adjustments. Potential benefits of the prolonged-release design, which have not yet been formally demonstrated in the pivotal trial program, include improved compliance and a potential for better symptomatic control, particularly in patients with early disease that can be managed with monotherapy.

Comparison of D2 dopamine receptor occupancy after oral administration of quetiapine fumarate immediate-release and extended-release formulations in healthy subjects

Quetiapine is an established drug for treatment of schizophrenia, bipolar disorder, and major depressive disorder. While initially manufactured as an immediate-release (IR) formulation, an extended-release (XR) formulation has recently been introduced. Pharmacokinetic studies show that quetiapine XR provides a lower peak and more stable plasma concentration than the IR formulation. This study investigated if the pharmacokinetic differences translate into different time curves for central D2 dopamine receptor occupancy. Eleven control subjects were examined with positron emission tomography (PET) and the radioligand [11C]raclopride. Eight subjects underwent all of the scheduled PET measurements. After baseline examination, quetiapine XR was administered once-daily for 8 d titrated to 300 mg/d on days 5–8, followed by 300 mg/d quetiapine IR on days 9–12. PET measurements were repeated after the last doses of quetiapine XR and IR at predicted times of peak and trough plasma concentrations. Striatal D2 receptor occupancy was calculated using the simplified reference tissue model. Peak D2 receptor occupancy was significantly higher with quetiapine IR than XR in all subjects (50±4% and 32±11%, respectively), consistent with lower peak plasma concentrations for the XR formulation. Trough D2 receptor occupancy was similarly low for both formulations (IR 7±7%, XR 8±6%). The lower peak receptor occupancy associated with quetiapine XR may explain observed pharmacodynamic differences between the formulations. Assuming that our findings in control subjects are valid for patients with schizophrenia, the study supports the view that quetiapine, like the prototype atypical antipsychotic clozapine, may show antipsychotic effect at lower D2 receptor occupancy than typical antipsychotics.

4β‐hydroxycholesterol, an endogenous marker of CYP3A4/5 activity in humans

We have proposed that 4β-hydroxycholesterol (4β-OHC) may be used as an endogenous marker of CYP3A activity. The cholesterol metabolite 4β-OHC is formed by CYP3A4. Treatment of patients with strong inducers of CYP3A enzymes, e.g. anti-epileptic drugs, resulted in 10-fold increased concentrations of plasma 4β-OHC, while treatment with CYP3A inhibitors such as ritonavir or itraconazole resulted in decreased plasma concentrations. There was a relationship between the 4β-OHC concentration and the number of active CYP3A5*1 alleles showing that 4β-OHC was not only formed by CYP3A4, but also by CYP3A5. The concentration of 4β-OHC was higher in women than in men, confirming previous studies indicating a gender difference in CYP3A4/5-activity. The rate of elimination of 4β-OHC is slow (half-life 17 days) which results in stable plasma concentrations within individuals, but limits its use to study rapid changes in CYP3A activity. In short-term studies exogenous markers such as midazolam or quinine may be superior, but in long-term studies 4β-OHC is a sensitive marker of CYP3A activity, especially to assess induction but also inhibition. Under conditions where the cholesterol concentration is changing, the ratio of 4β-OHC:cholesterol may be used as an alternative to 4β-OHC itself. The use of an endogenous CYP3A marker has obvious advantages and may be of value both during drug development and for monitoring CYP3A activity in patients.

Neutrophil gelatinase-associated lipocalin clearance during veno-venous continuous renal replacement therapy in critically ill patients

Dear Editor, Predicting recovery of renal function in patients with acute kidney injury (AKI) supported with renal replacement therapy (RRT) is one of the top ten questions in the field of current AKI research. However, defining renal recovery and accordingly the best time for discontinuation of RRT is difficult, as reliable biomarkers are lacking. The Beginning and Ending Supportive Therapy for the Kidney (BEST Kidney) study identified urine production (>500 mL/24 h) as the best predictor for successful discontinuation of RRT [area under the curve (AUC) 0.81] in contrast to serum creatinine (SCr, AUC 0.64); however, its predictive value is severely confounded by the use of diuretics [1]. Neutrophil gelatinase-associated lipocalin (NGAL), a 25-kDa protein involved in iron transportation, is a potential tool for determination of initiation of RRT [2, 3]. However, once a patient is initiated on RRT, it remains to be elucidated how plasma NGAL concentrations will change. To determine plasma NGAL clearance and sieving coefficient (SQ) during continuous RRT (CRRT), we measured prefilter and effluent NGAL concentrations in three subjects after informed consent was obtained. Patients were hemofiltered with zero fluid balance, 2 L postdilution mode in continuous veno-venous hemofiltration. Blood flow was set at 200 mL/min, and regional citrate anticoagulation was used. The filters were ethylene oxide (ETO)-sterilized Aquamax HF 19 with an in vitro cutoff point of 55 kDa. NGAL levels were measured using a research-based enzyme-linked immunosorbent assay with detection limit of 10–4,000 ng/mL. NGAL clearance per minute was estimated using the assumed stable plasma concentrations during CRRT over the first 12 h and the calculated amount of NGAL present in the total effluent. SQ was calculated by dividing the NGAL effluent concentration by the NGAL prefilter plasma concentration. Three male anuric patients were studied (age 40–64 years). Their admission diagnoses were hemorrhagic shock, cardiopulmonary resuscitation, and multitrauma. Baseline SCr values were 0.57, 0.66, and 0.68 mg/dL, with SCr at time of CRRT initiation of 3.7, 9.7, and 12.3 mg/dL. Estimated median (standard deviation, SD) plasma NGAL clearance was 4.8 (1.89) mL/min with median (SD) SQ of 0.147 (0.04). The prefilter and effluent NGAL concentrations are plotted against time in Fig. 1. Fig. 1 Temporal patterns of the prefilter plasma and effluent NGAL concentrations (ng/ml) in hours after initiation of continuous veno-venous renal replacement therapy in three individuals with anuric AKI Normally, plasma NGAL is cleared through glomerular filtration and entirely processed by proximal tubular cells [4]. However, in case of AKI, plasma concentrations rise quickly, even when estimated glomerular filtration rate (eGFR) is still normal, and tend to decrease quickly when the injurious event subsides [5]. Therefore, NGAL might have potential to be an early indicator of renal recovery in critically ill patients supported by RRT. Our results suggest that plasma NGAL is hardly cleared during continuous veno-venous hemofiltration. A possible explanation lies in the fact that larger serum proteins effectively lower the passage of small proteins by forming a gel layer over the membrane pores. In conclusion, we have shown that CRRT does not substantially influence plasma NGAL concentration and therefore does not need to be taken into account when kinetics of plasma NGAL levels are used as an indicator for persistent renal injury or renal recovery in hemofiltered critically ill patients.

Effects of AZD0837, a Novel Direct Thrombin Inhibitor, on the Electrophysiological Properties of the Human Heart

AZD0837 is an investigational oral anticoagulant that is bioconverted to its active form, AR-H067637, a selective direct thrombin inhibitor. The objectives of the present study were to investigate if there are any clinically relevant adverse effects of intravenous AZD0837 on cardiac conduction, refractoriness and repolarization, and to study its safety and tolerability. In this randomized, double-blind, parallel-group, placebo-controlled study (study code D1250C00026), invasive electrophysiological measurements were performed twice in 30 subjects with a history of, or ongoing, atrial flutter, starting 30 minutes after successful ablation of atrial flutter and then 60 minutes after start of an intravenous infusion of AZD0837. Pre-study warfarin therapy was not an exclusion criterion. The stimulation protocol was performed mainly at 500 and 400 ms drive cycle length. A 12-lead ECG was also recorded before and during AZD0837 infusion. Plasma concentrations of AZD0837 and its metabolites were obtained at predefined timepoints. Measurements were made at baseline and during stable plasma concentrations of the prodrug AZD0837 (mean +/- standard deviation 7.96 +/- 2.38 micromol/L, approximate target of 10 micromol/L), the intermediate metabolite AR-H69927 (1.26 +/- 0.39 micromol/L, target 1-2 micromol/L) and the active direct thrombin inhibitor AR-H067637 (0.35 +/- 0.14 micromol/L, target 0.5-1.0 micromol/L). There were no clinically relevant effects on cardiac conduction (QRS duration, PR interval, His bundle electrogram, Wenckebach point), refractoriness (atrial, atrioventricular and ventricular effective refractory periods) or repolarization (QT, QT interval corrected for heart rate using Fridericia's formula, QRS onset to the top of the T wave [QT(top)], QRS onset to the end of the T wave [QT(end)] or QT(top) - QT(end)). AZD0837 was well tolerated, and had no clinically relevant effects on cardiac electrophysiology of the target population, either in subjects previously treated with warfarin or in those without previous treatment.

Use of Hydromorphone, with Particular Reference to the OROS® Formulation, in the Elderly

The prevalence of pain increases with age. However, pain is often inadequately managed in elderly people, which undermines quality of life. Pain has been associated with depression, sleep disturbances, impaired ambulation, and increased healthcare use and costs. Effective treatment of pain improves the overall quality of life. However, pain management is complicated by the presence of multiple co-morbidities in elderly people, which increases the likelihood of polypharmacy, and therefore increases the chance of potential drug-drug interactions. Polypharmacy is also associated with poor adherence to therapy. Age-related pharmacokinetic and pharmacodynamic changes reduce the therapeutic index of drugs. Therefore, elderly people are more likely to suffer from adverse events and increased sensitivity to the analgesic properties of opioids. OROS hydromorphone (Jurnista) is a once-daily, extended-release formulation that uses the OROS push-pull technology to provide controlled release of the semi-synthetic opioid hydromorphone. Compared with conventional immediate-release hydromorphone, OROS hydromorphone provides more consistent delivery of hydromorphone with lower peak concentrations and less variability in plasma concentrations over time. The bioavailability of hydromorphone from OROS hydromorphone is minimally affected by food or alcohol (ethanol). Hydromorphone is mainly metabolized in the liver and is excreted in the urine. Unlike morphine, hydromorphone does not have an active 6-glucuronide metabolite. This metabolite of morphine can accumulate in the presence of renal failure; therefore, the lack of an active 6-glucuronide metabolite makes hydromorphone a useful alternative to morphine in elderly patients with renal failure. However, hydromorphone is similar to morphine in that it is metabolized to hydromorphone-3-glucuronide, which may be neuroexcitatory. Because of its low plasma protein binding and low probability of interfering with the metabolism of other drugs, hydromorphone may be especially suitable for patients taking multiple medications. OROS hydromorphone is an effective analgesic that is well tolerated and provides more stable plasma concentrations than immediate-release forms of hydromorphone. Its once-daily administration offers an advantage over immediate-release forms and longer-acting formulations that require twice-daily administration. This means OROS hydromorphone will be more convenient for elderly patients and may improve adherence, resulting in improved pain relief and quality of life.