Ritonavir boosting dose reduction from 100 to 50 mg does not change the atazanavir steady-state exposure in healthy volunteers.

OBJECTIVES: To evaluate the pharmacokinetics, tolerability and safety of 300 mg of atazanavir boosted with 100 or 50 mg of ritonavir, both once daily, at steady state. METHODS: This was a single-blind, multiple-dose, crossover, sequence-randomized trial. Thirteen healthy HIV-1-negative men received witnessed once-daily doses of atazanavir (300 mg) and 100 or 50 mg of ritonavir for 10 days (15 day washout). Atazanavir and ritonavir plasma concentrations were determined for 24 h on day 10. Log-transformed individual pharmacokinetic parameters were compared between treatments (analysis of variance); the difference between treatments on the log scale and 95% CIs were calculated. Fasting cholesterol, triglycerides, glucose and bilirubin plasma levels were measured at the beginning and end of each period and compared (Wilcoxon signed rank test). Gastrointestinal symptoms and other events were recorded. RESULTS: Ritonavir C(max) and the AUC0₋24 were lower after the 50 mg booster dose than after 100 mg [geometric mean ratio (GMR) (95% CI), 0.40 (0.31-0.51) and 0.35 (0.29-0.42), respectively]. No differences were observed in atazanavir exposure with 50 or 100 mg of ritonavir [GMR C(max) (95% CI), 1.00 (0.79-1.28); GMR AUC0₋24 (95% CI), 0.98 (0.79-1.21)]. Atazanavir trough concentration was >0.15 mg/L in all volunteers. Total and low-density lipoprotein cholesterol increased 0.40 mM (P = 0.01) and 0.37 mM (P = 0.003) from their corresponding baseline value during the 100 mg dosing period; there were no significant changes on 50 mg. Mild increases in bilirubin were detected on day 10 after both treatments without differences between treatments. CONCLUSIONS: In spite of higher exposure to ritonavir with 100 mg, atazanavir exposure was equivalent; the lipid profile was better under the lower booster dose (50 mg).

Sex differences in sleep after a single oral morning dose of olanzapine in healthy volunteers.

OBJECTIVE: Polysomnography abnormalities are frequent in schizophrenia and have been correlated with clinical variables. Because women with schizophrenia present a general better clinical outcome than men, we aimed to determine whether sex differences in antipsychotic-induced effects on sleep could contribute to this difference. METHODS: Single oral morning doses of olanzapine (5 mg) were administered to 10 men and 10 women. Sleep variables were evaluated using traditional polysomnography Rechstschaffen and Kales criteria and all-night sleep electroencephalogram spectral analysis. Drug plasma concentrations were also measured. RESULTS: Significant sex-by-drug interactions were obtained in slow-wave sleep. After olanzapine, women showed an increase in slow-wave sleep, whereas men showed a decrease. We did not observe sex differences in olanzapine-induced hypnotic effects. Neither did we find any significant differences in pharmacokinetic parameters between sexes. Significant sex effects were observed in deep sleep, with women showing longer periods than men. CONCLUSION: Our results showed significant pharmacodynamic differences in olanzapine sleep effects between men and women. Further studies in clinical populations are needed to assess if these sex-based differences suggest that optimal treatment and doses should differ between men and women.

Characterization of the cerebral activity by time-frequency representation of evoked EEG potentials.

Event-related brain potentials (ERPs) are the electrical response of the brain while performing a particular task. Methods traditionally used to study ERPs measure the amplitude and duration of the waveform in order to quantify the changes, being signal morphology dependent. However, the frequency characteristics of those events remain uncovered. The aim of this work was the study of new measures to characterize, by means of time-frequency representation (TFR) techniques, the ERPs recorded while subjects conducted a choice reaction time task (Ericksen flanker task) following the administration of different alprazolam doses. Several measures defined from energy, instantaneous frequency and group delay functions were obtained by means of TFR techniques applied to the Choi-Williams distribution (CWD) of EEG signals. These measures, which are signal morphology independent, were studied in four frequency bands, δ (0-4 Hz), θ (4-8 Hz), α (8-15 Hz), ß (15-30 Hz), and for certain time periods. Based on these measures, differences between ERPs were analyzed by comparing the different response types (successes or successfully corrected failures) of the subject performing the task, and comparing the applied drug doses. For each subject, the CWD of EEG signals was applied in two different ways: (a) all ERPs were averaged per channel, and then the CWD was applied; (b) the CWD was applied to each one of the ERPs. When the CWD was applied to each ERP, the energy measures in the δ, θ and ß bands, the instantaneous frequency measures in the α and ß bands, and the group delay measures in the δ, θ and α bands showed a statistically significant level p < 0.0005 in the analysis of the response type. Also, the energy measures in the θ and ß bands and the instantaneous frequency measures in the α band showed statistically significant differences (p < 0.0005) between placebo and low and high drug doses. In contrast, poor results were obtained when all epochs of each subject were averaged per channel. Finally, it was concluded that these results showed that the new proposed measures based on the energy offered a new and more robust way to characterize ERP signals.

Waking and sleep electroencephalogram variables as human sleep homeostatic process biomarkers after drug administration.

BACKGROUND/AIMS: The correlation between theta activity during wakefulness and slow-wave activity (SWA) during sleep observed after sleep deprivation suggests such patterns can be used as electroencephalogram (EEG) biomarkers of the sleep homeostasis process. Since these EEG components would be very useful objective measures to assess CNS drug effects, we investigated whether the relationship between sleep homeostatic EEG biomarkers could be reproduced after an experimental pharmacological intervention. METHODS: Seventeen healthy volunteers took part in a phase I randomized, double-blind, crossover design study. To increase sleep propensity, all participants received a single morning oral dose of olanzapine (5 mg) and placebo. Quantitative EEG analysis was done by power spectra calculations: theta activity (3.5-7.5 Hz) during wakefulness and SWA (0.5-4.0 Hz) during sleep. The relationship between the 2 EEG parameters was assessed by correlating the rise rate (percent/hour) of theta activity in wakefulness and the increase (percent) of SWA in the first non-REM sleep episode. RESULTS: Following olanzapine administration we observed increases in theta activity during wakefulness, and increases in total sleep time, sleep efficiency and slow-wave sleep time during sleep. However, a weak and unreliable correlation was observed between the increases in theta activity and changes in sleep SWA. CONCLUSIONS: From these results, we cannot affirm that these waking and sleep EEG variables behave as biomarkers of human sleep homeostasis after drug administration. It is possible that these EEG biomarkers reflect different physiological mechanisms if they are assessed during drug CNS effects.

Plasma and intracellular (peripheral blood mononuclear cells) pharmacokinetics of once-daily raltegravir (800 milligrams) in HIV-infected patients.

The aim of this study was to evaluate the plasma and intracellular pharmacokinetics of raltegravir in HIV-infected patients receiving once-daily raltegravir. Five HIV-infected patients on stable therapy with lopinavir-ritonavir monotherapy whose HIV-1 RNA load was <50 copies/ml were included in this open-label, pilot study. Raltegravir was added to the antiretroviral regimen at a dose of 800 mg once daily from days 0 to 10. On day 10, a full pharmacokinetic profile was obtained for each participant. Raltegravir concentrations in plasma and peripheral blood mononuclear cells (PBMCs) were determined by high-performance liquid chromatography with a fluorescence detector and by liquid chromatography-tandem mass spectrometry (LC-MS/MS), respectively. The values of the raltegravir pharmacokinetic parameters in plasma and PBMCs were calculated by noncompartmental analysis. Raltegravir was well tolerated, and all participants completed the study. No differences in the times to the maximum concentration of raltegravir in plasma or the raltegravir half-lives were observed between plasma and PBMCs. The geometric mean raltegravir maximum concentration, the concentration at the end of the dosing interval, and the area under the concentration-time curve during the dose interval in plasma versus PBMCs were 2,640 ng/ml (range, 887 to 10,605 ng/ml) versus 199 ng/ml (range, 82 to 857 ng/ml) (geometric mean ratio [GMR], 13.30; 95% confidence interval [CI], 3.11 to 56.89; P = 0.003); 89 ng/ml (range, 51 to 200 ng/ml) versus 7 ng/ml (range, 2 to 15 ng/ml) (GMR, 13.21; 95% CI, 3.94 to 44.26; P = 0.001); and 12,200 ng·h/ml (range, 5,152 to 30,130 ng·h/ml) versus 909 ng·h/ml (range, 499 to 2,189 ng·h/ml) (GMR, 13.43; 95% CI, 5.13 to 35.16; P < 0.001), respectively. Raltegravir does not accumulate in PBMCs, with intracellular concentrations being about 1/10 of the concentrations in plasma. Despite once-daily dosing, mean raltegravir concentrations at the end of the dosing interval in plasma and PBMCs exceeded the reported protein-binding-adjusted 95% inhibitory concentration (IC(95)) and IC(50) for wild-type viral strains, respectively.

Herb-drug interaction between Echinacea purpurea and darunavir-ritonavir in HIV-infected patients.

The aim of this open-label, fixed-sequence study was to investigate the potential of Echinacea purpurea, a commonly used botanical supplement, to interact with the boosted protease inhibitor darunavir-ritonavir. Fifteen HIV-infected patients receiving antiretroviral therapy including darunavir-ritonavir (600/100 mg twice daily) for at least 4 weeks were included. E. purpurea root extract capsules were added to the antiretroviral treatment (500 mg every 6 h) from days 1 to 14. Darunavir concentrations in plasma were determined by high-performance liquid chromatography immediately before and 1, 2, 4, 6, 8, 10, and 12 h after a morning dose of darunavir-ritonavir on days 0 (darunavir-ritonavir) and 14 (darunavir-ritonavir plus echinacea). Individual darunavir pharmacokinetic parameters were calculated by noncompartmental analysis and compared between days 0 and 14 with the geometric mean ratio (GMR) and its 90% confidence interval (CI). The median age was 49 (range, 43 to 67) years, and the body mass index was 24.2 (range, 18.7 to 27.5) kg/m(2). Echinacea was well tolerated, and all participants completed the study. The GMR for darunavir coadministered with echinacea relative to that for darunavir alone was 0.84 (90% CI, 0.63-1.12) for the concentration at the end of the dosing interval, 0.90 (90% CI, 0.74-1.10) for the area under the concentration-time curve from 0 to 12 h, and 0.98 (90% CI, 0.82-1.16) for the maximum concentration. In summary, coadministration of E. purpurea with darunavir-ritonavir was safe and well tolerated. Individual patients did show a decrease in darunavir concentrations, although this did not affect the overall darunavir or ritonavir pharmacokinetics. Although no dose adjustment is required, monitoring darunavir concentrations on an individual basis may give reassurance in this setting.

Rupatadine does not potentiate the CNS depressant effects of lorazepam: randomized, double-blind, crossover, repeated dose, placebo-controlled study.

AIM: The main objective was to assess whether benzodiazepine intake when rupatadine plasma concentrations were at steady-state would increase the CNS depressant effects. Rupatadine is a new H(1)-antihistamine which also inhibits platelet activating factor (PAF) release and has been shown to be clinically effective at doses of 10 mg. METHODS: Sixteen healthy young volunteers took part in a crossover, randomized, double-blind, placebo controlled trial comprising two experimental periods (repeated administration for 7 days of rupatadine 10 mg or placebo as single oral daily doses, separated by a washout of 14 days). On days 5 and 7, according to a fully balanced design, a single oral dose of lorazepam 2 mg or placebo was added. CNS effects were evaluated on these days by seven objective tests of psychomotor performance and eight subjective visual analogue scales (VAS) at pre-dose and several times after drug intake. Four treatment conditions were evaluated: placebo, rupatadine 10 mg, lorazepam 2 mg and rupatadine 10 mg + lorazepam 2 mg. RESULTS: Significant CNS effects, either impairment of psychomotor performance or subjective sedation, were observed when lorazepam was administered, either alone or in combination with steady state concentrations of rupatadine. No significant differences were found between these two conditions. In addition, rupatadine was not different from placebo. All treatments were well tolerated. CONCLUSION: Repeated doses of rupatadine (10 mg orally) did not enhance the CNS depressant effects of lorazepam (2 mg orally, single dose) either in objective psychomotor tasks or in subjective evaluations.

Treatment simplification to once daily darunavir/ritonavir guided by the darunavir inhibitory quotient in heavily pretreated HIV-infected patients.

BACKGROUND: We explored a treatment simplification strategy to darunavir/ritonavir 900/100 mg once daily guided by the darunavir virtual inhibitory quotient (vIQ) in patients receiving salvage therapy with darunavir/ritonavir 600/100 mg twice daily. METHODS: Open-label, randomized pilot study in HIV-infected patients on darunavir/ritonavir 600/100 mg twice daily (viral load <50 copies/ml; darunavir vIQ >2). Thirty patients were randomized to darunavir/ritonavir 900/100 mg once daily (once-daily group, n=15) or 600/100 mg twice daily (twice-daily group, n=15). Viral load, blood chemistry, and darunavir and ritonavir trough plasma concentrations (C(trough)) were determined up to 48 weeks. If the darunavir vIQ fell to <1.5, the dosage was switched to 600/100 mg twice daily. The primary end point was the percentage of 48-week treatment failure. RESULTS: Patients had taken a mean 11.6 (sd +/-3.9) antiretroviral regimens before darunavir/ritonavir administration. The proportion of patients without 48-week treatment failure was 86.7% in both groups. The median (interquartile range [IQR]) darunavir C(trough) decreased from 3.09 mg/l (IQR 2.43-3.93) at baseline to 1.60 mg/l (IQR 1.25-2.04) at week 48 (P=0.001) in the once-daily group. Three once-daily group patients switched to darunavir/ritonavir 600/100 mg twice daily. Fewer patients had triglyceride levels >200 mg/dl at week 48 in the once-daily group (20.0%) than in the twice-daily group (20.0% versus 57.1%; P=0.046). CONCLUSIONS: Treatment simplification to darunavir/-ritonavir 900/100 mg once daily guided by the darunavir vIQ in treatment-experienced HIV-infected patients receiving darunavir/ritonavir 600/100 mg twice-daily seems to be safe enough to be tested in adequately powered clinical trials.

No cardiac effects of therapeutic and supratherapeutic doses of rupatadine: results from a 'thorough QT/QTc study' performed according to ICH guidelines.

AIMS: To evaluate the effects of therapeutic and supratherapeutic doses of rupatadine on cardiac repolarization in line with a 'thorough QT/QTc study' protocol performed according to International Conference on Harmonization guidelines. METHODS: This was a randomized (gender-balanced), parallel-group study involving 160 healthy volunteers. Rupatadine, 10 and 100 mg day(-1), and placebo were administered single-blind for 5 days, whilst moxifloxacin 400 mg day(-1) was given on days 1 and 5 in open-label fashion. ECGs were recorded over a 23-h period by continuous Holter monitoring at baseline and on treatment days 1 and 5. Three 10-s ECG samples were downloaded at regular intervals and were analysed independently. The primary analysis of QTc was based on individually corrected QT (QTcI). Treatment effects on QTcI were assessed using the largest time-matched mean difference between the drug and placebo (baseline-subtracted) for the QTcI interval. A negative 'thorough QT/QTc study' is one where the main variable is around < or =5 ms, with a one-sided 95% confidence interval that excludes an effect >10 ms. RESULTS: The validity of the trial was confirmed by the fact that the moxifloxacin-positive control group produced the expected change in QTcI duration (around 5 ms). The ECG data for rupatadine at both 10 and 100 mg showed no signal effects on the ECG, after neither single nor repeated administration. Furthermore, no pharmacokinetic/pharmacodynamic relationship, gender effects or clinically relevant changes in ECG waveform outliers were observed. No deaths or serious or unexpected adverse events were reported. CONCLUSIONS: This 'thorough QT/QTc study' confirmed previous experience with rupatadine and demonstrated that it had no proarrhythmic potential and raised no concerns regarding its cardiac safety.

Nuevos hipnóticos, desde la perspectiva del farmacólogo / New hynotics, from the pharmacologist perspective

El insomnio es una condición extremadamente común con importantes consecuencias personales, sociales y económicas. El tratamiento farmacológico actual se centra principalmente en el GABA, el neurotransmisor inhibidor más importante del sistema nervioso central. Los agonistas del receptor benzodiacepínico han sido el pilar de la farmacoterapia de este trastorno. Las clásicas benzodiacepinas y los hipnóticos Z comparten un modo de acción similar, potenciando alostéricamente las corrientes de cloro a través de los receptores GABAA. A pesar del avance que supuso su descubrimiento en los 1960s, en relación a los tratamientos previos disponibles en cuanto al “cociente riesgo/beneficio”, todavía no se dispone de ningún compuesto que presente las propiedades que debería tener un “hipnótico ideal”. Diversas son las estrategias seguidas para mejorar la situación actual. Se continúan desarrollando fármacos GABAérgicos, mejorando sus perfiles farmacocinéticos (duración, inicio) o haciéndolos más específicos (selección del enantiómero óptimo a partir del racémico o selectividad con relación a los subtipos de receptor con los que interactuar), pero también se están desarrollando compuestos que actúan a través de nuevas dianas neuroquímicas, identificadas merced a los avances en los conocimientos sobre la estructura del sueño y sus bases neurobiológicas. Así hay compuestos en desarrollo que interactúan con determinados subtipos de receptores de otros sistemas de neurotransmisión, como el melatoninérgico y el serotoninérgico, e incluso fármacos que lo hacen con sistemas desconocidos hasta hace relativamente poco, como la neurotransmisión mediada por orexinas. Están apareciendo nuevos términos que permiten discernir diferencias en el perfil de efectos que se asocia a la actividad principal como productores de sueño y que sin duda en un futuro tendrán una importante traducción clínica con el objetivo de ofrecer una mejor, más segura e individualizada opción terapéutica para los pacientes. Además de hipnóticos, se empiezan a identificar: promotores del sueño, intensificadores del sueño, modificadores de la biestabilidad o cronobióticos (AU)

Insomnia is an extremely common condition with major personal, social and economic consequences. Current pharmacological treatments focus primarily on GABA, the major inhibitory neurotransmitter in the central nervous system. Benzodiazepine receptor agonists have been a mainstay of the pharmacotherapy of this disorder. Classical benzodiazepines and Z-hypnotics share a similar mode of action and allosterically enhance chloride currents through the GABAA receptor. In spite of the advance that its discovery in 1960s supposed, in relation to the previous available treatments as for the “risk/benefit ratio”, there is no existing compound with the characteristics of an “ideal hypnotic” yet. Several strategies have been followed in order to improve the current situation. There are still other drugs being developed to target the GABAergic system, with better pharmacokinetic profiles (duration, onset) or with more specificity (optimal enantiomer selection from the racemic or receptor subtype selectivity through which to interact). Other approaches take advantage to develop compounds which bind to new neurochemical targets, that have been identified thanks to the acquired knowledge about sleep structure ant its neurobiological bases. Thus, there are compounds under development that interact with certain receptor subtypes from other neurotransmitter systems, as the melatoninergic or the serotoninergic, and even drugs that interact with systems that have been unknown until recently, as the neurotransmission through orexins. New expressions are turning up that allow distinguish differences in the effect profile associated with the sleep producers major activity and that undoubtedly in a future they will have important clinical consequences with the objective to provide to patients the best, safer and individualized therapeutic option. In addition to hypnotics, the following labels start to be used: sleep promoters, sleep intensificators, bistability modifiers or chronobiotics (AU)

Comparison of peripheral and central effects of single and repeated oral dose administrations of bilastine, a new H1 antihistamine: a dose-range study in healthy volunteers with hydroxyzine and placebo as control treatments.

Peripheral anti-H1 and central nervous system (CNS) activities after single (day 1) and repeated (day 7) administrations of increasing doses of bilastine (BIL) were assessed in 20 healthy volunteers throughout a crossover, randomized, double-blind, placebo (PLA)-controlled study. Repeated doses of BIL 20, 40, or 80 mg and hydroxyzine 25 mg (HYD) as positive standard were administered on 7 consecutive days. Before and at several time points after drug intake, skin reactivity to the intradermal injection of histamine, objective tests of psychomotor performance, and subjective mood scales were evaluated. All active treatments led to a significant and similar reduction in the wheal reaction in relation to PLA after both the single (P < 0.001) and repeated administrations (P < 0.001). No delay was observed in the onset of its peripheral activity after the first dose of BIL as compared with HYD. No tolerance or sensitization was seen when comparing acute and repetitive assessments. Central nervous system effects showed that HYD induced the greatest psychomotor impairment (P < 0.05). Repeated HYD intake showed a lower number of significant alterations in comparison to acute administration. Bilastine 80 mg also showed some impairment (P < 0.05). Subjectively, the only active treatment that could not be differentiated from PLA was BIL 20 mg. Hydroxyzine 25 mg showed the greatest differentiation (P < 0.01). A clear dissociation between peripheral anti-H1 and CNS activity was found after BIL treatment. Significant and sustained peripheral H1-blocking effects were observed after both single and repeated administrations of the therapeutic dose of 20 mg BIL. The 40-mg dose of BIL produced subjective report of sedation, whereas unwanted objective CNS side effects were observed only with the 80-mg dose.

Simultaneous population pharmacokinetic model for lopinavir and ritonavir in HIV-infected adults.

BACKGROUND: Lopinavir is a protease inhibitor indicated for the treatment of HIV infection. It is coformulated with low doses of ritonavir in order to enhance its pharmacokinetic profile. After oral administration, plasma concentrations of lopinavir can vary widely between different HIV-infected patients. OBJECTIVE: To develop and validate a population pharmacokinetic model for lopinavir and ritonavir administered simultaneously in a population of HIV-infected adults. The model sought was to incorporate patient characteristics influencing variability in the drug concentration and the interaction between the two compounds. METHODS: HIV-infected adults on stable therapy with oral lopinavir/ritonavir in routine clinical practice for at least 4 weeks were included. A concentration-time profile was obtained for each patient, and blood samples were collected immediately before and 1, 2, 4, 6, 8, 10 and 12 hours after a morning lopinavir/ritonavir dose. Lopinavir and ritonavir concentrations in plasma were determined by high-performance liquid chromatography. First, a population pharmacokinetic model was developed for lopinavir and for ritonavir separately. The pharmacokinetic parameters, interindividual variability and residual error were estimated, and the influence of different patient characteristics on the pharmacokinetics of lopinavir and ritonavir was explored. Then, a simultaneous model estimating the pharmacokinetics of both drugs together and incorporating the influence of ritonavir exposure on oral clearance (CL/F) of lopinavir was developed. Population analysis was performed using nonlinear mixed-effects modelling (NONMEM version V software). The bias and precision of the final model were assessed through Monte Carlo simulations and data-splitting techniques. RESULTS: A total of 53 and 25 Caucasian patients were included in two datasets for model building and model validation, respectively. Lopinavir and ritonavir pharmacokinetics were described by one-compartment models with first-order absorption and elimination. The presence of advanced liver fibrosis decreased CL/F of ritonavir by nearly half. The volume of distribution after oral administration (Vd/F) and CL/F of lopinavir were reduced as alpha1-acid glycoprotein (AAG) concentrations increased. CL/F of lopinavir was inhibited by ritonavir concentrations following a maximum-effect model (maximum inhibition [Imax] = 1, concentration producing 50% of the I(max) [IC50] = 0.36 mg/L). The final model appropriately predicted plasma concentrations in the model-validation dataset with no systematic bias and adequate precision. CONCLUSION: A population model to simultaneously describe the pharmacokinetics of lopinavir and ritonavir was developed and validated in HIV-infected patients. Bayesian estimates of the individual parameters of ritonavir and lopinavir could be useful to predict lopinavir exposure based on the presence of advanced liver fibrosis and the AAG concentration in an individual manner, with the aim of maximizing the chances of treatment success.

Study of the EEG changes during the combined ingestion of alcohol and H1-antihistamines by using the wavelet transform.

H(1)-antihistamines affect the central nervous system (CNS) and, therefore, electroencephalographic (EEG) changes should be expected to occur. The principal aim of this work was to assess the effects on the EEG when hydroxyzine 10 mg (HY) and cetirizine 25 mg (CE) were administered with and without alcohol 0.8 g/kg (AL). Thirty-three healthy young subjects participated in two placebo-controlled trials. In the first one, 15 subjects received placebo (PL), HY and CE. In the second trial, 18 volunteers took PL, AL, and AL in combination with HY and CE. CNS effects of the different treatment conditions were evaluated at baseline, as well as at +4 h and +1 h post-medication for each study, respectively. EEG recordings from electrodes O1 and O2 were analyzed using the wavelet transform. Then, several entropies were calculated from wavelet decomposition to detect changes in the pattern of regularity of the signals. The obtained results suggest that the concomitant ingestion of AL with HY reduces the changes in the irregularity of the EEG, opposite to the behavior observed for CE. Hence, wavelet entropies could be useful descriptors of the EEG alterations induced by several drugs in a different way that the conventional Fourier-based methods.

Comparison of inhibition of cutaneous histamine reaction of ebastine fast-dissolving tablet (20 mg) versus desloratadine capsule (5 mg): a randomized, double-blind, double-dummy, placebo-controlled, three-period crossover study in healthy, nonatopic adults.

BACKGROUND: Ebastine is a long-acting, second-generation, selective histamine H1-receptor antagonist. A fast-dissolving tablet formulation of ebastine has been developed at 10- and 20-mg doses, with the intention of facilitating administration to patients experiencing problems with swallowing, including those confined to bed and elderly people, as well as those who may need to use ebastine when they do not have easy access to water to aid swallowing a tablet. OBJECTIVES: This study was conducted to assess the pharmacodynamic effects (ie, inhibition of wheal response to cutaneous histamine challenge, and subjective assessments of itching, flare, and pain) and tolerability of the fast-dissolving 20-mg ebastine tablet formulation compared with desloratadine 5-mg capsule and placebo. Acceptability and convenience of the fast-dissolving tablet were also evaluated. METHODS: This double-blind, double-dummy, randomized, placebo-controlled, 3-period crossover study was conducted at the Drug Research Centre, Department of Clinical Pharmacology, the Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. Healthy, nonatopic, white adults aged 18 to 40 years were randomly assigned to 1 of 6 study sequences: ABC, ACB, BAC, BCA, CBA, or CAB, where A was the ebastine fast-dissolving 20-mg tablet, B was the desloratadine 5-mg capsule, and C was placebo. All study drugs were given orally once daily (8-9 AM) on days 1 to 5 of each study period. Study periods were separated by a washout period of 7 to 10 days. Histamine skin-prick test (SPT) challenge was performed before study drug administration on day 1 of each period (baseline), and then every 20 minutes for 2 hours after administration and again after 24 hours. The final SPT was 24 hours after the day-5 dose was administered. The primary end point was inhibition o f the histamine response, defined as the percentage reduction from baseline wheal area 24 hours after 5 days of administration. Subjective symptoms (itching, flare, and pain) were assessed by subjects using visual analog scales every 20 minutes for 2 hours after administration on day 1. At study end, acceptability (taste, convenience, and overall preference) of the fast-dissolving tablet and capsule formulations were assessed using a questionnaire completed by subjects. Tolerability was assessed using physical examination, laboratory analysis, physician questioning, and spontaneous reporting. RESULTS: Thirty-six people were randomized (22 women, 14 men; mean [SD] age, 24.7 [4.1] years; mean [SD] weight, 63.2 [9.9] kg); 35 completed the study (1 subject was lost to follow-up after the second study period). Unadjusted mean (SD) wheal areas 24 hours after dose administration on day 5 were 72.9 (29.5), 115.0 (32.1), and 146.7 (32.2) mm(2), for ebastine, desloratadine, and placebo, respectively. Mean differences in reduction from baseline in wheal area were 29.0% for ebastine versus desloratadine and 43.7% for ebastine versus placebo (both, P < 0.001). Corresponding unadjusted mean (SD) wheal areas 24 hours after administration of the first dose on day 1 were 76.5 (22.5), 128.9 (24.0), and 140.5 (33.1) mm(2). Mean itching, flare, and pain ratings were not significantly different between study drugs. Results from the preference questionnaire indicated that the majority (80%) preferred the ebastine fast-dissolving tablet to the desloratadine capsule (and hypothetically also to tablets and oral solution, which were not tested in this study). Ninety-seven percent of subjects were of the opinion that compliance in the home setting would be facilitated by the fas-tdissolving tablet formulation. Fourteen adverse events (AEs) were reported in 9 (25%) volunteers; all AEs were of mild or moderate intensity. Five occurred with ebastine 20 mg (intermittent somnolence, back pain, pharyngolaryngeal pain, pyrexia, and oral pain [1 patient each]), 5 occurred with desloratadine 5 mg (asthenia [2 patients] and dry mouth, somnolence, and back pain [1 patient each]), and 4 occurred with placebo (diarrhea [2 patients] and somnolence and headache [1 patient each]). The relationship with the study drugs was considered unlikely in 6 cases and possible in the remaining 8 cases. An additional AE (back pain) occurred during a washout period. CONCLUSIONS: In this small study in healthy, nonatopic white subjects, inhibition of the response to histamine injection was significantly greater with the ebastine 20-mg fast-dissolving tablet compared with desloratadine 5-mg capsule and placebo after 1 and 5 days of administration. Most participants expressed an overall preference for the fast-dissolving tablet formulation over capsules. All study drugs were well tolerated.

A comparison of ebastine 10 mg fast-dissolving tablet with oral desloratadine and placebo in inhibiting the cutaneous reaction to histamine in healthy adults.

BACKGROUND AND OBJECTIVE: Ebastine is a long-acting, second-generation selective histamine H(1) receptor antagonist. The pharmacodynamics of a new 10mg fast-dissolving tablet (FDT) oral lyophilisate tablet formulation of ebastine were compared with those of desloratadine and placebo following histamine skin intradermal test challenge. The acceptability of the FDT was also assessed. METHODS: This was a double-blind, double-dummy, placebo-controlled, randomised, crossover, three-period study in 36 healthy adults. The histamine skin intradermal test (0.05 mL of 100 microg/mL solution) was administered into volunteers' forearms, and wheal area was measured 15 minutes later. Ebastine 10 mg FDT, desloratadine 5mg capsule or placebo were given on days 1-5. On day 1, a skin intradermal test was performed at baseline, then every 20 minutes for 2 hours after administration and at 24 hours. The final skin intradermal test was on day 6, 24 hours after the last drug dose. Subjective symptoms (itching, heat and pain) were assessed on day 1 for 2 hours following the first drug dose. There was a washout period of 7-10 days between treatments. At study end, the acceptability of the new ebastine formulation was evaluated using a questionnaire. RESULTS: Ebastine 10mg inhibited the wheal response to histamine significantly more than desloratadine 5 mg or placebo 24 hours after 5 days' treatment (mean difference between treatments in wheal area reduction from baseline: 26.7%, p < 0.0001; 46.9%, p < 0.0001, respectively), and after 24 hours on day 1 (mean difference: 16.2%, p = 0.0082; 34.2%, p < 0.0001, respectively). The results with desloratadine were also significantly different from placebo on day 1 and after 5 days, but less than with ebastine after 5 days (difference, desloratadine vs placebo: 20.2%, p = 0.0001). No differences in itching, heat and pain were observed between the treatments. Most participants (70%) preferred the FDT, and all reported that it made adherence easier. CONCLUSION: Ebastine 10 mg FDT demonstrated significantly superior antihistamine activity compared with desloratadine and placebo.

Variability in non-nucleoside reverse transcriptase and protease inhibitors concentrations among HIV-infected adults in routine clinical practice.

AIMS: The objective of this study was to assess interindividual variability in plasma trough concentrations of non-nucleoside reverse transcriptase inhibitors (NNRTI) and protease inhibitors (PI) among HIV-infected adults in an outpatient routine clinical practice setting. METHODS: The study included 117 patients who attended our clinic for routine outpatient blood tests and who were receiving antiretroviral therapy which included NNRTI or PI. Patients were not informed that drug concentrations were going to be assessed until blood sampling. The time of the last antiretroviral treatment intake and blood sampling were recorded. Drug concentrations were considered optimal if they were above the proposed minimum effective concentration. In addition, efavirenz, nevirapine and atazanavir concentrations were considered potentially toxic if they were higher than 4.0 mg l(-1), 6.0 mg l(-1), and 0.85 mg l(-1), respectively. RESULTS: Overall, interindividual variability in NNRTI and PI plasma concentrations was approximately 50%, and only 68.4% of the patients had drug concentrations within the proposed therapeutic range. Inappropriate adherence only explained 35% of subtherapeutic drug concentrations. CONCLUSION: Interindividual variability in trough concentrations of NNRTI and PI among HIV-infected adults is large in routine clinical practice, with drug concentrations being outside the therapeutic window in a significant proportion of patients. Therapeutic drug monitoring may be useful to guide antiretroviral therapy in clinical practice.

Lopinavir/ritonavir pharmacokinetics in HIV and hepatitis C virus co-infected patients without liver function impairment: influence of liver fibrosis.

BACKGROUND AND OBJECTIVE: To assess the influence of hepatitis C virus (HCV) co-infection and the extent of liver fibrosis on lopinavir/ritonavir pharmacokinetics in HIV-infected patients without liver function impairment. METHODS: Cross-sectional, comparative study enrolling HIV-infected adults receiving lopinavir/ritonavir (400 mg/100 mg twice daily). HIV/HCV co-infected patients were grouped as having advanced fibrosis (HCV+/FIB+, n=7) or not (HCV+/FIB-, n=8) based on the FIB-4 index. A full concentration-time profile was obtained for each patient, and blood samples were collected before (0), and 1, 2, 4, 6, 8, 10 and 12 hours after a lopinavir/ritonavir dose. Lopinavir and ritonavir concentrations in plasma were determined by high-performance liquid chromatography. Maximum and minimum plasma concentrations (Cmax and Cmin), area under the plasma concentration-time curve from 0 to 12 hours (AUC12), apparent oral clearance at steady state (CLss/F), and apparent volume of distribution after oral administration (Vd/F) were calculated for each individual using a non-compartmental approach. RESULTS: Twenty-six HCV- and 22 HCV+patients were enrolled. Lopinavir and ritonavir pharmacokinetics were comparable between HCV- and HCV+patients. However, the Vd/F of lopinavir was 125% higher in HCV+/FIB+patients than in HCV-patients (p=0.015) and 107% higher than in HCV+/FIB-(p=0.040) patients. The CLss/F of ritonavir was 40% lower in HCV+/FIB+patients than in HCV-patients (p=0.005) and 44% lower than in HCV+/FIB-patients (p=0.040). Thus, for ritonavir AUC12, Cmax and Cmin in HCV+/FIB+patients were 63%, 86% and 100% higher, respectively, when compared with those parameters in HCV-patients (p=0.005, p=0.012 and p=0.015, respectively), and 80%, 86% and 100% higher, respectively, when compared with levels in HCV+/FIB- patients (p=0.040, p=0.040 and p=0.029, respectively). CONCLUSION: Lopinavir exposure is similar in HIV-infected patients with or without HCV co-infection and without liver function impairment. However, ritonavir exposure may be higher in this setting, particularly in individuals with advanced liver fibrosis.

Effects of olanzapine, risperidone and haloperidol on sleep after a single oral morning dose in healthy volunteers.

OBJECTIVES: To compare the effects of typical and atypical antipsychotic drugs on sleep activity and subjective sleep quality. DESIGN: Randomised, double-blind, placebo-controlled, four-period cross-over, clinical trial was used to evaluate the effects of active treatments on objective and subjective sleep variables. SETTING: Sleep laboratory evaluation. PARTICIPANTS: Twenty healthy young volunteers, both sexes. INTERVENTIONS: Single oral morning administrations of olanzapine 5 mg, risperidone 1 mg, haloperidol 3 mg and placebo. MEASUREMENTS AND RESULTS: Five polysomnographic nights were evaluated: one control night and one after each intervention. Significant increase in total sleep time, sleep efficiency, slow wave sleep (SWS) and rapid eye movement (REM) sleep with decreases in wake time were observed after olanzapine. Decreases in wake time, REM sleep and stage shifts together with increases in stage 2 were obtained after risperidone. Haloperidol showed only a tendency to increase sleep efficiency and stage 2 and to decrease wake time. Olanzapine showed decreases in power density in frequencies higher than 10 Hz during all sleep stages and in frequencies lower than 5 Hz range in SWS; decreases in the dynamics of spindle frequency activity (SFA) in the second and fourth non-rapid eye movement (NREM) episodes were also obtained. Risperidone presented increases in the 3.6-10.8 Hz frequency range in NREM sleep stages and in stage 2. Haloperidol also showed increases in NREM sleep stages and in stage 2, but these were in frequencies higher than 10 Hz, with increases in the dynamics of SFA in the first NREM episode. Only a significant improvement in subjective sleep quality was observed after olanzapine. CONCLUSIONS: Antipsychotics showed different sleep changes as their neurochemical profiles were distinct. These changes were observed even when the drug was administered 15 h before going to bed.

Variability in non-nucleoside reverse transcriptase and protease inhibitor concentrations among HIV-infected adults in routine clinical practice.

AIMS: The objective of this study was to assess interindividual variability in trough concentrations of plasma of non-nucleoside reverse transcriptase inhibitors (NNRTI) and protease inhibitors (PI) among HIV-infected adults in a routine outpatient setting. METHODS: One hundred and seventeen patients who attended our clinic for routine blood tests, and who were receiving antiretroviral therapy which included NNRTI or PI were studied. Patients were not informed that drug concentrations were going to be measured until blood sampling. The times of the last antiretroviral dose and of blood sampling were recorded. Drug concentrations were considered optimal if they were above the proposed minimum effective value. In addition, efavirenz, nevirapine and atazanavir concentrations were considered potentially toxic if they were > 4.0 mg l(-1), > 6.0 mg l(-1) and > 0.85 mg l(-1), respectively. RESULTS: Overall, interindividual variability of NNRTI and PI concentrations in plasma was approximately 50%, and only 68.4% of the patients had drug concentrations within the proposed therapeutic range. Poor adherence explained only 35% of subtherapeutic drug concentrations. CONCLUSION: Interindividual variability in trough concentrations of NNRTI and PI among HIV-infected adults is large in routine clinical practice, with drug concentrations being outside the therapeutic window in a significant proportion of patients. These findings provide further evidence that therapeutic drug monitoring may be useful to guide antiretroviral therapy in clinical practice.

Pharmacokinetic profile of the somatostatin analogue lanreotide in individuals with chronic hepatic insufficiency.

BACKGROUND AND OBJECTIVES: The somatostatin analogue lanreotide is indicated for the treatment of acromegaly and to relieve the symptoms of neuroendocrine tumours. The objective of the present study was to compare the pharmacokinetic profile and safety of intravenous lanreotide in healthy volunteers and individuals with hepatic impairment. METHODS: Immediate-release lanreotide was administered at 7 microg/kg during a 20-minute intravenous infusion. Blood samples were collected over 24 hours and lanreotide serum levels determined by radioimmunoassay. Pharmacokinetic parameters were estimated by non-compartmental analyses. RESULTS: Two study centres recruited 53 individuals. Study A comprised 10 individuals with hepatic insufficiency Child-Pugh grade A (mild), 7 with grade B (moderate) and 12 healthy volunteers - all Caucasian. Study B comprised 4 individuals with hepatic insufficiency Child-Pugh grade A, 6 with grade B, 2 with grade C (severe) and 12 healthy volunteers - all Chinese. All participants were included in the safety analysis. The pharmacokinetic analysis included all participants from study B, but only 12 with hepatic impairment and 11 healthy volunteers from study A. Combined analysis of both studies showed an increased serum elimination half-life (57%; p < or = 0.001), mean residence time (53%; p < or = 0.001) and volume of distribution (at steady state, 57%; at terminal disposition phase, 64%; both p < or = 0.001) in individuals with mild hepatic insufficiency compared with healthy volunteers. These differences were more pronounced in individuals with moderate-to-severe hepatic insufficiency compared with healthy volunteers; additionally, the area under the serum concentration-time curve from time zero to infinity (AUC(infinity)) was increased (23%; p < or = 0.05) and clearance (CL) decreased (19%; p < or = 0.05) compared with healthy volunteers. The peak serum concentration of lanreotide tended to be lower in individuals with hepatic insufficiency than in healthy volunteers (statistically non-significant). There were no pharmacokinetic differences between the two groups of healthy volunteers. Lanreotide was well tolerated with only two mild adverse events that were considered to be possibly related to treatment (both nausea and headache with either vomiting or dizziness). There were no clinically relevant changes in laboratory parameters or vital signs during the study. CONCLUSION: The pharmacokinetic profile of lanreotide depends on the severity of hepatic insufficiency with CL and AUC(infinity), which are only slightly altered with moderate-to-severe insufficiency. The changes in exposure do not, however, require dosage adjustment. Moreover, lanreotide is usually given as a prolonged-release microparticle or Autogel formulation, and terminal half-life and serum concentrations depend on the release properties of the formulation. Dosing is also adapted for each patient, based on therapeutic response. Thus, hepatic insufficiency does not require additional dosage adjustments.