Influence of Different Populations on Pharmacokinetic Bioequivalence Results: Can We Extrapolate Bioequivalence Results from One Population to Another?

Purpose: Over the last 15 years, an ever-increasing proportion of pharmacokinetic bioequivalence studies for European/North American generic submissions appeared to have been conducted in geographical/ethnic populations other than those for which the drug is marketed for. The results of pharmacokinetic bioequivalence studies have traditionally been considered to be insensitive to the population studied. However, several recent studies have suggested that this may not necessarily be true. The objective of this study was to investigate whether there were any concerns regarding the current practice of extrapolating bioequivalence study results from one geographic/ethnic population to another. METHODS: In order for a regulatory agency to use bioequivalence results from one population to another, two formulations assessed as bioequivalent under fasted and fed conditions in one population must be bioequivalent in a geographically/ethnically different population under both conditions. Unfortunately, bioequivalence studies between a generic and its reference product for one submission are conducted using only one geographical/ethnic population. As bioequivalence study results between two populations for the same generic and reference products are not available, the food effect for the same reference product between two populations was compared. This is based on the rationale that if two products are bioequivalent under both fasted and fed conditions in two populations, even if there are PK differences in the product exposures between these two populations, the test to reference ratio, as well as the food effect, will remain constant within each population. Food effect (fed/fasted ratio) was calculated using pharmacokinetic data from publicly available regulatory resources and compared between two geographical/ethnic populations using the same reference for each studied drug product. Meta-analyses were conducted. RESULTS: Statistically significant differences (P<0.05) were found in the food effect between two populations for nine out of the ten (90%) available studied products. Among these, an observed clinical difference was suggested in three out of nine (33%) products. CONCLUSION: These results suggest that bioequivalence results from one population may not always be representative of what may be found in another population.

Pharmacokinetics and Pharmacodynamics of Nebulized and Intratracheal Milrinone in a Swine Model of Hypercapnia Pulmonary Hypertension.

OBJECTIVES: Milrinone pulmonary administration is used currently for the treatment of pulmonary hypertension. Several methods are available: simple jet nebulization, vibrating mesh nebulization, intratracheal instillation, and intratracheal atomization. The aim of this study was to explore the concentration-effect relationship of milrinone for each of these methods. DESIGN: Observational open-label pharmacokinetic/pharmacodynamics cohort study. SETTING: Single-center, hospital animal laboratory. PARTICIPANTS: Twelve swine. INTERVENTIONS: After hypercapnia pulmonary hypertension, swine were administered equivalent inhaled milrinone doses of 15 or 50 µg/kg through simple jet nebulization, vibrating mesh nebulization, intratracheal instillation, and intratracheal atomization. MEASUREMENTS AND MAIN RESULTS: Blood and urine samples were taken up to 360 minutes postadministration. The ratio of mean systemic arterial pressure to mean pulmonary arterial pressure was monitored continuously. Right heart echographies were taken before and after hypercapnia and after drug administration. Mean elimination half-lives were similar for the 4 administrations. Mean percent changes in the ratio were of 37 (60%), 18 (31%), 17 (36%), and 20 (20%), for simple jet nebulization, vibrating mesh nebulization, intratracheal instillation, and intratracheal atomization, respectively. Mean maximum plasma concentrations for intratracheal administrations were reached at 8 and 45 min for atomization and instillation, respectively. Significant increases in right atrial diameter and right ventricular end-diastolic area were witnessed during pulmonary hypertension as well as a return to baseline values after milrinone administration. CONCLUSIONS: The intratracheal methods, particularly intratracheal atomization, showed less hemodynamic effect than nebulizations and, in the case of intratracheal instillation, unpredictable drug exposure. Nebulization methods on the other hand, especially simple jet nebulization, suggest better efficacy and sensitivity but are less fit for emergency situations.

Use of nebulized milrinone in cardiac surgery; Comparison of vibrating mesh and simple jet nebulizers.

Cardiopulmonary bypass triggers an ischemia-reperfusion injury with endothelial dysfunction in the pulmonary circulation which can result in pulmonary hypertension. Inhaled milrinone reduces this reperfusion phenomenon and two methods commonly available for administering it are simple jet and vibrating mesh nebulizations. However, neither their generated milrinone particle size profiles, nor their ability to aid endothelial relaxation have been compared. Simple jet and vibrating mesh particle size distributions of milrinone were verified through cascade impaction and their efficacy was tested on a cardiopulmonary bypass (CPB) swine model. Post-nebulizations, animals underwent 90 min of CPB, followed by 60 min of reperfusion and lung excision. Pulmonary arterial endothelium-dependent relaxations to acetylcholine and bradykinin were then performed on pulmonary vasculature rings and were subsequently modeled as inhibitory Emax functions. In vitro studies showed lower emitted and inhaled doses from the simple jet nebulizer and its particle size distribution indicated upper and middle airway targeting. During in vivo studies, milrinone pre-treated, unlike saline groups maintained baseline pulmonary pressures up to 30 min post-CPB. Ex vivo studies showed better endothelial relaxation of arteries from the two milrinone groups over those from the control group in an administration/pathway-dependent manner, favoring simple jet administration.

A multicentre randomized-controlled trial of inhaled milrinone in high-risk cardiac surgical patients.

PURPOSE: Inhaled milrinone (iMil) has been used for the treatment of pulmonary hypertension (PH) but its efficacy, safety, and prophylactic effects in facilitating separation from cardiopulmonary bypass (CPB) and preventing right ventricular (RV) dysfunction have not yet been evaluated in a clinical trial. The purpose of this study was to investigate if iMil administered before CPB would be superior to placebo in facilitating separation from CPB. METHODS: High-risk cardiac surgical patients with PH were randomized to receive iMil or placebo after the induction of anesthesia and before CPB. Hemodynamic parameters and RV function were evaluated by means of pulmonary artery catheterization and transesophageal echocardiography. The groups were compared for the primary outcome of the level of difficulty in weaning from CPB. Among the secondary outcomes examined were the reduction in the severity of PH, the incidence of RV failure, and mortality. RESULTS: Of the 124 patients randomized, the mean (standard deviation [SD]) EuroSCORE II was 8.0 (2.6), and the baseline mean (SD) systolic pulmonary artery pressure (SPAP) was 53 (9) mmHg. The use of iMil was associated with increases in cardiac output (P = 0.03) and a reduction in SPAP (P = 0.04) with no systemic hypotension. Nevertheless, there was no difference in the combined incidence of difficult or complex separation from CPB between the iMil and control groups (30% vs 28%, respectively; absolute difference, 2%; 95% confidence interval [CI], -14 to 18; P = 0.78). There was also no difference in RV failure between the iMil and control groups (15% vs 14%, respectively; difference, 1%; 95% CI, -13 to 12; P = 0.94). Mortality was increased in patients with RV failure vs those without (22% vs 2%, respectively; P < 0.001). CONCLUSION: In high-risk cardiac surgery patients with PH, the prophylactic use of iMil was associated with favourable hemodynamic effects that did not translate into improvement of clinically relevant endpoints. This trial was registered at ClinicalTrials.gov; identifier: NCT00819377.

RéSUMé: OBJECTIF: La milrinone inhalée est utilisée pour traiter l'hypertension pulmonaire (HP) mais son efficacité, son innocuité et ses effets prophylactiques pour faciliter le sevrage de la circulation extracorporelle (CEC) et prévenir la dysfonction ventriculaire droite (VD) n'ont pas encore été évalués dans le cadre d'une étude clinique. L'objectif de cette étude était d'examiner si la milrinone inhalée avant la CEC serait supérieure à un placebo pour faciliter le sevrage de la CEC. MéTHODE: Des patients de chirurgie cardiaque à risque élevé et souffrant d'HP ont été randomisés à recevoir de la milrinone inhalée ou un placebo après l'induction de l'anesthésie et avant la CEC. Les paramètres hémodynamiques et la fonction VD ont été évalués à l'aide d'un cathéter de l'artère pulmonaire et d'une échocardiographie transœsophagienne. Les groupes ont été comparés selon notre critère d'évaluation principal, soit le niveau de difficulté du sevrage de la CEC. Parmi les critères d'évaluation secondaires examinés figuraient la réduction de la gravité de l'HP, l'incidence d'insuffisance cardiaque droite et la mortalité. RéSULTATS: Au total, 124 patients ont été randomisés. Le score EuroSCORE II moyen (écart type [ÉT]) était de 8,0 (2,6), et la pression systolique de l'artère pulmonaire moyenne de base (ÉT) était de 53 (9) mmHg. L'utilisation de milrinone inhalée a été associée à des augmentations du débit cardiaque (P = 0,03) et à une réduction de la pression systolique de l'artère pulmonaire (P = 0,04) sans hypotension systémique. Toutefois, aucune différence n'a été observée dans l'incidence combinée de sevrage difficile ou complexe de la CEC entre le groupe milrinone inhalée et le groupe témoin (30 % vs 28 %, respectivement; différence absolue, 2 %; intervalle de confiance [IC] 95 %, −14 à 18; P = 0,78). Aucune différence n'a été observée non plus en matière d'insuffisance cardiaque droite entre le groupe milrinone inhalée et le groupe témoin (15 % vs 14 %, respectivement; différence, 1 %; IC 95 %, −13 à 12; P = 0,94). La mortalité était augmentée chez les patients avec insuffisance cardiaque droite (22 % vs 2 %, respectivement; P < 0.001). CONCLUSION: Chez les patients de chirurgie cardiaque à risque élevé atteints de HP, l'utilisation prophylactique de milrinone inhalée a été associée à des effets hémodynamiques favorables qui ne se sont pas traduits en améliorations des critères pertinents d'un point de vue clinique. Cette étude a été enregistrée au ClinicalTrials.gov; identifiant : NCT00819377.

Modeling the anesthetic effect of ropivacaine after a femoral nerve block in orthopedic patients: a population pharmacokinetic-pharmacodynamic analysis.

BACKGROUND: Even though ropivacaine is frequently used during orthopedic surgery, the relationship between plasma concentrations and degree of sensory anesthesia after a peripheral nerve block is currently unknown. The aim of this study was to characterize this relation using population pharmacokinetic-pharmacodynamic modeling. METHODS: Femoral nerve block was performed by the anterior approach using a single injection (20 ml) of 0.5% ropivacaine hydrochloride in 20 patients scheduled for total knee arthroplasty under spinal anesthesia. Sensory thresholds in response to a gradual increase in transcutaneous electrical stimulation (primary endpoints), loss and recovery of ice-cold sensation, as well as total ropivacaine plasma concentrations were determined up to 4 days after administration of the local anesthetic. Using NONMEM (ICON, USA), sensory block was modeled by assuming an equilibration delay (ke0) between amount in the depot and effect-site compartments. RESULTS: Mean effect-site amount producing 90% of the maximum possible effect (AE90) was estimated as 20.2 mg. At 2 × AE90, the sigmoid Emax model predicted a mean onset time of 23.4 min and mean duration of 22.9 h. Interindividual variability (IIV) for AE50 was 49%. Typical ke0 half-life was 34.7 min (IIV = 52%) and steepness parameter 8.7 (IIV = 48%). None of the pharmacodynamic model parameters showed sex, age, or body weight dependency. CONCLUSIONS: A population pharmacokinetic/pharmacodynamic model was developed that quantitatively describes the sensory component of a femoral nerve block in orthopedic patients. Further clinical studies will be needed to validate the clinical relevance of this finding.

The reliability of the current perception threshold in volunteers and its applicability in a clinical setting.

BACKGROUND: Even though current perception threshold (CPT) has been used for evaluating the effectiveness of sensory block in patients before surgery, its reliability under controlled conditions has not been investigated. Two independent investigations were performed. The primary objective of the first study was to determine the test-retest reliability of CPT measures after repeated stimulations in a group of healthy volunteers. The primary objective of the second study was to evaluate the clinical applicability of this technique to assess the sensory onset of a femoral nerve block in patients undergoing knee surgery. METHODS: Thirty healthy subjects participated in 2 identical sessions, separated by at least 24 hours, in which CPTs were measured after 5 consecutive stimulations over the anteromedial aspect of the thigh. Similar measures were obtained in 15 orthopedic patients receiving a femoral nerve block with 20 mL of ropivacaine 0.5%. Test-retest reliability was assessed using intraclass correlation (ICC) and standard error of measurement (expressed as coefficient of variation [CV(SEM)]), whereas Student t test (P < 0.05) compared the increase in CPTs over baseline. RESULTS: Within-day ICC values ranged (% confidence interval [CI]) from 0.66 to 0.95 with a CV(SEM) of approximately 39% (% CI: 17%-58%). Between-day ICC values, ranging from 0.57 to 0.94 (CV(SEM): approximately 45%, % CI: 13%-71%), indicated that day-to-day CPT measurements are also variable. The current intensity needed for sensory perception in orthopedic patients significantly increased, varying from a mean CPT value of 82.5 ± 66.5 µA (SD) at time zero to an average of 481 ± 338 µA, 22 ± 8 minutes after the administration of the local anesthetic. CONCLUSIONS: CPT proved to be a reliable assessment tool for within-day sensory perception in healthy volunteers. Our study also suggests that CPT can be applied to characterize, in a quantitative manner, the sensory onset of a peripheral nerve block in a clinical setting, thereby supporting its use in future studies comparing different regional anesthetic modalities or approaches.

A specific and sensitive HPLC-MS/MS micromethod for milrinone plasma levels determination after inhalation in cardiac patients.

BACKGROUND: Milrinone administered through inhalation is an emerging method aimed at specifically reducing pulmonary hypertension without affecting systemic pressures. Its administration has been shown to be useful both in patients undergoing cardiac surgery and for persistent pulmonary hypertension of the newborn. These populations are prone to receive many concomitant medications and/or blood sampling may require a low volume quantification method. To address these issues in view of pharmacokinetic studies, this article aims to develop and validate a specific and sensitive analytical assay using high performance liquid chromatography (HPLC) and tandem mass spectrometry (MS/MS) detection for the quantification of milrinone plasma concentrations after inhalation in patients undergoing cardiac surgery. METHODS: Plasma samples (50 µL) were extracted using ethyl acetate. Milrinone was separated on a C18 analytical column at 50°C. The mobile phase consisted of methanol and 10 mM ammonium acetate (45:55 vol/vol). The electrospray was operated in the negative ionization mode and monitored the following mass transitions: m/z 212.1 → 140.0 at 36 eV for milrinone and m/z 252.1 → 156.1 at 32 eV for olprinone. RESULTS: Calibration curves followed a quadratic regression in the concentration range of 0.3125-640 ng/mL. The lower limit of quantification is 0.3125 ng/mL and is based on a low plasma volume of 50 µL. Mean drug recovery and accuracy were ≥72.3% and 96.0%, respectively. Intraday and interday precision coefficient of variation (%) was ≤7.4% and ≤11.5%, respectively. The specificity allowed milrinone quantification in the multidrug administration conditions of cardiopulmonary bypass. CONCLUSIONS: This validated micromethod proved to be highly sensitive and specific while using a low volume of plasma. Its low volume and its lower limit of quantification indicate that this approach is suitable for further characterization of milrinone pharmacokinetics in both adults (inhalation) and neonates.

High-performance liquid chromatography assay using ultraviolet detection for urinary quantification of milrinone concentrations in cardiac surgery patients undergoing cardiopulmonary bypass.

An analytical assay using liquid-liquid extraction and high-performance liquid chromatography with ultraviolet detection was developed for the quantification of total (conjugated and unconjugated) urinary concentrations of milrinone after the inhalation of a 5 mg dose in 15 cardiac patients undergoing cardiopulmonary bypass. Urine samples (700 µL) were extracted with ethyl-acetate and subsequently underwent acid back-extraction before and after deconjugation by mild acid hydrolysis. Milrinone was separated on a strong cation exchange analytical column. The mobile phase consisted of a constant mixture of acetonitrile:tetrahydrofurane-NaH2 PO4 buffer (40:60 v/v, pH 3.0). Thirteen calibration curves were linear in the concentration range of 31.25-4000 ng/mL, using olprinone as the internal standard (r(2) range 0.9911-0.9999, n = 13). Mean milrinone recovery and accuracy were respectively 85.2 ± 3.1% and ≥93%. Intra- and inter-day precisions (coefficients of variation) were ≤5% and ≤8%, respectively. Over a 24 h collection period, the cumulative urinary milrinone recovered from 15 patients was 26.1 ± 7.7% of the nominal 5 mg dose administered. The relative amount of milrinone glucuronic acid conjugate was negligible in the urine of patients undergoing cardiopulmonary bypass This method proved to be reliable, specific and accurate to determine the cumulative amount of total milrinone recovered in urine after inhalation.

Inhaled milrinone in cardiac surgical patients: pharmacokinetic and pharmacodynamic exploration.

Mean arterial pressure to mean pulmonary arterial pressure ratio (mAP/mPAP) has been identified as a strong predictor of perioperative complications in cardiac surgery. We therefore investigated the pharmacokinetic/pharmacodynamic (PK/PD) relationship of inhaled milrinone in these patients using this ratio (R) as a PD marker. Following approval by the ethics and research committee and informed consent, we performed the following experiment. Before initiation of cardiopulmonary bypass in 28 pulmonary hypertensive patients scheduled for cardiac surgery, milrinone (5 mg) was nebulized, plasma concentrations measured (up to 10 h) and compartmental PK analysis carried out. Baseline (R0) and peak (Rmax) ratios as well as magnitude of peak response (∆Rmax-R0) were measured. During inhalation, individual area under effect-time (AUEC) and plasma concentration-time (AUC) curves were correlated. Potential relationships between PD markers and difficult separation from bypass (DSB) were explored. In this study, we observed that milrinone peak concentrations (41-189 ng ml-1) and ΔRmax-R0 (- 0.12-1.5) were obtained at the end of inhalation (10-30 min). Mean PK parameters agreed with intravenous milrinone published data after correction for the estimated inhaled dose. Paired comparisons yielded a statistically significant increase between R0 and Rmax (mean difference, 0.58: 95% CI 0.43-0.73; P < 0.001). Individual AUEC correlated with AUC (r = 0.3890, r2 = 0.1513; P = 0.045); significance increased after exclusion of non-responders (r = 4787, r2 = 0.2292; P = 0.024). Individual AUEC correlated with ∆Rmax-R0 (r = 5973, r2 = 0.3568; P = 0.001). Both ∆Rmax-R0 (P = 0.009) and CPB duration (P < 0.001) were identified as predictors of DSB. In conclusion, both magnitude of peak response of the mAP/mPAP ratio and CPB duration were associated with DSB.

A population pharmacokinetic model for the complex systemic absorption of ropivacaine after femoral nerve block in patients undergoing knee surgery.

Because of its slow systemic absorption and flip-flop kinetics, ropivacaine's pharmacokinetics after a peripheral nerve block has never been thoroughly characterized. The purpose of this study was to develop a population pharmacokinetic model for ropivacaine after loco-regional administration and to identify patient characteristics that may influence the drug's absorption and disposition. Frequent plasma samples were taken up to 93 h after a 100 mg dose given as femoral block for postoperative analgesia in 15 orthopedic patients. Ropivacaine plasma concentration-time data were analyzed using a nonlinear mixed effects modeling method. A one-compartment model with parallel inverse Gaussian and time-dependent inputs best described ropivacaine plasma concentration-time curves. Ropivacaine systemic absorption was characterized by a rapid phase (mean absorption time of 25 ± 4.8 min) followed by a much slower phase (half-life of 3.9 ± 0.65 h). Interindividual variability (IIV) for these parameters, 58 and 9 %, indicated that the initial absorption phase was more variable. The apparent volume of distribution (V/F = 77.2 ± 11.5 L, IIV = 26 %) was influenced by body weight (Δ 1.49 % per kg change) whereas the absorption rate constant (slower phase) of ropivacaine was affected by age (Δ 2.25 % per year change). No covariate effects were identified for the apparent clearance of the drug (CL/F =10.8 ± 1.0 L/h, 34  IIV = 34 %). These findings support our hypothesis that modeling a complex systemic absorption directly from plasma concentration-time curves exhibiting flip-flop kinetics is possible. Only the age-effect was considered as relevant for possible dosing adjustments.

Cisatracurium pharmacokinetics and pharmacodynamics during hypothermic cardiopulmonary bypass in infants and children.

BACKGROUND: Hypothermia potentiates neuromuscular blockade in adults during cardiopulmonary bypass (CPB) but the pediatric literature is sparse. Temperature-dependent Hoffman degradation of cisatracurium may allow reduction in infusion rate (IR) during hypothermia. The effect of hypothermic CPB on the pharmacokinetics (PK) and pharmacodynamics (PD) of cisatracurium has not been described in children. METHODS AND MATERIALS: Using neuromuscular monitoring with a Datex Relaxograph, cisatracurium IR was adjusted to obtain a pseudo-steady state during each phase of surgery (pre-CPB, CPB, post-CPB). Paired samples were taken at each phase. Cisatracurium plasma concentrations (Cpss) were determined by HPLC. Core and skin temperatures were recorded. RESULTS: Data from ten infants were analyzed: Group 1: mean 33.6°C; Group 2: mean 21.9°C. To maintain T1% between 5% and 10% in Group 2, the IR was decreased by a mean of 89% (P < 0.001). IR was not significantly different in Group 1. Post-CPB IR approximated pre-CPB rates in both groups. During CPB, Cpss fell by 27% in Group 1 and by 50% in Group 2 (P = 0.039). Post-CPB Cpss was not significantly different to pre-CPB in either group. Clearance did not change significantly in Group 1 but fell significantly in Group 2 during CPB (P = 0.002). Clearance post-CPB was unchanged from pre-CPB. CONCLUSIONS: Cisatracurium IR may be decreased by around 60% during CPB with moderate hypothermia but can be maintained at baseline during mild hypothermia.

Simultaneous percutaneous implantation of a microdialysis probe for monitoring perineural concentrations of local anaesthetics during peripheral nerve block in rabbits.

OBJECTIVE: To develop a technique that allows simultaneous percutaneous implantation of both a microdialysis probe and injection catheter in order to monitor the perineural pharmacokinetics of local anaesthetics (LA) after a femoral block. STUDY DESIGN: Prospective experimental study. ANIMALS: Five anaesthetized male New Zealand rabbits with a mean ± SD weight of 3.2 ± 0.2 kg. METHODS: After femoral nerve localization by electrostimulation, an injection catheter and a microdialysis probe were slowly and simultaneously inserted into a cannula left into place in the perineural region. Both were then secured into place, after removal of the cannula. At the end of the experiment, methylene blue was injected to confirm the distance from the femoral nerve during subsequent postmortem anatomical dissection of the injection site. RESULTS: Staining was adequate and the catheter found to be located within 4 mm of the femoral nerve in three out of five rabbits. CONCLUSIONS AND CLINICAL RELEVANCE: This procedure allows direct implantation of a microdialysis probe near the injection site of LA during a femoral nerve block without loosing nerve localization accuracy. This procedure has been used successfully to monitor the regional pharmacokinetics of LA after a peripheral nerve block.

Circadian variation of sleep during the follicular and luteal phases of the menstrual cycle.

STUDY OBJECTIVES: Women experience insomnia more frequently than men. Menstrual cycle changes in reproductive hormones and circadian rhythms may contribute to sleep disruptions. Our aim, therefore, was to clarify the interaction between menstrual and circadian processes as it affects sleep. DESIGN: Participants entered the laboratory during the mid-follicular (MF) and mid-luteal (ML) phases of their menstrual cycle for an ultra-rapid sleep-wake cycle (URSW) procedure, consisting of 36 cycles of 60-min wake episodes alternating with 60-min nap opportunities. This procedure concluded with an ad libitum nap episode. SETTING: Time-isolation suite. PARTICIPANTS: Eight unmedicated, physically and mentally healthy females with regular ovulatory menstrual cycles. INTERVENTIONS: N/A. MEASUREMENTS: Polysomnographic sleep from nocturnal sleep episodes and 60-min naps; subjective alertness; core body temperature (CBT); salivary melatonin; urinary estradiol; and urinary progesterone. RESULTS: Increased CBT values at night and decreased CBT amplitude were observed during ML compared to MF. Circadian phase of CBT and the circadian melatonin profile were unaffected by menstrual phase. All analyzed sleep parameters showed a circadian variation throughout the URSW procedure, with no menstrual phase differences observed for most, including slow wave sleep (SWS). The circadian variation of REM sleep duration, however, was sensitive to menstrual phase, with reduced REM sleep during ML at circadian phase 0 degrees and 30 degrees. CONCLUSIONS: Moderate but significant changes in REM sleep across the menstrual and circadian cycles were observed. These results support an interaction between circadian and menstrual processes in the regulation of REM sleep.

Inhaled milrinone in cardiac surgical patients: a pilot randomized controlled trial of jet vs. mesh nebulization.

Inhaled milrinone administered before cardiopulmonary bypass (CPB) reduces the severity of pulmonary hypertension during cardiac surgery. However, milrinone pharmacokinetics has not been determined for this route of administration. The objective of this study was to investigate inhaled milrinone dosing in vitro and early plasma concentrations in vivo after jet and mesh nebulization. Twelve pulmonary hypertensive patients scheduled for cardiac surgery were randomized to receive milrinone (5 mg) by inhalation before CPB using a jet or mesh nebulizer. In vitro experiments were conducted to determine the inhaled dose delivered with either jet or mesh nebulization. In vivo experiments involved hemodynamic monitoring and blood samples drawn from patients for the first 15 min after the end of inhalation to determine early plasma concentrations. After mesh nebulization, the mean in vitro inhaled dose was almost 3-fold higher compared to jet nebulization (46.4% vs 16.6% for mesh and jet, respectively; mean difference, 29.8%; 95% CI, 14.1 to 45.5; P = 0.006). Consistent with this, the early plasma concentrations in vivo were also 2-3 fold higher after mesh nebulization (P = 0.002-0.005). After inhalation (jet or mesh nebulization), milrinone early plasma concentrations remained within the therapeutic range. No systemic hypotension was reported in our patients.

High-performance liquid chromatography using UV detection for the simultaneous quantification of ropivacaine and bupivacaine in human plasma.

A specific high-performance liquid chromatography assay coupled with UV detection has been developed and validated for the simultaneous determination of ropivacaine and bupivacaine in human plasma. A liquid-liquid back extraction procedure was used to increase specificity, and very good and consistent recoveries were obtained: 93%-95% for ropivacaine and 90%-96% for bupivacaine. The lowest limit of quantification was 4 and 8 ng/mL for ropivacaine and bupivacaine, respectively. The method was sensitive, reproducible (coefficient of variation

Population Pharmacokinetic/Pharmacodynamic Modeling of O-Desmethyltramadol in Young and Elderly Healthy Volunteers.

BACKGROUND: Age-related changes in the concentration-effect relationship of (+)-O-desmethyl-tramadol [(+)-ODM], tramadol's active metabolite, are not documented in the elderly. OBJECTIVE: The objective of this study was to characterize, in elderly and young subjects, the (+)-ODM pharmacokinetic and pharmacodynamic relationship to examine the effect of age after single-dose administration of tramadol 200 mg extended-release tablets. METHODS: A population analysis of a double-blind, randomized, placebo-controlled, two-period cross-over study including 13 elderly (aged ≥75 years) subjects with mild renal insufficiency and 16 young (aged 18-40 years) subjects was conducted. For 48 h post-dose, blood samples were collected and pain tolerance thresholds measured using an electrically stimulated pain model. A pharmacokinetic/pharmacodynamic model incorporating a one-compartment pharmacokinetic model for (+)-ODM parameterized with first-order formation rate, clearance (CL/fm), volume of distribution (V/fm) and a sigmoid maximum effect (Emax) model incorporating baseline (E0) and placebo effect was used. RESULTS: Maximum plasma concentrations of (+)-ODM occurred later and plasma concentrations declined more slowly in the elderly than in young subjects. In the elderly, V/fm was 76% larger and CL/fm 16% slower. Baseline (E0) and sensitivity (C50) for pain tolerance were similar between young and elderly subjects. However, the Emax parameter was 2.5 times higher in the elderly and maximum possible treatment-related effect was 169 (135-221) in the young and 194 (149-252) in the elderly; that is, 15% higher in the elderly. CONCLUSIONS: This exploratory analysis suggests that age-related differences exist in the distribution and elimination of (+)-ODM, including a 76% larger distribution outside the central compartment and 16% slower clearance of (+)-ODM. These pharmacokinetic changes are associated with a 15% higher maximum possible treatment-related effect and carry the potential for greater efficacy but also the potential for increased side effects at the same dose in elderly subjects. Clinicaltrials.gov identifier: NCT02329561.

Evaluation of an Experimental Pain Model by Noncompartmental Analysis of Results from a Randomized Placebo Controlled Trial.

BACKGROUND: Understanding analgesic pharmacodynamics (PD) in the elderly is key to optimising pain management. Electrically stimulated pain models (ESPM) permit assessment of pain responses in humans. C and A-delta sensory fibres convey pain and respond to low frequency electrical stimulus (5 and 250 Hz, respectively). Human research suggests pain tolerance threshold (PTT) is similar or decreases with age. OBJECTIVES: To determine whether an ESPM is able to detect a difference in PTT in elderly (>/= 75 years) and young (20-40 years) subjects after single dose administration of a placebo and tramadol, a low potency analgesic. STUDY DESIGN: Two-cohort, randomized, placebo-controlled, cross-over study. METHODS: A noncompartmental analysis of data at 17 timepoints on 5 Hz and 250 Hz PTT over 24 h. RESULTS: Young (16) and elderly (13) patients showed similar baseline (E0) PTT between active and placebo both overall and by age group in both frequencies. Net drug effect took into account negative and positive changes from E0. In the elderly, net peak effect on PTT produced by active treatment was significantly greater for both 5 Hz (34%) and 250 Hz (30%). Net area under the 24-h effect-time curve during active treatment was significantly higher for both 5 Hz (163 %) and 250 Hz (175%) stimulations in the elderly. No clinically significant difference was observed in the young. LIMITATIONS: High variability in young subjects, despite efforts to remove outliers limited our ability to draw conclusions in that age group. Generalizability of results obtained from an experimental pain model in volunteers to treatment of elderly patients may be limited. CONCLUSION: ESPM can detect a difference for pain tolerance threshold between placebo and tramadol administration in the elderly. Although both 5 Hz and 250 Hz stimulations can detect a difference, the effect size for 5 Hz is larger and seems more precise and reliable, particularly in the elderly. KEY WORDS: Electrical pain model, elderly, geriatric, tramadol, placebo, opioid, area under the effect curve, noncompartmental analysis.

Dose-Exposure Simulation for Piperacillin-Tazobactam Dosing Strategies in Infants and Young Children.

BACKGROUND: Extended piperacillin-tazobactam (TZP) infusions have been associated with favourable outcomes. There are currently no pediatric dosing recommendations. OBJECTIVES: To determine appropriate TZP dosing strategies in children 2 months - 6 years according to age and different minimal inhibitory concentrations (MICs). METHODS: Age and weight were simulated for 1000 children. Post-hoc pharmacokinetic parameter estimates were generated using published clearance and volume of distribution data. For different dosing regimens, we estimated the probability of target attainment (PTA) over a range of MICs from 4 to 128 mg/L. The pharmacodynamic (PD) target was defined as free piperacillin concentrations above the MIC for ≥ 50% of the dosing interval. A PTA ≥ 90% was defined as optimal. RESULTS: PTA decreased as MIC and age increased. In all age groups, standard dosing regimens (240-300 mg/kg/day, 0.5h infusions) failed to reach PTAs ≥ 90% at MICs ≥ 16 mg/L. Standard 0.5h infusions reached PTAs ≥ 90% at MICs up to 8 mg/L in infants > 2 to 6m. No 0.5h infusion reached PTAs ≥ 90% for MICs ≥ 4 mg/L in children > 6m. While none of the tested regimens were optimal at MICs > 16 mg/L in children > 6m, 100 mg/kg/dose every 6h as a 3h infusion reached PD target at MICs of 32 mg/L in infants > 2 to 6m. CONCLUSIONS: Up to MICs of 16 mg/L, 90 mg/kg/dose every 8h as a 2h infusion in infants > 2 to 6m and 100 mg/kg/dose every 8h as a 4h infusion in children > 6m-6y achieved PTAs ≥ 90%.

Comparison of inhaled milrinone, nitric oxide and prostacyclin in acute respiratory distress syndrome.

AIM: To evaluate the safety and efficacy of inhaled milrinone in acute respiratory distress syndrome (ARDS). METHODS: Open-label prospective cross-over pilot study where fifteen adult patients with hypoxemic failure meeting standard ARDS criteria and monitored with a pulmonary artery catheter were recruited in an academic 24-bed medico-surgical intensive care unit. Random sequential administration of iNO (20 ppm) or nebulized epoprostenol (10 µg/mL) was done in all patients. Thereafter, inhaled milrinone (1 mg/mL) alone followed by inhaled milrinone in association with inhaled nitric oxide (iNO) was administered. A jet nebulization device synchronized with the mechanical ventilation was use to administrate the epoprostenol and the milrinone. Hemodynamic measurements and partial pressure of arterial oxygen (PaO2) were recorded before and after each inhaled therapy administration. RESULTS: The majority of ARDS were of pulmonary cause (n = 13) and pneumonia (n = 7) was the leading underlying initial disease. Other pulmonary causes of ARDS were: Post cardiopulmonary bypass (n = 2), smoke inhalation injury (n = 1), thoracic trauma and pulmonary contusions (n = 2) and aspiration (n = 1). Two patients had an extra pulmonary cause of ARDS: A polytrauma patient and an intra-abdominal abscess Inhaled nitric oxide, epoprostenol, inhaled milrinone and the combination of inhaled milrinone and iNO had no impact on systemic hemodynamics. No significant adverse events related to study medications were observed. The median increase of PaO2 from baseline was 8.8 mmHg [interquartile range (IQR) = 16.3], 6.0 mmHg (IQR = 18.4), 6 mmHg (IQR = 15.8) and 9.2 mmHg (IQR = 20.2) respectively with iNO, epoprostenol, inhaled milrinone, and iNO added to milrinone. Only iNO and the combination of inhaled milrinone and iNO had a statistically significant effect on PaO2. CONCLUSION: When comparing the effects of inhaled NO, milrinone and epoprostenol, only NO significantly improved oxygenation. Inhaled milrinone appeared safe but failed to improve oxygenation in ARDS.

Pharmacokinetics of Lidocaine Hydrochloride Administered with or without Adrenaline for the Paravertebral Brachial Plexus Block in Dogs.

Adrenaline is known to prolong the duration of local anesthesia but its effects on the pharmacokinetic processes of local anesthetic drugs are not fully understood. Our objective was to develop a compartmental model for quantification of adrenaline's impact on the pharmacokinetics of perineurally-injected lidocaine in the dog. Dogs were subjected to paravertebral brachial plexus block using lidocaine alone or adrenalinated lidocaine. Data was collected through a prospective, randomised, blinded crossover protocol performed over three periods. Blood samples were collected during 180 minutes following block execution. Compartmental pharmacokinetic models were developed and their goodness-of-fit were compared. The lowering effects of adrenaline on the absorption of lidocaine were statistically determined with one-sided tests. A one-compartment disposition model with two successive zero-order absorption processes best fitted our experimental data. Adrenaline decreased the peak plasma lidocaine concentration by approximately 60% (P < 0.001), decreased this local anesthetic's fast and slow zero-order absorption rates respectively by 50% and 90% (P = 0.046, and P < 0.001), which respective durations were prolonged by 90% and 1300% (P < 0.020 and P < 0.001). Lidocaine demonstrated a previously unreported atypical absorption profile following its paravertebral injection in dogs. Adrenaline decreased the absorption rate of lidocaine and prolonged the duration of its absorption.