A Recirculatory Model for Pharmacokinetics and the Effects on Bispectral Index After Intravenous Infusion of the Sedative and Anesthetic AZD3043 in Healthy Volunteers.

BACKGROUND: AZD3043 is a positive allosteric modulator of the γ-aminobutyric acid type A receptor, with sedative and anesthetic properties. We describe a population pharmacokinetic (PK) model of arterial and venous concentrations of AZD3043 and the pharmacodynamic effects on bispectral index (BIS) in healthy volunteers. METHODS: Arterial and venous plasma concentrations of AZD3043 and BIS were measured in 2 clinical studies in 125 healthy volunteers, where AZD3043 was given as a 1-minute bolus (1-6 mg/kg), a 30-minute infusion (1-81 mg/kg/h), or 0.8 + 10, 1 + 15, 3 + 30, and 4 + 40 (mg/kg bolus + mg/kg/h infusion for 30 minutes). Population PK/pharmacodynamic analysis was performed with NONMEM. RESULTS: A recirculatory model, comprising a series of 5 compartments for the transit of drug between venous and arterial plasma, 2 peripheral distribution compartments, and 1 compartment for the nondistributive transit of drug from arterial to venous plasma, described the PK of AZD3043. Systemic clearance was high (2.2 L/min; 95% confidence interval, 2.12-2.25), and apparent volumes of distribution were low, leading to a short elimination half-life. The apparent volumes of distribution of the arterial and peripheral compartments increased with increasing administered dose, giving a total apparent volume of distribution of 15 L after the lowest dose and 37 L after the greatest dose. A sigmoid maximum effect (Emax) model with an EC50 of 15.6 µg/mL and a γ of 1.7 described the relationship between AZD3043 effect-site concentrations and BIS. The between-subject variability in EC50 was 37%. An effect compartment model, with a half-life of the equilibration rate constant ke0 of 1.1 min, described the delay in effect in relation to the arterial plasma concentrations. CONCLUSIONS: AZD3043 had a high clearance and a low apparent volume of distribution, leading to a short half-life. However, the apparent volume of distribution was dose dependent (P < 0.001), leading to an increased half-life with increasing dose. The distribution to the effect site was fast and together with the short plasma half-life led to a fast onset and offset of effects.

A Bolus and Bolus Followed by Infusion Study of AZD3043, an Investigational Intravenous Drug for Sedation and Anesthesia: Safety and Pharmacodynamics in Healthy Male and Female Volunteers.

BACKGROUND: AZD3043 (THRX-918661) is an investigational phenylpropanoid sedative/anesthetic that is rapidly metabolized by esterases in blood and liver. In the first-in-man study, a 30-minute constant IV infusion of AZD3043 induced anesthesia without major safety or tolerability concerns and with rapid recovery characteristics. METHODS: The primary objective of this phase 1, single-center, open-label study (clinicaltrials.gov NCT00984880) was to evaluate the safety and tolerability of AZD3043 administered as a single IV bolus and as a bolus followed by infusion. Secondary objectives included evaluation of AZD3043 pharmacodynamics and efficacy. Sequential ascending dose cohorts of 8 healthy volunteers aged 18 to 65 years received either a single 1-minute bolus IV infusion (part A) or a 1-minute bolus followed by a 30-minute infusion (part B). Assessments included adverse events, vital signs, blood gases, laboratory values, clinical signs of sedation/anesthesia, and bispectral index score. RESULTS: Seventy-two subjects (8 females, 64 males) received AZD3043 doses of 1, 1.5, 2, 4, and 6 mg/kg bolus over 1 minute (part A) or 0.8 + 10, 1 + 15, 3 + 30, and 4 + 40 mg/kg bolus + mg/kg/h infusion for 30 minutes (part B). There were no discontinuations. Adverse events occurring in >1 subject were headache (n = 15; 21%), nausea (n = 7; 10%), vomiting (n = 3; 4%), and fatigue (n = 2; 3%). Twenty-one subjects experienced at least 1 adverse event. There seemed to be no dose relationship associated with any adverse event. Ventilation was maintained, but there was a dose-dependent increase in heart rate. There were no spontaneous reports of pain on injection. Thirty-two subjects were anesthetized, including all subjects in the highest dose group in part A and all subjects in the 2 highest dose groups in part B. Recovery from anesthesia was rapid, with swift return of orientation and proprioception. All subjects were able to walk 10 m without support at their first assessment, 30 minutes after end of dosing, except for 1 subject in each of the 2 mg/kg bolus (part A) and 4 mg/kg bolus + 40 mg/kg/h 30-minute infusion (part B) dose groups, who passed this test at the subsequent assessment, 45 minutes after the end of dosing. Involuntary movements were observed at higher doses, accompanied by increased muscle tone. CONCLUSIONS: AZD3043 provided rapid recovery from anesthesia with maintained ventilation. Further studies are warranted in a clinical setting.

First Human Study of the Investigational Sedative and Anesthetic Drug AZD3043: A Dose-Escalation Trial to Assess the Safety, Pharmacokinetics, and Efficacy of a 30-Minute Infusion in Healthy Male Volunteers.

BACKGROUND: AZD3043 is a positive allosteric modulator of the γ-aminobutyric acid type A receptor that is rapidly metabolized to an inactive metabolite by esterases present in blood and liver. Preclinical results suggest that AZD3043 has the potential as a short-acting IV sedative/anesthetic drug with rapid and predictable recovery characteristics and a favorable safety and tolerability profile. METHODS: Our primary objective in this phase 1, single-center, open-label study was to evaluate the safety and tolerability of AZD3043 after IV infusion and to estimate the maximal tolerated dose. Secondary objectives included the evaluation of AZD3043 pharmacokinetics, pharmacodynamics, and efficacy. Sequential ascending-dose cohorts of 5 or 6 healthy male volunteers aged 18 to 45 years received a single 30-minute IV infusion of AZD3043. Assessments included adverse events, vital signs, blood gases, laboratory values, clinical signs of sedation/anesthesia, and bispectral index. RESULTS: Fifty-three subjects received AZD3043 in infusion rate cohorts of 1, 3, 6, 12, 18, 27, 36, 54, and 81 mg/kg/h. There were no discontinuations, and dose escalation was stopped on reaching the predefined exposure limit. Adverse events occurring in >1 subject were headache (n = 4), erythema (n = 3), chest discomfort (n = 2), nausea (n = 2), and dyspnea (n = 2). The frequency and character of adverse events appeared unrelated to dose. There were no spontaneous reports of pain on injection and no clinically relevant changes in respiratory rate or arterial blood pressure. However, heart rate increased dose-dependently at infusion rates >18 mg/kg/h. Occurrence of sedation/anesthesia corresponded with dose; the lowest applied infusion rate to induce anesthesia according to clinical signs of sedation/anesthesia at predefined time points was 12 mg/kg/h (1 of 6 subjects anesthetized), and all subjects in the 3 highest dose groups were anesthetized. The onset of anesthesia ranged from 4 minutes in the highest infusion rate group to 29 minutes in the 12-mg/kg/h infusion rate group. Return of response to oral command occurred at 3 minutes after the end of infusion in the single subject who was anesthetized in the 12-mg/kg/h group and median 25 minutes in the 81-mg/kg/h group. Involuntary movements ranging from minor twitches to extensive movements were accompanied by increased muscle tone. CONCLUSIONS: AZD3043 was well tolerated in this first human study and seems to exhibit rapid onset and recovery, indicating potential use as a short-acting drug for anesthesia and sedation.

Modelling of pain intensity and informative dropout in a dental pain model after naproxcinod, naproxen and placebo administration.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: • Modelling has been used to describe the pain relief and dropout for a few non-steroidal anti-inflammatory drugs. WHAT THIS STUDY ADDS: • This study shows the relationship between dose, plasma concentration, pain intensity and dropout for naproxen and naproxcinod. It also extends previous models by using a visual analogue scale for pain intensity instead of modelling pain relief on a categorical scale, and shows the value of including informative dropout in the simulations for visual predictive checks. AIMS: To describe pain intensity (PI) measured on a visual analogue scale (VAS) and dropout due to request for rescue medication after administration of naproxcinod, naproxen or placebo in 242 patients after wisdom tooth removal. METHODS Non-linear mixed effects modelling was used to describe the plasma concentrations of naproxen, either formed from naproxcinod or from naproxen itself, and their relationship to PI and dropout. Goodness of fit was assessed by simultaneous simulations of PI and dropout. RESULTS: Baseline PI for the typical patient was 52.7 mm. The PI was influenced by placebo effects, using an exponential model, and by naproxen concentrations using a sigmoid E(max) model. Typical maximal placebo effect was a decrease in PI by 20.2%, with an onset rate constant of 0.237 h(-1). EC(50) was 0.135 µmol l(-1). A Weibull time-to-event model was used for the dropout, where the hazard was dependent on the predicted PI and by the PI at baseline. Since the dropout was not at random, it was necessary to include the simulated dropout in visual predictive checks (VPC) of PI. CONCLUSIONS: This model describes the relationship between drug effects, PI and the likelihood of dropout after naproxcinod, naproxen and placebo administration. The model provides an opportunity to describe the effects of other doses or formulations, after dental extraction. VPC created by simultaneous simulations of PI and dropout provides a good way of assessing the goodness of fit when there is informative dropout.

A two-compartment effect site model describes the bispectral index after different rates of propofol infusion.

Different estimates of the rate constant for the effect site distribution (k(e0)) of propofol, depending on the rate and duration of administration, have been reported. This analysis aimed at finding a more general pharmacodynamic model that could be used when the rate of administration is changed during the treatment. In a cross-over study, 21 healthy volunteers were randomised to receive a 1 min infusion of 2 mg/kg of propofol at one occasion, and a 1 min infusion of 2 mg/kg of propofol immediately followed by a 29 min infusion of 12 mg kg(-1) h(-1) of propofol at another occasion. Arterial plasma concentrations of propofol were collected up to 4 h after dosing, and BIS was collected before start of infusion and until the subjects were fully awake. The population pharmacokinetic-pharmacodynamic analysis was performed using NONMEM VI. A four-compartment PK model with time-dependent elimination and distribution described the arterial propofol concentrations, and was used as input to the pharmacodynamic model. A standard effect compartment model could not accurately describe the delay in the effects of propofol for both regimens, whereas a two-compartment effect site model significantly improved the predictions. The two-compartment effect site model included a central and a peripheral effect site compartment, possibly representing a distribution within the brain, where the decrease in BIS was linked to the central effect site compartment concentrations through a sigmoidal E(max) model.

Clinical pharmacokinetics of the cyclooxygenase inhibiting nitric oxide donator (CINOD) AZD3582.

The clinical pharmacokinetics of the COX-inhibiting nitric oxide donator (CINOD) AZD3582 and its metabolites, including naproxen, nitric oxide and nitrate, are summarized. AZD3582 has low aqueous solubility, moderate and passive intestinal permeability and is degraded by intestinal esterases. Its oral bioavailability (F) appears to be maximally a few per cent, and increases by several-fold after food intake. Ninety-four per cent or more of an AZD3582 dose is absorbed, of which at least 9-20% appears to be taken up as intact substance. AZD3582 has a predicted plasma protein binding degree of approximately 0.1%, a half-life (t1/2) of 3 to 10 h and does not accumulate after repeated once- and twice-daily dosing. In patients AZD3582 does not provide a significantly better gastrointestinal (GI) side-effect profile than the highly permeable and locally irritating naproxen. Possible reasons for this include considerable GI uptake as naproxen, limited duration and extent of nitric oxide donation in the GI mucosa and the circulation, tolerance development (involving auto-inhibition of nitric oxide catalysing enzymes) and mucosal damage caused by nitric oxide. Blood pressure data suggest that nitric oxide is mainly donated within 3 h. The uptake of naproxen is slightly slower and lower (> or = 94% relative GI uptake and 80-85% relative F) after AZD3582 administration compared with naproxen dosing. The naproxen t1/2 and trough steady-state concentrations after AZD3582 and naproxen dosing are similar. The average systemic nitrate exposure is approximately doubled after dosing of 375 to 750 mg AZD3582 twice daily.

Performance of nonlinear mixed effects models in the presence of informative dropout.

Informative dropout can lead to bias in statistical analyses if not handled appropriately. The objective of this simulation study was to investigate the performance of nonlinear mixed effects models with regard to bias and precision, with and without handling informative dropout. An efficacy variable and dropout depending on that efficacy variable were simulated and model parameters were reestimated, with or without including a dropout model. The Laplace and FOCE-I estimation methods in NONMEM 7, and the stochastic simulations and estimations (SSE) functionality in PsN, were used in the analysis. For the base scenario, bias was low, less than 5% for all fixed effects parameters, when a dropout model was used in the estimations. When a dropout model was not included, bias increased up to 8% for the Laplace method and up to 21% if the FOCE-I estimation method was applied. The bias increased with decreasing number of observations per subject, increasing placebo effect and increasing dropout rate, but was relatively unaffected by the number of subjects in the study. This study illustrates that ignoring informative dropout can lead to biased parameters in nonlinear mixed effects modeling, but even in cases with few observations or high dropout rate, the bias is relatively low and only translates into small effects on predictions of the underlying effect variable. A dropout model is, however, crucial in the presence of informative dropout in order to make realistic simulations of trial outcomes.

In vitro-in vivo correlation in man of a topically applied local anesthetic agent using numerical convolution and deconvolution.

The aim of this study was to evaluate the relevance of the in vitro permeation method used at our laboratory in predicting in vivo dermal and transdermal absorption. Two different emulsions, a submicron oil-in-water (o/w) emulsion and a semisolid water-in-oil (w/o) emulsion, containing a model compound were investigated. The in vitro permeation rate of the compound from these emulsions was measured using static diffusion cells with human skin as membrane. The emulsions were allowed to remain in contact with the skin in the donor chamber for 15, 60, and 240 min. The study was monitored for 240 min and the steady state flux was calculated. The systemic concentration of the compound was measured in vivo as a function of time after dermal application to healthy volunteers with 15 and 60 min of application. A short-lasting i.v. infusion study in healthy volunteers was used to simulate the i.v. bolus dose. Numerical convolution was used to predict the in vivo plasma concentration of the compound while the in vivo absorption rate of the compound was estimated using numerical deconvolution. To establish correlation, the predicted in vivo flux was compared with the corresponding observed in vitro parameter after adjusting for the lag time. No major differences were seen in the systemic plasma levels between the two emulsions, which is in close agreement with the steady state flux measured in vitro. A linear correlation representing a point-to-point relationship was established for each of the investigated formulations and application times. The longer application time was predicted more accurately for both emulsions.