Alan Bye

Absolute quantification of cerebral blood flow with magnetic resonance, reproducibility of the method, and comparison with H215O positron emission tomography

While H215O positron emission tomography (PET) is still the gold standard in the quantitative assessment of cerebral perfusion (rCBF), its technical challenge, limited availability, and radiation exposure are disadvantages of the method. Recent work demonstrated the feasibility of magnetic resonance (MR) for quantitative cerebral perfusion imaging. There remain open questions, however, especially regarding reproducibility. The main purpose of this study was to assess the accuracy and reproducibility of MR-derived flow values to those derived from H215O PET. Positron emission tomography and MR perfusion imaging was performed in 20 healthy male volunteers, who were chronic smokers, on day 1 and day 3 of a 4-day hospitalization. Subjects were randomly assigned to one of two groups, each with 10 subjects. One group was allowed to smoke as usual during the hospitalization, while the other group stopped smoking from day 2. Positron emission tomography and MR images were coregistered and rCBF was determined in two regions of interest, defined over gray matter (gm) and white matter (wm), yielding rCBFPETgm, rCBFMRgm, rCBFPETwm, and rCBFMRwm. Bland-Altman analysis was used to investigate reproducibility by assessing the difference rCBFday3 - rCBFday1 in eight continual-smoker volunteers. The analysis showed a good reproducibility for PET, but not for MR. Mean ± SD of the difference rCBFday3 - rCBFday1 in gray matter was 6.35 ± 21.06 and 0.49 ± 5.27 mL · min−1 · 100 g−1 for MR and PET, respectively; the corresponding values in white matter were 2.60 ± 15.64 and −1.14 ± 4.16 mL · min−1 · 100 g−1. The Bland-Altman analysis was also used to assess MRI and PET agreement comparing rCBF measured on day 1. The analysis demonstrated a reasonably good agreement of MR and PET in white matter (rCBFPETwm - rCBFMRwm; −0.09 ± 7.23 mL · min−1 · 100 g−1), while in gray matter a reasonable agreement was only achieved after removing vascular artifacts in the MR perfusion maps (rCBFPETgm - rCBFMRgm; −11.73 ± 14.52 mL · min−1 · 100 g−1). In line with prior work, these results demonstrate that reproducibility was overall considerably better for PET than for MR. Until reproducibility is improved and vascular artifacts are efficiently removed, MR is not suitable for reliable quantitative perfusion measurements.

Dynamic Modeling of Cortisol Reduction after Inhaled Administration of Fluticasone Propionate

Fluticasone propionate (FP) is a new corticosteroid that has been developed for the treatment of asthma. The compound has a very high receptor affinity, 18 times that of dexamethasone. After inhalation, FP is systemically available because of inhaled bioavailability. In healthy subjects this may lead to measurable systemic effects, such as cortisol reduction. A clinical study was conducted in 12 healthy volunteers to determine the systemic effects after inhaled administration of single 500‐μg, 1,000‐μg, and 2,000‐μg doses of FP. Blood samples were collected over a 24‐hour period after administration. Concentrations of FP and cortisol were measured in plasma by immunoassay. Cortisol reduction was chosen as the pharmacodynamic parameter. A novel linear release rate model was used to parameterize the cortisol data. The pharmacokinetics of FP were linear over the dose range studied. The cortisol release parameters were determined from baseline data (before drug administration). Based on these results, the E50 values for cortisol reduction were then determined for each dose of FP. The average E50 was 0.134 ng/mL for total FP concentrations and 0.013 ng/mL for unbound FP concentrations; these results were not dose dependent. These in vivo pharmacodynamic values measured in healthy subjects are in good agreement with the relatively high receptor affinity of FP.

Mathematical modeling of cortisol circadian rhythm and cortisol suppression

Abstract One of the major systemic side effects of topically administered corticosteroids is the suppression of endogenous cortisol production by a negative feedback mechanism. Due to the marked circadian rhythm in cortisol release, the precise quantification of this cortisol suppression is quite complex. It was the purpose of these studies to look for novel approaches to describe the circadian variation of cortisol secretion and develop a consistent PK/PD model to evaluate the effect of administered exogenous corticosteroids. A proposed linear release model allows characterization of the cortisol baseline and cortisol suppresion in a better way than other approaches proposed in the literature. The model assumes a linear decrease in cortisol production during the day from approximately 4–5 a.m. to about midnight followed by a shorter linear increase of secretion rate from midnight to approximately 4–5 a.m. on the following day. Furthermore, the model takes into account the elimination of cortisol. Comparison of experimentally measured cortisol levels over 72 h with the respective model predictions showed good agreement. The model was also able to account for the suppressive effect of triamcinolone acetonide after intravenous, oral and pulmonary administration.

Results from 2 randomized, double-blind, placebo-controlled studies of the novel NK1 receptor antagonist casopitant in patients with major depressive disorder.

Clinical study results for neurokinin (NK) receptor antagonists in the treatment of depression have been mixed, with Phase III studies failing to fulfill the early promise demonstrated in Phase II studies. Casopitant, a selective NK1 antagonist that achieves nearly complete receptor occupancy was studied in 2 randomized, placebo-controlled, double-blind, Phase II trials in depressed outpatients to test the hypothesis that nearly complete NK1 receptor occupancy is required to achieve antidepressant efficacy. Study 092 used an interactive voice response system to recruit depressed patients with baseline Hamilton Depression (17-item, HAMD17) total scores higher than 24 who were randomized to fixed-dose casopitant 30 mg/d, 80 mg/d, or placebo for 8 weeks (n = 356). Study 096 required Carroll Depression Scale-Revised self-assessment scores of higher than 24 for randomization to casopitant 120 mg/d, paroxetine 30 mg/d (both reached via forced titration), or placebo for 8 weeks (n = 362). In study 092, casopitant 80 mg but not 30 mg achieved statistically significant improvement versus placebo on the primary outcome measure, week 8 last observation carried forward change from baseline HAMD17 (difference = −2.7; 95% confidence interval, −5.1 to −0.4, P = 0.023). In study 096, neither casopitant nor paroxetine achieved statistical separation from placebo at end point on HAMD17 (casopitant difference = −1.7; 95% CI, −3.8 to 0.4, P = 0.282). Casopitant and paroxetine were generally well tolerated in most patients. These studies suggest that NK1 antagonists that have nearly complete receptor occupancy may be effective in the treatment of depression.

Bioavailability of Orally Administered Micronised Fluticasone Propionate

ObjectiveThe aim of this study was to determine the absolute oral bioavailability of fluticasone propionate (FP) in healthy volunteers.MethodsA 3-period incomplete block crossover design was used. On separate occasions, 21 male volunteers received a single 250μg intravenous dose of FP (n = 21) and twice daily oral doses of either micronised FP 0.1mg (n = 9), 1mg (n = 12), 10mg (n = 11) or placebo (n = 9) for 4 days.ResultsFP was not measurable in the plasma after twice daily oral administration of a 0. 1mg dose. FP concentrations just above the limit of quantification could be measured in only 5 volunteers, and only at some time points, after administration of FP 1mg twice daily. At a dose of 10mg twice daily the absolute oral bioavailability of the drug was <1% when a liquid chromatography-mass spectrometry assay was used to assess plasma concentrations. Only oral doses of FP 10mg twice daily, 10 times greater than the recommended maximum inhaled dose, produced any detectable change in urinary cortisol excretion.ConclusionThe results of this study confirm that oral absorption of FP into the systemic circulation is negligible. The swallowed portion of an inhaled dose of FP is unlikely to increase the systemic exposure to the drug, thus decreasing the likelihood of adverse systemic effects.

Pharmacokinetics of Fluticasone Propionate Inhaled via the Diskhaler® and Diskus® Powder Devices in Healthy Volunteers

ObjectiveThe aim of these studies was to determine the absolute bioavailability in healthy volunteers of inhaled fluticasone propionate (FP) administered as a single dose via the Diskhaler® and Diskus® powder devices, and the pharmacokinetics of inhaled FP after repeated administration via the Diskhaler® device.MethodsIn 2 of the studies, single inhaled doses of FP were administered via the Diskhaler® and the Diskus® powder devices, and, in the third study, repeated doses of FP were administered via the Diskhaler®. In the single dose studies, 12 healthy volunteers were randomised to receive FP 1000μg by inhalation and FP 250μg intravenously, using a double-blind crossover design. In the repeated dose study, 24 healthy volunteers received FP 1000μg twice daily for 7.5 days.ResultsSystemic exposure to FP after administration of a single 1000μg inhaled dose of FP via the 2 powder devices was similar; the area under the plasma FP concentration-time curve (AUC) to infinite time (AUC∞) was 2.08 μg/L · h [95% confidence intervals (CI): 1.63–2.64] for Diskhaler® and 2.49 μg/L · h (95% CI: 2.09–2.96) for Diskus®. Maximum plasma FP concentration (Cmax) was 0.34 μg/L for both devices. Mean bioavailability values via the Diskhaler® and Diskus® were 11.9% (95% CI: 9.0–15.7%) and 16.6% (95% CI: 13.6–20.3%), respectively. No clinically significant reductions in urinary cortisol excretion were recorded in these 2 studies.After repeated administration with the Diskhaler®, steady state was achieved by dose 3 (i.e. day 2) onwards. After dose 15, the AUC up to 12 hours (AUC12h) was 2.25 μg/L · h and Cmax was 0.38 μg/L. The mean steady-state to single dose accumulation ratio after twice-daily administration was 1.49 (95% CI: 1.36–1.62).ConclusionThe pharmacokinetics of FP administered by the 2 powder devices are similar in healthy volunteers, although systemic bioavailability was greater with the Diskus®.

Systemic exposure to fluticasone propionate administered via metered-dose inhaler containing chlorofluorocarbon or hydrofluoroalkane propellant

ObjectiveThe pharmacokinetic profile of a single dose of inhaled fluticasone propionate (FP) administered via a metered-dose inhaler (MDI), containing either a chlorofluorocarbon (CFC) or hydrofluoroalkane (HFA) propellant was investigated in healthy volunteers.MethodsTwo randomised, double-blind, crossover studies were conducted, each in 12 male volunteers. Both studies compared pharmacokinetic data after a single inhaled dose of FP 1000μg from a MDI containing either CFC (CFC MDI) or HFA (HFA MDI) with a single intravenous dose of FP 250μg.ResultsThe maximum plasma FP concentrations after inhalation via the 2 types of MDI were almost identical (0.56 and 0.54μg/L for CFC MDI and HFA MDI, respectively); bioavailability values of inhaled FP from the 2 MDIs were also similar (geometric mean values: 26.4% via the CFC MDI and 28.6% via the HFA MDI). Inhalation of FP via both MDI formulations produced similar reductions in urinary cortisol excretion over 12 and 24 hours postdose.ConclusionThe bioavailability values of FP after inhalation via a CFC MDI and an HFA MDI are similar. The 2 formulations deliver comparable amounts of FP, and systemic exposures to FP from the 2 devices, measured by urinary cortisol excretion, are not significantly different.

Absorption Kinetics after Inhalation of Fluticasone Propionate via the Diskhaler®, Diskus® and Metered-Dose Inhaler in Healthy Volunteers

ObjectiveThe aim of this analysis was to assess the rate and extent of systemic availability of inhaled fluticasone propionate (FP) from 2 dry powder systems (Diskhaler® and Diskus®) and a metered-dose inhaler (MDI) by deconvolution analysis.MethodsThe inhalation devices were evaluated in 3 separate studies with identical protocols. 12 healthy male volunteers were randomised to receive FP given as a 1000μg inhaled dose and 250μg by intravenous infusion according to a double-blind double-dummy crossover design. The bioavailability of FP after inhalation represents absorption of the drug from the lungs, since the bioavailability of the swallowed portion of the inhaled dose is negligible.ResultsWhen corrected for the bioavailability (of FP) achieved by each inhalation device, the rate of absorption of FP over the first 2 hours was rapid from all devices. The mean time for absorption of 50% of the bioavailable dose was 1.6, 2.4, and 2.2 hours for the Diskhaler®, Diskus® and MDI, respectively. Thereafter, absorption from each device was prolonged, with approximately 10% of the dose remaining in the lungs 12 hours after inhalation.ConclusionIrrespective of the inhalation device used, the prolonged absorption of FP into the systemic circulation indicates a long residence time in the lungs.

Estimate the time varying brain receptor occupancy in PET imaging experiments using non-linear fixed and mixed effect modeling approach

Positron-Emission Tomography (PET) is an imaging technology currently used in drug development as a non-invasive measure of drug distribution and interaction with biochemical target system. The level of receptor occupancy achieved by a compound can be estimated by comparing time-activity measurements in an experiment done using tracer alone with the activity measured when the tracer is given following administration of unlabelled compound. The effective use of this surrogate marker as an enabling tool for drug development requires the definition of a model linking the brain receptor occupancy with the fluctuation of plasma concentrations. However, the predictive performance of such a model is strongly related to the precision on the estimate of receptor occupancy evaluated in PET scans collected at different times following drug treatment. Several methods have been proposed for the analysis and the quantification of the ligand-receptor interactions investigated from PET data. The aim of the present study is to evaluate alternative parameter estimation strategies based on the use of non-linear mixed effect models allowing to account for intra and inter-subject variability on the time-activity and for covariates potentially explaining this variability. A comparison of the different modeling approaches is presented using real data. The results of this comparison indicates that the mixed effect approach with a primary model partitioning the variance in term of Inter-Individual Variability (IIV) and Inter-Occasion Variability (IOV) and a second stage model relating the changes on binding potential to the dose of unlabelled drug is definitely the preferred approach.

Computer-assisted drug development (CADD): an emerging technology for designing first-time-in-man and proof-of-concept studies from preclinical experiments.

Computer-assisted drug development (CADD) is an emerging technology for accelerating drug development based on the integration of mathematical modelling and simulation. This methodology provides a knowledge-based decisional tool on alternative development strategies based on the evaluation of potential risks on drug safety, and the definition of experimental design of new trials with expected power and probability of success. An example of CADD implementation is presented to design the first-time-in-man (FTIM) and the proof-of-concept (PoC) study of a new CNS compound. The final objective of the example presented is not necessarily to supply a success story of a correct prediction of human data from animal studies but to define a credible strategy suitable to design FTIM and PoC studies using preclinical data without the support of any human in vivo information. Rhesus monkey and human PK were initially estimated using allometric scaling on data collected in dogs, cynomolgus monkeys and rats. A PK/PD model was derived from a study conducted in rodent and validated by comparing the model predicted response to the one observed in a PET experiment conducted in rhesus monkey. The final PK/PD model, incorporating potential variability and uncertainty on scaled human prediction together with a receptor affinity adjustment derived from in vitro binding studies, was used to design the first-time-in-man and the proof-of-concept study.