Roberto Gomeni

Circadian rhythm of 5-fluorouracil population pharmacokinetics in patients with metastatic colorectal cancer.

Purpose: The purpose of this work was to estimate the population pharmacokinetic parameters of 5-fluorouracil (5-FU) in patients with advanced colorectal cancer using circadian change kinetics. Methods: Eighty-five patients (32 females, 53 males) were enrolled onto this study. All patients received folinic acid (200 mg/m2) by intravenous infusion over 2 h followed by a 5-FU loading dose (400 mg/m2) and then continuous infusion (600 mg/m2) for 22 h. This whole regimen was repeated on day 2 and was given on a 14-day cycle. Plasma 5-FU determinations were performed by high-performance liquid chromatography with ultraviolet absorbance detection. Pharmacokinetic analyses were performed using the NONMEM computer program through the Visual-NM graphical interface. An open one-compartment pharmacokinetic model with zero-order input rate was used to describe the kinetics of 5-FU; moreover, circadian time-dependent changes in 5-FU concentrations were taken into account in the model. The circadian model was defined as the sum of two cyclic components; the amplitude of the first cyclic component (over 24 h) was about 30% of the average clearance and the amplitude of the second cyclic component (over 12 h) was about 50% of the amplitude of the first component. The acrophase (peak) times of the first and the second periodic component were 04 h 12 m and 00 h 25 m, respectively. The potential sources of variability on the population parameters (65 patients) were investigated using patients sex, body area, age, body weight, height, liver enzymes and serum creatinine as covariables. Results: Only the estimated clearance circadian changes were different for the two sexes. The population parameter estimates of mean clearance (CLmean) and initial volume of distribution (V), were as follows: the male subgroup showed a CLmean value twice larger (125 l/h) than the value observed in the female subgroup (65 l/h), and V = 21 l. A validation group of 20 additional patients was used to evaluate the predictive performances of the population parameters. The individual pharmacokinetic parameters were computed by means of a Bayesian fitting procedure. From the resulting individualized parameter values, concentrations of 5-FU in the plasma were calculated. To evaluate the performance of the Bayesian estimation, the experimental concentrations were compared with the predicted ones. Conclusion: In conclusion, a chronomodulated delivery schedule of 5-FU should be performed, using a perfusion rate inversely proportional to the circadian variations of clearance in order to maintain stable 5-FU plasma levels. Such a treatment schedule may result in increased effectiveness of the treatment and decreased occurrence of drug-associated side-effects. The present study develops a complete procedure to efficiently estimate 5-FU clearance in order to optimize dosage regimens in individual patients.

Sensitivity of the individual items of the Hamilton depression rating scale to response and its consequences for the assessment of efficacy

The Hamilton depression rating scale (HAM-D(17)) has been the gold standard in depression trials since its introduction in 1960 by Max Hamilton. However, several authors have shown that the HAM-D(17) is multi-dimensional and that subscales of the HAM-D(17) outperform the total scale. In the current study, we assess the sensitivity of the individual HAM-D(17) items in differentiating responders from non-responders over the typical treatment period used in clinical efficacy trials. Based on data from randomised, placebo-controlled trials with paroxetine, a graphical analysis and a statistical analysis were performed to identify the items that are most sensitive to the rate and extent of response irrespective of treatment. From these analyses, two subscales consisting of seven items each were derived and compared to the Bech and Maier and Philip subscales using a linear mixed-effects modelling approach for repeated measures. The evaluation of two clinical trials revealed endpoint sensitivity comparable to the existing subscales. Using a bootstrap technique, we show that the subscales consistently yield higher statistical power compared to the HAM-D(17), although no subscale consistently outperforms the others. In conclusion, this study provides further evidence that not all items of the HAM-D(17) scale are equally sensitive to detect responding patients in a clinical trial. A HAM-D(7) subscale with higher sensitivity to drug effect is proposed consisting of the HAM-D(6) and the suicide item. This response-based subscale increases signal-to-noise ratio and could reduce failure rate in efficacy trials with antidepressant drugs.

A New Population‐Enrichment Strategy to Improve Efficiency of Placebo‐Controlled Clinical Trials of Antidepressant Drugs

The rate‐limiting factor in the discovery of novel antidepressants is the inefficient methodology of traditional multicenter randomized clinical trials (RCTs). We applied a model‐based approach to a large clinical database (five RCTs in major depressive disorder (MDD), involving 1,837 patients from 124 recruitment centers) with two objectives: (i) to learn about the role of center‐specific placebo response in RCT failure and (ii) to apply what is learned to improve the efficiency of RCTs by enhancing the detection of treatment effect (TE). Sensitivity analysis indicated that center‐specific placebo response was the most relevant predictor of RCT failure. To reduce the statistical “noise” generated by centers with nonplausible, excessively high/low placebo responses, we developed an enrichment‐window strategy. Clinical trial simulation was used to assess the enrichment strategy applied before the standard statistical analysis, resulting in an overall reduction in failure of RCTs from _50 to _10%.

Steady-state pharmacokinetics of ciprofloxacin in plasma from patients with nosocomial pneumonia: penetration of the bronchial mucosa.

A 30-min intravenous (i.v.) infusion of 200 mg of ciprofloxacin was administered twice daily to 12 patients with nosocomial pneumonia scheduled to undergo diagnostic fiberoptic bronchoscopy. The pharmacokinetics of ciprofloxacin were examined at the presumed steady state after 5 days of treatment. Eleven successive plasma samples were collected in the interval from 0 to 12 h after administration, and bronchial mucosa samples were taken 2 h after administration. Concentrations of drug in all samples were assayed by high-performance liquid chromatography with fluorimetric detection. The results showed that the kinetics in plasma did not differ from those determined previously in healthy volunteers. The mean concentrations in plasma peaked at 4.94 +/- 2.90 mg/liter at the end of infusion. The terminal half-life was 4.95 +/- 2.81 h, and the mean residence time 6.13 +/- 3.17 h. A large volume of distribution was calculated: 2.59 +/- 1.43 liters/kg. Mean total body clearance was 23.3 +/- 10.1 liters/h. The concentrations in bronchial mucosa reached 21.6 +/- 5.63 micrograms/g 2 h after drug intake. The tissue-versus-plasma concentration ratios ranged from 10.1 to 26.3 (mean value, 16.9 +/- 5.43). After 6 to 12 days of i.v. treatment, four patients were switched to oral ciprofloxacin. We propose a model for the simultaneous fit of the concentration-time curves obtained after i.v. infusion and oral dosing. The concentrations in tissue observed in this study were in excess of the MICs for bacteria considered to be susceptible to ciprofloxacin.

Multiple Dose Pharmacokinetics of Paroxetine in Children and Adolescents with Major Depressive Disorder or Obsessive–Compulsive Disorder

The current study examined the pharmacokinetics (PK), safety, and tolerability of paroxetine after repeated multiple oral dosing in children and adolescents with major depressive or obsessive–compulsive disorder. In this 6-week, open-label, repeat dose, dose-rising study, 62 patients (27 children and 35 adolescents) were treated with paroxetine 10 mg/day for the first 2 weeks of the study, 20 mg/day for the next 2 weeks, and 30 mg/day for the final 2 weeks. Pharmacokinetic sampling and safety assessments occurred at baseline and subsequently on the final treatment day of each dosing level. Between-patient variability in PK was pronounced at the 10 mg dose level, but markedly reduced at higher doses. A supra-proportional increase in plasma concentrations with increasing dose was evident in both age groups. Data for Cmax and AUC(0−24) indicated that, at each dose level, paroxetine steady-state systemic exposure was higher in children than in adolescents. The differences between age groups, however, diminished with each increasing dose, and were virtually abolished when differences in weight among different age groups were considered. Stepwise regression analysis indicated that both oral clearance and volume of distribution were highly dependent on paroxetine dose, cytochrome P4502D6 genotype, and weight (p<0.0001), but not age or sex. Paroxetine was generally safe and well tolerated in both age groups, with the most frequently observed adverse events being largely consistent with those observed in prior paroxetine studies of adult psychiatric patients. Certain gastrointestinal and behavioral activation events (aggressive reaction and nervousness) were reported more frequently in the youngest age group.

Population Pharmacodynamics for Monitoring Epoetin in Athletes

SummaryEpoetin (recombinant human erythropoietin) is used by some endurance athletes to increase oxygen transport and aerobic power in an attempt to improve endurance capacity and recovery during training and competition. Although currently on the list of banned substances issued by the medical commission of the International Olympic Committee, the use of epoetin as an ergogenic agent remains uncontrollable using classical analytical techniques. In the present paper, after subcutaneous administration of repeated high doses (200 units/kg), the pharmacokinetics of epoetin were evaluated in 18 athletes. The mean elimination half-life was 42.0 hours. The total clearance/bioavailability (F) and the volume of distribution/F averaged 0.05 L/h/kg and 2.95 L/kg, respectively. Significant changes in ferritin (fr), soluble transferrin receptor (sTfR) and ratio (sTfR/fr) were observed after administration. A population sigmoidal asymptotic maximum expected effect concentration (emax) model has been developed to assess and quantify the relationship between the changes in sTfR, fr and the ratio sTfR/fr secondary to the repeated administration of epoetin. The mean population parameters were as follows: emax: 12.6 mg/L, 44.9 µtg/Land 2313.5; the concentration producing 50% of the emax(C50): 18.3,18.1 and 37.7 IU/L; the sigmoidicity factor (gamma): 2.96, 4.17 and 5.15; and ke0 (rate constant of transfer between central and effect compartment): 1.29 × 10−3, 7.14 × 10−3 and 3.47 × 10−3/h for the 3 markers, respectively. Moreover, in this paper, we propose an appropriate statistical methodology based on the measurement of sTfR, fr and sTfR/fr from blood samples to decide if the observed values of these markers could be related, at a given probability risk, to the administration of epoetin. Values greater than 10 mg/L for sTfR and 403 for sTfR/fr indicate a probable intake of epoetin. Because of the large interindividual variability of fr, it has not been possible to define a threshold value for this parameter. The sTfR seems to be the most effective marker in doping control. An increased haematocrit with concomitant changes in sTfR and sTfR/fr values seems to supply a valuable diagnostic tool that avoids false-positive doping and allows the identification of epoetin abusers. Blood samples could be collected using capillary blood from the fingertip or earflap. These controls could be carried out during training because they are easy to perform and do not add substantially to total screening costs. At present, this is the only tool available for detecting epoetin abusers during competition.

Full central neurokinin-1 receptor blockade is required for efficacy in depression: evidence from orvepitant clinical studies

Full, persistent blockade of central neurokinin-1 (NK1) receptors may be a potential antidepressant mechanism. The selective NK1 antagonist orvepitant (GW823296) was used to test this hypothesis. A preliminary positron emission tomography study in eight male volunteers drove dose selection for two randomized six week studies in patients with major depressive disorder (MDD). Displacement of central [11C]GR205171 binding indicated that oral orvepitant doses of 30–60 mg/day provided >99% receptor occupancy for ≥24 h. Studies 733 and 833 randomized patients with MDD and 17-item Hamilton Depression Rating Scale (HAM-D)≥22 to double-blind treatment with orvepitant 30 mg/day, orvepitant 60 mg/day or placebo (1:1:1). Primary outcome measure was change from baseline in 17-item HAM-D total score at Week 6 analyzed using mixed models repeated measures. Study 733 (n=328) demonstrated efficacy on the primary endpoint (estimated drug-placebo differences of 30 mg: −2.41, 95% confidence interval (CI) (−4.50 to −0.31) p=0.0245; 60 mg: –2.86, 95% CI (−4.97 to −0.75) p=0.0082). Study 833 (n=345) did not show significance (estimated drug-placebo differences of 30 mg: −1.67, 95% CI (−3.73 to 0.39) p=0.1122; 60 mg: −0.76, 95% CI (−2.85 to 1.32) p=0.4713). The results support the hypothesis that full, long lasting blockade of central NK1 receptors may be an efficacious mechanism for the treatment of MDD.

Adaptive-Optimal Design in PET Occupancy Studies

Positron emission tomography (PET) is an imaging technique that is used to investigate ligand–receptor binding in the living brain and to determine the time course of plasma concentration/receptor occupancy (RO). The purpose of this work was to demonstrate the added value of an adaptive‐optimal design for PET scan timings and dose selection over traditional study designs involving fixed or educated selections of timings and doses. A kon–koff model relating plasma concentration to PET data was applied to generate the simulated data. Optimization was performed on scanning timings and doses using the D‐optimality criterion. Optimal designs as applied to scanning timings provided unbiased estimates and improved the accuracy of results relative to those of fixed and educated designs. Optimization of both timings and dose provided improvements in accuracy and precision when the initial dose selection was noninformative regarding the time course of RO. These results indicate that adaptive‐optimal designs can provide an efficient experimental design for RO studies using PET, by minimizing the number of subjects required and maximizing information related to the plasma concentration–RO relationship.

Pharmacokinetics and time-course of D2 receptor occupancy induced by atypical antipsychotics in stabilized schizophrenic patients

The 123I-IBZM SPECT measured D2 receptor occupancy (D2RO) in chronically dosed, stabilized schizophrenic patients and its relationship with antipsychotic (AP) pharmacokinetics (PK) over time is still unclear. The aims of this study were: 1) To define the relationship between striatal D2 receptor occupancy (D 2RO) and plasma concentration (C P) in stabilized schizophrenic patients on clinically relevant doses using 123I-IBZM SPECT; 2) To investigate the time course of AP-induced D2RO and corresponding C P. Forty-six schizophrenic patients on their clinically required doses of risperidone, olanzapine, clozapine or quetiapine were included. D 2RO and C P were measured over time following a sparse-sampling experimental design, and individual PK and D2RO-time profiles were estimated using a population approach. Observed striatal D2RO and C P ranges were 28—75% and 9.4—60.5 ng/mL for risperidone, 22—84% and 8.6—89.5 ng/mL for olanzapine, 5—53% and 41.6—818.2 ng/mL for clozapine and 0—64% and 37.9—719.6 ng/mL for quetiapine. A PK—D2RO relationship was found for the four APs. D2RO pattern over time was stable for risperidone, olanzapine and clozapine but fluctuating for quetiapine. Stabilized schizophrenic patients show a wide range of both D2RO and C P at clinically effective doses of the four AP, suggesting that clinical response to these AP may be maintained with D2RO below 65%. D2RO patterns over time differ between AP. These results should be considered for accurate interpretation of D2RO measurements, proper design of studies and optimization of drug regimens for patients on AP treatment.

Amyotrophic lateral sclerosis disease progression model

Abstract Our objective was to develop: 1) a longitudinal model to describe amyotrophic lateral sclerosis (ALS) disease progression using the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R); and 2) a probabilistic model to estimate the presence of clusters of trajectories in ALS progression over 12 months of treatment. Three hundred and thirty-eight patients treated with placebo from the PRO-ACT database were included in the analyses. A non-linear Weibull model best described the ALS disease progression, and a stepwise logistic regression approach was used to select the variables predicting a slow or fast disease progression. Results identified two clusters of trajectories: 1) slow disease progressors (46% of patients with a change from baseline of 13%); 2) fast disease progressors (54% of patients with a change from baseline of 49%). ROC curve analysis estimated the optimal cut-off for classifying patients as slow or fast disease progressors given ALSFRS-R measurements at 2–4 weeks. Results showed that the degree of ALS disease progression quantified by the ALSFRS-R symptomatic change on placebo is highly heterogeneous. In conclusion, this finding indicates the potential interest of disease progression models for implementing a population enrichment strategy to control the level of heterogeneity in the patients included in new trials.