Romain Sechaud

Effectiveness and safety of ICL670 in iron-loaded patients with thalassaemia: a randomised, double-blind, placebo-controlled, dose-escalation trial

BACKGROUND Transfusional iron overload is a potentially fatal complication of the treatment of thalassaemia. We aimed to investigate short-term efficacy, pharmacokinetic/pharma- codynamic (PK/PD) relations, and safety of ICL670, a novel, tridentate, orally active iron chelator. METHODS We enrolled 24 patients and divided them into three cohorts consisting of a minimum of seven individuals. Patients were admitted to a metabolic unit and consumed a diet with a defined content of iron. Two patients in each cohort were randomly allocated placebo. Five or more patients received one daily dose of ICL670 at 10, 20, or 40 mg x kg(-1) x day(-1), from day 1 to 12. Net iron excretion (NIE) was measured between days 1 and 12. Primary objectives included assessment of safety and tolerability (measured by adverse events and clinical laboratory monitoring), pharmacokinetics (measured as drug and drug-iron complex), and cumulative net iron excretion (measured by faecal and urine output minus food input). Analysis was for efficacy. FINDINGS ICL670 was absorbed promptly and was detectable in the blood for 24 h. Exposure (area under the curve of plasma concentration) to ICL670 at pharmacokinetic steady state was proportional to dose. All three doses resulted in positive NIE. The NIE achieved at 20mg x kg(-1) day(-1) would prevent net iron accumulation in most patients transfused with 12-15 mL packed red-blood-cells kg(-1) month(-1), equivalent to 0.3-0.5 mg iron kg(-1) x day(-1). A linear relation (PK/PD) was recorded between exposure to ICL670 and total iron excretion, by contrast with placebo (r2=0.54, p<0.0001). Skin rashes were noted in four patients treated at 20 and 40 mg x kg(-1) x day(-1), and one patient also developed grade 2 transaminitis. INTERPRETATION ICL670 given once daily at 20 mg/kg seems to be an effective orally active iron chelator and is reasonably well tolerated. Long-term studies are now necessary to establish the practical contribution of this drug.

Safety, Tolerability, and Pharmacokinetics of ICL670, a New Orally Active Iron-Chelating Agent in Patients with Transfusion-Dependent Iron Overload Due to β-Thalassemia

ICL670 is an orally active representative of a new class of tridentate iron chelator developed for the treatment of blood transfusion–dependent iron overload in chronic anemias. In this randomized, double‐blind study, patients with transfusion‐dependent β‐thalassemia received single oral doses of ICL670 ranging from 2.5 to 80 mg/kg to investigate its safety, tolerability, and pharmacokinetics and to obtain preliminary information on pharmacodynamic effects. ICL670 was well tolerated, and no safety problems occurred up to 80 mg/kg. A plasma half‐life of 11 to 19 hours was found for ICL670, supporting once‐daily oral administration. AUC0–24h and Cmax of ICL670 increased nearly proportionally with the dose. The urinary excretion of ICL670 and its iron complex was less than 0.1% of the dose, and this was in accordance with the expected predominant iron fecal excretion induced by ICL670 (based on preclinical experiments). Notwithstanding, a positive trend toward increased amounts of urinary excreted iron was observed when the AUC0–24 h of ICL670 and the iron complex exceeded specific threshold values at the 40‐ and 80‐mg/kg dose levels.

Randomized calcineurin inhibitor cross over study to measure the pharmacokinetics of co‐administered enteric‐coated mycophenolate sodium

Abstract:  Enteric‐coated mycophenolate sodium (EC‐MPS) (myfortic®) is an advanced formulation delivering mycophenolic acid (MPA), designed to improve MPA‐related upper gastrointestinal adverse events by delaying the release of MPA until the small intestine. A randomized, calcineurin inhibitor crossover, steady‐state pharmacokinetic study in stable renal transplant patients receiving EC‐MPS demonstrated increased MPA exposure of 19% higher, MPA Cmax,ss 19% lower and MPA Cmin,ss approximately twofold higher with tacrolimus, than cyclosporine microemulsion. No study drug‐related adverse events were recorded, but mean blood glucose concentration was higher in patients receiving tacrolimus (p = 0.031). The dose changes in relation to MPA exposure in patients is dependent on the clinical situation and may not always be warranted. These observations should be taken into consideration when switching from one calcineurin inhibitor to another, but the final dosage should be based on both this pharmacokinetic data and the clinical situation.

Sinistrin Clearance for Determination of Glomerular Filtration Rate: A Reappraisal of Various Approaches Using a New Analytical Method

Several approaches are available to estimate the glomerular filtration rate (GFR) from the sinistrin clearance. To compare such approaches, GFR was estimated in six healthy volunteers, both after a bolus injection and a bolus dose followed by a 6‐hour infusion. A recently developed high‐performance liquid chromatography method was used for the determination of sinistrin levels, enabling precise measurements in plasma and urine samples with high sensitivity. Blood and urine were sampled up to 6 hours. Four calculation methods for estimating GFR were applied: 1) classical ratio of urinary excretion rate over plasma concentration (UV/P); 2) two‐point (log‐linear regression slope times monocompartmental volume of distribution) after bolus; 3) ratio of dose over area under the curve (D/AUC) after bolus; and 4) ratio of infusion rate over steady‐state concentration during infusion (Rinf/P). The results obtained by fitting a pharmacokinetic model to all the plasma and urine data served as the standard against which the performance of the respective calculation methods were examined. The UV/P method performed poorly on bolus data, mainly by underestimating GFR at late times; on both bolus and infusion data, it suffered from important imprecisions on the urinary volume. The two‐point method appeared applicable only between 2 and 4 hours after the bolus dose. The D/AUC method with extrapolation to infinity was highly reliable when integrating the concentrations up to 3 hours or more after the bolus dose. The Rinf/P method was satisfactory if applied later than 2 to 3 hours after the loading dose. The advantages and drawbacks of each method have to be evaluated in relation to the particular clinical setting in which GFR is to be estimated.

Effect of Food, Type of Food, and Time of Food Intake on Deferasirox Bioavailability: Recommendations for an Optimal Deferasirox Administration Regimen

Deferasirox (ICL670) is representative of a new class of tridentate iron chelators, formulated as tablets for dispersion. Deferasirox has exhibited high potency and a clinically manageable safety profile in preclinical models and in an extensive clinical program. The effect of food and time of food intake on the pharmacokinetics of deferasirox was investigated in healthy volunteers and patients with transfusional hemosiderosis. The bioequivalence of a single oral dose of deferasirox (20 mg/kg) was assessed following administration either before a high‐fat or standard breakfast or concurrent with a standard breakfast in comparison with fasted conditions in healthy volunteers. The bioavailability of deferasirox was determined following a single oral dose (20 mg/kg) under fed and fasted conditions in patients. These data show that the type of food, caloric content, and fat content of the meal influence the bioavailability of deferasirox when consumed concomitantly. In contrast, this is not the case when deferasirox is administered at least 30 minutes before a meal. In conclusion, it is recommended that deferasirox be administered at least 30 minutes prior to meals. When this is not feasible, deferasirox should be administered consistently at the same time before meals to limit the sources of variability that affect absorption.

Enteric-coated mycophenolate sodium provides higher mycophenolic acid predose levels compared with mycophenolate mofetil: Implications for therapeutic drug monitoring

Abstract: The delayed release of mycophenolic acid (MPA) from enteric-coated mycophenolate sodium (EC-MPS) may lead to different MPA predose (C0) levels compared with mycophenolate mofetil (MMF). A post hoc analysis was performed on MPA morning predose values assessed in 88 maintenance renal transplant patients from three studies converted from MMF (1000 mg twice a day) to equimolar EC-MPS (720 mg twice a day) or vice versa, both in combination with cyclosporine. The median MPA predose level was approximately 30% higher when patients received EC-MPS (2.40 μg/mL; range, 0.49-39.30 μg/mL) compared with MMF (1.83 μg/mL; range, <0.1-12.80 μg/mL). Rare cases (3.0%) of high MPA C0 levels 15 μg/mL or greater were observed with EC-MPS consistent with a very prolonged release of MPA from this formulation. Both EC-MPS and MMF exhibited a poor correlation between MPA C0 levels and exposure as assessed by MPA area under the curve. Physicians targeting a certain MPA predose level have to be aware of the higher morning C0 levels with EC-MPS, whereas the overall MPA exposure is not different to MMF.

Pharmacokinetics and variability of mycophenolic acid from enteric-coated mycophenolate sodium compared with mycophenolate mofetil in de novo heart transplant recipients

Abstract:  Sequential pharmacokinetic assessments were performed at five centers within the context of a multicenter, single‐blind, randomized clinical trial comparing the efficacy and safety of enteric‐coated mycophenolate sodium (EC‐MPS, myfortic®) and mycophenolate mofetil (MMF, CellCept®) in de novo heart transplant recipients. Patients were randomized to either EC‐MPS 1080 mg bid or MMF 1500 mg bid, as part of a triple immunosuppressive therapy including cyclosporine microemulsion. Steady‐state pharmacokinetic profiles of mycophenolic acid (MPA) and its inactive phenolic glucuronide (MPAG) were assessed at weeks 2, 12, and 52. Pharmacokinetic parameters were evaluated in 32 patients (17 on EC‐MPS and 15 on MMF). Dose‐normalized peak (Cmax,ss) and area under the curve (AUCτ,ss) of MPA and MPAG increased between week 2 and week 12 assessments for both treatments. Comparisons between EC‐MPS and MMF showed no statistically significant differences in MPA and MPAG AUCτ,ss, Cmax,ss, and trough (Cmin,ss) values (p‐values ranged from 0.225 to 0.990). Consistent with the delayed release characteristics of EC‐MPS, Cmax,ss occurred approximately one hour later compared with MMF. Inter‐subject coefficients of variation (%CV) for MPA pharmacokinetic parameters of both EC‐MPS and MMF were high (37–72% for AUCτ,ss at weeks 2 and 12). Also within patients, the pharmacokinetics of MPA varied considerably. Specifically, intra‐subject %CVs for MPA AUCτ,ss, Cmax,ss, and Cmin,ss were 28%, 63%, and 34% with EC‐MPS and 54%, 139%, and 41% with MMF respectively. These results indicate that a dose of EC‐MPS 1080 mg bid in combination with cyclosporine provides adequate systemic MPA exposure in de novo heart transplant patients, comparable with MMF 1500 mg bid. Overall, there is a large inter‐ and intra‐subject variability in MPA pharmacokinetic parameters with both treatments.

Absolute Oral Bioavailability and Disposition of Deferasirox in Healthy Human Subjects

Deferasirox is a novel iron chelator formulated as tablets for dispersion (suspension) for once‐a‐day oral administration. The current study evaluated the absolute bioavailability of a single 375‐mg oral dose of deferasirox administered in the form of tablets compared with a 130‐mg intravenous infusion of deferasirox. Since this was a first‐in‐man study using the deferasirox intravenous (IV) formulation, the safety and tolerability of the IV formulation was evaluated in a pilot phase with a lower dose (65 mg) in 3 subjects prior to the main phase. The main study phase consisted of 17 healthy male volunteers. Plasma concentrations of deferasirox were measured following each treatment, and pharmacokinetic parameters including absolute oral bioavailability were determined. Absolute oral bioavailability of the deferasirox tablets was 70% (90% confidence interval, 62%‐80%). Deferasirox was characterized as having a low plasma clearance of 3.53 (± 0.87) L/h. A small volume of distribution of deferasirox at steady state (Vss) of 14.37 (±2.69 L) was determined, indicating a low tissue distribution.

Determination of the pharmacokinetics of glycopyrronium in the lung using a population pharmacokinetic modelling approach

AIMS Glycopyrronium bromide (NVA237) is a once-daily long-acting muscarinic antagonist recently approved for the treatment of chronic obstructive pulmonary disease. In this study, we used population pharmacokinetic (PK) modelling to provide insights into the impact of the lung PK of glycopyrronium on its systemic PK profile and, in turn, to understand the impact of lung bioavailability and residence time on the choice of dosage regimen. METHODS We developed and validated a population PK model to characterize the lung absorption of glycopyrronium using plasma PK data derived from studies in which this drug was administered by different routes to healthy volunteers. The model was also used to carry out simulations of once-daily and twice-daily regimens and to characterize amounts of glycopyrronium in systemic compartments and lungs. RESULTS The model-derived PK parameters were comparable to those obtained with noncompartmental analysis, confirming the usefulness of our model. The model suggested that the lung absorption of glycopyrronium was dominated by slow-phase absorption with a half-life of about 3.5 days, which accounted for 79% of drug absorbed through the lungs into the bloodstream, from where glycopyrronium was quickly eliminated. Simulations of once-daily and twice-daily administration generated similar PK profiles in the lung compartments. CONCLUSIONS The slow absorption from the lungs, together with the rapid elimination from the systemic circulation, could explain how once-daily glycopyrronium provides sustained bronchodilatation with a low incidence of adverse effects in patients with chronic obstructive pulmonary disease. Its extended intrapulmonary residence time also provides pharmacokinetic evidence that glycopyrronium has the profile of a once-daily drug.

Early clinical development of artemether-lumefantrine dispersible tablet: palatability of three flavours and bioavailability in healthy subjects

BackgroundEfforts to ease administration and enhance acceptability of the oral anti-malarial artemether-lumefantrine (A-L) crushed tablet to infants and children triggered the development of a novel dispersible tablet of A-L. During early development of this new formulation, two studies were performed in healthy subjects, one to evaluate the palatability of three flavours of A-L, and a second one to compare the bioavailability of active principles between the dispersible tablet and the tablet (administered crushed and intact).MethodsStudy 1 was performed in 48 healthy schoolchildren in Tanzania. Within 1 day, all subjects tasted a strawberry-, orange- and cherry-flavoured oral A-L suspension for 10 seconds (without swallowing) in a randomized, single-blind, crossover fashion. The palatability of each formulation was rated using a visual analogue scale (VAS). Study 2 was an open, randomized crossover trial in 48 healthy adults given single doses of A-L (80 mg artemether + 480 mg lumefantrine) with food. The objectives were to compare the bioavailability of artemether, dihydroartemisinin (DHA) and lumefantrine between the dispersible tablet and the tablet administered crushed (primary objective) and intact (secondary objective).ResultsStudy 1 showed no statistically significant difference in VAS scores between the three flavours but cherry had the highest score in several ratings (particularly for overall liking). Study 2 demonstrated that the dispersible and crushed tablets delivered bioequivalent artemether, DHA and lumefantrine systemic exposure (area under the curve [AUC]); mean ± SD AUC0-tlast were 208 ± 113 vs 195 ± 93 h.ng/ml for artemether, 206 ± 81 vs 199 ± 84 h.ng/ml for DHA and 262 ± 107 vs 291 ± 106 h.μg/ml for lumefantrine. Bioequivalence was also shown for peak plasma concentrations (Cmax) of DHA and lumefantrine. Compared with the intact tablet, the dispersible tablet resulted in bioequivalent lumefantrine exposure, but AUC and Cmax values of artemether and DHA were 20-35% lower.ConclusionsConsidering that cherry was the preferred flavour, and that the novel A-L dispersible tablet demonstrated similar pharmacokinetic performances to the tablet administered crushed, a cherry-flavoured A-L dispersible tablet formulation was selected for further development and testing in a large efficacy and safety study in African children with malaria.