Safety study and therapeutic drug monitoring of the oral tablet formulation of posaconazole in patients with haematological malignancies.

PURPOSE: Posaconazole is a triazole antifungal widely used for prophylaxis of invasive fungal disease (IFI). Posaconazole tablets allow reaching higher plasma levels than the oral suspension, but safety data with this formulation in real life are scarce. This study aimed at evaluating the safety profile, the pharmacokinetic variability, and the concentration-toxicity relationship of posaconazole tablets in patients with haematological malignancies. METHODS: Sixty neutropenic patients treated with posaconazole tablets for prophylaxis of IFI were prospectively included in the study. Adverse drug reactions (ADR) were recorded and analyzed by the Regional Pharmacovigilance Centre to assess posaconazole implication. Blood samples were drawn once a week and plasma trough concentrations (C min) were assayed by LC-MS/MS. The rates of ADR by quartile of C min were compared. RESULTS: Eighteen patients (30%) experienced at least one ADR attributed to posaconazole. Liver function test (LFT) abnormalities were encountered in 20% of patients and resulted in four (6.7%) treatment discontinuations. Posaconazole median (range) C min was 1.36 (< 0.1-3.44) µg/mL (inter-patient CV = 43.9%). During follow-up, 28.6% of patients had at least one concentration < 0.7 µg/mL, and 35.7% had at least one concentration > 2 µg/mL. Rates of ADR by quartile of C min were not different. CONCLUSIONS: Posaconazole was well tolerated; however, LFT abnormalities were frequent. ADR occurrence was not linked to posaconazole exposure. Because posaconazole concentrations were highly variable, TDM can be helpful to avoid underexposure to the drug and increase its efficacy in preventing IFI. Conversely, a large proportion of patients was overexposed and might have benefited of a dose reduction.

Population Pharmacokinetics of Posaconazole Tablets and Monte Carlo Simulations To Determine whether All Patients Should Receive the Same Dose.

Posaconazole is extensively used for prophylaxis for invasive fungal infections. The gastro-resistant tablet formulation has allowed the bioavailability issues encountered with the oral suspension to be overcome. However, overexposure is now frequent. This study aimed to (i) describe the pharmacokinetics of posaconazole tablets in a real-life cohort of patients with hematological malignancies and (ii) perform Monte Carlo simulations to assess the possibility that the daily dose can be reduced while keeping a sufficient exposure. Forty-nine consecutive inpatients were prospectively included in the study. Posaconazole trough concentrations (TC) were measured once a week, and biological and demographic data were collected. The concentrations were analyzed by compartmental modeling, and Monte Carlo simulations were performed using estimated parameters to assess the rate of attainment of the target TC after dose reduction. The pharmacokinetics of posaconazole were well described using a one-compartment model with first-order absorption and elimination. The values of the parameters (interindividual variabilities) were as follows: the absorption constant (ka ) was 0.588 h-1 (fixed), the volume of distribution (V/F) was 420 liters (28.2%), and clearance (CL/F) was 7.3 liters/h (24.2%) with 31.9% interoccasion variability. Forty-nine percent of the simulated patients had TC at steady state of ≥1.5 µg/ml and maintained a TC above 1 µg/ml after a reduction of the dose to 200 mg daily. A third of these patients eligible for a dose reduction had TC of ≥1.5 µg/ml as soon as 48 h of treatment. Though posaconazole tablets were less impacted by bioavailability issues than the oral suspension, the pharmacokinetics of posaconazole tablets remain highly variable. Simulations showed that approximately half of the patients would benefit from a reduction of the dose from 300 mg to 200 mg while keeping the TC above the minimal recommended target of 0.7 µg/ml, resulting in a 33% savings in the cost of this very expensive drug.

Increased inhibition of cytochrome P450 3A4 with the tablet formulation of posaconazole.

Being a substrate of the cytochrome P450 3A4 (CYP3A4) isoenzyme, sirolimus metabolism is decreased when posaconazole is administered concomitantly. However, because of the poor bioavailability of the oral suspension of posaconazole with which low plasma concentrations are obtained, CYP3A4 inhibition is weak and a 50-75% dose reduction of sirolimus is sufficient to avoid sirolimus overdosage. The new tablet formulation allows reaching posaconazole concentrations 3-4 fold higher than those obtained with the oral suspension. Based on a case of sirolimus overdosage following posaconazole tablets administration, we modelled the inhibition of sirolimus clearance by posaconazole, and then simulated several dosage regimens of sirolimus taken together with posaconazole tablets. We were able to describe well the interaction, and found a value of IC50 of posaconazole towards sirolimus clearance of 0.68 µg/mL. The simulations showed that even a 80% decrease of the daily dose of sirolimus is unsuitable in many cases with trough concentrations of posaconazole of 2 µg/mL. A decrease of 40% of the dose with spacing administrations of 3 days may be considered. The clinicians and pharmacologists must be warned that the use of posaconazole tablets may result in an inhibition of CYP3A4 of greater magnitude than with the oral suspension.

MR delayed enhancement imaging findings in suspected acute myocarditis.

The purpose of the study was to prospectively assess the clinical impact of routinely performed delayed enhancement imaging in suspected acute myocarditis. A two-centre prospective study was performed in patients with suspected acute myocarditis. The protocol included horizontal long axis, vertical long axis and short axis ciné MR and delayed enhancement imaging after Gd-DTPA infusion (0.2 mmol/kg). Sixty consecutive patients were enrolled (aged 49.4 +/- 17.8 years). MRI demonstrated delayed enhancement sparing the subendocardicardial layer in 51.6% of patients, concordant with the diagnosis of acute myocarditis; 16.7% of patients exhibited delayed enhancement involving the subendocardial layer with irregular margins, concordant with the diagnosis of acute myocardial infarction; 31.7% of patients had delayed enhancement imaging that was considered normal. Routine imaging to identify delayed enhancement provided crucial information in suspected acute myocarditis by reinforcing the diagnosis in 51.6% of patients and correcting a misdiagnosed acute myocardial infarction in 16.7% of patients.

[Percutaneous treatment of aortic stenosis]. / Traitement percutané du rétrécissement aortique.

Degenerative aortic stenosis is the most frequent valvular disease in developed countries. The reference treatment is surgical valve replacement but one third of the patients are not eligible for surgery. Alternative options have been recently proposed using transcatheter valve implantation (transfemoral or trans-apical approaches) in this subset of patients. Two models of valve (balloon expandable or self-expandable) have demonstrated their efficacy and have been implanted to date in over 4000 patients worldwide. These techniques are promising but several issues remain such as the selection of patients, and the safety and durability of the devices currently used.

Mechanical circulatory assistance in myocardial infarction with refractory cardiogenic shock: clinical experience in 10 patients at a teaching hospital in Rouen.

BACKGROUND: In patients with acute myocardial infarction (MI), cardiogenic shock (CS) remains associated with a high mortality (close to 50%) despite optimal therapeutic strategy. For those patients who are unlikely to survive, mechanical circulatory support (MCS) might be an additional life saving strategy. OBJECTIVE: To evaluate the efficacy of circulatory assistance in myocardial infarction complicated by cardiogenic shock. METHODS: We retrospectively studied the characteristics and clinical outcome of 10 patients hospitalized with acute MI and CS who required MCS. Mean age was 52+/-8 years; location of MI was anterior in 80% of cases. Immediate coronary angiography was performed in all cases 5.8+/-7.0 hours from the onset of symptoms. Intra-aortic balloon pumping was used in 70% of patients and 30% received thrombolysis. Angioplasty with stent implantation was performed in 8 patients. RESULTS: In all patients MCS was placed within a mean of 57+/-92 hours after admission for hemodynamic instability (systolic aortic pressure: 85+/-13 mmHg; mean: 64+/-10 mmHg). Extracorporeal membrane oxygenation (ECMO) was implanted in 8 patients followed by Thoratec in one. The other 2 patients received a Thoratec and a Heartmate II system respectively. Survival rate was 40% (4 patients): 3 patients underwent heart transplantation at a mean of 93+/-97 days and one patient is alive with definitive implantable Heartmate. The other six patients died in hospital. CONCLUSION: Mechanical circulatory support appeared life saving in 4 out of 10 patients with acute MI and cardiogenic shock refractory to optimal treatment. In this situation, circulatory assistance deserves discussion and the choice of optimal device should be further evaluated.

Transcatheter aortic valve implantation: technical aspects, results and indications.

The development of the percutaneous heart valve (PHV) may become a primary therapeutic modality for the high risk and inoperable patients with critical symptomatic aortic stenosis. The first human percutaneous aortic valve implant was performed by our group in April 2002. To date, more than 500 Cribier-Edwards-PHV have been implanted worldwide using arterial trans-femoral or trans-apical approach. Data on the retrograde transfemoral approach is growing with more than 270 patients implanted as of October 2007. Procedural success rate is high (86%) and the 30-day mortality is 12%. Today, 2 patients are alive at a follow-up of more than 4 years. The same Cribier-Edwards-PHV can be implanted using trans-apical approach. In this procedure, PHV is introduced under direct vision into the left ventricle via a mini-thoracotomy. This obviates the concerns regarding vascular access in the presence of small caliber vessels and/or vascular occlusive disease. More than 200 patients have been treated with this approach. In the European experience 30-day mortality is 14%. There is intense interest in PHV technology, and there are multiple devices at various stages of development in animals and humans. The most developed is the CoreValve Revalving Technology. More than 350 patients have been treated with this technique. The immediate and mid-term results with this device are promising with a procedural success of 92% and a 30-day mortality of 15%. The future of this technology and its application is dependent on the continued collaboration between general internists, cardiologists, surgeons, engineers, and industry.

[Troponin dosage in a patient with asymptomatic myocarditis due to trichinellosis]. / Myocardite asymptomatique au cours d''un cas de trichinellose: intérêt du dosage de la troponine.

Human trichinellosis is a potentially severe parasitic disease occurring after ingestion of undercooked meat infected with Trichinella sp. larvae. We report the case of a patient who ate an undercooked bear meat hunted in Canada; he presented with the usual symptoms of trichinellosis (i.e, facial oedema, myalgias and fever) complicated with an asymptomatic myocarditis. Myocarditis is a rare, but potentially lethal complication of trichinellosis. Myocarditis should be screened systematically even when specific symptoms are missing; dosage of troponin serum is a simple and reliable mean for such screening.

[Revascularisation of unprotected left main coronary artery disease: an update]. / Revascularisation du tronc commun coronaire gauche non protégé.

Coronary bypass grafting is the reference treatment of unprotected left main coronary disease. Nevertheless, the experience of invasive cardiologists and the introduction of active stents make angioplasty possible in selected cases. Only the results of controlled clinical trials (SYNTAX trial currently under way) will enable physicians to choose the most appropriate method of revascularisation for their patients.

[Aortic bioprosthesis implanted percutaneously: three year follow up]. / Bioprothèse aortique implantée par voie percutanée: suivi à trois ans.

Percutaneous implantation of a bioprosthesis for the treatment of degenerative aortic stenosis ushered in a new era for interventional cardiology, and now represents the best therapeutic option for a growing number of patients for whom surgical aortic replacement would be too risky. This is the case in about a third of symptomatic patients affected. Between 2003 and 2005, we performed initial feasibility studies (I-REVIVE and RECAST) in Rouen, on non-operable patients in a critical state, included for purely compassionate reasons. The valve used was a pericardial bioprosthesis mounted in an expandable balloon stent. The mean age of the patients was 80 years, all had multiple co-morbidity and had been turned down by the cardiac surgeons. In 33 of the 36 included patients, the technique was attempted by the anterograde trans-septal approach (n=27, success rate 80%) or by the retrograde arterial route (n=7, success rate 57%). Echocardiography following implantation revealed a final aortic surface area of 1.70 cm2 and a transvalvular gradient of 9 mmHg. A significant paravalvular aortic leak was noted in 5 cases. There were 6 deaths by 1 month, related to the procedure, and 10 deaths by 6 months, from non-cardiac causes and not related to the procedure. There was no occurrence of coronary occlusion, secondary displacement or dysfunction of the prosthesis. In December 2006, 8 patients reached 2 years of follow up, and two others reached 3 years, symptom free and still with an unchanged valvular function. Significant technological improvements have made the technique simpler, quicker and safer, with very much improved short and long term results. The new trans-apical approach is under evaluation with some promising initial results. More than 280 patients have been implanted to date. Other implantable prostheses are under evaluation. This therapeutic modality looks likely to develop rapidly, and in the near future it should offer a new and optimal solution for all high surgical risk or non-operable patients.

[Immediate results and clinical follow-up of patients treated with drug eluting stents implantation in routine clinical practice]. / Résultats immédiats et suivi clinique des patients traités par implantation de stents actifs en pratique courante.

Multiple recent randomized studies have demonstrated the superiority of drug eluting stents (DES) compared to bare stents for reduction of restenosis rates after angioplasty. We sought to study if the results obtained in these studies with highly selected patients could be translated to patients treated in routine clinical practice. To this end, we retrospectively reviewed hospital charts of 134 consecutive patients treated in our center with 202 DES implantation between November 2002 and January 2004. Thirty nine % of patients had diabetes and 59% had multivessel disease. Coronary lesions were often complex (type B2: 24%, type C: 35%). Mean percent diameter stenosis was 68 +/- 13% with a reference artery diameter of 2.62 +/- 0.5 mm. One patient (0.75%) died in-hospital from cardiogenic shock. At a mean follow-up of 12 +/- 2.6 months, 7 patients (5.3%) died, including 2 extracardiac deaths. Recurrent chest pain occurred in 16 patients (12%), with only 3 (2.3%) in-stent restenosis. Major adverse cardiac event rate was 8.2%. This study confirms that in a non-selected population, the rate of subsequent revascularization after DES implantation is very low. It can be hoped that the indications of implantations will progressively spread with a lowered cost of these DES.

[Myocarditis versus myocardial infarction in diabetic patients: a new role for non invasive imaging]. / Myocardite ou infarctus chez le diabétique: un nouveau rôle pour l'imagerie non invasive.

A young diabetic patient was referred to our institution for clinical symptoms of myopericarditis. Cardiac MRI and MDCT of the coronary arteries were performed successively. They demonstrated an acute myocardial infarction related to a left circumflex coronary artery occlusion which was treated by stent angioplasty. This case suggests that cardiac MR and possibly cardiac MDCT could be proposed in patients with a suspected myopericarditis, especially if diabetes mellitus is associated.

[Balloon aortic valvuloplasty in the adult. Immediate results and in-hospital complications in the latest series of 141 consecutive patients at the University Hospital of Rouen (2002-2005)]. / Valvuloplastie aortique par ballonnet chez l'adulte. Résultats immédiats et complications intrahospitalières dans la dernière série de 141 patients consécutifs au CHU de Rouen (2002-2005).

UNLABELLED: With the aging population, elderly patients with degenerative, severely calcified, and symptomatic aortic stenosis are becoming a frequent problem in medical decision making, particularly because many are declined for surgical valve replacement. For these patients, balloon aortic dilatation could be a palliative treatment. PATIENTS AND METHODS: we analyzed retrospectively our techniques and complications during hospitalization for percutaneous aortic balloon dilatation in 141 consecutive patients (45% women, mean age 83 +/- 10 y) from January 2002 to April 2005. The Parsonnet's score was 41 +/- 8 and the Euroscore was 10 +/- 2. We excluded the patients enrolled for percutaneous aortic valve implantation. This technique was performed under local anesthesia, from retrograde or antegrade approach. Rapid pacing stimulation (220/bpm) with a pacing-lead placed in the right ventricle was performed during balloon inflation. RESULTS: the aortic valve area was increased from 0.59 +/- 0.19 to 1.02 +/- 0.34 cm2 (p < 0.001) and the transvalvular mean gradient decreased from 49.3 +/- 21.2 to 22.2 +/- 11.8 mmHg (p < 0.001). Six patients (4%) died (3 during aortic valve dilatation) and 9 patients (6%) had non fatal complications: 2 transitory strokes, 8 non surgical vascular complications and 5 episodes of atrio-ventricular complete block (these complication were non exclusive). The patients were discharged at 5, 6 +/- 3 days. CONCLUSION: In the hands of skilled operators, aortic percutaneous balloon dilatation has become a simple technique, associated with a low risk of complications despite a very ill patient population. This technique remains a good option for a number of patients before the onset of percutaneous aortic valve implantation.

[Intra-stent restenosis following implantation of a bare endoprosthesis]. / Resténose intra-stent après implantalion d'une endoprothèse nue.

The aim of this retrospective study was to evaluate the immediate and long-term results of various treatments for patients with a primary lesion of intra-stent restenosis (ISR). The study included 214 patients (233 endoprostheses, site of a primary ISR), with an average age of 61+/-11 years. These patients had received one of the following treatments: balloon angioplasty alone (101 patients), implantation of a second endoprosthesis (32 patients), medical treatment (65 patients), or revascularisation surgery with aorto-coronary bypass (16 patients). After retrospective analysis of the initial data, clinical follow-up was studied for all patients, and severe cardiac events were recorded. The immediate treatment of the ISR with angioplasty or bypass had an initial success rate of 100%. At the end of follow up (26+/-1.8 months) for the series as a whole, 9 patients (4.1%) had died, 7 (3.2%) had suffered a myocardial infarction, and 22 (10.3%) had had to undergo a secondary revascularisation procedure. 111 (52%) patients had angiographic follow up. A second ISR was noted in 43 cases (39%). The type of treatment provided was not a predictive factor for the occurrence of a severe cardiac event. In conclusion, whatever treatment of ISR is used, the immediate result is satisfactory. The rate of severe cardiac events is acceptable and in 10.3% of cases necessitates a secondary revascularisation procedure within 2 years. The very promising recent development of new active endoprostheses could alter the management of coronary patients in the years to come.

[Macromolecular complex of cardiac troponin I: differences of reactivity with DPC and Dade-Behring assays]. / Complexe macromoléculaire de troponine I cardiaque: différence de réactivité des trousses de dosage DPC et Dade-Behring.

We have recently identified a macromolecular 440-kDa cardiac troponin I (cTnI) complex after successful percutaneous transluminal coronary angioplasty (PTCA) (Clin Chem 2003; 49: 505-7). The aim of the work was to confirm the existence of such a complex by using another cTnI assay (Dimension RXL, Dade-Behring). We have first studied the correlation between the two assays by using heparinized samples [cTnI(Immulite) = 2.00 cTnI(Dimension) - 0.01 (n = 176; r = 0,987)]. Then, cTnI taken 120 minutes after PTCA for two patients was measured with the two assays after fractionation by FPLC. The obtained results confirmed the existence of the 440-kDa cTnI complex and showed that the reactivity between the assays (DPC/Dade-Behring ratio) depended on the nature of the complex: the ratio increased from 0.7 (440-kDa cTnI complex) to 3 (80-kDa cTnI complex) therefore suggesting caution in the comparison between the different cTnI assays in the context of reperfusion therapy.