Long-Term Follow-Up on a Cohort Temporary Utilization Authorization (ATU) Survey of Patients Treated with Pheburane (Sodium Phenylbutyrate) Taste-Masked Granules.

OBJECTIVES: The aim was to describe the status of patients with urea cycle disorders (UCD) at the latest long-term clinical follow-up of treatment with a new taste-masked formulation of sodium phenylbutyrate (NaPB) granules (Pheburane). These patients are a subset of those treated under a cohort temporary utilisation study (ATU) previously reported and now followed for 2 years. METHODS: From a French cohort temporary utilization authorization (ATU) set up to monitor the use of Pheburane on a named-patient basis in UCD patients in advance of its marketing authorization, a subset of patients were followed up in the long term. Data on demographics, dosing characteristics of NaPB, concomitant medications, adverse events and clinical outcomes were collected at a follow-up visit after 1-2 years of treatment with the drug administered under marketing conditions. This paper reports on the subset of patients who were included in further long-term follow-up at the principal recruiting metabolic reference center involved in the original cohort. RESULTS: No episode of metabolic decompensation was observed over a treatment period ranging from 8 to 30 months with Pheburane, and the range of ammonia and glutamine levels continued to improve and remained within the normal range, thus adding valuable longer-term feedback to the original ATU report. In all, no adverse events were reported with Pheburane treatment. These additional data demonstrate the maintenance of the safety and efficacy of Pheburane over time. CONCLUSIONS: The recently developed taste-masked formulation of NaPB granules (Pheburane) improved the quality of life for UCD patients. The present post-marketing report on the use of the product confirms the original observations of improved compliance, efficacy and safety with this taste-masked formulation of NaPB.

Results from a Nationwide Cohort Temporary Utilization Authorization (ATU) survey of patients in france treated with Pheburane(®) (Sodium Phenylbutyrate) taste-masked granules.

OBJECTIVES: The aim of this study was to describe a nationwide system for pre-marketing follow-up (cohort temporary utilization authorization [ATU] protocol; i.e., 'therapeutic utilization') of a new taste-masked formulation of sodium phenylbutyrate (NaPB) granules (Pheburane(®)) in France and to analyze safety and efficacy in this treated cohort of patients with urea cycle disease (UCD). METHODS: In October 2012, a cohort ATU was established in France to monitor the use of Pheburane(®) on a named-patient basis. All treated UCD patients were included in a follow-up protocol developed by the Laboratory (Lucane Pharma) and the French Medicines Agency (ANSM), which recorded demographics, dosing characteristics of NaPB, concomitant medications, adverse events, and clinical outcome during the period of treatment. Following the granting of the Marketing Authorization in Europe, the cohort ATU was terminated approximately 1 year after its initiation, as the product was launched on the French market. RESULTS: The ease of administration and acceptability were much better with the new taste-masked formulation than with the previous treatment. No episodes of metabolic decompensation were observed over a treatment period ranging from 3 to 11 months with Pheburane(®) and the range of ammonia and glutamine plasma levels improved and remained within the normal range. In all, no adverse events were reported with Pheburane(®) treatment. CONCLUSIONS: The recently developed taste-masked formulation of NaPB granules improved the quality of life for UCD patients. This may translate into improved compliance, efficacy, and safety, which may be demonstrated either in further studies or in the post-marketing use of the product.

Dose regimen of para-aminosalicylic acid gastro-resistant formulation (PAS-GR) in multidrug-resistant tuberculosis.

BACKGROUND AND OBJECTIVES: Resurgence of multidrug-resistant tuberculosis (MDR-TB) has raised a renewed interest in para-aminosalicylic acid (PAS) and other efficacious drugs. A gastro-resistant granule formulation (PAS-GR) was designed to be better tolerated than earlier forms of PAS, with fewer adverse effects from reduced production of meta-aminophenol. PAS release from PAS-GR granules is slower than with earlier formulations. Pharmacokinetic data are, however, limited and only a few studies have assisted in defining the best PAS-GR dose regimen. Interest in refining the latter continues and recent data contributed in better defining the optimal PAS-GR dose regimen in adults and children. The present paper draws on these recent studies, synthesizes pharmacokinetic results from different population groups, and draws comparisons with in vitro data and the results of earlier pharmacokinetic studies in order to discuss the most appropriate dosing regimen for PAS-GR. METHODS: A comparative in vitro dissolution study was carried out with a 1 g acid PAS equivalent of various formulations of PAS and PAS-GR and in vitro-in vivo correlations. Retrospective comparisons between recent and earlier clinical studies were also gathered to clarify the dose regimen of PAS-GR in adults and children. RESULTS: Exposure after a 4 g twice- or three times daily dose regimen in adult MDR-TB patients confirmed that both dose regimens can be used. The twice-daily dose regimen does not, however, confer any safety margin over the potentiality of "too" high plasma concentrations after a three times daily dose regimen and may lead to under-dosage when a dose is missed, as compliance often decreases over time. CONCLUSIONS: Based on available data and practical considerations, a 4 g three times daily dose regimen of PAS-GR should be the preferred dose in hospital settings, where it remains the best regimen to cover the around-the-clock suppression of mycobacteria based on the minimal inhibitory concentration for PAS. In MDR-TB adults and in hospital settings, there is no safety advantage in administering a regimen of 4 g twice daily. As compliance is critical to the effectiveness of the treatment, a 4 g three times daily dose regimen may be more forgiving if the patient misses a dose.

French Nationwide Cohort Temporary Utilization Authorization Survey of GranuPAS(®) in MDR-TB patients.

BACKGROUND: Para-aminosalicylic acid (PAS) is again needed for the treatment of multidrug and extensively drug-resistant tuberculosis (M/XDR-TB). The study of a new granulated formulation (PAS-GR, 'GranuPAS(®)'), which might have fewer adverse events, was made possible by the statutory requirement that data be collected regarding its use in France in multidrug-resistant TB (MDR-TB) patients under a 'therapeutic utilization' follow-up for safety and efficacy system called 'Autorisation Temporaire d'Utilisation' (ATU). METHODS: In May 2011 an ATU cohort was established to monitor the named patient use of PAS-GR. All patients were included in a follow-up protocol developed by Lucane Pharma and the French Medicines Agency (ANSM) which recorded demographics, dosing characteristics, concomitant medications, adverse events, and outcome. Following EU marketing authorization, the ATU terminated about 3 years after initiation. RESULTS: PAS-GR was used for the treatment of 231 MDR-TB patients. PAS-GR was used at 12 g/day in 114 cases and 8 g/day in 80 cases. PAS-GR-containing combinations resulted in sputum conversion in a median of 94 days (IQR 48-143) in the 55 patients with information after treatment initiation. Adverse effects of PAS-GR-containing combinations were mostly gastrointestinal (GI; 9% of patients experiencing a GI event at any time) and led to interrupt PAS-GR in 6% of cases (2.1% GI). CONCLUSIONS: The efficacy of PAS-GR appears equivalent to that of PAS, and its tolerance improved over earlier PAS formulations, thus supporting the use of PAS-GR as part of drug combinations for the treatment of MDR and XDR-TB.

Developing a new formulation of sodium phenylbutyrate.

BACKGROUND: Sodium phenylbutyrate (NaPB) is used as a treatment for urea cycle disorders (UCD). However, the available, licensed granule form has an extremely bad taste, which can compromise compliance and metabolic control. OBJECTIVES: A new, taste-masked, coated-granule formulation (Luc 01) under development was characterised for its in vitro taste characteristics, dissolution profiles and bioequivalence compared with the commercial product. Taste, safety and tolerability were also compared in healthy adult volunteers. RESULTS: The in vitro taste profile of NaPB indicated a highly salty and bitter tasting molecule, but Luc 01 released NaPB only after a lag time of ∼10 s followed by a slow release over a few minutes. In contrast, the licensed granules released NaPB immediately. The pharmacokinetic study demonstrated the bioequivalence of a single 5 g dose of the two products in 13 healthy adult volunteers. No statistical difference was seen either for maximal plasma concentration (C(max)) or for area under the plasma concentration-time curve (AUC). CI for C(max) and AUC(0-inf) of NaPB were included in the bioequivalence range of 0.80-1.25. One withdrawal for vomiting and five reports of loss of taste perception (ageusia) were related to the licensed product. Acceptability, bitterness and saltiness assessed immediately after administration indicated a significant preference for Luc 01 (p<0.01), confirming the results of the taste prediction derived from in vitro measurements. CONCLUSIONS: In vitro dissolution, in vitro and in vivo taste profiles support the view that the newly developed granules can be swallowed before release of the bitter active substance, thus avoiding stimulation of taste receptors. Moreover, Luc 01 was shown to be bioequivalent to the licensed product. The availability of a taste-masked form should improve compliance which is critical to the efficacy of NaPB treatment in patients with UCD.

Unbound bilirubin does not increase during ibuprofen treatment of patent ductus arteriosus in preterm infants.

OBJECTIVE: To determine whether ibuprofen displaces bilirubin from albumin in preterm infants. STUDY DESIGN: A total of 34 preterm neonates (<32 weeks gestation) treated by ibuprofen (10-5-5 mg/kg) were included in this prospective open-label study. Total bilirubin (TB), unbound bilirubin (UB), and ibuprofen concentrations were measured before, 1 hour, and 6 hours after the first dose; before and 1 hour after the second dose; and 72 hours after the beginning of treatment. The infants were screened by auditory brainstem responses and by neurologic examination at term. RESULTS: At baseline, TB, UB, apparent binding affinity of albumin (Ka), and albumin concentrations were 6.0±1.6 mg/dL, 1.9±2.2 µg/dL, 14.1±5.8 L·µmol(-1), and 28.7±2.3 g/L, respectively. Ibuprofen treatment had no effect on TB, UB, or Ka values. No correlation between UB or Ka and ibuprofen concentrations was found. No neurologic symptoms or significant modifications of auditory brainstem responses were observed at term. CONCLUSION: Ibuprofen (10-5-5 mg/kg) did not displace bilirubin in preterm infants with a baseline TB concentration <8.8 mg/dL.

Efficacy and tolerability of enteral formulations of ibuprofen in the treatment of patent ductus arteriosus in preterm infants.

BACKGROUND: The persistence of a patent ductus arteriosus (PDA) in preterm infants complicates their clinical course and may contribute to increased morbidity. Intravenous preparations of ibuprofen constitute one of the standard therapies for closure of a PDA. However, the unavailability of intravenous ibuprofen in certain regions of the world and the availability of inexpensive oral preparations has led to off-label nasogastric administration of oral ibuprofen in preterm infants with PDA. OBJECTIVE: This article reviews and comments on the evidence for the enteral use of oral formulations of racemic ibuprofen for PDA closure in preterm infants, with a focus on the risk of necrotizing enterocolitis (NEC). METHODS: MEDLINE, Current Contents, and Google Scholar were searched in April 2010 for trials of enteral ibuprofen in the treatment of PDA in preterm or low-birth-weight infants using the terms treatment, pharmacokinetics, ibuprofen, oral, enteral, patent ductus arteriosus, PDA, preterm, premature, low birth weight, infant, and newborn. Relevant congress Web sites were also searched for relevant abstracts. RESULTS: The literature search identified 2 pharmacokinetic studies involving 32 infants and 13 clinical efficacy studies involving 306 infants treated with enteral ibuprofen. The clinical studies reported some benefit for enteral ibuprofen relative to the comparators. However, these studies had methodologic limitations, including small numbers of subjects, lack of blinding, inclusion of preterm infants with a higher gestational age, customized treatment regimens, and second-order statistical error that prevented conduct of a systematic review. When the results of all studies were pooled, NEC was reported in a total of 46 of 281 infants (16%) receiving enteral ibuprofen and 21 of 83 infants (25%) receiving indomethacin. This rate of NEC with enteral ibuprofen was twice that reported for intravenous ibuprofen in a recent meta-analysis (27/356 [8%]). CONCLUSIONS: The evidence supporting the off-label use of enteral ibuprofen for PDA in preterm infants is weak. Well-designed, appropriately powered pharmacologic and controlled clinical studies are needed before use of enteral ibuprofen can be recommended. In countries where an intravenous formulation of racemic ibuprofen is approved, off-label use of enteral racemic ibuprofen cannot be supported.

Population pharmacokinetic analysis of Ibuprofen enantiomers in preterm newborn infants.

The aim of this pharmacokinetic analysis was to develop and validate a population pharmacokinetic model for R- and S-ibuprofen from samples obtained after 3 successive administrations of ibuprofen (10-5-5 mg/kg) at 24-hour intervals to preterm newborn infants aged from <6 hours to 8 days of life. A model including unilateral bioconversion of R-ibuprofen into S-ibuprofen was developed using the software NONMEM. R- and S-ibuprofen plasma concentrations were adequately fitted by this model. Estimated clearance and volume of distribution were 3.5 mL/h/kg and 173 mL/kg, respectively, with a calculated half-life (t((1/2))) of 34.3 hours for S-ibuprofen. Estimated clearance at birth and volume of distribution were 25.5 mL/h/kg and 306 mL/kg with a t((1/2)) at birth of 8.3 hours for R-ibuprofen. R-ibuprofen elimination increased during the first week of life, whereas S-ibuprofen pharmacokinetics were weakly modified. Therefore, because the activity of the 2 enantiomers differs, it is important that subsequent studies consider R- and S-enantiomers separately. Mean simulated ibuprofen concentrations at various dose regimens were in agreement with observed concentrations. The present analysis allows a more accurate estimation of the ibuprofen pharmacokinetics as parameters could be estimated separately for each enantiomer and the effect of postnatal age on the elimination of R-ibuprofen was elicited.