Influence of food on pharmacokinetics and pharmacodynamics of 4-phenylbutyrate in patients with urea cycle disorders.

Urea cycle disorders (UCDs), inborn errors of hepatocyte metabolism, cause hyperammonemia and lead to neurocognitive deficits, coma, and even death. Sodium 4-phenylbutyrate (NaPB), a standard adjunctive therapy for UCDs, generates an alternative pathway of nitrogen deposition through glutamine consumption. Administration during or immediately after a meal is the approved usage of NaPB. However, we previously found that preprandial oral administration enhanced its potency in healthy adults and pediatric patients with intrahepatic cholestasis. The present study evaluated the effect of food on the pharmacokinetics and pharmacodynamics of NaPB in five patients with UCDs. Following an overnight fast, NaPB was administered orally at 75 mg/kg/dose (high dose, HD) or 25 mg/kg/dose (low dose, LD) either 15 min before or immediately after breakfast. Each patient was treated with these four treatment regimens with NaPB. With either dose, pre-breakfast administration rather than post-breakfast administration significantly increased plasma PB levels and decreased plasma glutamine availability. Pre-breakfast LD administration resulted in a greater attenuation in plasma glutamine availability than post-breakfast HD administration. Plasma levels of branched-chain amino acids decreased to the same extent in all tested regimens. No severe adverse events occurred during this study. In conclusion, preprandial oral administration of NaPB maximized systemic exposure of PB and thereby its efficacy on glutamine consumption in patients with UCDs.

Optimal sampling time-point for cyclosporin A concentration monitoring in heart transplant recipients.

The present study was performed to determine an optimal time-point for monitoring the concentration of the immunosuppressive drug cyclosporin A (CsA) in heart transplant patients and its efficacy in the prevention of transplant rejection. A total of 32 transplant recipients were randomly assigned for three treatment approaches. Recipients in groups A (n=11), B (n=13) and C (n=8) received oral administration of CsA at doses of 3.2, 3.5 and 4.4 mg/kg, respectively. The plasma CsA concentrations were examined at 2 h intervals over 12 h. Furthermore, their correlation with the 4 h pharmacokinetic profiles as the area under the plasma CsA concentration vs. time curve (AUC0-4 h) were calculated The efficacy of CsA in inhibiting cardiac allograft rejection was assessed at 2 h after oral CsA intake (C2) and adverse events of the drug were examined in the C2-monitored recipients. The plasma CsA concentration rapidly increased in most recipients with a peak level detected at ~2 h after dosing. Regression analysis revealed that among all time-points assessed, the CsA had the highest correlation with the AUC0-4 h at C2. At C2, increasing CsA doses exhibited a positive association with the measure of AUC0-4 h. The efficacy of increasing CsA target levels at C2 in preventing heart transplant rejection was comparable, as the survival rate was 100% in all of the treatment groups. However, the proportion of recipients with side effects in group A was obviously lower than that in the other two groups. In conclusion, C2 is an ideal time-point for monitoring plasma CsA levels with a utility for individualising the next scheduled dose for each patient to ensure that target levels are maintained and achieve a high efficacy and safety of CsA therapy in heart transplant recipients (clinical trial no. 12002610).

Efficacy and safety of QVA149 compared to the concurrent administration of its monocomponents indacaterol and glycopyrronium: the BEACON study.

INTRODUCTION: The BEACON study evaluated the efficacy and safety of QVA149, a once-daily dual bronchodilator containing a fixed-dose combination of the long-acting ß2-agonist (LABA) indacaterol and long-acting muscarinic antagonist (LAMA) glycopyrronium (NVA237), in development for the treatment of patients with chronic obstructive pulmonary disease (COPD), compared with the free-dose concurrent administration of indacaterol plus glycopyrronium (IND+GLY). METHODS: In this multicenter, double-blind, parallel group study, patients with stage II or stage III COPD (Global initiative for chronic Obstructive Lung Disease [GOLD] 2010) were randomized (1:1) to once-daily QVA149 (110 µg indacaterol/50 µg glycopyrronium) or concurrent administration of indacaterol (150 µg) and glycopyrronium (50 µg) via the Breezhaler® device (Novartis AG, Basel, Switzerland) for 4 weeks. The primary endpoint was to evaluate the noninferiority of QVA149 as compared with concurrent administration of IND+GLY, for trough forced expiratory volume in 1 second (FEV1) after 4 weeks of treatment. The other assessments included FEV1 area under the curve from 0 to 4 hours (AUC0-4 hours) at day 1 and week 4, symptom scores, rescue medication use, safety, and tolerability over the 4-week study period. RESULTS: Of 193 patients randomized, 187 (96.9%) completed the study.Trough FEV1 at week 4 for QVA149 and IND+GLY was 1.5 L ± 0.02 [DOSAGE ERROR CORRECTED] and 1.46 L ± 0.18, respectively. The FEV1 AUC0-4 hours at day 1 and week 4 were similar between the two treatment groups. Both treatment groups had a similar reduction in symptom scores and rescue medication use for the 4-week treatment period. Overall, 25.6% of patients in QVA149 group and 25.2% in the IND+GLY group experienced an adverse event, with the majority being mild-to-moderate in severity. No deaths were reported during the study or during the 30 days follow-up period. CONCLUSION: The BEACON study demonstrated that once-daily QVA149 provides an efficacy and safety profile similar to the concurrent administration of its monocomponents indacaterol and glycopyrronium.

MDR1 polymorphisms effect cyclosporine AUC0-4 values in Behçet's disease patients.

Cyclosporine (CYA) is used to preventing ocular attacks in Behçet's disease patients. Yet there are inter-individual variations in efficacy. In order to analyze the relationship between CYA fluctuation with treatment effectiveness and genetic factors, an association of area under the plasma concentration time at 0-4 hours (AUC0-4) values and polymorphism for multidrug resistance 1 (MDR1) and cytochrome3A5 (CYP3A5) genes was investigated. Genomic DNA was collected from 17 Japanese patients with Behçet's disease. MDR1 polymorphisms were determined by direct sequencing from amplified products for promoter and two exons regions and CYP3A5 polymorphisms were analyzed using polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) method. AUC0-4 value was determined by the trapezoidal rule from the data of 5 times blood sampling at 0-4 hours. The haplotype 2 in the promoter region of MDR1 influenced significantly lower AUC0-4 values, implying absorption decline of CYA. The CYP3A5 polymorphisms had no direct influence on the effectiveness for CYA treatment. In the relation of CYA and AUC0-4 in the patients, 7 cases were grouped effective and 4 ineffective. Though there was no difference in dosage, the trough values for AUC0-4 were higher in the effective group compared to the ineffective group.

The Assessment of the Method of Monitoring in Liver Transplant Recipients Treated with Microemulsion Cyclosporine (Neoral(R)) and Mycophenolate Mofetil (CellCept(R)) / 대한이식학회지

PURPOSE: Cyclosporine (CsA) dosing is traditionally based on trough levels (C0) rather than area under the concentration- time curve (AUC), although AUC correlates better with post- transplantation acute rejection and toxicity. It was reported that C2 (2-hour post-dose blood level) is an accurate single- sample marker for AUC0-4 in patients receiving CsA. No trials of C2 monitoring have been carried out in liver transplant recipients who are immunosuppressed with the combination of CsA and Mycophenolate Mofetil (MMF). The purpose of this study was to evaluate the correlation between C0, 1, 2, 3, 4 levels and AUC0-4 and define recommended target C2 in liver transplant recipients who are treated with CsA and MMF. METHODS: Thirty adult living donor liver transplant recipients were followed up 12 weeks after transplantation. CsA and MMF were administered in all recipients. CsA dose was reduced to the half level of target C0 in recipients treated solely with CsA. C0 and C2 were measured during in-patient period post-transplant. RESULTS: The best correlation between CsA concentration at various time points and the AUC0-4 was found at C2 (r2=0.931) (P<0.05). Mean C2 was 543.2+/-260.1 ng/mL (mean+/-SD). We observed complications associated with the immunosuppressants in six patients (20%). But, only one patient experienced acute rejection proven by biopsy and, there is no the graft loss and nephrotoxicity. CONCLUSION: In early post-transplant days, AUC0-4 was strongly correlated with C2. Reduced CsA dosing can be attempted in recipients who are immunosuppressed with the combination of CsA and MMF. The optimal target C2 probably can be suggested as about 543.2+/-260.1 ng/mL (mean+/-SD). During the in-patient period, C0 matched with target C2 can be decided. Target C0 can be individualized because C0 matched with target C2 differs in each recipients and C2 can't be checked routinely during the out-patient period.

Efficacy of Cyclosporine Microemulsion C2 Monitoring in Renal Transplants / 대한이식학회지

PURPOSE: In monitoring blood concetration of cyclosporine after transplantation, four-hour under the conentration-time curve (AUC0-4) was reported superior to C0, and C2 was well correlated with AUC0-4. The purpose of this study is to evaluate the validity and usefulness of C2 monitoring compared with C0 monitoring in kidney transplants using cyclosporine microemulsion. METHODS: From Jan. 2002 to Dec. 2002, twenty primary living donor kidney transpant patients were selected and followed up for 6 months after transplantation. C0 was checked daily for 2 weeks after transplantation then every week for a month, every two week for a month and monthly thereafter. C2 was checked at 1, 7, 14 days after operation then checked every 4, 8, 12, 16, 20, 24 weeks. AUC0-4 was calculated at 1 day, 1 week, 2 week and 6 months after transplantation. Historical control group was made of 20 cosecutive kidney transplants who had had transplanted just before the start of the study. The were monitored according to the C0 level. RESULTS: CsA absorption kinetics were different that of caucasian data. Twelve patients (63%) at 7th post-operative day and 17 patients (85%) at 14th post-operative day reached Cmax at 2 or 3 hours after ingestion of cyclosporine irrespective of rejection. AUC0-4 was best correlated with C2 levels at 14th post-operative day (R2>0.800). Most of patients did not reach recommended therapeutic level of international consensus. Only one patient had experienced acute rejection after transplantation but three patients had experienced nephrotoxicity after transplantation although they had shown the relatively low levels of AUC0-4 and C2. No statistical differences were found in AUC0-4, C2, and C0 levels compared with patients without rejection. CONCLUSION: AUC0-4 was better correlated with C2 than C0. There was no statistical difference in the incidence of the acute rejection between C2 group and C0 group. Although AUC0-4, and C2 levels were relatively low, C2 group had shown good renal function. Further study is needed to define optimal guidelines for monitoring C2 and AUC0-4 in korean.