The use of modeling and simulation to guide clinical development of olmesartan medoxomil in pediatric subjects

Modeling and simulation were used extensively in the development of an indication for the use of olmesartan medoxomil in pediatric patients with hypertension. Simulations based on models developed in adult patients indicated that two dose groups were sufficient to estimate a dose-response relationship, thereby reducing by one-third the number of subjects required for the phase III pediatric study. Model-based predictions for blood pressure reduction agreed with the observed results of the subsequent phase III study, showing statistically significant dose-response relationships with respect to both systolic and diastolic blood pressure. Previously established pharmacokinetic and exposure-response relationships in adults, adjusted for the influence of body weight on clearance (wt(0.80)), were confirmed in the pediatric population. Together, these findings support an olmesartan dosing recommendation in pediatric subjects aged 6 to 16 years of 10 mg for subjects weighing <35 kg and 20 mg for those weighing ≥35 kg.     

Modelling and simulation of edoxaban exposure and response relationships in patients with atrial fibrillation

Edoxaban is a novel, orally available, highly specific direct inhibitor of factor Xa and is currently being developed for the treatment and prevention of venous thromboembolism and prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF). The objectives of the present analyses were to characterise edoxaban population pharmacokinetics (PPK) and identify potential intrinsic and extrinsic factors affecting variability in edoxaban exposure, determine if there are relationships between edoxaban pharmacokinetics or biomarkers and the risk of bleeding in patients with NVAF using an exposure-response model, and to use the PPK and exposure-response model to support dose selection for a phase III trial of edoxaban in patients with NVAF. PPK analysis of data from 1,281 edoxaban-dosed subjects with intrinsic factors such as renal impairment or NVAF and extrinsic factors such as concomitant medications revealed significant effects of renal impairment and concomitant strong P-glycoprotein (P-gp) inhibitors on the pharmacokinetics of edoxaban. Exposure-response analysis found that in patients with NVAF, the incidence of bleeding events increased significantly with increasing edoxaban exposure, with steady-state minimum concentration (Cmin,ss) showing the strongest association. Clinical trial simulations of bleeding incidence were used to select 30 mg and 60 mg once-daily edoxaban with 50% dose reductions for patients with moderate renal impairment or receiving concomitant strong P-gp inhibitors as the treatment regimens in the ENGAGE AF-TIMI 48 (NCT00781391) trial.     

Pathophysiological mechanisms of dominant and recessive KVLQT1 K+ channel mutations found in inherited cardiac arrhythmias

The inherited long QT syndrome (LQTS), characterized by a prolonged QT interval in the electrocardiogram and cardiac arrhythmia, is caused by mutations in at least four different genes, three of which have been identified and encode cardiac ion channels. The most common form of LQTS is due to mutations in the potassium channel gene KVLQT1, but their effects on associated currents are still unknown. Different mutations in KVLQT1 cause the dominant Romano-Ward (RW) syndrome and the recessive Jervell and Lange-Nielsen (JLN) syndrome, which, in addition to cardiac abnormalities, includes congenital deafness. Co- expression of KvLQT1 with the IsK protein elicits slowly activating potassium currents resembling the cardiac Iks current. We now show that IsK not only changes the kinetics of KvLQT1 currents, but also its ion selectivity. Several mutations found in RW, including a novel mutation (D222N) in the putative channel pore, abolish channel activity and reduce the activity of wild-type KvLQT1 by a dominant-negative mechanism. By contrast, a JLN mutation truncating the carboxyterminus of the KvLQT1 channel protein abolishes channel function without having a dominant-negative effect. This fully explains the different patterns of inheritance. Further, we identified a novel splice variant of the KVLQT1 gene, but could not achieve functional expression of this nor of a previously described heart-specific isoform.      

低聚果糖口服补液盐的试制

目的：改良口服补液盐（ＯＲＳ）,使其具有微生态调节作用、并与肠道内渗透压相似。方法：将氯化钠２．６ｇ、氯化钾１．５ｇ、枸橼酸钠２．９ｇ、低聚果糖（ＦＯＳ）２０ｇ和葡萄糖１０ｇ等混合后低聚果糖口服液盐（ＦＯＳ－ＯＲＳ）。密封包装,使用时加开水１０００ｍｌ冲服。可采用高效液相色谱法测定ＦＯＳ的含量。结果：ＦＯＳ－ＯＲＳ为白色散剂,加水后为无色透明液体,味甜中微咸,其浓度（ｍｍｏｌ／Ｌ）为钠７５、钾２０     

Mutations in purine nucleoside phosphorylase deficiency

Purine nucleoside phosphorylase deficiency is an inherited disease of purine metabolism characterized clinically as combined immunodeficiency. The molecular defects have been published for 4 different alleles in 3 patients. We report four new mutations including two amino acid substitutions, A 174P and G190V, a single codon deletion, ΔI129, and a point mutation in intron 3 which leads to aberrant splicing and creation of a premature stop codon in exon 4 (286 -18G→A). Of the previously reported mutations, E89K was found in one additional patient, and R234P was found in 3 unrelated patients, making R234P the most common mutation reported to date in this disease. Hum Mutat 9:118–121, 1997. © 1997 Wiley-Liss, Inc.     

Population pharmacokinetic model for a novel oral hypoglycemic formed in vivo: comparing the use of active metabolite data alone versus using data of upstream and downstream metabolites

The purpose of this analysis was to develop a population pharmacokinetic model for CS-917, an oral hypoglycemic prodrug, and its 3 metabolites. The population pharmacokinetic model was used to predict exposure of the active moiety R-125338 and thus to identify potential CS-917 dosage reduction criteria. The dataset included 6 phase I and IIa studies in patients with type 2 diabetes mellitus. The pharmacokinetic profile of CS-917 and its metabolites was described by a series of linked 1- and 2-compartmental models. Simulations showed that moderate renal impairment has a clinically significant impact on exposure to R-125338. A separate population pharmacokinetic analysis of R-125338 alone revealed similar results. In conclusion, a population pharmacokinetic model fit to the active moiety alone yielded similar predictions and substantially reduced the analysis time compared to the more complex model developed for CS-917 and its metabolites. Increased exposure to R-125338 in the presence of moderate renal impairment may be an important consideration for dose selection.     

The active components of effective training in obstetric emergencies

Confidential enquiries into poor perinatal outcomes have identified deficiencies in team working as a common factor and have recommended team training in the management of obstetric emergencies. Isolated aviation-based team training programmes have not been associated with improved perinatal outcomes when applied to labour ward settings, whereas obstetric-specific training interventions with integrated teamwork have been associated with clinical improvements. This commentary reviews obstetric emergency training programmes from hospitals that have demonstrated improved outcomes to determine the active components of effective training. The common features identified were: institution-level incentives to train; multi-professional training of all staff in their units; teamwork training integrated with clinical teaching and use of high fidelity simulation models. Local training also appeared to facilitate self-directed infrastructural change.