Potential effects of the selective β(3)-adrenoceptor agonist mirabegron on cardiac repolarization were studied in healthy subjects. The four-arm, parallel, two-way crossover study was double-blind and placebo- and active (moxifloxacin)-controlled. After 2 baseline ECG days, subjects were randomized to one of eight treatment sequences (22 females and 22 males per sequence) of placebo crossed over with once-daily (10 days) 50, 100, or 200 mg mirabegron or a single 400-mg moxifloxacin dose on day 10. In each period, continuous ECGs were recorded at two baselines and on the last drug administration day. The lower one-sided 95% confidence interval for moxifloxacin effect on QTcI was >5 ms, demonstrating assay sensitivity. According to ICH E14 criteria, mirabegron did not cause QTcI prolongation at the 50-mg therapeutic and 100-mg supratherapeutic doses in either sex. Mirabegron prolonged QTcI interval at the 200-mg supratherapeutic dose (upper one-sided 95% CI >10 ms) in females, but not in males.

Micafungin is an echinocandin with potent activity against Candida spp. Hematogenous Candida meningoencephalitis (HCME) is a frequent complication of disseminated Candida infection in premature infants. A preclinical model of HCME suggests that micafungin may be an effective agent for this syndrome, but relatively high weight-based dosages are required. This prompted the further study of the safety and pharmacokinetics (PK) of micafungin in infants. Here, we describe the population pharmacokinetics of micafungin in 47 infants with a proven or presumptive diagnosis of disseminated candidiasis, who received 0.75, 1.5, 3, 7, 10, and 15 mg/kg of micafungin. The drug was infused daily, and samples were taken in the first dosing interval and at steady state. Serum concentrations were measured using high-performance liquid chromatography (HPLC). Data were modeled using an allometric pharmacokinetic model using a three-fourths scaling exponent for clearance and parameters normalized to a 70-kg adult. Drug exposures were estimated using Monte Carlo simulation. Optimal sampling times were determined using D-optimal design theory. The fit of the allometric model to the data was highly acceptable. The pharmacokinetics of micafungin were linear. The weightnormalized estimates of clearance and volume of distribution approximated those previously described for adults. The original population parameter values could be recapitulated in the Monte Carlo simulations. A dosage of 10 mg/kg/day resulted in 82.6% of patients with areas under the concentration-time curve (AUCs) that are associated with near-maximal decline in fungal burden within the central nervous system (CNS).

No abstract

This first-in-human, phase I study evaluated the safety, tolerability, pharmacokinetic and pharmacodynamic profile of ASKP1240 in healthy subjects. Twelve sequential groups (each 6 active and 3 placebo) were randomly assigned to placebo or single ascending doses of intravenous ASKP1240 (0.00003-10 mg/kg). ASKP1240 exhibited nonlinear pharmacokinetics, with mean maximal serum concentrations and area under the serum concentration-time curves ranging from 0.7 to 251.6 lg/mL and 6.5 to 55409.6 h·lg/mL following doses 0.1 mg/kg-10 mg/kg, respectively. CD40 receptor occupancy by ASKP1240, which was dose-dependent, reached a maximum at doses above 0.01 mg/kg. ASKP1240 was well tolerated, with no evidence of cytokine release syndrome or thromboembolic events. Treatment emergent antibodies to ASKP1240 were detected in 5/70 (7.1%) ASKP1240 recipients. In conclusion, antagonism of the CD40/CD154 interaction with ASKP1240 was safe and well tolerated at the doses tested. Key words: ASKP1240, anti-CD40, pharmacodynamics, pharmacokinetics, randomizedAbbreviations: AEs, adverse events; AUC inf , area under the concentration-time curve from time zero extrapolated to the infinite time; C max , maximal antibody serum concentration; INR, international normalized ratio; LLOQ, lower limit of quantification; MABEL, minimal anticipated biological effect level; MedDRA, Medical Dictionary for Regulatory Activities; MFI, mean fluorescent intensity; PD, pharmacodynamic; PDAS, pharmacodynamic analysis set; PK, pharmacokinetic; PKAS, pharmacokinetic analysis set; SAF, safety analysis set; SD, standard deviation; t 1/2 , terminal half-life; t max , time to C max ; ULN, upper limit of normal.

Quality population modeling and simulation analyses and reports are something every modeler desires. However, little attention in the literature has been paid to what constitutes quality regarding population analyses. Very rarely do published manuscripts contain any statement about quality assurance of the modeling results contained therein. The purpose of this manuscript is to present guidelines for the quality assurance of population analyses, particularly with regards to the use of NONMEM from an industrial perspective. Quality guidelines are developed for the NONMEM installation itself, NONMEM data sets, control streams, output listings, output data files and resultant post-processing, reporting of results, and the review processes. These guidelines were developed to be thorough yet practical, though are not meant to be completely comprehensive. It is our desire to ensure that what is reported accurately reflects the collected data, the modeling process, and model outputs for a modeling project.

The object of this analysis was to develop a population pharmacokinetic model of micafungin, a new anti-fungal agent of the echinocandin class, to optimize dosing in Japanese patients with fungal infections. Population pharmacokinetics parameters were determined using NONMEM based on pharmacokinetic data from 198 subjects in seven clinical studies, comprising four phase I, two phase II and one pediatric phase III study. The healthy subjects received intravenous infusion of 2.5-150 mg micafungin. Adult and pediatric patients, age range of 8 month to 15 yeras old, were received 25-150 mg and 1-6 mg/kg daily, respectively. A total of 1825 micafungin plasma samples were available for this analysis. Two-compartment pharmacokinetic model was adopted. The clearance of micafungin was influenced by body weight in children and platelet counts (PLT). However the PLT accounted for less than 20% of the variation of micafungin clearance in Japanese subjects. In conclusions, body weight is the primary covariate factor in pediatric patients. The dose adjustment by body weight would be required only pediatric patients for the micafungin therapy in Japanese patients with fungal infection.

The aim of this analysis was to identify therapeutic micafungin regimens for children that produce the same micafungin exposures known to be effective for the prevention and treatment of Candida infections in adults. Pediatric pharmacokinetic data from 229 patients between the ages of 4 months and <17 years were obtained from four phase I and two phase III clinical trials. Population pharmacokinetic models were used to simulate the proportion of children who had a steady-state area under the concentration-time curve at 24 hours (AUC 24 ) of micafungin within the 10th to 90th percentile range observed in a population of adults receiving a dose of micafungin with established efficacy for invasive candidiasis (100 mg/day), i.e., 75 to 139 g · h/ml. Simulated pediatric dosages of 0.5 to 5 mg/kg of body weight/day were explored. A two-compartment model was used that incorporated body weight as a predefined covariate for allometric scaling of the pharmacokinetic parameters. During construction of the model, aspartate aminotransferase and total bilirubin were also identified as covariates that had a significant effect on micafungin clearance. A dose of 2 mg/kg resulted in the highest proportion of children within the predefined micafungin AUC 24 target range for invasive candidiasis. Cutoffs of 40 or 50 kg for weight-based dosing resulted in heavier children being appropriately dosed. Thus, dose regimens of 1, 2, and 3 mg/kg/day micafungin are appropriate for the prevention of invasive candidiasis, the treatment of invasive candidiasis, and the treatment of esophageal candidiasis, respectively, in children aged 4 months to <17 years. Micafungin is an echinocandin antifungal agent with activity against medically important fungal pathogens such as Candida spp. and Aspergillus spp. (1). It is licensed worldwide for the treatment of adults with invasive candidiasis, the prevention of invasive Candida infections, and the treatment of esophageal candidiasis. A dosage of 100 mg/day is used in adults weighing Ͼ40 kg with candidemia and/or invasive candidiasis. There is no additional benefit in using a higher dosage of 150 mg/day in these patients (2). A dosage of 50 mg/day is used for the prevention of invasive Candida infections in neutropenic patients, while a dosage of 150 mg/day is used for the treatment of esophageal candidiasis.The U.S. Food and Drug Administration (FDA) has approved the use of micafungin for pediatric patients Ͼ4 months of age for the same indications as adults (3). Micafungin is licensed by the European Medicines Agency (EMA) for the treatment of children (including neonates) and adolescents Ͻ16 years of age with invasive candidiasis and as prophylaxis in patients Ͻ16 years of age who are undergoing hematopoietic stem cell transplant or who are expected to have neutropenia (1).The safety and pharmacokinetics (PK) of micafungin in neonates, children, and adolescents have been determined in a number of clinical studies (4, 5). These studies enrolled patients across different age groups and have led to th...

SummaryPurpose Population pharmacokinetics (PK) of sepantronium bromide (YM155) was characterized in patients with non-small cell lung cancer, hormone refractory prostate cancer, or unresectable stage III or IV melanoma and enrolled in one of three phase 2 studies conducted in Europe or the U.S. Method Sepantronium was administered as a continuous intravenous infusion (CIVI) at 4.8 mg/m2/day over 7 days every 21 days. Population PK analysis was performed using a linear one-compartment model involving total body clearance (CL) and volume of distribution with an inter-individual random effect on CL and a proportional residual errors to describe 578 plasma sepantronium concentrations obtained from a total of 96 patients by NONMEM Version VI. The first-order conditional estimation method with interaction was applied. Results The one-compartment model with one random effect on CL and two different proportional error models provided an adequate description of the data. Creatinine clearance (CLCR), cancer type, and alanine aminotransferase (ALT) were recognized as significant covariates of CL. CLCR was the most influential covariate on sepantronium exposure and predicted to contribute to a 25 % decrease in CL for patients with moderately impaired renal function (CLCR = 40 mL/min) compared to patients with normal CLCR. Cancer type and ALT had a smaller but nonetheless significant contribution. Other patient characteristics such as age, gender, and race were not considered as significant covariates of CL. Conclusions The results provide the important information for optimizing the therapeutic efficacy and minimizing the toxicity for sepantronium in cancer therapy.