Population Pharmacokinetics of Naloxegol in Pediatric Subjects Receiving Opioids.

The pharmacokinetics (PK) of naloxegol were characterized in pediatric subjects, aged 6 months or older to less than 18 years who either have or are at risk of developing opioid-induced constipation following single dose administration. Subjects grouped as aged 12 years or older to less than 18 years, 6 months or older to less than 12 years, and 6 months or older to less than 6 years, received a single oral dose of naloxegol at doses that were estimated to achieve plasma exposures comparable to adult 12.5- or 25-mg doses. Intensive and sparse plasma naloxegol samples were collected to assess naloxegol concentrations. Data were combined with previously collected adult PK data and used to estimate PK parameters using population PK analyses. Naloxegol PK was described using a 2-compartment model with Weibull-type absorption. Neither age nor body weight was identified as a significant covariate indicating similar PK properties in adult and pediatric subjects. PK estimates in the youngest age group were approximately 80% less than those in adults (12.5-mg equivalent dose). Exposures in the other pediatric groups were similar to those in adult equivalent doses. The PK of naloxegol were characterized as linear over the dose range, with no clinically significant covariates and comparable PK characteristics in adults and pediatric subjects aged 6 months or older.

Item Response Theory Quantifies the Relationship Between Improvements in Serum Phosphate and Patient-Reported Outcomes in Adults With X-Linked Hypophosphatemia.

Burosumab is indicated for treatment of a rare bone disease, X-linked hypophosphatemia (XLH). The aim of this analysis was to evaluate the relationship between a treatment response biomarker and patient-reported outcomes (PROs). Longitudinal data for PROs were obtained from adults with XLH from a phase III study. Individual rich time profiles of the biomarker, serum phosphate were simulated using a prior population pharmacokinetic-pharmacodynamic model to calculate serum phosphate exposure metrics for each 28-day treatment cycle, which were then merged with PROs data. Item response theory parameters were first estimated to map a latent variable, ψ, that is, disability score, relative to baseline. Next, the relationships between serum phosphate exposures and ψ were modeled using a nonlinear mixed-effect (NLME) modeling approach. A combined item response theory-NLME model with average serum phosphate as a predictor of ψ described PROs data well. The model estimates suggested 28%, 31%, and 25% reduction in Western Ontario and McMaster Universities Osteoarthritis Index, brief pain inventory, and brief fatigue inventory scores, respectively, with every unit increase in average serum phosphate from the lower limit of normal (2.5 mg/dL). Additionally, a time effect of ~ 0.08% improvements each week was estimated. The analysis suggested that burosumab treatment-induced improvements in serum phosphate levels are associated with improvements in PROs in adults with X-linked hypophosphatemia. The analyses confirmed the importance of prolonged serum phosphate level correction in adult patients with XLH. These results can be useful to guide the design of further studies and to design treatment optimization strategies.

Population Pharmacokinetics of the Novel Adenosine A2A Antagonist/Inverse Agonist KW-6356 and Its Active Metabolite Following Single and Multiple Oral Administration in Healthy Individuals and Patients with Parkinson's Disease.

KW-6356 is a selective antagonist and inverse agonist of the adenosine A2A receptor. The primary aim of the present analysis was to characterize the pharmacokinetics (PK) of KW-6356 and its active metabolite M6 in healthy subjects and patients with Parkinson's disease (PD). We pooled concentration-time data from healthy subjects and patients with PD who were administered KW-6356. Using these data, we developed a population PK model by sequentially fitting the KW-6356 parameters followed by the M6 parameters. A first-order absorption with a 1-compartment model for KW-6356 and a 1-compartment model for M6 best described the profiles. The covariates included in the final models were food status (fed/fasted/unknown) on first-order absorption rate constant, baseline serum albumin level on apparent clearance of KW-6356, and baseline body weight on apparent volume of distribution of KW-6356 and apparent clearance of M6. No covariate had a clinically meaningful impact on KW-6356 or M6 exposure.