Pharmacokinetics (PK) plays a key role in bridging drug efficacy and safety from adults to pediatric patients. The principal purpose of projecting dosing in pediatrics is to guide trial design, not to waive the study per se. This research was designed to evaluate whether the allometric scaling (AS) approach is a satisfactory method to design PK studies in pediatric patients aged 2 years and older. We systematically evaluated drugs that had pediatric label information updated from 1998 to 2015. Only intravenous (IV) or oral administration drugs with available PK information in both children and adults from FDA-approved labels were included. The allometric scaling approach was used to extrapolate adult clearance to pediatric clearance. The relative difference between the observed and the allometric scaling approach-predicted clearance was summarized and used to evaluate the predictive power of the allometric scaling approach. A total of 36 drugs eliminated by a metabolic pathway and 10 drugs by the renal pathway after intravenous (IV) or oral administration were included. Regardless of the administration route, elimination pathway, and age group, the allometric scaling approach can predict clearance in pediatric patients within a 2-fold difference; 18 of the included drugs were predicted within a 25% difference, and 31 drugs within a 50% difference. The allometric scaling approach can adequately design PK studies in pediatric subjects 2 years and older.

Conducting and analyzing clinical trials in vulnerable neonates are extremely challenging. The aim of this analysis is to develop a morphine population pharmacokinetics (PK) model using data collected during a randomized control trial in neonates with Abstinence Syndrome (NAS). Three compartment morphine structural PK model after intravenous (IV) administration from previously published work was utilized as prior, while allometric scaling method with physiological consideration was used to extrapolate PK profile from adults to pediatrics. Absorption rate constant and bioavailability were estimated in neonates with abstinence syndrome after oral administration of diluted tincture of opium (DTO). Goodness-of fit plots along with normalized prediction distribution error and bootstrap method were performed for model evaluation. We successfully extrapolated the PK profile from adults to pediatrics after IV administration. The estimated first-order absorption rate constant and bioavailability were 0.751 hour -1 and 48.5%, respectively. Model evaluations showed that the model can accurately and precisely describe the observed data. The population pharmacokinetic model we derived for morphine after oral administration of DTO is reasonable and acceptable; therefore, it can be used to describe the PK and guide future studies. The integration of the previous population PK knowledge as prior information successfully overcomes the logistic and practical issue in vulnerable neonate population.

Aim: To investigate the pharmacokinetics, pharmacodynamics, and safety of higenamine, an active ingredient of Aconite root, in healthy Chinese volunteers. Methods: Ten subjects received continuous, intravenous infusion of higenamine at gradually escalating doses from 0.5 to 4.0, each dose was given for 3 min. Blood and urine samples were collected at designated time points to measure the concentrations of higenamine. Pharmacodynamics was assessed by measuring the subject's heart rate. A nonlinear mixed-effect modeling approach, using the software Phoenix NLME, was used to model the plasma concentration-time profiles and heart rate. .3% (range, 4.6%-12.4%) of higenamine was recovered in the urine. The pharmacokinetics of higenamine was successfully described using a two-compartment model with nonlinear clearance. In the pharmacodynamic model, heart rates were related to the plasma drug concentrations using a simple direct effect model with baseline. The E 0 , E max , and EC 50 were 68 bpm, 73 bpm and 8.1 μg/L, respectively. Conclusion: Higenamine has desirable pharmacokinetic and pharmacodynamic characteristics. The results provide important information for future clinical studies on higenamine.

Oral metolazone was noninferior to IV chlorothiazide for enhancing net UOP in patients with ADHF and loop diuretic resistance and was similarly safe with regard to renal function and electrolyte abnormalities. Given the significant cost disparity between the two agents, these findings suggest that oral metolazone may be considered a first-line option in this patient population.