A simple extemporaneous oral suspension of aprepitant yields sufficient pharmacokinetic exposure in children

Introduction: Aprepitant is used for the treatment of chemotherapy induced nausea and vomiting. A liquid formulation is needed for treatment of young children. However, the commercial (powder for) suspension was not available worldwide for a prolonged period of time and, therefore, a 10 mg/mL aprepitant oral suspension was extemporarily prepared to prevent suboptimal antiemetic treatment. The current pharmacokinetic study was developed to investigate whether this extemporaneous oral suspension offers an appropriate treatment option.Methods: From 49 pediatric patients (0.7–17.9 years) 235 plasma concentrations were collected. Patients were either treated with our extemporaneous oral suspension (n = 26; 53%), commercially available capsules (n = 18; 37%), or the intravenous prodrug formulation of aprepitant (fosaprepitant, n = 5; 10%). Pharmacokinetic analyses were performed using nonlinear mixed effects modelling.Results: A one-compartment model adequately described the pharmacokinetics of aprepitant in children. The bioavailability of the extemporaneous oral suspension was not significantly different to that of the capsules (P = 0.26). The observed bioavailability throughout the total population was 83% (95% CI 69%-97%). The absorption of the extemporaneous oral suspension was 39.4% (95%CI 19.5–57.4%) faster than that of capsules (mean absorption time of 1.78 h (95%CI 1.32–2.35), but was comparable to that of the commercial oral suspension. The median area under the curve after (fos)aprepitant was 22.2 mg/L*h (range 8.9–50.3 mg/L*h) on day 1.Conclusion: Our extemporaneous oral suspension is an adequate alternative for the commercially (un)available oral suspension in young children. An adequate exposure to aprepitant in children was yielded and the bioavailability of the extemporaneous suspension was comparable to capsules.</p

Testing for Helicobacter pylori in dyspeptic patients suspected of peptic ulcer disease in primary care: cross sectional study

OBJECTIVES: To develop an easily applicable diagnostic scoring method to determine the presence of peptic ulcers in dyspeptic patients in a primary care setting; to evaluate whether Helicobacter pylori testing adds value to history taking. DESIGN: Cross sectional study. SETTING: General practitioners' offices in the Utrecht area of the Netherlands. PARTICIPANTS: 565 patients consulting a general practitioner about dyspeptic symptoms of at least two weeks' duration. MAIN OUTCOME MEASURES: The presence or absence of peptic ulcer; independent predictors of the presence of peptic ulcer as obtained from history taking and the added value of H pylori testing were quantified by using multivariate logistic regression analyses. RESULTS: A history of peptic ulcer, pain on an empty stomach, and smoking were strong and independent diagnostic determinants of peptic ulcer disease, with odds ratios of 5.5 (95% confidence interval 2.6 to 11.8), 2.8 (1.0 to 4.0), and 2.0 (1.4 to 6.0) respectively. The area under the receiver operating characteristic curve (ROC area) of these determinants together was 0.71. Adding the H pylori test increased the ROC area only to 0.75. However, in a group of patients at high risk, identified by means of a simple scoring rule based on history taking, the predictive value for the presence of peptic ulcer increased from 16% to 26% after a positive H pylori test. CONCLUSIONS: In the total group of dyspeptic patients in primary care, H pylori testing has no value in addition to history taking for diagnosing peptic ulcer disease. In a subgroup of patients at high risk of having peptic ulcer disease, however, it might be useful to test for and treat H pylori infections

Overestimation of the effect of (fos)aprepitant on intravenous dexamethasone pharmacokinetics requires adaptation of the guidelines for children with chemotherapy-induced nausea and vomiting

Purpose: Chemotherapy-induced nausea and vomiting (CINV) are common side effects in pediatric oncology treatment. Besides 5-HT3-antagonists, both dexamethasone and aprepitant are cornerstone drugs in controlling these side effects. Based on results of adult studies, the dexamethasone dose is reduced by 50% when combined with aprepitant, because of a drug-drug interaction, even though data on the interaction in children is lacking. The current study was developed to investigate the effect of aprepitant on dexamethasone clearance (CL) in children, in order to assess if dexamethasone dose reduction for concomitant use of aprepitant is appropriate in the current antiemetic regimen. Methods: In total, 65 children (0.6–17.9 years), receiving intravenous or oral antiemetic therapy (dexamethasone ± aprepitant) as standard of care, were included. 305 dexamethasone plasma concentrations were determined using LC–MS/MS. An integrated dexamethasone and aprepitant pharmacokinetic model was developed using non-linear mixed effects modelling in order to investigate the effect of aprepitant administration on dexamethasone CL. Results: In this population, dexamethasone CL in patients with concomitant administration of aprepitant was reduced by approximately 30% of the uninhibited CL (23.3 L/h (95% confidence interval 20.4–26.0)). This result is not consistent with the results of adult studies (50% reduction). This difference was not age dependent, but might be related to the route of administration of dexamethasone. Future studies are needed to assess the difference in oral/intravenous dexamethasone. Conclusion: When dexamethasone is given intravenously as a component of triple therapy to prevent CINV in children, we advise to reduce the dexamethasone dose by 30% instead of 50%

A simple extemporaneous oral suspension of aprepitant yields sufficient pharmacokinetic exposure in children

Introduction: Aprepitant is used for the treatment of chemotherapy induced nausea and vomiting. A liquid formulation is needed for treatment of young children. However, the commercial (powder for) suspension was not available worldwide for a prolonged period of time and, therefore, a 10 mg/mL aprepitant oral suspension was extemporarily prepared to prevent suboptimal antiemetic treatment. The current pharmacokinetic study was developed to investigate whether this extemporaneous oral suspension offers an appropriate treatment option. Methods: From 49 pediatric patients (0.7–17.9 years) 235 plasma concentrations were collected. Patients were either treated with our extemporaneous oral suspension (n = 26; 53%), commercially available capsules (n = 18; 37%), or the intravenous prodrug formulation of aprepitant (fosaprepitant, n = 5; 10%). Pharmacokinetic analyses were performed using nonlinear mixed effects modelling. Results: A one-compartment model adequately described the pharmacokinetics of aprepitant in children. The bioavailability of the extemporaneous oral suspension was not significantly different to that of the capsules (P = 0.26). The observed bioavailability throughout the total population was 83% (95% CI 69%-97%). The absorption of the extemporaneous oral suspension was 39.4% (95%CI 19.5–57.4%) faster than that of capsules (mean absorption time of 1.78 h (95%CI 1.32–2.35), but was comparable to that of the commercial oral suspension. The median area under the curve after (fos)aprepitant was 22.2 mg/L*h (range 8.9–50.3 mg/L*h) on day 1. Conclusion: Our extemporaneous oral suspension is an adequate alternative for the commercially (un)available oral suspension in young children. An adequate exposure to aprepitant in children was yielded and the bioavailability of the extemporaneous suspension was comparable to capsules

A Population Pharmacokinetic Modelling Approach to Unravel the Complex Pharmacokinetics of Vincristine in Children

Background Vincristine, a chemotherapeutic agent that extensively binds to beta-tubulin, is commonly dosed at 1.4-2.0 mg/m(2) capped at 2 mg. For infants, doses vary from 0.025-0.05 mg/kg or 50-80% of the mg/m(2) dose. However, evidence for lower doses in infants compared to older children is lacking. This study was conducted to unravel the complex pharmacokinetics of vincristine, including the effects of age, to assist optimal dosing in this population. Methods 206 patients (0.04-33.9 years; 25 patients < 1 years), receiving vincristine, with 1297 plasma concentrations were included. Semi-mechanistic population pharmacokinetic analyses were performed using non-linear mixed effects modelling. Results A three-compartment model, with one saturable compartment resembling saturable binding to beta-tubulin and thus, saturable distribution, best described vincristine pharmacokinetics. Body weight and age were covariates significantly influencing the maximal binding capacity to beta-tubulin, which increased with increasing body weight and decreased with increasing age. Vincristine clearance (CL) was estimated as 30.6 L/h (95% confidence interval (CI) 27.6-33.0), intercompartmental CL (Q) as 63.2 L/h (95%CI 57.2-70.1), volume of distribution of the central compartment as 5.39 L (95%CI 4.23-6.46) and of the peripheral compartment as 400 L (95%CI 357-463) (all parameters correspond to a patient of 70 kg). The maximal binding capacity was 0.525 mg (95%CI 0.479-0.602) (for an 18 year old patient of 70 kg), with a high association rate constant, fixed at 1300 /h and a dissociation constant of 11.5 /h. Interpretation A decrease of vincristine beta-tubulin binding capacity with increasing age suggests that young children tolerate higher doses of vincristine