Population pharmacokinetics and Bayesian forecasting of vancomycin in neonates requiring intensive care

PURPOSE The primary objective of this investigation was to develop a population-based pharmacokinetic model of vancomycin in neonates that can be utilized in the individualization of drug therapy. The second objective was to evaluate the accuracy and precision of a Bayesian forecasting method, based on an optimum population pharmacokinetic model, for predicting serum vancomycin concentrations in neonates. METHODS Patients All neonates with a post-conceptional age (PCA) of < 44 weeks admitted to the special care nursery (SCN) of Children's and Women's Health Centre of British Columbia (C & W) between January 01, 1996 and December 31, 1999 and prescribed vancomycin by their attending physicians were eligible for enrollment. Population Pharmacokinetic Modeling Population pharmacokinetic models, using an iterative stepwise approach, were developed for vancomycin with data from 185 patients using a nonlinear mixed effects modeling program (NONMEM). Significant covariates were those that resulted in a decrease in the minimum value of the objective function (MOF) of > 6.6 points. Final one- and twocompartment models were evaluated with data from a naive cohort of 65 patients. Following model validation, combined population pharmacokinetic models were fully developed using data from all 250 patients. As with the original model development, an iterative process was implemented to generate base, full, and final models. Bayesian Forecasting Serum vancomycin concentration predictions based on Bayesian estimates were provided in a NONMEM generated output using the POSTHOC function. Vancomycin concentrations were independently supplied as feedback observations to the final, one-and two-compartment models to obtain case-specific predictions of vancomycin peak and trough concentrations.' The precision and accuracy of Bayesian predictions were assessed using mean absolute error and mean error, respectively, and compared using 95% confidence intervals. RESULTS At all sequential stages, the one-compartment model appeared inferior to the twocompartment model. The minimum values of the objective function (MOF) from the onecompartment unadjusted, base model and revised model, were respectively, 438.52 and 29.84 points greater than the comparable two-compartment values. Weight and PCA (relative to term gestation), modeled as power functions, yielded significant reductions in the MOF when included as covariates on vancomycin clearance. Dopamine exposure was associated with a 34% decrease in vancomycin clearance. Patient weight was modeled as a linear function on the central volume of distribution. Chronic lung disease was associated with a 276% increase in the peripheral volume (Vp). The Vp represented 50% of the volume of distribution at steady-state in the youngest patients, but only 9% in the oldest patients. Model validation demonstrated better accuracy of the two-compartment model. The final, combined models were similar, except that indomethacin was associated with a 16% decrease in vancomycin clearance in the twocompartment model. The two-compartment model was more accurate than the one-compartment model in the Bayesian prediction of initial peak and trough concentrations in neonates < 36 weeks PCA. Bayesian predictions using trough samples as feedback yielded relative mean errors of < 3% for both initial and future peak concentrations. Relative mean absolute error was 6% and 12% for initial and future peak concentrations, respectively. CONCLUSIONS The two-compartment model was superior to the one-compartment model, particularly in neonates < 36 weeks PCA. The better specified two-compartment model also generated more accurate Bayesian predictions of peak and trough concentrations in neonates < 36 weeks PCA. Single trough samples using the two-compartment model and Bayesian forecasting appear to be clinically useful for therapeutic drug monitoring of vancomycin in the SCN population.Pharmaceutical Sciences, Faculty ofGraduat

On-the-Road Driving Performance the Morning after Bedtime Use of Suvorexant 20 and 40 mg: A Study in Non-Elderly Healthy Volunteers

Study Objective: To evaluate next-morning driving performance in adults younger than 65 years, after single and repeated doses of suvorexant 20 and 40 mg. Design: Double-blind, placebo-controlled, 4-period crossover study. Setting: Maastricht University, The Netherlands. Participants: 28 healthy volunteers (15 females), aged 23 to 64 years. Interventions: Suvorexant (20 and 40 mg) for 8 consecutive nights; zopiclone 7.5 mg nightly on day 1 and 8; placebo. Measurements: Performance on day 2 and 9 (9 h after dosing) using a one-hour standardized highway driving test in normal traffic, measuring standard deviation of lateral position (SDLP). Drug-placebo changes in SDLP > 2.4 cm were considered to reflect meaningful driving impairment. Results: Mean drug-placebo changes in SDLP following suvorexant 20 and 40 mg were 1.01 and 1.66 cm on day 2, and 0.48 and 1.31 cm on Day 9, respectively. The 90% CIs of these changes were all below 2.4 cm. Symmetry analysis showed that more subjects had SDLP changes > 2.4 cm than < -2.4 cm following suvorexant 20 and 40 mg on day 2, and following suvorexant 40 mg on day 9. Four female subjects requested that a total of 5 driving tests-all following suvorexant-stop prematurely due to self-reported somnolence. Conclusions: As assessed by mean changes in standard deviation of lateral position (SDLP), there was no clinically meaningful residual effect of suvorexant in doses of 20 and 40 mg on next-morning driving (9 h after bedtime dosing) in healthy subjects < 65 years old. There may be some individuals who experience next-day effects, as suggested by individual changes in SDLP and prematurely stopped tests

On-the-road driving performance the morning after bedtime use of suvorexant 15 and 30 mg in healthy elderly

Suvorexant is a first-in-class orexin receptor antagonist for treating insomnia. There is a general concern that hypnotics may impair next-morning driving ability. The objective of this study was to evaluate next-morning driving performance in older adults after single and repeated doses of suvorexant. Double-blind, randomized, placebo-controlled, 4-period crossover study in 24 healthy volunteers (10 females), aged 65-80 years. Subjects were treated with suvorexant (15 and 30 mg) for eight consecutive nights, zopiclone 7.5 mg nightly on days 1 and 8, and placebo. Driving performance was assessed on days 2 and 9 (9 h after dosing) using a 1-h standardized highway driving test in normal traffic, measuring standard deviation of lateral position (SDLP). Drug-placebo differences in SDLP > 2.4 cm were considered to reflect clinically meaningful driving impairment. Driving performance as measured by SDLP was not impaired following suvorexant. Mean drug-placebo differences in SDLP following suvorexant 15 and 30 mg on day 2 and 9 were 0.6 cm or less. Their 90 % CIs were all below the threshold of 2.4 cm for clinical relevance and included zero, indicating effects were not clinically meaningful or statistically significant. Symmetry analysis showed no significant differences between the number of participants who had SDLP differences > 2.4 cm and those who had SDLP differences There was no clinically meaningful residual effect of suvorexant 15 and 30 mg on next-morning driving (9 h after bedtime dosing) in healthy older adults, as assessed by mean changes in SDLP and by the number of participants on drug versus placebo that exceeded a predetermined threshold for clinically meaningful impairment