Software for Dosage Individualization of Voriconazole for Immunocompromised Patients

Hope, William; VanGuilder, Michael; Donnelly, J. Peter; Blijlevens, Nicole M A; Brüggemann, Roger J. M.; Jelliffe, Roger W.; Neely, Michael

doi:10.1128/aac.02025-12

Cited by 40 publications

(39 citation statements)

References 21 publications

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“…TDM should be considered a component of routine care, although further work is required to identify drug exposure targets. The population PK model can now be used to construct algorithms for individualized dosing, as we described previously (33,34).…”

Section: Discussionmentioning

confidence: 99%

Population Pharmacokinetics of Teicoplanin in Children

Ramos-Martín

Paulus

Siner

et al. 2014

Antimicrob Agents Chemother

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Teicoplanin is frequently administered to treat Gram-positive infections in pediatric patients. However, not enough is known about the pharmacokinetics (PK) of teicoplanin in children to justify the optimal dosing regimen. The aim of this study was to determine the population PK of teicoplanin in children and evaluate the current dosage regimens. A PK hospital-based study was conducted. Current dosage recommendations were used for children up to 16 years of age. Thirty-nine children were recruited. Serum samples were collected at the first dose interval (1, 3, 6, and 24 h) and at steady state. A standard 2-compartment PK model was developed, followed by structural models that incorporated weight. Weight was allowed to affect clearance (CL) using linear and allometric scaling terms. 2). A significant rise in infections caused by methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant coagulasenegative staphylococci (CoNS) has led to increased use of glycopeptides in the last decade (3, 4). Both vancomycin and teicoplanin are used for treatment of invasive infections caused by Gram-positive organisms, especially those that are resistant to ␤-lactam antibiotics (5, 6). The currently recommended regimen for teicoplanin in adults is 3 loading doses of 400 mg every 12 hours followed by a maintenance dose of 400 mg/day. In contrast, children receive 3 loading doses of 10 mg/kg of body weight every 12 hours followed by a maintenance dose of 10 mg/kg daily (7). However, there is a relative paucity of information to justify these regimens in children and even less information to identify optimal dosing strategies.Regulatory authorities such as the European Medicines Agency (EMA) have developed strategies to facilitate the safe and effective use of medicines in neonates and children (8). EMA supports the extrapolation of information from adults to children provided there are adequate safety data in the latter and the pharmacodynamics can reasonably assumed to be the same in both populations. This approach requires the development of robust population pharmacokinetic (PK) models in both adults and children, which facilitates the design of regimens that enable drug exposures in both populations to be matched (8).Teicoplanin is largely used without routinely measuring concentrations in the majority of pediatric patients. In our pediatric hospital setting, we have observed anecdotal cases of clinical failures with teicoplanin therapy and have observed "MIC creep" for CoNS with MICs at the breakpoint (4 mg/ liter) (unpublished data). To further investigate the clinical pharmacology of teicoplanin and to provide an insight into effective regimens for children, we performed a population PK study. The specific objectives of this study were to (i) describe the population PK of teicoplanin in children in a hospital setting, (ii) explore the percentage of patients attaining a predose minimum concentration (C min ) of Ͼ10 mg/liter, (iii) define the area under the concentration-time curve (AUC) distributions follo...

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Section: Discussionmentioning

confidence: 99%

Population Pharmacokinetics of Teicoplanin in Children

Ramos-Martín

Paulus

Siner

et al. 2014

Antimicrob Agents Chemother

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“…The voriconazole cartridge included the structural model equations relating input (voriconazole dosing) to output (voriconazole plasma concentrations) and the discrete joint probability distribution of the values of the equation variables (pharmacokinetic parameters) in the population, consisting of support points. The software used the cartridge and each patient's weight and voriconazole dosing and concentration data to find the least biased and most precise dosage regimen relative to a target concentration, as previously described (29).…”

Section: Subjects and Proceduresmentioning

confidence: 99%

“…In this paper, we present a validation scheme that is similar to what we devised for the adult controller software (29) but that is now applied to children. The algorithm is able to track measured concentrations in the past and either to calculate doses to achieve future target drug exposures or to predict future exposures for a given dose.…”

Section: Figmentioning

confidence: 99%

Achieving Target Voriconazole Concentrations More Accurately in Children and Adolescents

Neely

Margol

et al. 2015

Antimicrob Agents Chemother

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f Despite the documented benefit of voriconazole therapeutic drug monitoring, nonlinear pharmacokinetics make the timing of steady-state trough sampling and appropriate dose adjustments unpredictable by conventional methods. We developed a nonparametric population model with data from 141 previously richly sampled children and adults. We then used it in our multiplemodel Bayesian adaptive control algorithm to predict measured concentrations and doses in a separate cohort of 33 pediatric patients aged 8 months to 17 years who were receiving voriconazole and enrolled in a pharmacokinetic study. Using all available samples to estimate the individual Bayesian posterior parameter values, the median percent prediction bias relative to a measured target trough concentration in the patients was 1.1% (interquartile range, ؊17.1 to 10%). Compared to the actual dose that resulted in the target concentration, the percent bias of the predicted dose was ؊0.7% (interquartile range, ؊7 to 20%). Using only trough concentrations to generate the Bayesian posterior parameter values, the target bias was 6.4% (interquartile range, ؊1.4 to 14.7%; P ‫؍‬ 0.16 versus the full posterior parameter value) and the dose bias was ؊6.7% (interquartile range, ؊18.7 to 2.4%; P ‫؍‬ 0.15). Use of a sample collected at an optimal time of 4 h after a dose, in addition to the trough concentration, resulted in a nonsignificantly improved target bias of 3.8% (interquartile range, ؊13.1 to 18%; P ‫؍‬ 0.32) and a dose bias of ؊3.5% (interquartile range, ؊18 to 14%; P ‫؍‬ 0.33). With the nonparametric population model and trough concentrations, our control algorithm can accurately manage voriconazole therapy in children independently of steady-state conditions, and it is generalizable to any drug with a nonparametric pharmacokinetic model. (This study has been registered at ClinicalTrials.gov under registration no. NCT01976078.) V oriconazole is the approved first-line therapy for aspergillosis in patients who are at least 12 years of age in the United States and at least 2 years of age elsewhere. Numerous reports of studies in both adults (1-7), including a prospective randomized trial (8), and children (9-11) have documented improved outcomes when trough concentrations are maintained above 1 mg/liter, which is a readily measured clinical surrogate for the full area under the concentration-time curve (AUC) that drives efficacy (12-15).However, the pharmacokinetic behavior of voriconazole is complex and nonlinear, such that in many patients, small dose changes are associated with disproportionately large changes in the plasma concentrations of the drug. While it is more common in adults, nonlinear, saturated pharmacokinetic behavior is readily observed in children who receive doses higher than those that have been approved by regulatory agencies (16). This nonlinearity also makes the half-life and the time to steady state dependent on the dose and concentration, complicating the ability to compare steady-state trough concentrations to the accepted therapeu...

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“…Optimised dosing using an estimation of an individual's PK to identify the optimal dosage has not been undertaken with anti-bacterial agent. Pilot studies, within other infectious diseases areas, have demonstrated with HIV drugs in paediatric patients and in the management of invasive pulmonary aspergillosis with voriconazole (Neely and Jelliffe 2010;Hope et al 2013). The impact of dosage adaptation on patient outcome requires further study.…”

Section: Accepted Manuscriptmentioning

confidence: 99%