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Determining population and developmental pharmacokinetics of metronidazole using plasma and dried blood spot samples from premature infants.

ABSTRACT: BACKGROUND:Limited pharmacokinetic (PK) data of metronidazole in premature infants have led to various dosing recommendations. Surrogate efficacy targets for metronidazole are ill-defined and therefore aimed to exceed minimum inhibitory concentration of organisms responsible for intra-abdominal infections. METHODS:We evaluated the PK of metronidazole using plasma and dried blood spot samples from infants ?32 weeks gestational age in an open-label, PK, multicenter (N = 3) study using population PK modeling (NONMEM). Monte Carlo simulations (N = 1000 virtual subjects) were used to evaluate the surrogate efficacy target. Metabolic ratios of parent and metabolite were calculated. RESULTS:Twenty-four premature infants (111 plasma and 51 dried blood spot samples) were enrolled: median (range) gestational age at birth 25 (23-31) weeks, postnatal age 27 (1-82) days, postmenstrual age 31 (24-39) weeks and weight 740 (431-1466) g. Population clearance (L/h/kg) was 0.038 × (postmenstrual age/30) and volume of distribution (L/kg) of 0.93. PK parameter estimates and precision were similar between plasma and dried blood spot samples. Metabolic ratios correlated with clearance. CONCLUSION:Simulations suggested the majority of infants in the neonatal intensive care unit (>80%) would meet the surrogate efficacy target using postmenstrual age-based dosing.

SUBMITTER: Cohen-Wolkowiez M

PROVIDER: S-EPMC3769518 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Determining population and developmental pharmacokinetics of metronidazole using plasma and dried blood spot samples from premature infants.

Cohen-Wolkowiez Michael M Sampson Mario M Bloom Barry T BT Arrieta Antonio A Wynn James L JL Martz Karen K Harper Barrie B Kearns Gregory L GL Capparelli Edmund V EV Siegel David D Benjamin Daniel K DK Smith P Brian PB

The Pediatric infectious disease journal 20130901 9

<h4>Background</h4>Limited pharmacokinetic (PK) data of metronidazole in premature infants have led to various dosing recommendations. Surrogate efficacy targets for metronidazole are ill-defined and therefore aimed to exceed minimum inhibitory concentration of organisms responsible for intra-abdominal infections.<h4>Methods</h4>We evaluated the PK of metronidazole using plasma and dried blood spot samples from infants ≤32 weeks gestational age in an open-label, PK, multicenter (N = 3) study usi ...[more]

PMID: 23587979

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Project description:BackgroundTo improve efficacy, therapeutic drug monitoring is often used in clozapine therapy. Trough level monitoring is regular, but trough levels provide limited information about the pharmacokinetics of clozapine and exposure in time. The area under the concentration time curve (AUC) is generally valued as better marker of drug exposure in time but calculating AUC needs multiple sampling. An alternative approach is a limited sampling scheme in combination with a population pharmacokinetic model meant for Bayesian forecasting. Furthermore, multiple venepunctions can be a burden for the patient, whereas collecting samples by means of dried blood spot (DBS) sampling can facilitate AUC-monitoring, making it more patient friendly.ObjectiveDevelopment of a population pharmacokinetic model and limited sampling strategy for estimating AUC0-12h (a twice-daily dosage regimen) and AUC0-24h (a once-daily dosage regimen) of clozapine, using a combination of results from venepunctions and DBS sampling.MethodFrom 15 schizophrenia patients, plasma and DBS samples were obtained before administration and 2, 4, 6, and 8 h after clozapine intake. MwPharm® pharmacokinetic software was used to parameterize a population pharmacokinetic model and calculate limited sampling schemes.ResultsA three-point sampling strategy with samples at 2, 6, and 8 h after clozapine intake gave the best estimation of the clozapine AUC0-12h and at 4, 10, and 11 h for the AUC0-24h. For clinical practice, however, a two-point sampling strategy with sampling points at 2 and 6 h was sufficient to estimate AUC0-12h and at 4 and 11 h for AUC0-24h.ConclusionA pharmacokinetic model with a two-time point limited sampling strategy meant for Bayesian forecasting using DBS sampling gives a better prediction of the clozapine exposure in time, expressed as AUC, compared to trough level monitoring. This limited sampling strategy might therefore provide a more accurate prediction of effectiveness and occurrence of side effects compared to trough level monitoring. The use of DBS samples also makes the collection of clozapine samples easier and wider applicable.

Project description:The preferred sampling medium for measuring human exposures of persistent organic compounds (POPs) is blood, and relevant sample types include whole blood, plasma, and dried blood spots (DBS). Because information regarding the performance and comparability of measurements across these sample types is limited, it is difficult to compare across studies. This study evaluates the performance of POP measurements in plasma, whole blood and DBS, and presents the distribution coefficients needed to convert concentrations among the three sample types. Blood samples were collected from adult volunteers, along with demographic and smoking information, and analyzed by GC/MS for organochlorine pesticides (OCPs), chlorinated hydrocarbons (CHCs), polychlorinated biphenyls (PCBs), and brominated diphenyl ethers (PBDEs). Regression models were used to evaluate the relationships between the sample types and possible effects of personal covariates. Distribution coefficients also were calculated using physically-based models. Across all compounds, concentrations in plasma were consistently the highest; concentrations in whole blood and DBS samples were comparable. Distribution coefficients for plasma to whole blood concentrations ranged from 1.74 to 2.26 for pesticides/CHCs, averaged 1.69 ± 0.06 for the PCBs, and averaged 1.65 ± 0.03 for the PBDEs. Regression models closely fit most chemicals (R (2) > 0.80), and whole blood and DBS samples generally showed very good agreement. Distribution coefficients estimated using biologically-based models were near one and did not explain the observed distribution. Among the study population, median concentrations of several pesticides/CHCs and PBDEs exceeded levels reported in the 2007-2008 National Health and Nutrition Examination Survey, while levels of other OCPs and PBDEs were comparable or lower. Race and smoking status appeared to slightly affect plasma/blood concentration ratios for several POPs. The experimentally-determined distribution coefficients can be used to compare POP exposures across studies using different types of blood-based matrices.

Dataset Information

Determining population and developmental pharmacokinetics of metronidazole using plasma and dried blood spot samples from premature infants.

Publications

Determining population and developmental pharmacokinetics of metronidazole using plasma and dried blood spot samples from premature infants.

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