Population Pharmacokinetics of Metronidazole Evaluated Using Scavenged Samples from Preterm Infants

Abstract

g Pharmacokinetic (PK) studies in preterm infants are rarely conducted due to the research challenges posed by this population. To overcome these challenges, minimal-risk methods such as scavenged sampling can be used to evaluate the PK of commonly used drugs in this population. We evaluated the population PK of metronidazole using targeted sparse sampling and scavenged samples from infants that were <32 weeks of gestational age at birth and <120 postnatal days. A 5-center study was performed. A population PK model using nonlinear mixed-effect modeling (NONMEM) was developed. Covariate effects were evaluated based on estimated precision and clinical significance. Using the individual Bayesian PK estimates from the final population PK model and the dosing regimen used for each subject, the proportion of subjects achieving the therapeutic target of trough concentrations >8 mg/liter was calculated. Monte Carlo simulations were performed to evaluate the adequacy of different dosing recommendations per gestational age group. Thirty-two preterm infants were enrolled: the median (range) gestational age at birth was 27 (22 to 32) weeks, postnatal age was 41 (0 to 97) days, postmenstrual age (PMA) was 32 (24 to 43) weeks, and weight was 1,495 (678 to 3,850) g. The final PK data set contained 116 samples; 104/116 (90%) were scavenged from discarded clinical specimens. Metronidazole population PK was best described by a 1-compartment model. The population mean clearance (CL; liter/h) was determined as 0.0397 ؋ (weight/1.5) ؋ (PMA/32) 2.49 using a volume of distribution (V) (liter) of 1.07 ؋ (weight/1.5). The relative standard errors around parameter estimates ranged between 11% and 30%. On average, metronidazole concentrations in scavenged samples were 30% lower than those measured in scheduled blood draws. The majority of infants (>70%) met predefined pharmacodynamic efficacy targets. A new, simplified, postmenstrual-age-based dosing regimen is recommended for this population. Minimal-risk methods such as scavenged PK sampling provided meaningful information related to development of metronidazole PK models and dosing recommendations. P reterm infant pharmacokinetic (PK) studies are exceptionally scarce due to the research challenges posed by this population, such as limited blood volume for PK sampling, difficulty in timing of PK samples due to the critical medical condition of the infants, difficult access to obtain samples, and low rates of informed parental consent. Feasibility issues also are imposed by traditional PK study designs, which require large numbers of specifically timed PK blood samples. These difficulties have encouraged investigators to explore novel minimal-risk methods to evaluate the PK of antimicrobials in this population. One proposed method is the use of scavenged samples left over from the normal clinical care of infants. The use of scavenged samples for PK studies in preterm infants offers several advantages over traditional timed PK trials. These include avoiding the need for heel sticks specif...

Population Pharmacokinetics of Fluconazole in Premature Infants with Birth Weights Less than 750 Grams

“…The scavenged samples were as informative as the scheduled samples and did not bias parameter estimates. Scavenged PK sampling is particularly effective in populations that are difficult to study, such as infants, and has been successfully used in population PK studies of anti-infection drugs (16,17). In addition, scavenged sampling is useful for drugs with long half-lives where traditional sampling schemes may not capture the full PK profile.…”

Developmental Pharmacokinetics of Piperacillin and Tazobactam Using Plasma and Dried Blood Spots from Infants

“…This suggests that piperacillin-tazobactam dosing guidelines for premature infants must consider developmental differences in the drugs' CL similar to what has been successfully achieved using PMA-based dosing for other therapeutics (e.g., metronidazole [9,28], amikacin [29], vancomycin [30], and acetaminophen [31]). Other piperacillin dosing regimens using an array of body weight and PNA have been recently developed for infants (7); however, these target lower MICs and are challenging to implement clinically.…”

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