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Metronidazole Population Pharmacokinetics in Preterm Neonates Using Dried Blood-Spot Sampling

Maysa Suyagh, Paul S. Collier, Jeffrey S. Millership, Godwill Iheagwaram, Muriel Millar, Henry L. Halliday and James C. McElnay
Pediatrics February 2011, 127 (2) e367-e374; DOI: https://doi.org/10.1542/peds.2010-0807
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Abstract

OBJECTIVES: To characterize the population pharmacokinetics of metronidazole in preterm neonates.

PATIENTS AND METHODS: Data were collected prospectively from 32 preterm neonates who received intravenous metronidazole for the treatment of or prophylaxis against necrotizing enterocolitis. Dried blood spots (n = 203) on filter paper were analyzed by high-performance liquid chromatography, and the data were subjected to pharmacokinetic analysis performed by using nonlinear mixed-effect modeling.

RESULTS: A 1-compartment model best described the data. Significant covariates were weight (WT) and postmenstrual age (PMA). The final population models for metronidazole clearance (CL) and volume of distribution (V) were: CL = 0.0247 × (WT/1.00)0.75 × (1 + 0.107 × [PMA − 30]) and V = 0.726 × WT, where CL is in liters per hour, WT is in kilograms, PMA is in weeks, and V is in liters. This model predicts that the half-life of metronidazole decreases rapidly from ∼40 hours at 25 weeks' PMA to 19 hours at 32 weeks' PMA, after which it starts to plateau. This decrease in half-life is the result of a 5-fold increase in CL compared with only a 2.5-fold increase in V during the same period.

CONCLUSIONS: Currently, there are no specific dose recommendations for metronidazole in preterm neonates. However, a dosing scheme for preterm neonates that takes into consideration both the weight and PMA has been suggested and should avoid administration of doses that are excessive or more frequent than necessary.

WHAT'S KNOWN ON THIS SUBJECT:

Little is known about the pharmacokinetics and required dosage of metronidazole in preterm neonates.

WHAT THIS STUDY ADDS:

In this study the pharmacokinetics of metronidazole in preterm neonates was investigated by measurement of the drug in dried blood-spot samples. A dosage regimen is proposed that should result in more appropriate, less frequent dosing in the most preterm neonates.

Necrotizing enterocolitis (NEC) is the most common gastrointestinal emergency seen in neonates,1 and it has a mortality rate of 20% to 50%.2 The incidence of NEC has been reported to vary from 1% to 8%3; ∼10% of infants with very low birth weight develop signs of NEC.4,5

Medical management of infants with NEC consists of supportive care, antibiotic treatment, and close monitoring.3,6 Parenteral antibiotics are usually given for 7 to 10 days to cover Gram-negative, Gram-positive–aerobic, and anaerobic microorganisms. Fungal sepsis may also occur7 and is usually treated with a combination of amoxicillin (or ampicillin), a third-generation cephalosporin, or an aminoglycoside and metronidazole.5,7

The pharmacokinetics of metronidazole has been well characterized in adults8 and children.9,10 However, despite being commonly used in NICUs, metronidazole is unlicensed for use in infants younger than 1 year, and the pharmacokinetics of metronidazole has not been well studied in neonates, especially preterm neonates. A correlation between gestational age (GA) and total clearance has been reported,11,12 but no attempt was made to measure the degree of interindividual variability in various pharmacokinetic parameters.

Traditional pharmacokinetic studies are difficult to perform in infants because of the need for multiple blood samples, which creates ethical and technical problems. Population analysis, however, allows the estimation of pharmacokinetic parameters from sparse data and enables the identification of patient characteristics that have a significant influence on drug disposition, and may thereby account for some of the variability. The aim of this study was to characterize the population pharmacokinetics of metronidazole in preterm neonates who were given the drug intravenously for the treatment of and/or prophylaxis against anaerobic infection associated with NEC or other conditions.

PATIENTS AND METHODS

Patients and Data Collection

The study was approved by the research ethics committee of Queen's University Belfast, and before enrollment in the study written informed consent was obtained from each infant's legal guardian. Samples and patient data were collected prospectively from 32 preterm infants who had received metronidazole as part of their care in the NICU at the Royal Jubilee Maternity Service, Belfast. Metronidazole (Flagyl Sanofi-Aventis, Guilford, United Kingdom) was administered as a constant-rate intravenous infusion for a period of 30 minutes.

Blood samples were collected as blood spots on Guthrie cards, usually at times when other blood samples were collected for routine clinical tests. Samples were usually taken via a heel prick, but were collected from venous or arterial catheters if these were in place. Each sample was allowed to dry for at least 3 to 4 hours in the dark at ambient temperature and then stored at −20°C until analyzed.

The date and time of sampling and the dates and times of previous metronidazole doses were accurately recorded for each sample. Samples with missing data related to sampling time were rejected. The following data were recorded from each patient's medical notes: weight, postmenstrual age (PMA), postnatal age (PNA), GA, gender, Apgar scores (measured 1 and 5 minutes after birth), serum creatinine, serum albumin, and hematocrit, together with concomitant medications.

Drug Analysis

A selective and sensitive high-performance liquid chromatography method with ultraviolet detection for determination of metronidazole in dried blood spots was developed and validated.13 The limits of detection and quantification were 0.6 μg/mL and 1.8 μg/mL, respectively. Intraday accuracy ranged from −7.4% to 4.5% and precision from 2.6% and 8.8% relative SD. Interday accuracy ranged from −1.4% to 3.1% and precision from 2.1% to 13.1% relative SD.

Response to Treatment

The minimum inhibitory concentration (MIC) of metronidazole when it is used for prophylaxis against and treatment of anaerobic infections was reported to be 6 to 8 μg/mL.9 Therefore, effectiveness of treatment was assessed by the absence of anaerobic infection and by metronidazole concentrations obtained and maintained above the MIC. Infants were also assessed for any possible clinical or biochemical adverse effects that might be related to metronidazole.

Population Pharmacokinetic Modeling

Population pharmacokinetic analysis was performed by means of nonlinear mixed-effect modeling (NONMEM) by using first-order conditional estimation with interaction (NONMEM version VI, level 1.0, ICON Development Solutions, Ellicott City, MD).14

Step 1

The complete data set was used for development of the pharmacokinetic model. Potential models considered were classical linear 1-compartment and 2-compartment models.

Interindividual variability (IIV) in each pharmacokinetic parameter was estimated by using an exponential scale because the pharmacokinetic parameters must be constrained to be greater than 0 and their distribution is often right skewed.15

Proportional and additive components of residual variability were estimated throughout model development by use of this equation: Embedded Image

During the model-building process simplification was carried out by deletion of the residual variance component with a value close to 0.

Clearance (CL, in liters per hour) and apparent volume of distribution (V, in liters) were scaled to the median weight of the studied population (WT, in kilograms) and adjusted for size as follows16,17: Embedded Image

Step 2

We used visual examination of scatter plots (or box-and-whisker plots in case of categorical covariates) of individual Bayesian estimates and IIV variability (ETAs) obtained for each pharmacokinetic parameter from step 1 versus each covariate to help identify whether the pharmacokinetic parameter might be significantly related to the covariate. Direct covariate testing was then performed to see if this relationship was significant.

Step 3

The final model was established by using the forward inclusion–backward elimination method.18 Forward inclusion of a covariate required a reduction in the minimum value of the objective function (MOFV) of at least 6.63, (P < .01, df = 1). During stepwise backward elimination a more stringent criterion of statistical significance was required and a covariate was retained in the model only if the MOFV increased at least 10.83 units (P < .001; df = 1) when removed.

Graphical inspection of the goodness of fit was used throughout model building and evaluation.19 The bias (mean prediction error), and the precision (root-mean-square prediction error) of pharmacokinetic parameters were calculated and used as descriptions of the predictive performance of the model.20

Internal validation of the model was undertaken by using the technique of bootstrapping (Wings for NONMEM [WFN 611, http://wfn.sourceforge.net/index.html]).

Dosage-Regimen Design

Using the parameters obtained from the final fitted model, we performed Monte Carlo simulations (1000 for each PMA investigated in the range 24–37 weeks) to estimate dosage regimens that would achieve steady-state concentrations that remained above 6 mg/L throughout the dosage interval. The loading dose required to give an initial blood concentration of 20 mg/L was determined by use of the same method.

RESULTS

Patients and Data Collection

The data set consisted of 203 metronidazole observations from 32 neonates; the demographics of study patients are presented in Table 1.

View this table:
TABLE 1

Characteristics of Infants Included in the Study (n = 32)

Response to Treatment

None of the neonates recruited in this study showed any adverse events demonstrated by clinical or laboratory findings that may have been linked to the exposure to metronidazole, and no cases of anaerobic sepsis were identified in any of the infants during this study. In all cases, the measured levels of metronidazole were above the reported MIC.9

Pharmacokinetic Analysis

Because of the small number of samples taken during the first hour (n = 6), it was not possible to describe a distribution phase, and the 2-compartment model did not provide a better fit to the data. Therefore, a linear 1-compartment model was chosen for additional development (MOFV: 933.7; Table 2).

View this table:
TABLE 2

Part of the Model-Building Process to Reach the Final Pharmacokinetic Model of Metronidazole Showing the Effect on the Variance of Clearance and Volume (ω2) of the Final Covariates Included in the Model

Building of the Base and Covariate Models

The a priori inclusion of weight in the base model by use of allometric scaling with fixed-power values resulted in significant improvement in goodness of fit (ΔMOFV: 28.5; Table 2).

The inclusion of age in each of its different forms (PMA, GA, PNA) as a covariate of clearance provided a significant improvement in goodness of fit, but PMA as a linear function on clearance was incorporated into the forward inclusion step because it gave the largest decrease in MOFV. The only other significant covariates on clearance were serum creatinine (both a continuous and a discrete covariate) and concomitant administration of indometacin; none of the tested covariates proved significant for V. Forward inclusion revealed PMA as the only significant covariate on clearance. In the final backward-exclusion step, the MOFV increased significantly (43.687; P < .001, Table 2) when PMA was omitted from the model. Therefore, the final model contained PMA as the only covariate. No improvement in goodness of fit was obtained by inclusion of IIV (ηPMA, CLi) in θPMA. IIV (percentage coefficient of variation [CV%]) in clearance and V were reduced from 50.7% to 23.4% and from 33.2% to 31.9%, respectively, by the inclusion of PMA as a covariate on clearance in the model (Table 3). The correlation between the population parameter variability for clearance and V was 0.47.

View this table:
TABLE 3

Metronidazole Population-Parameter Estimates From the Base and Final Models Developed From the Original Data Set of 32 Neonates, and Mean Parameter Estimates From the Final Model Fitted to the 1000 Bootstrap Samples

Testing PMA as a Time-Varying Covariate

In rapidly developing preterm neonates, PMA is considered to be an important uncontrollable covariate, which leads to significant changes in pharmacokinetics of drugs even within a short time period. Therefore, PMA was tested as a time-varying covariate21 that may result in reduced variability in the model. When separate within-individual and between-individual relationships for PMA were applied, a significant improvement in goodness of fit was obtained (ΔMOFV: 3.9; P < .05; df = 1), but the estimate of the confidence interval of the fractional change in clearance within an individual with changes in PMA included 0. This finding indicates that θPMA was sufficient to describe the variability in the study population.

Final Model

Because the proportional term of the residual error variance approached 0, it was removed resulting in an additive error model. The residual variability (SD) was 4.0 μg/mL, corresponding to a CV% of 13.3% at the mean detected metronidazole concentration of 30 μg/mL.

The final model for metronidazole was as follows: Embedded Image

where clearance (CL) is in liters per hour, weight (WT) is in kilograms, PMA is in weeks, and V is in liters.

Therefore, estimates of clearance and V in preterm neonates at 30 weeks' PMA who weigh 1.00 kg are 0.0247 L/hour and 0.726 L, respectively, resulting in a half-life (t½) elimination of 20.37 hours.

Graphical Evaluation

The agreement between measured and model-predicted metronidazole concentrations in the final model is illustrated in Fig 1; there are neither substantial nor systematic deviations from the line of identity.

FIGURE 1
FIGURE 1

Plots of measured versus population-predicted and individual-predicted metronidazole concentrations from the final model. The solid line indicates the line of perfect agreement.

The results shown in Figure 2 indicate that the assumption of random effects was appropriate because both residuals and conditional weighted residuals were evenly distributed around 0 and almost all conditional weighted residuals were contained within ± 3 units of the null ordinate.

FIGURE 2
FIGURE 2

Plots of residuals and conditional weighted residuals versus population-predicted metronidazole concentration from the final model.

Predictive Performance

Bias of estimated population pharmacokinetic parameters decreased for the final model compared with the base model (mean prediction error reduced from 11.8% to 2.6% for clearance and from 4.6% to 4.0% for V) and precision of population estimates improved for clearance (root-mean-square prediction error decreased from 55.1% to 20.9%) but was unchanged for V (changed slightly: 27.4% –28.4%). There was good agreement between the typical (model-predicted) value of clearance and the Bayesian estimated value for each patient (r2 = 0.871).

Model Validation

Of the 1000 bootstrap data sets, 989 were successfully minimized and 11 were terminated because of rounding errors. With the exception of ωV, the variability of the estimated parameters from bootstrap data sets was low (CV < 20%), which indicated that the parameters were precisely estimated. For all parameters, 95% CIs were precise and did not overlap 0. Close agreement in mean parameter values (final model versus bootstrapping) with absolute differences of <4%, demonstrates that the model is robust (Table 3).

Parameter Estimates and Simulation of Half-Life

The median individual Bayesian estimates for clearance, V and t½ in the study population (obtained from the final model) are given in Table 4.

View this table:
TABLE 4

Individual Bayesian Estimates Obtained from the Final Model

The t½ of metronidazole decreased rapidly at lower PMA, with a tendency to plateau at ∼32 weeks (Fig 3). In addition, there was a significant difference (independent-sample t test) in metronidazole t½ (P < .0001) between neonates with a PMA of <32 weeks (n = 20; mean ± SD: 29.0 ± 8.3 hours) and those with a PMA of ≥32 weeks (n = 12; mean ± SD: 15.7 ± 2.3 hours).

FIGURE 3
FIGURE 3

Plot of predicted metronidazole half-life obtained from the final model versus the infant's PMA (calculations are based on the developed model and median weights derived from the Gairdner-Pearson growth chart31,32).

Dosage-Regimen Design

Simulations performed by using the derived pharmacokinetic model indicated that a loading dose of 15 mg/kg is adequate for obtaining an initial blood concentration of ∼20 mg/L in preterm neonates. However, depending on PMA, 1 of 4 separate maintenance dosage regimens, ranging from 7.5 mg/kg per day to 10 mg/kg per 12 hours, was necessary to maintain blood concentrations above 6 mg/L (see Table 5).

View this table:
TABLE 5

Blood Concentrations of Metronidazole Simulated by Using the Developed Pharmacokinetic Model With Suggested Dosing Regimens

DISCUSSION

To our knowledge, this is the first population pharmacokinetics study of metronidazole that was performed exclusively in preterm neonates to identify covariates that explain the pharmacokinetic variability observed in these neonates. We also believe this to be the first reported pharmacokinetic study in which all investigations were performed with dried blood-spot samples. The combination of sparse sampling and low sample volume helped to overcome ethical and practical difficulties associated with traditional pharmacokinetic studies and proved an acceptable alternative to the use of larger sample quantities.

Modeling

Allometric size adjustment, with fixed exponents of 0.75 for clearance and 1 for V, was used for a priori inclusion of weight. This method is well established, has a strong scientific and physiologic basis16,17,22 and has been adopted by many researchers during development of population pharmacokinetic models in neonates.22,–,26 Weight was scaled to the median body weight (1000 g) of the study population to increase numerical stability within NONMEM and to give a more meaningful and interpretable standard parameter.

Jager-Roman et al11 could not measure hydroxy-metronidazole in infants whose age was <35 weeks' gestation. These investigators concluded that hepatic hydroxylation is not spontaneously activated at birth in preterm infants, and that in this age group renal excretion is the predominant factor that influences metronidazole clearance. Neonates in the current study were more immature in terms of GA but generally older in terms of PNA, and the maturation of hepatic function may have played an additional role in these infants. However, although the assay was capable of detecting hydroxyl-metronidazole, the relevant peak was not observed in any of the samples analyzed. Nevertheless, an attempt was made to study the effect of renal function on metronidazole clearance by inclusion of serum creatinine. The inclusion of serum creatinine initially resulted in a significant improvement of goodness of fit; however, this effect was eliminated after inclusion of PMA, possibly because these 2 variables are correlated because, in neonates, levels of serum creatinine usually decrease with age.

Distribution of metronidazole into erythrocytes contributes to its high volume of distribution.27 Therefore, hematocrit was tested as a covariate on V but did not prove to be significant. Other than the a priori inclusion of weight, the absence of any other significant covariate effects on volume of distribution is in agreement with other studies.11,12

The final model accounted for 92.8% of the interindividual variance in clearance in preterm neonates and 60% of the IIV of V (Table 2) and predicted observed metronidazole concentrations accurately (Fig 1).

Metronidazole Clearance and V

The median estimated clearance and V in the current study were 0.0244 L/hour (ranging from 0.0078 to 0.0867 L/hour, 5th–95th percentiles) and 0.76 L/kg (ranging from 0.50 to 0.99 L, 5th–95th percentiles), respectively. Allowing for differences in patient demographic characteristics, these values are comparable to those obtained by Jager-Roman et al,11 which ranged from 0.0072 to 0.059 L/hour for clearance and 0.54 to 0.81 L/kg for V.

In a recent study in adults, average estimates for clearance and V were 3.08 ± 1.00 L/hour and 35.4 ± 21.63 L, respectively.28 When scaled to a weight of 70 kg, mean estimates of clearance and V in the present study were 0.6 L/hour and 50.8 L, respectively. This estimate of clearance is ∼5 times lower than that reported in adults, which reflects immature renal and hepatic functions in preterm neonates. The slightly higher estimate of V in neonates compared with that observed in adults is to be expected because metronidazole distributes mainly in total body water, of which there is a higher percentage in preterm neonates, and is not highly protein bound (<10%). In the present study, unlike all previous studies, blood rather than plasma concentrations were measured, and because of the limited sample volumes (∼30 μL blood) it was not possible to compare blood and plasma concentrations. Kaye et al,29 however, reported similar concentrations of metronidazole in blood and plasma. The similarity in pharmacokinetic parameters between those observed in our study and those observed by Jager-Roman et al,11 and the absence of a significant correlation between hematocrit and volume of distribution also suggest that plasma and blood concentrations are equivalent.

Change of Half-Life With Time

Jager-Roman et al11 observed a marked reduction in metronidazole t½ over time in 3 preterm neonates, but these findings were not replicated by Hall et al.12 However, both groups observed an inverse correlation between GA and t½. In the present study, the mean t½ for all neonates was 24 hours; (range: 43.3 hours [740 g; PNA: 9 days; GA: 24.6 weeks] to 11.8 hours [3400 g; PNA: 31 days; GA: 31 weeks]. If the different study designs and patient demographic characteristics are taken into consideration, the average values of t½ in the present study are closer to those of Hall et al.12

Dosage-Regimen Design

The predicted decrease in t½ (40 hours at 25 weeks' PMA to 19 hours at 32 weeks' PMA) is the result of a fivefold increase in clearance compared with only a 2.5-fold increase in V. Because it is clearance, and not V, that determines the maintenance dose of a drug, it can be postulated that neonates with PMAs lower than 32 weeks, in whom drug clearances are lower and half-lives are longer, will not need to receive doses as frequently as neonates with higher PMAs. Although the BNF-C (2010)30 has recommended that intravenous metronidazole be administered at a loading dose of 15 mg/kg followed after 24 hours by a maintenance dose of 7.5 mg/kg every 12 hours for neonates and 7.5 mg/kg every 8 hours for infants, currently there are no specific dose recommendations for preterm neonates. Our suggested dosage regimens for preterm neonates (Table 5) must be prospectively validated in a separate study. Results of the present study, however, indicate that metronidazole concentrations should remain above the MIC in very young preterm neonates throughout the longer dosage interval, with reduced risk of metronidazole accumulation. In addition, an increased dosage interval should reduce the risk of adverse effects and reduce both staff time and the cost of care.

CONCLUSIONS

A pharmacokinetic model has been developed and validated in a group of preterm neonates, and the findings suggest that both weight and PMA should be used as the basis for determination of the metronidazole dosage regimen.

Currently there are no specific dose recommendations of metronidazole for preterm neonates. However, in light of our study results, we suggest a dosing scheme that takes into consideration both the weight and PMA of the neonates. With this dosing scheme the administration of metronidazole doses that are excessive or more frequent than necessary should be avoidable.

ACKNOWLEDGMENT

We gratefully acknowledge the wholehearted support of Dr David Sweet (Regional Neonatal Unit, Royal Maternity Hospital, Belfast) in this work.

Footnotes

    • Accepted October 13, 2010.
  • Address correspondence to Paul S. Collier, PhD, Clinical and Practice Research Group, School of Pharmacy, Queen's University Belfast, 97 Lisburn Rd, Belfast BT9 7BL, United Kingdom. E-mail: p.collier{at}qub.ac.uk

  • FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.

  • NEC =
    necrotizing enterocolitis •
    GA =
    gestational age •
    PMA =
    postmenstrual age •
    PNA =
    postnatal age •
    MIC =
    minimum inhibitory concentration •
    NONMEM =
    nonlinear mixed-effect modeling •
    IIV =
    interindividual variability •
    V =
    apparent volume of distribution •
    MOFV =
    minimum value of the objective function •
    CV =
    coefficient of variation

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Pediatrics
Vol. 127, Issue 2
1 Feb 2011
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Metronidazole Population Pharmacokinetics in Preterm Neonates Using Dried Blood-Spot Sampling
Maysa Suyagh, Paul S. Collier, Jeffrey S. Millership, Godwill Iheagwaram, Muriel Millar, Henry L. Halliday, James C. McElnay
Pediatrics Feb 2011, 127 (2) e367-e374; DOI: 10.1542/peds.2010-0807
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