Oseltamivir Dosing for Influenza Infection in Premature Neonates

Abstract

Under the Emergency Use Authorization issued in April 2009,¹ oseltamivir can be used to treat 2009 influenza A (2009 H1N1) virus infection in children <1 year of age. No data exist on dosing oseltamivir in premature babies. A hospital health care worker inadvertently exposed 32 neonatal intensive care unit babies to 2009 H1N1; a protocol was expeditiously implemented to collect samples for pharmacokinetics and dose evaluation. Results suggest 1.0 mg/kg/dose twice daily in premature babies produces oseltamivir carboxylate exposures similar to older children receiving 3.0 mg/kg/dose twice daily. These results provide initial guidance on dosing oseltamivir in this vulnerable population.

Introduction

Oseltamivir is approved for the treatment and prevention of influenza in patients greater than or equal to 1 year of age, although few published data are available regarding the pharmacokinetics of oseltamivir in 1 year old children.² In response to the 2009 novel H1N1 (2009 H1N1) pandemic, the U.S. Food and Drug Administration issued an Emergency Use Authorization (EUA) for oseltamivir use in infants less than 1 year of age. Initially under the EUA, children less than 3 months of age were recommended to receive 12 mg twice daily for five days, regardless of weight, for the treatment of influenza infection.^3,4 These guidelines subsequently have been changed to a weight-based dosing approach (3.0 mg/kg/dose orally twice daily for children 0 to <12 months) based on CASG 114 interim study results.⁵ The CASG 114 protocol is enrolling infants and children under 2 years of age in an oseltamivir pediatric dose-finding trial. For inclusion into CASG 114, participants must fall into one of five chronological age strata (12–23, 9–11, 6–8, 3–5, and 0–2 months), have confirmed diagnosis of influenza, and have duration of symptoms ≤ 96 hours. Steady-state pharmacokinetic data are collected in each cohort to determine the appropriate oseltamivir dose using an area-under-the-curve (AUC) targeted design. However, no data exist on dosing oseltamivir in premature babies and it was for this reason that the sampling study reported herein (CASG 119) was undertaken.

The prodrug oseltamivir phosphate is rapidly and efficiently converted to its active metabolite, oseltamivir carboxylate, which is then cleared unchanged by the kidney.⁶ It has been well-documented that infants and young children exhibit diminished renal capacity, and drugs or drug metabolites eliminated by the kidneys require dose adjustments to account for this decrease in clearance.⁷ Consequently, premature babies likely will require an even lower dose than term infants and young children, as their renal function is severely under-developed. Other factors such as altered enzymatic conversion and changes in oral bioavailability may also contribute to determination of neonatal dosing.

Developing a prospective, dose-finding trial of a drug to treat influenza in premature babies is exceedingly difficult. Due to blood volume restraints, few samples for pharmacokinetic analyses can be collected in any one baby, thereby limiting the trial design and robustness of the dataset. Importantly, most premature babies will be in a neonatal intensive care unit (NICU). The primary method of these babies contracting influenza is by exposure from an adult health care worker or NICU visitor, most of whom will not realize that they have influenza until after the exposure has occurred. For this reason, a prospective study design to evaluate oseltamivir dosing in premature neonates is impractical. As it would be unethical to perform a dose-finding trial in otherwise healthy premature babies, the only options for collecting these important data are to open a trial whereby multiple NICU's have a standing protocol to collect blood samples for pharmacokinetic analysis just in case an exposure occurs and treatment or prophylaxis ensues, or rapidly implement a study to collect these specimens when an exposure and subsequent therapy actually does occur. The latter situation forms the basis for this report.

Methods

A hospital health care worker treated an adult patient with documented 2009 H1N1 several days before going to work in the hospital's NICU. The health care worker became ill, including fever, during her NICU shift caring for 32 babies. She remained at work, however, and did not wear gloves or masks. Following her shift, she tested positive for influenza and was subsequently confirmed to have 2009 H1N1. Following the NICU exposure, the treating neonatologist elected to administer oseltamivir prophylactically to these neonates at a scheduled dose of 1.5 mg/kg/dose twice daily for 10 days. This dose was an educated guess based on data already collected from the CASG 114 study and knowledge of developmental pharmacology, with premature babies generally having diminished renal function relative to term babies. All doses were administered using a standard mL-marked oral syringe. The CASG 119 protocol was then drafted expeditiously to collect plasma samples for drug measurement and to determine whether the selected dose produced similar oseltamivir carboxylate exposures (area-under-the-curve, AUC) relative to those observed in infants and young children in the ongoing CASG 114 protocol.⁵

Demographic data such as gestational age, chronologic age, weight, serum creatinine (S_cr), and dosing information were obtained upon enrollment. A single whole blood sample (0.5 mL) from each patient was collected after the fifth dose to measure steady-state plasma oseltamivir and oseltamivir carboxylate concentrations. This single sample was scheduled to be obtained from each baby during a specific time window in order to fully encompass the 12 hour dosing interval. The sample collection time windows were: 0 through 3 hours, 4–6 hours, 7–9 hours, and 10–12 hours. The goal of this design was to have samples evenly distributed across the collection windows. Mass spectrometry was used to quantitate oseltamivir and oseltamivir carboxylate from plasma samples; lower limits for the assay were 1 and 10 ng/mL, respectively.⁸

Several approaches were undertaken in order to optimally describe the CASG 119 concentration-time data. First, data were modeled using the ADAPT 5.0 systems analysis software.⁹ The CASG 114 dataset was used to establish a combined parent-metabolite model. A two-compartment model for oseltamivir phosphate and one-compartment model for oseltamivir carboxylate was applied, and maximum likelihood estimation maximization (MLEM) was used to conduct a population pharmacokinetic analysis of a portion of the CASG 114 dataset (n=43 subjects) and the CASG 119 data. CASG 119 data were modeled as if one subject had received the oseltamivir dose at steady-state, and the average of all available concentrations at each time point was taken to be obtained following that steady-state dose. Absorption, metabolite formation, and clearance processes were assumed to be linear. Second, a noncompartmental analysis (WinNonlin 5.2.1, Mountain View, CA) of the average concentrations at each time point collected in CASG 119 was also performed. Lastly, raw oseltamivir carboxylate concentrations were averaged for each dataset to estimate the average steady-state concentration (C_avg).

Results

Twenty of the 32 exposed babies were enrolled on this pharmacokinetic sampling study. Nine babies were discharged prior to sampling, two refused oseltamivir prophylaxis, and one declined study participation. Subject demographics are presented in Table 1. The median gestational age was 27.5 weeks; one subject was term at delivery (38 weeks). The median weight and chronologic age at time of pharmacokinetic sampling were 1684 grams and 2.5 weeks, respectively. Seven subjects were extremely premature, with gestational ages ≤26 weeks. Eight subjects weighed <1,000 grams at delivery, two of whom weighed <500 grams. The median dose received and number of doses administered prior to pharmacokinetic sampling were 1.79 mg/kg/dose (range, 1.33–2.55) and 11 (range, 9–13), respectively. The range of actual doses received by the premature neonates was 1.3 to 6.9 mg twice daily. None of the babies developed influenza infection or experienced drug-related adverse effects over the course of therapy.

Table 1.

Participant Demographics

Race
	Caucasian	11 (55%)
	African-American	9 (45%)
Gender
	Male	10 (50%)
	Female	10 (50%)
Ethnicity
	Hispanic	2 (10%)
	Non-Hispanic	18 (90%)
Birth Weight (grams)
	Mean	1226
	Median	1063
	Range	480–2750
Gestational Age at Delivery (weeks)
	Mean	29
	Median	27.5
	Range	24–38
Chronological Age at Sample Collection (weeks)
	Mean	4.6
	Median	2.5
	Range	1.5–17.5
Serum Creatinine (mg/dL)
	Mean	0.54
	Median	0.47
	Range	0.3–1.31

One baby was dosed with oseltamivir on a once daily basis, and these data were not included in the analysis. A second baby had an oseltamivir concentration 23 times that of the average concentration of the remaining babies (335 ng/mL vs. 14.3 ng/mL for the remaining babies). This subject also had the highest S_cr at 1.31 mg/dL. Due to the low robustness of the dataset (n=1 sample per subject), this subject's results were not used as they strongly influenced the best model fit. The oseltamivir result for another subject was below the limit of assay quantitation. Therefore, 17 oseltamivir and 18 oseltamivir carboxylate concentrations were available for analyses.

Figure 1 illustrates the raw concentration-time data from premature babies in the current study compared with those from all cohorts in the ongoing CASG 114 study. The average dose (± standard deviation) administered in the current study was 1.73 ± 0.17 mg/kg. In CASG 114, the current average dose and AUC₁₂ (± standard deviation) across all cohorts is 3.0 ± 0.25 mg/kg and 4326 ± 1878 ng·h/mL, respectively. The modeled CASG 119 AUC₁₂ was 9250 ng·h/mL. A linearly adjusted dose of 0.81 mg/kg twice daily would be needed to achieve a similar AUC₁₂ in the premature babies. Similarly, a noncompartmental analysis of the mean oseltamivir carboxylate concentration-time data at each time point yielded an AUC₁₂ of 8079 ng·h/mL at an average dose of 1.73 mg/kg. This analysis suggests a linearly adjusted dose of 0.93 mg/kg twice daily in premature babies would produce an AUC₁₂ similar to the CASG 114 cohort. The final analysis included simply averaging the oseltamivir carboxylate concentrations in both studies. For CASG 119, the average of all raw oseltamivir carboxylate concentrations was 728 ng/mL, compared with 346 ng/mL in CASG 114. Again using a linear dose adjustment, 0.82 mg/kg/dose twice daily would be needed to produce a similar C_avg in premature babies.

Figure 1.

Measured oseltamivir phosphate concentrations (top panel) from all cohorts in CASG 114 (blue triangles) and from premature neonates in the current study (red circles). Bottom panel: measured oseltamivir carboxylate concentrations from all cohorts in CASG 114 (blue triangles) and from premature neonates in the current study (red circles).

Discussion

Analysis of these data suggest metabolic differences occur between premature neonates and term infants and young children with regard to oseltamivir and oseltamivir carboxylate disposition following oral administration. The average oseltamivir dose in the youngest age cohort in CASG 114 (term babies 0–2 months of age, n=18) is 3.02 mg/kg/dose twice daily (12.4 mg/dose twice daily), while premature neonates from the current study (n=18) received an average oseltamivir dose of 1.73 mg/kg/dose twice daily (2.97 mg/dose twice daily). Although the premature neonates received an actual dose 4-fold lower than the term babies on average, the oseltamivir carboxylate exposures were approximately 2-fold higher compared with term babies (Figure 1). Data from both studies imply dosing oseltamivir in premature babies, infants, and young children using a mg/kg approach may be more accurate in terms of achieving desired exposures relative to an age-based fixed dose regimen. Comparatively, adults with normal renal function receiving 75 mg twice daily achieve an average carboxylate AUC₁₂ of 2719 ng·h/mL.¹⁰

This dataset is limited by a relative lack of robustness, as only one sample could be collected from each participant and the average concentration at each time point had to be modeled as if one subject had received the oseltamivir dose at steady-state. From Figure 1, it is clear the premature babies had similarly shaped concentration-time curves, but increased oseltamivir carboxylate exposure relative to the older children. Several different approaches were taken to quantify this difference. We first applied a population pharmacokinetic approach in order to maximize prior knowledge of oseltamivir and oseltamivir carboxylate absorption and disposition in infants and young children. Since only one sample was collected per subject, obtaining individual post-hoc pharmacokinetic parameter estimates was not feasible. We also used a noncompartmental analysis of the mean oseltamivir carboxylate data to compare with the CASG 114 data, and estimated the C_avg in both studies by simply averaging the raw oseltamivir carboxylate concentrations. All three approaches led to the similar conclusion that premature neonates achieved an average oseltamivir carboxylate exposure approximately 2-fold higher compared to infants and young children, even though their dose was nearly 50% lower (1.73 vs. 3.0 mg/kg/dose).

Oseltamivir is converted to its active metabolite, oseltamivir carboxylate, primarily by hepatic esterases. Oseltamivir carboxylate is then renally eliminated through both glomerular filtration and tubular secretion processes. Both processes are diminished in neonates and young children, and do not reach adult capacity until 6–12 months of age.⁷ Results from the current study are consistent with known aspects of developmental pharmacology and the ontogeny of drug disposition in that lower doses are required in this population to achieve exposures similar to older children and adult values.

These modeled results, noncompartmental analysis, and average of raw concentrations suggest an oseltamivir dose of approximately 1.0 mg/kg/dose twice daily should achieve oseltamivir carboxylate exposures in premature neonates (<38 weeks) comparable to infants and young children receiving 3 mg/kg/dose twice daily. Additional pharmacokinetic data from this age group are necessary, however, to more precisely define the optimal oseltamivir dose. Given that further 2009 H1N1 exposures may occur in NICU settings around the world as the pandemic continues or as other influenza viruses circulate, these data provide initial oseltamivir dosing guidance in premature babies, which is vital to the global public health response.