Data from Phase 1 trials have determined that peramivir displays a linear relationship between dose and drug exposure (AUC and Cmax). Although our patient did not receive the same dose as those reported from the phase 1 trials, some comparisons of drug exposure can be made. In brief, the peramivir half-life for our patient was shorter, clearance was more rapid, and overall drug exposure was lower than previously reported in phase 1 trials. Our patient received a dose of 5.8 mg/kg once daily with an AUC0-∞
of 34,590 ng•hr/mL. In the previously reported trials, six non-pregnant subjects received an IV dose of 4 mg/kg once daily, with a mean AUC0-∞
of 49,902 ng•hr/mL (2
). Additionally, the calculated half-life in our patient was 2.4 hours, whereas the half-life is reported to range from 7.5 to 20.8 hours in the phase 1 patients (2
). Our patient’s clearance of peramivir was 0.16 L/hr/kg, compared to the reported clearance of peramivir (0.11 L/hr/kg) in influenza-infected patients in phase 1 trials (3
). Notably, since the half-life of peramivir was 2.4 hours, by the third dose she would have reached steady-state with respect to peramivir pharmacokinetics, assuming stable renal clearance at that time. Also, with such a short half-life, she would have had minimal accumulation of peramivir.
There are several plausible explanations for the pharmacokinetic parameter differences between this patient case and the parameters previously reported in clinical trials. Pregnant and postpartum patients typically display an increased renal plasma flow as well as an increase in plasma volume (5
). Peramivir is primarily eliminated unchanged via the kidney, accounting for approximately 90% of total clearance (3
). Comparing the reported peramivir clearance (0.11 L/hr/kg) to the average creatinine clearance for a 70 kg adult (0.10 L/hr/kg) suggests that peramivir is excreted mainly by glomerular filtration, with a possible contribution of net tubular secretion, given the minimal plasma protein binding (<30%) (3
). The glomerular filtration rate (GFR) is known to increase by approximately 50% in the first trimester of pregnancy (5
). The GFR continues to increase throughout the remainder of the pregnancy and is elevated compared to 8-week postpartum values (5
). In our patient, the creatinine clearance (CrCl, as calculated by the Crockcoft-Gault equation) increased over the first few days postpartum (see ), potentially related to improvements in renal function. Her CrCl was variable over the duration of hospitalization, peaking on day 5 (peramivir day 1) and reaching 139 mL/min on day 7 when pharmacokinetic sampling occurred. This supranormal rate could have contributed to the peramivir clearance of 0.16 L/hr/kg which is higher than what was previously reported in phase 1 trials (3
Pregnant women also have an increase in plasma volume which may result in an increase in the apparent volume of distribution of peramivir (6
). Plasma volume in a recently postpartum patient could be rapidly changing, causing further fluctuations in apparent volume of distribution of drugs. We were unable to find any reports of the volume of distribution of peramivir, so a direct comparison to our patient’s volume of distribution (59 L) cannot be made, although this value clearly exceeds blood volume. Although changes in plasma protein binding may occur post-partum, the plasma protein binding of peramivir is minimal (<30%), so even a two-fold decrease would not meaningfully increase this patient’s total peramivir clearance (3
Comparing the CrCl (0.087 L/hr/kg) to the peramivir clearance (0.16 L/hr/kg) of this patient suggests that her increased clearance would be consistent with either an increase in net renal tubular secretion, or an increase in non-renal clearance. Consistent with its relative hydrophilicity, peramivir is not extensively metabolized (3
). As a result, this patient’s rapid clearance may likely involve one or more transporters for renal tubular secretion. The effects of infection or inflammation on drug transport mechanisms are not clearly established; however, they appear to differ by tissue, cytokine, transporter, and species. Since peramivir is zwitterionic at pH 7.4, it is difficult to predict the transport mechanism, which may include renal organic anion or organic cation transporters.
Compared to previously reported pharmacokinetic parameters (in non-pregnant patients), the parameters in our patient were unexpected. Our patient had decreased drug exposure compared to patients in phase 1 clinical trials, despite the fact that she received a higher dose than the patients from reported studies. Our patient did receive peramivir at the dose that is currently recommended for adults with influenza. However because of the shorter half-life observed here, one could suggest the need for an increased dose (or decreased dosing interval) in pregnant and postpartum patients.
Incorrect or ineffective dosing of drugs in pregnant and postpartum patients could lead to subtherapeutic treatment, harm to the mother and fetus and the development of drug resistance (7
). Because our patient had lower drug exposure than would have been predicted, this case supports the growing viewpoint that more studies for the treatment of 2009 H1N1 influenza in pregnant and postpartum patients are needed in order to adequately assess whether these patients have altered pharmacokinetics that would lead to the need for an increase in dosage (8
). The results herein were unexpected and raise the question of whether the differences are due to inter-patient variability or the postpartum status of the patient. The authors recognize the limitations of generalizations made from a single case report. Additional data obtained as a condition of the eIND from use of peramivir in pregnant and postpartum patients should include pharmacokinetics whenever possible, analyzed and published to aid physicians and pharmacists involved in the management of this at risk population. Finally, the clearance mechanism(s) for peramivir need to be further characterized.