Pharmacokinetic Properties of Peramivir After Single and Multiple Intravenous Infusions in Healthy Chinese Volunteers

Headnote

Published online: 17 June 2016

© Springer International Publishing Switzerland 2016

Abstract

Background and Objectives Peramivir, an antiviral agent for intravenous administration, is used to treat progressive influenza in patients with serious complications. The present study was designed to determine the pharmacokinetics of single and multiple intravenous infusions of peramivir in healthy Chinese subjects.

Methods Single (150, 300 and 600 mg) and multiple (600 mg) doses of peramivir were intravenously administered to 12 healthy Chinese subjects. There was a 7-day washout period between dosing periods. Blood samples were collected in heparinized tubes at various times. Plasma peramivir and urine peramivir concentrations were measured using a high-performance liquid chromatography-tandem mass spectrometry method.

Results Following single doses of peramivir (150, 300 and 600 mg), the maximum concentration (Cmax) values were 12,416 ± 3078, 23,147 ± 3668 and 44,113 ± 3787 lg/L, respectively, and the area under the plasma concentration- time curve (AUC) from 0 h to infinity post-dose (AUC?) values were 24.68 ± 6.48, 47.33 ± 9.22 and 92.43 ± 12.72 mg^h/L, respectively. Cmax, AUC from 0 to 36 h (AUC0-36) and AUC? of peramivir increased proportionally with the dose, and no trend towards accumulation after multiple doses was observed. About 65 % of the peramivir was excreted unchanged in the urine within the first 24 h.

Conclusions Peramivir pharmacokinetics were dose proportional with increasing doses, with no accumulation after multiple dosing. Peramivir was generally well tolerated, and no serious adverse events occurred.

1 Introduction

Influenza, which can be caused by a number of different strains of the influenza virus, is associated with severe illness and high rates of hospitalization, and it has become a serious global public health threat. Neuraminidase inhibitors (NAIs)-including oseltamivir, zanamivir and peramivir-specifically inhibit the function of the influenza neuraminidase enzyme, thereby inhibiting release of highly infectious virions from infected cells [1].

Different NAI formulations have been developed to provide more treatment options for management of influenza. Peramivir, the first antiviral agent to be approved for intravenous administration in Japan and South Korea in 2010 and also approved in the USA in 2014, is intended to provide rapid control of progressive influenza in patients with serious complications [2]. A single administration of peramivir once daily was able to achieve treatment by stable binding with NA with the N9 subtype in a mouse model [3].

A population pharmacokinetic analysis of peramivir has previously been performed in healthy volunteers and influenza patients in Japan and the USA [4]. In that population pharmacokinetic research study, total peramivir clearance (CL) was found to be strongly related to creatinine clearance (CLCR), and CLCR was supposed to be the main factor influencing the pharmacokinetics of peramivir, while the volume of distribution (Vd) was related to body weight and sex. As peramivir is a compound mainly eliminated by the kidney in its unchanged form, the close relation between CL and CLCR suggested that the main elimination mechanism for peramivir is glomerular filtration rather than tubular secretion [1]. Dose adjustment was recommended for patients with severe renal impairment [5, 6] and for pregnant women, who have faster renal clearance (CLR)[7]. No differences in CL and the volume of distribution in the central compartment were found between US and Japanese subjects.

To the best of our knowledge, there have been only a few reports presenting pharmacokinetic profiles in Chinese subjects. Only one report describing the pharmacokinetic profiles of single 300 and 600 mg doses of peramivir has been published in an English-language journal [8]. Analysis of pharmacokinetics after lower doses and multiple intravenous infusions in Chinese subjects is still lacking.

The purpose of our study was to present the pharmacokinetic profiles of single (150, 300 and 600 mg) and multiple (600 mg) intravenous doses of peramivir in healthy Chinese male and female subjects, to enable further pharmacokinetic investigation.

2 Subjects and Methods

2.1 Subjects

The study protocols were reviewed and approved by the ethics committee of the Guangzhou Huiai Hospital before enrolment of study subjects. This study complied with the principles of the Declaration of Helsinki and the Good Clinical Practice: Consolidated Guidelines approved by the International Conference on Harmonization.

Healthy male and female Chinese adults aged 18-40 years, with body mass index (BMI) values of 19-24 kg/m2, were eligible to participate in the study after a satisfactory medical examination. Each subject provided informed written consent before participation in the study. The medical evaluation included a detailed recent medical history, a physical examination with vital sign measurements, an electrocardiogram (ECG) and laboratory testing (liver function, kidney function, routine examinations of blood and urine, and tests for use of alcohol and other drugs of abuse).

Subjects were excluded from the study if they had taken any prescription or non-prescription drugs within 2 months of the first dose of peramivir. Other key exclusion criteria were significant uncontrolled medical conditions; allergy to peramivir, other NAIs or any component of the injection solution; regular excessive intake of tea or coffee ([8 cups per day); ingestion of beverages containing caffeine or alcohol products within 24 h of the start of each study session and during the whole pharmacokinetic period; donation of blood within 3 months of the start of the study; and confirmed pregnancy, suspicion of pregnancy or likelihood of pregnancy during the course of the study. Individuals who could not comply strictly with the protocol were also excluded, and samples from participants who were dosed incorrectly and samples that were taken at the wrong time were excluded from the analysis. Subjects were allowed to withdraw from the study at any time if a serious adverse event (AE) occurred, and AEs related to drugs had to be documented according to the study protocol.

2.2 Study Design

In this open-label study, single and multiple doses of peramivir (150 mg per 15 mL vial; Shanxi Pude Pharmaceutics Co., Ltd, Datong, China) were administered to 12 healthy Chinese subjects by intravenous infusion in a 100 mL sodium chloride solution. Each eligible volunteer was randomly assigned a number between 1 and 12, using data analysis software from Drug and Statistics (DAS, version 3.2.4; Shanghai University of Traditional Chinese Medicine, Shanghai, China). All subjects were fasted for at least 10 h before drug administration and were allowed no food for at least 4 h after treatment.

In the single-dose part of the study, a single dose of 150, 300 or 600 mg of peramivir was administered to the subjects by a slow intravenous infusion at a constant speed controlled by an electronic intravenous infusion pump. The subjects were divided into three groups, and the drug was administered according to a 3 9 3 crossover protocol.

The multiple-dose study began after a 7-day washout period following administration of the third single dose. The administration interval was set according to the label information for Rapiacta^, once daily. The subjects received seven consecutive daily doses of peramivir (600 mg), and steady state was confirmed by measurement of three consecutive trough concentrations prior to the last intravenous infusion.

The total time for each intravenous infusion was expected to be 30 min, and drinking of water was not allowed for 2 h before and after dosing. An indwelling cannula was inserted into the basilic vein to allow blood sampling at predetermined time points before each administration of the drug. All subjects received standardized meals served 4 and 10 h post-infusion. All subjects were asked to remain in the facility during the study- including the fasting time (10 h before medication), the infusion time for sampling and the safety evaluation-and they were free to leave the facility during the washout periods between doses. A 7-day washout period separated the treatments, and all subjects were required to attend a post-study follow-up visit, which included a thorough health check, within 7 days of the last medication.

2.3 Sample Collection

In the single-dose part of the study, blood samples were collected in heparinized tubes pre-dose and at 0.083 (5 min), 0.25 (15 min), 0.5 (30 min), 0.58 (35 min), 0.75 (45 min), 1, 2, 3, 4, 6, 8, 12, 24 and 36 h post-injection. In the multiple-dose part of the study, blood samples were collected on days 4, 5, 6 (pre-dose) and 7 [at 0 h (pre-dose) and at 0.083, 0.25, 0.5, 0.58, 0.75, 1, 2, 3, 4, 6, 8, 12, 24 and 36 h (post-dose)].

Each period required 15*18 blood draws, and every blood draw contained a 4 mL blood sample. All volunteers provided about 60 mL of blood every week, and a total volume of about 250 mL was needed during the whole study, lasting a month. Urine samples (300 mg) were collected in polypropylene tubes during the following time intervals: 2-0 h before drug administration and 0-2, 2-4, 4-8, 8-12 and 12-24 h after the single-dose part of the study. Biological samples were separated by centrifugation (17609g for 3 min), stored in polypropylene tubes at - 70 ^C and thawed to ambient temperature before analysis.

2.4 Bioanalytical Methods

The development and validation of a high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method for determination of peramivir has been reported previously [9]. Briefly, peramivir concentrations in biological fluids were determined using an Agilent 1200 HPLC system (Agilent Technologies, Inc., CA, USA) coupled with an Agilent 6410 triple-quadrupole mass spectrometer equipped with an electrospray ionization source. Chromatographic separation was achieved on an Agilent ZORBAX Plus C18 column (100 mm 9 4.6 mm, particle size 5 lm), with a column temperature of 35 ^C. Deuterated [2H3]-peramivir was used as an internal standard (IS). The mobile phase consisted of 70 % methanol, 30 % water, 0.1 % formic acid and 0.06 M ammonium formate at a flow rate of 0.5 mL/min. The mass transition ion pair m/z 329.1 ? 270.1 was used for peramivir and m/z 332.1 ? 273.1 was used for the IS. Interference by endogenous substances did not significantly affect retention times.

Peramivir standard solutions were prepared in methanol and diluted with blank plasma to provide concentrations of 5, 10, 30, 300, 1000, 3000, 8000 and 10,000 lg/L. The IS working solution (5000 lg/L, 20 lL) was added and mixed with 100 lL of the calibrators, quality control (QC) standards and test plasma samples. Precipitation with methanol (0.7 mL) followed by centrifugation at 20,1569g for 5 min was carried out to remove plasma proteins. Urine calibrators were prepared in drug-free urine at concentrations of 1, 2, 20, 200, 1000, 1500 and 2000 mg/L. The IS working solution (100 mg/L, 10 lL) was added and then vortexed with 10 lL of the urine calibrators, QCs and test urine samples. The samples were treated with methanol (0.9 mL) and centrifuged at 20,1569g for 5 min to remove matrix components. Samples of the supernatant (1 lL) were then analysed by HPLC-MS/MS.

The lower limits of quantification of peramivir in plasma and urine samples were 5 lg/L and 1 mg/L, respectively. The calibration curves for peramivir in plasma and urine were linear under a weighting regression of 1/x2 (r2 [ 0.999) over the concentration ranges described above. At each concentration, the overall bias was within ±10 % of the nominal value. QCs for plasma at concentrations of 10, 1000 and 8000 lg/L and QCs for urine at concentrations of 2, 200 and 1500 mg/L, together with inter- and intra-batch precisions (\10 %) and accuracies (less than ±10 %), were well within the recommendations of the US Food and Drug Administration and were in compliance with the principles of good clinical practice. The matrix effects and extraction efficiencies were 90-100 % in both plasma and urine samples, indicating no significant interference from endogenous substances, and good reproducibility. Calculated concentrations less than the lower limits were assigned to 'zero' in absorption and 'undetectable' in elimination.

2.5 Assessment of Pharmacokinetics

All subjects who received peramivir were included in the pharmacokinetic analysis. Individual pharmacokinetic parameters were derived by standard non-compartmental analysis using DAS software, and key pharmacokinetic parameters such as the maximum concentration (Cmax) and time to reach Cmax (tmax) were calculated on the basis of actual time points.

The following pharmacokinetic parameters were summarized for the single-dose study: Cmax and tmax, obtained directly from the observed concentration of peramivir; the area under the plasma concentration-time curve (AUC) from 0 to 24 h (AUC0-24), AUC from 0 to 36 h (AUC0-36) and AUC from 0 h to infinity (AUC?), determined by the linear trapezoidal rule; and the half-life (t^), calculated as 0.693/kz, where the terminal elimination rate constant (kz) was calculated by linear least-squares regression of the terminal portion of the plasma log-transformed concentration-time curve, and the mean retention time (MRT) was calculated in DAS software. Total CL was calculated as Dose/AUC? for each dosage group. The percentage of the dose recovered in urine (%UR) was calculated by dividing the cumulative amount excreted in urine during the 24 h period (A0-24) by the dose, and CLR was derived from the ratio A0-24/AUC0-24(plasma).

Pharmacokinetic parameters obtained from the multipledose study were t^, tmax, Cmax and AUC from 0 to 24 h at steady state (AUCss), together with additional parameters outlined below. Observed and steady-state cumulative data were obtained from the single- and multiple-dose studies, using DAS software, where the steady-state accumulation ratio (Rss) was calculated as AUCss (multiple-dose period)/ AUC0-s (single-dose period, where s refers to the dosing interval of 24 h).

2.6 Tolerability and Safety

Subjects were closely monitored throughout the studies. Tolerability and safety were assessed by AE reports, vital signs measurements, and ECG and laboratory testing, which were recorded in the case report form. To avoid introducing bias in the assessment of AEs, open-ended and non-leading questions were asked by trained researchers during examinations. The principal investigator would then evaluate the severity of AEs and their relevance to the study drug. Death, hospitalization, prolongation of ongoing hospitalization, persistent or significant disability, congenital abnormality, birth defects and other life-threatening events were judged by the principal investigator before being defined as severe AEs.

2.7 Statistical Analysis

Means and standard deviations (SDs) were calculated for all pharmacokinetic parameters, except for tmax, which is shown as median (range) in Table 2. P values \0.05 were considered to be statistically significant. A regression analysis of the power function formulated as PK = a 9 Doseb was built using DAS software to test dose proportionality, where a refers to the intercept and b refers to the slope in the logarithmic equation. If the 90 % confidence intervals (CIs) of the slope (b) in the equation were totally included in the linear ranges of the respective criteria-that is, 0.8-1.25 for AUC0-36 and AUC?, and 0.75-1.33 for Cmax-the pharmacokinetics of peramivir was supposed to be dose proportional. The lower limit of the 90 % CI (90 % CIL) of Rss was used as the criterion for accumulation following repeated doses, and a value between 0.8 and 1.25 indicated an insignificant trend towards accumulation.

3 Results

3.1 Subjects

Twelve healthy Chinese subjects were enrolled in the study and included in the pharmacokinetic analysis. None of the subjects withdrew during the studies. Baseline demographic characteristics were comparable within the group (Table 1). At baseline, the mean age of the subjects was 22 years (range 18-28), the mean body weight was 57 kg (range 50-68) and the mean BMI was 22.02 kg/m2 (range 19.27-22.46). The mean CLCR was 99.79 mL/min (range 87.53-116.71) before medication, and a small increase in CLCR could be observed in most subjects (mean CLCR 110.12 mL/min, range 95.53-132.13) after the dosage.

3.2 Pharmacokinetics

The mean plasma concentration-time profiles for peramivir in healthy Chinese subjects after a single intravenous peramivir infusion of 150, 300 or 600 mg over 30 min are shown in Fig. 1. The main pharmacokinetic parameters for single and multiple doses of peramivir are summarized in Table 2.

3.2.1 Single-Dose Pharmacokinetics

After Cmax was reached (tmax range 0.50-0.58 h), plasma concentrations typically decreased from the peak for all dose periods. The mean t^ ranged between 2.30 and 3.35 h was significantly prolonged at the middle dose of 300 mg (P \ 0.05). Vd was slightly increased at higher doses (range 20.47-31.80 L).

The mean Cmax increased from 12,416 lg/L with the 150 mg dose to 23,147 lg/L with the 300 mg dose and 44,113 lg/L with the 600 mg dose, representing a *1.9-fold increase in Cmax for every 2-fold increase in dose. AUC0-36 and AUC? also showed corresponding increases, indicating that exposure was proportional to the dose. The CI of the slope in the dose proportionality equation was totally included in the linear range of the respective criteria [Cmax 0.969 (CI 0.850-1.088), AUC0-36 0.969 (CI 0.850-1.088) and AUC? 0.934 (CI 0.826-1.042)], suggesting that the pharmacokinetic parameters for peramivir were dose proportional.

3.2.2 Multiple-Dose Pharmacokinetics

The mean plasma concentration-time profiles for peramivir after seven consecutive days of intravenous infusions of peramivir (600 mg) over 30 min are shown in Fig. 1. The key pharmacokinetic parameters, after seven daily doses, were similar to those after single administration of the same dose (Table 2). Elimination was slower in the multiple-dose study than in the single-dose study of the same dose (t^ 4.49 versus 3.35 h, P \ 0.05), but clearance was not significantly altered. The 90 % CIL of Rss after multiple doses (1.03-1.14) was included in the boundaries of 0.80-1.25, demonstrating that there was no significant accumulation effect. Repeated measurements of trough concentrations (the mean values ranged from 51.96 to 56.15 lg/L) showed no significant differences in plasma concentrations on days 4, 5, 6 and 7, demonstrating that steady state was attained at day 4 of a 7-day successive administration schedule. In the current study, urinary recovery of peramivir was 65.01 ± 7.10 % (Fig. 2)-lower than the previously reported value of about 80 % [8, 10]-which could have been due to the fact that urine samples were collected for only 24 h in this study, shorter than the collection period of 36 h for urine samples in the previous studies.

3.3 Tolerability and Safety

All four treatment regimens were well tolerated. Mild diarrhoea was reported by two study participants in the single-dose period and was considered by the investigator to be related to the treatment. No clinically significant changes in blood pressure, heart rate, ECG, serum chemistry, chest X-ray or routine blood and urine examinations were found.

4 Discussion

The present study investigated the pharmacokinetic properties and tolerability of peramivir in healthy Chinese men and women following a single dose (150, 300 or 600 mg) and after multiple dosing.

The values of Cmax, AUC? and t^ for peramivir at three doses (150 mg: 12.42 ± 3.08 mg/L, 24.68 ± 6.48 mg h/L and 2.30 ± 0.70 h, respectively; 300 mg: 23.15 ± 3.67 mg/L, 47.33 ± 9.22 mg h/L and 3.07 ± 1.00 h, respectively; 600 mg: 44.11 ± 3.79 mg/L, 92.43 ± 12.72 mg h/L and 3.35 ± 0.79 h, respectively) were in agreement with values reported in the drug datasheet and in the literature (300 mg: 21.4 ± 3.7 mg/L, 56.13 ± 10.64 mg h/L and 2.60 ± 0.61 h, respectively; 600 mg: 41.1 ± 5.3 mg/L, 112.3 ± 13.2 mg h/L and 3.28 ± 1.15 h, respectively) [8] and were linear over the three doses.

The plasma concentration of peramivir was 9.81 ± 4.55 lg/L at 24 h after a single dose of peramivir 150 mg. This concentration far exceeded the 50 % inhibitory concentration of peramivir (0.0923-0.1586 lg/L against pH1N1 viruses [11]), suggesting that a dose of 150 mg could be an effective treatment option for patients who are unable to tolerate higher doses.

Plasma concentrations of peramivir were proportional to the dose over the study range, and an equivalent enhancement of exposure could be achieved by dose adjustment. The accumulation effect after repeated dosing was not significant, suggesting possible linear pharmacokinetics for doses ranging from 150 to 600 mg in healthy Chinese men and women [4].

The question about the significant increase in t^ between the low and middle dosage groups (2.30 vs. 3.07 h, P \ 0.05), which was consistent with findings in a previous study [8], could have been explained by the limited sensitivity of the analytical method that was used, since calculated t^ values can be influenced by detection sensitivity. The end points in the low dosage group were partly undetectable, and these individuals displayed faster apparent elimination than real. Because their t^ values were calculated using the peramivir concentration-time curve of 0-24 h, lower individual and mean t^ values than the real values were assessed, which was consistent with lower calculated Vd values. The true t^ would be likely to be close to 3.35 h at the high dose of 600 mg. No accumulation effect was seen in our study, in agreement with previous findings [4].

Single and multiple infusions of peramivir appeared to be well tolerated and safe in all subjects. Only two mild cases of diarrhoea were observed during the study, and no serious AEs were reported.

The study was conducted in healthy young volunteers with very similar BMIs. Caution should be exercised when extrapolating these data to patients and special groups, especially patients with renal disease or pregnant women. The study protocol also had other limitations (lack of a placebo group and a small sample size), which could have led to possible bias and insufficient accuracy.

5 Conclusion

In this study, pharmacokinetic profiles of peramivir after single doses of 150, 300 and 600 mg were determined, and linear pharmacokinetic behaviour was observed. Steady state was achieved on day 4 after repeated administration of peramivir. No evidence of drug accumulation in plasma was seen, and most of the drug was excreted in urine in an unmetabolized form. No clinically significant AEs were reported, and all dose regimens were well tolerated in healthy volunteers, with only a small number of mild AEs.

Acknowledgments The authors thank all subjects who participated in this study.

Funding This work was funded by Shanxi Pude Pharmaceuticals Co., Ltd, and the National Natural Science Foundation of China (Grant No. 81403016). Grammar checking support was provided by International Science Editing (Co. Clare, Ireland) and sponsored by the National Natural Science Foundation of China (Grant No. 81403016).

Compliance with Ethical Standards This study complied with the principles of the Declaration of Helsinki, the Good Clinical Practice: Consolidated Guidelines approved by the International Conference on Harmonization and local Chinese laws on clinical research involving human subjects. The protocols and informed consent form were reviewed and approved by the ethics committee of the Guangzhou Huiai Hospital before subject enrolment. Each subject was informed of the nature and purpose of the study, and provided informed written consent, before the screening procedures were conducted for the study.

Conflict of interest Li-Zhong Li, who was responsible for the study design and oversight, was an employee of Shanxi Pude Pharmaceuticals Co., Ltd, at the time when the study was conducted. Ming Zhang, Zhan-Zhang Wang, Xiao-Jia Ni, Hao-Yang Lu, De-Wei Shang, Wen-Can Huang and Yu-Guan Wen, who were responsible for conduct of the study and manuscript preparation, were employees of the Clinical Research Unit at Guangzhou Brain Hospital. Doctor YueFeng Zhang, Nurse Huan Peng, Nurse Ling-Fang Shen and Nurse Ling-Hui Xiong, who were also responsible for conduct of the study, especially for clinical care, were also employees of Guangzhou Brain Hospital. Ming Zhang, Zhan-Zhang Wang, Xiao-Jia Ni, Yue-Feng Zhang, Huan Peng and De-Wei Shang have received a research grant from the National Natural Science Foundation of China (Grant No. 81403016).

Sidebar

Key Points

The pharmacokinetics of peramivir intravenous infusion were approximately dose proportional.

There was no accumulation after multiple dosing of peramivir injections, and the increased time to reach the maximum concentration after repeated doses suggested that a more sensitive analytical method was needed.

Sixty-five percent of the drug was excreted in urine in an unmetabolized form.

Peramivir intravenous infusion was well tolerated, and no serious adverse events occurred.

References

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