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Research Article Article OpenOpen Access Access Pharmacokinetics of Laninamivir after a Single Administration of its Prodrug, Laninamivir Octanoate, a Long-Acting Neuraminidase Inhibitor, Using an Easy-to-Use Inhaler in Healthy Volunteers Satoshi Yoshiba*, Hiromi Okabe and Hitoshi Ishizuka Translational Medicine and Clinical Pharmacology Department, Daiichi Sankyo Co., Ltd., 1-2-58, Hiromachi, Shinagawa, Tokyo 140-8710, Japan

Abstract Pharmacokinetic profiles of laninamivir after a single inhalation of laninamivir octanoate (LO), a prodrugof laninamivir, using a newly developed easy-to-use inhaler were evaluated in healthy volunteers. LO appeared rapidly

in plasma after an inhaled administration in healthy volunteers with a median value of tmax of 0.25 hr, and the plasma

concentrations decreased below the detection limit after 24 hr of inhalation. The median tmax of laninamivir was 4.0

hr and laninamivir slowly declined after Cmax with a mean t1/2 of 66.6 and 74.4 hr at a dose of 20 mg and 40 mg,

respectively. The average AUC0-inf and Cmax for LO and laninamivir almost increased proportionally with the dose. The mean cumulative excretion amounts of LO in urine for 144 hr after inhaling 20 mg or 40 mg dose of LO were 4.7 and 5.5% of the dose, respectively, and those of laninamivir were 19.2 and 23.3%, respectively. No clinical or laboratory adverse experiences were reported and no subject discontinued because of an adverse experience. As plasma concentrations of both LO and laninamivir revealed a similar pattern between using the prototype and this new inhaler, LO exhibited potential for long lasting anti-influenza activity using this easy-to-use inhaler.

Keywords: Laninamivir; Laninamivir octanoate; CS-8958; adult seasonal influenza. LO was also an effective and well-tolerated Pharmacokinetics; Human; Safety; Neuraminidase inhibitor treatment for children with oseltamivir-resistant influenza A (H1N1) Abbreviations: LO: laninamivir octanoate; DPIs: Dry Powder virus infection [17]. Inhalers; BMI: Body Mass Index; AUC0-tz:Area Under the Concentration- The pharmacokinetics of LO and laninamivir after a single inhaled time curve up to the time of the last measurable concentration dose of LO in human volunteers were previously investigated [5, 6] data; AUC0-inf: AUC values extrapolated to infinity; Cmax: Maximum Concentration; tmax: Time to Cmax; t1/2: Half-Life; CL/F: Apparent total body clearance; Vz/F: Apparent volume of distribution; Xu0-144h: The (A) (B) cumulative percentage of dose excreted in urine up to 144 hours; CLR : Renal clearance; APSD: Aerodynamic Particle Size Distribution H C O H 3 OCH HO H 3 OCH3 O CO H Introduction O HO 2 HO O CO2H HH H H Laninamivir (Figure 1) is a new neuraminidase inhibitor which has O H HO NH2 NH 3-acyl form N N 2 been shown to be sensitive against various influenza A and B viruses, H H N H HN H3C H H3C H including subtypes N1 to N9, oseltamivir-resistant viruses [1] and NH NH new swine-origin H1N1 strains like A/California/04/09 in vitro and and in vivo [7, 8]. The prophylactic and therapeutic efficacy of laninamivir HO H octanoate (LO, Figure 1), the octanoyl esterified form of laninamivir, OCH3 against highly pathogenic H5N1 influenza viruses has been reported H C O O CO2H 3 H [15]. The increase of lipophilicity by acylating the active form provided H O O H NH prolonged the survival effects in accordance with the chain length in a N 2 H H N mouse infection model [4]. Also, LO conferred more potent and long- 2-acyl form H3C H lasting protection to mice against H5N1 influenza viruses, including NH oseltamivir-resistant mutants than did oseltamivir [7]. In mice, after Figure 1: Chemical structures of laninamivir octanoate (A) and laninamivir (B). being intranasally administered [14C]LO, the radioactivity was retained in the respiratory tract over extended time periods with high levels in the trachea and lung equal to those of laninamivir over 24 hours post- Corresponding author: Satoshi Yoshiba, MSc. Translational Medicine and dose [9]. Long retention in the trachea and lung was also observed Clinical Pharmacology Department, Daiichi Sankyo Co., Ltd., 1-2-58, Hiromachi, after intratracheal administration to rats, and plasma concentration Shinagawa, Tokyo 140-8710, Japan,Tel: +81-3-5740-3412; Fax: +81-3-5740-3625; of laninamivir in rats was slowly eliminated. Hydrolysis of LO in the E-mail: [email protected] respiratory tract was observed in human lung S9 in vitro by various Received January 20, 2011; Accepted February 09, 2011; Published February kinds of esterase (unpublished data). In addition, its half-life was 11, 2011 considerably longer than that after intravenous administration of Citation: Yoshiba S, Okabe H, Ishizuka H (2011) Pharmacokinetics of Laninamivir laninamivir [10]. after a Single Administration of its Prodrug, Laninamivir Octanoate, a Long-Acting A double-blind, randomized controlled trial to compare the Neuraminidase Inhibitor, Using an Easy-to-Use Inhaler in Healthy Volunteers. J Bioequiv Availab 3: 001-004. doi:10.4172/jbb.1000048 efficacy of LO with oseltamivir in adult patients that have suffered from influenza virus has been conducted recently [18]. The time to illness Copyright: © 2011 Yoshiba S, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted alleviation after a single inhalation of LO was not inferior to that of use, distribution, and reproduction in any medium, provided the original author and multiple oral treatment of oseltamivir, and it was sufficient to treating source are credited.

J Bioequiv Availab ISSN:0975-0851 JBB, an open access journal Volume 3(1): 001-004 (2011) - 001 Citation: Yoshiba S, Okabe H, Ishizuka H (2011) Pharmacokinetics of Laninamivir after a Single Administration of its Prodrug, Laninamivir Octanoate, a Long-Acting Neuraminidase Inhibitor, Using an Easy-to-Use Inhaler in Healthy Volunteers. J Bioequiv Availab 3: 001-004. doi:10.4172/ jbb.1000048

500 AUC and Cmax of laninamivir increased almost linearly with a dose 20 mg administered up to 120 mg in healthy volunteers, and the plasma 40 mg )

L 400 concentration of laninamivir slowly decreased from the body, even m / e g t lasting for as long as 144 hours after administration with t for about n

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a 3 days apart from the renal insufficiency. These pharmacokinetic i

t 300 c t a r o t

n characteristics suggest the potential for long lasting anti-influenza v i i c e n m activity. a 200 c o n

i a n a L s m Dry powder inhalers (DPIs) have become widely known as a very a l p 100 attractive platform for drug delivery. Many patients have traditionally used DPIs to treat asthma and chronic obstructive pulmonary disease. 0 Recently, the development of new DPIs for delivering therapeutic 0 4 8 12 16 20 24 proteins such as insulin has been accelerated through patient demand time (h) 50 and innovative research [16]. A new, simple and easy-to-use inhaler 20 mg was developed to reduce potential operational error and the number

) 40 mg of inhalation of LO. It consists of a main body including a mouthpiece L 40 m /

g and a shuttle with two dose compartments for powder formulation. n (

n r

o Powder formulation containing 20 mg of LO is directly filled in i v i t i 30 a r m t

a the dose compartments in the manufacturing process. This inhaler n n i c e n n a becomes ready to use by just pushing the shuttle sideways to align

L 20 c o

a the dose compartment with the mouthpiece for the first dose, and s m a

l then by pushing the shuttle in the other direction for the second dose. p 10 The prototype inhaler required changing the 5 mg capsule every one inhalation, therefore 4 or 8 times of changing capsule and inhalation 0 0 24 48 72 96 120 144 were needed. On the other hand, the new inhaler requires no changing time (h) capsules and less inhalation is needed than the prototype inhaler. Due to the simplicity and low risk of operational error, this inhaler may be Figure 2: Plasma laninamivir octanoate (LO, upper) and laninamivir (lower) suitable for high dose and single treatment pharmaceutical products concentration profiles following a single inhaled administration of LO using a like LO. In addition, the reduced number of inhalation by its ease of new easy-to-use inhaler in healthy human volunteers. Symbols are the mean +/- SD of 8 subjects per group. use is another advantage for LO, especially for a pandemic requiring immediate treatment of large populations. On the basis of this work, the pharmacokinetic of laninamivir in 5 20mg healthy volunteers was evaluated to characterize the feature of LO using

) 40mg g a new easy-to-use inhaler.

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c Materials and Methods a t x 3 c e

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i Clinical pharmacokinetic study n r i m u a 2 n e i v n i A randomized, parallel study to evaluate the safety and t a a L l u pharmacokinetics of LO and laninamivir was conducted at Kyushu m 1 u c Clinical Pharmacology Research Clinic (Fukuoka, Japan). The protocol was approved by the institutional review boards of Kyushu Clinical 0 0 24 48 72 96 120 144 Pharmacology Research Clinic (Fukuoka, Japan). The protocol was time (h) conducted in accordance with the guidelines on Good Clinical Practice

and with ethical standards for human experimentation established by the Declaration of Helsinki Principles. Every subject gave written 10 20mg informed consent to participate in this study. 40mg ) g 8

( m Subjects and study designs

n o i t

r e Male subjects (aged 20~45 years) with a body mass index in the c r 6 x v i 2 e

m range of 18.5–25.0 kg/m were eligible for inclusion if they were deemed a r y n a i n n

r i healthy in terms of medical history, physical examination findings, 12- a 4 u L

v lead electrocardiogram findings and clinical laboratory evaluations. i t a l u 2 Evidence of organ dysfunction or any clinically significant deviation m u c from the norm in a physical examination, vital signs, electrocardiogram

0 0 24 48 72 96 120 144 Characteristic Laninamivir octanoate dose 20 mg (N=8) 40 mg (N=8) time (h) Age yrs 21 (20-24) 21 (20-24) Height cm 170 (161-183) 171 (164-178) Figure 3. Cumulative urinary excretion of laninamivir octanoate (LO, upper) and Body weight kg 63.3 (56.3-75.6) 62.0 (56.0-67.6) laninamivir (lower) profiles following a single inhaled administration of LO using BMI kg/m2 21.9 (20.2-23.3) 21.1 (19.4-24.4) a new easy-to-use inhaler in healthy human volunteers. Symbols are the mean Values are arithmetic mean (range). BMI, body mass index +/- SD of 8 subjects per group. Table 1: Demographic characteristics of the study subjects for pharmacokinetics.

J Bioequiv Availab ISSN:0975-0851 JBB, an open access journal Volume 3(1): 001-004 (2011) - 002 Citation: Yoshiba S, Okabe H, Ishizuka H (2011) Pharmacokinetics of Laninamivir after a Single Administration of its Prodrug, Laninamivir Octanoate, a Long-Acting Neuraminidase Inhibitor, Using an Easy-to-Use Inhaler in Healthy Volunteers. J Bioequiv Availab 3: 001-004. doi:10.4172/ jbb.1000048

PK parameters Laninamivir octanoate dose the concentration versus the time curve up to the time of the last

20 mg (N=8) 40 mg (N=8) measurable concentration data (AUC0-tz) was obtained by the linear ・ trapezoidal method. The AUC values were extrapolated to infinity Laninamivir AUC0-tz ng h/mL 440 (82) 1018 (242) ・ (AUC ) using the equation AUC + C /λ, where C is the last octanoate AUC0-inf ng h/mL 446 (83) 1023 (241) 0-inf 0-tz tz tz measurable concentration and λ is the terminal elimination rate. Cmax ng/mL 145 (40) 336 (112) The urine concentrations, urine volumes from individual collection tmax h 0.25 (0.25-0.25) 0.25 (0.25-0.25) intervals and nominal times of the collection intervals were used to t1/2 h 1.79 (0.11) 2.70 (0.40) CL/F mL/min 774 (174) 694 (207) calculate the urinary pharmacokinetic parameters. The amount of Vz/F L 121 (27) 160 (50) LO and laninamivir excreted in urine in each collection interval was determined by the product of the urine concentration and the urine Xu0-144h % 4.7 (1.1) 5.5 (1.5) volume. The renal clearance (CL ) was determined as the quotient of CLR mL/min 34.3 (5.1) 35.9 (6.1) R ・ the cumulative excretion amount of the drug and AUC. Laninamivir AUC0-tz ng h/mL 558 (96) 1080 (156) ・ AUC0-inf ng h/mL 693 (116) 1379 (210) Safety and tolerability C ng/mL 19.0 (3.1) 38.3 (9.8) max Each subject was confined to the Clinical Pharmacology Unit t h 4.0 (3.0-6.0) 4.0 (3.0-6.0) max from the previous day of dosing through the completion of 144- t h 66.6 (9.1) 74.4 (19.3) 1/2 hour post-dose procedures. Safety and tolerability were assessed in Xu % 19.2 (4.0) 23.3 (2.6) 0-144h each study by clinical evaluation (including physical examinations, CL mL/min 84.9 (18.5) 106.9 (18.1) R vital signs, lung function tests and 12-lead electrocardiograms) and Values are arithmetric mean (SD), except for t , which is expressed as median max laboratory measurements (including hematology, serum chemistry (range) and urinalysis). A physical examination was performed at screening, AUC0-tz, area under the concentration-time curve up to the time of the last measurable concentration data 144 hours after drug administration and at the end-of-study visit.

AUC0-inf, AUC values extrapolated to infinity; max C , maximum concentration; tmax, Vital signs (blood pressure and heart rate), temperature and a 12-lead time to C ; t , half-life max 1/2 electrocardiogram (ECG) were recorded. Standard clinical laboratory CL/F, apparent total body clearance; Vz/F, apparent volume of distribution profiles for hematology, serum chemistry and urinalysis were assessed Xu0-144h, the cumulative percentage of dose excreted in urine up to 144 hours; CLR, renal clearance at screening, 24 and 144 hours after drug administration and at the Table 2: Pharmacokinetic parameters of laninamivir octanoate (LO) and laninamivir end-of-study visit. Adverse experiences were monitored throughout after a single inhaled administration of LO using a new easy-to-use inhaler in the study. Subjects were questioned concerning their well being. healthy human volunteers. Investigators evaluated all the clinical adverse experiences in terms of or clinical laboratory determinations were criteria for exclusion. A intensity (mild, moderate or severe), duration, severity, outcome and total of 16 young healthy male subjects were planned to be enrolled in relationship to the study drug. this study. Subjects (N=8) were randomly assigned to receive a single Results inhaled dose of 20 or 40 mg of LO (DaiichiSankyo Co., Ltd., Tokyo, Japan). The subjects were instructed to inhale each dose using quiet Clinical pharmacokinetic study tidal breathing. LO was administered in a seated position and the Sixteen participants received LO and all participants were included subjects were prohibited from resting in a supine position for 2 hours in the pharmacokinetic analyses. The demographic and baseline after inhalation. characteristics of the study populations are shown in Table 1. The plasma LO and laninamivir concentration profiles after a single inhaled Blood and urine sampling for the pharmacokinetic analysis administration of LO using the new inhaler are shown in Figure 2, and Plasma and urine samples were collected and analyzed for LO and the pharmacokinetic parameters are summarized in Table 2. laninamivir concentrations. Blood (5 mL) was collected into vacutainers LO appeared rapidly in plasma after an inhaled administration containing heparin as an anticoagulant at predose and 0.25, 0.5, 1, 1.5, with a median value of tmax of 0.25 h, and the plasma concentrations 2, 3, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours after dosing. After decreased below the detection limit (1.0 ng/mL) after 24 hr of the addition of acidified AEBSF (4-(2-aminoethyl) benzenesulfonyl inhalation. The median tmax of laninamivir was 4.0 hr, and laninamivir fluoride hydrochloride) as an enzyme inhibitor to minimize slowly declined after Cmax with the mean t1/2 of 66.6 and 74.4 hr at the degradation, followed by centrifugation, the plasma supernatants were dose of 20 mg and 40 mg, respectively. The average AUC0-inf and Cmax for stored at -20°C until the assay. Urine for the LO and laninamivir assay LO and laninamivir increased almost proportionally with the dose. The was collected in several appropriate intervals to evaluate the urinary mean cumulative excretion amounts of LO in urine for 144 hr (Xu0-144h) excretion rate from predose to 144 h after dosing. For each collection after inhaling 20 mg or 40 mg dose of LO were 4.7 and 5.5% of the dose, period, the total urine volume was measured and 5-10 mL were collected respectively, and those of laninamivir were 19.2 and 23.3%, respectively. and stored at -20°C until the assay. LO and laninamivir concentrations LO was generally well tolerated. No clinical or laboratory adverse in human plasma and urine were determined by the validated sensitive experiences were reported and no subject discontinued because of an and specific LC-MSMS method as described previously [5]. adverse experience. No notable mean changes from the baseline were Pharmacokinetic analysis recorded in the vital signs or clinical laboratory variables. No clinically significant changes in electrocardiograms (ECGs) were reported in any The pharmacokinetic parameters were calculated by a non- participants during the study. compartment analysis using the computer software WinNonlin Professional (version 5.2.1, Pharsight Corp., CA). The maximum Discussion concentration (Cmax) and the time to Cmax (tmax) were obtained by The efficacy of a single LO dose of 40 mg using a prototype inhaler observation. The apparent elimination t1/2 was obtained by a linear was not inferior to that of 10 doses of oseltamivir administered regression of 3 or more log-transformed data points in the terminal orally over 5 days with seasonal influenza, including that caused by phase (calculated automatically by WinNonlin). The area under oseltamivir-resistant viruses in adult patients [18]. In addition, a single

J Bioequiv Availab ISSN:0975-0851 JBB, an open access journal Volume 3(1): 001-004 (2011) - 003 Citation: Yoshiba S, Okabe H, Ishizuka H (2011) Pharmacokinetics of Laninamivir after a Single Administration of its Prodrug, Laninamivir Octanoate, a Long-Acting Neuraminidase Inhibitor, Using an Easy-to-Use Inhaler in Healthy Volunteers. J Bioequiv Availab 3: 001-004. doi:10.4172/ jbb.1000048

inhalation of LO reduced the duration of influenza illness significantly, the new easy-to-use inhaler may exhibit efficacy against influenza virus. compared with oseltamivir, against H1N1 virus with the H274Y mutation in pediatric patients [17]. This long-acting characteristic of Acknowledgments LO is supported by the long plasma half-life of laninamivir (~3 days) This study was sponsored by Daiichi Sankyo Co., Ltd. All authors were after a single inhaled administration, which might predominantly employed by Daiichi Sankyo Co., Ltd. during the conduct of the studies described reflect the slow release from retaining tissues to plasma [5,6]. Plasma herein. half-life of laninamivir after a single inhaled administration using this inhaler was rather long and almost comparable with that reported References previously, suggesting potential for long-lasting anti-influenza activity 1. Boltz DA, Aldridge JR Jr, Webster RG, Govorkova EA (2010) Drugs in using this inhaler. development for influenza. Drugs 70: 1349-1362. 2. Hayden FG, Osterhaus ADME, John J,Fleming DM, Aoki FY Though plasma half-lives of LO and laninamivir after a single et al. (1997) Efficacy and safety of the neuraminidase inhibitor zanamivir in the inhaled administration using this inhaler were almost comparable with treatment of influenza virus infections. N Eng J Med 337: 874-880. those reported values, mean plasma concentrations, AUC, Cmax and 3. Hayden FG, Gubareva LV, Monto AS,Klein TC, Elliott MJ, Xu0-144h of LO and laninamivir using a new inhaler exhibited higher et al. (2000) Inhaled zanamivir for the prevention of Influenza in families.N Engl values than those using the prototype [5]. However, the emission J Med 343:1282-1289. performance of the inhaler used in this study evaluated by the cascade 4. Honda T, Kubo S, Masuda T, Arai M, Kobayashi Y, et al. (2009) Synthesis impactor was equivalent to that of the prototype inhaler (In-house and in vivo influenza virus-inhibitory effect of ester prodrug of 4-guanidino-7-O- data). Cascade impactor is the most widely encountered means for methyl-Neu5Ac2en. Bio org Med Chem Lett 19: 2938-2948. in vitro determination of the aerodynamic particle size distribution 5. Ishizuka H, Yoshiba S, Okabe H, Yoshihara K (2010) Clinical pharmacokinetics (APSD) from medical inhalers, both in product development, batch of laninamivir, a novel long-acting neuraminidase inhibitor, after single and multiple inhaled doses of its prodrug, CS-8958, in healthy male volunteers. J release and in applications with add-in devices [12]. Though it is Clin Pharmacol 50: 1319-1329. reported that the links between laboratory-measured APSD data 6. Ishizuka H, Yoshiba S, Yoshihara K, Okabe H. (2011) Assessment of the from the cascade impactor, particle deposition in the respiratory effects of renal impairment on the pharmacokinetic profile of laninamivir, a tract and clinical response are not straightforward [14]. APSD data novel neuraminidase inhibitor, after a single inhaled dose of its prodrug, CS- may principally provide the information which might be helpful in 8958. J Clin Pharmacol 51: 243-251. estimating the likelihood of clinical response in studies on the efficacy 7. Itoh Y, Shinya K, Kiso M, Watanabe T, Sakoda Y, et al. (2009) In vitro and in vivo characterization of new swine-origin H1N1 influenza viruses. Nature 460: and safety of inhaled drugs [13].Though mean values of AUC, Cmax and 1021-1027. Xu0-144h using a new inhaler were higher than those using the prototype, each parameter exhibited a relatively large inter-individual variation 8. Kiso M, Kubo S, Ozawa M, Le QM, Nidom CA, et al. (2010) Efficacy of the and the ranges of the individual parameters almost overlapped between new neuraminidase inhibitor CS-8958 against H5N1 influenza viruses. PLoS Pathog 6: e1000786. the two inhalers. Future population pharmacokinetic analysis together with other pharmacokinetic results might be a powerful tool to evaluate 9. Koyama K, Takahashi M, Oitate M, Nakai N, Takakusa H, et al. (2009) CS- 8958, a prodrug of the novel neuraminidase inhibitor R-125489, demonstrates the inter- and intra-individual variation and the covariates which affect a favorable long retention profile in mouse respiratory tract. Antimicrob Agents the pharmacokinetics of LO and laninamivir, including the difference Chemother 53: 4845-4851. between the two inhalers. 10. Koyama K, Takahashi M, Nakai N, Takakusa H, Murai T, et al. (2010) The value of neuraminidase inhibitors was clearly established Pharmacokinetics and disposition of CS-8958, a long-acting prodrug of the novel neuraminidase inhibitor laninamivir in rats. Xenobiotica 40:207-216. during the initial phases of the 2009 pandemic when vaccines were not available, i.e., stockpiles of anti-virals are valuable [1]. The development 11. LaForce C, Man CY, Henderson FW, McElhaney JE, Hampel FC Jr, et al. (2007) Efficacy and safety of inhaled zanamivir in the prevention of influenza of high-potency drugs requiring less frequent administration is in community-dwelling, high-risk adult and adolescent subjects: a 28-day, desirable because the amount of drug needed for pandemic stockpiling multicenter, randomized, double-blind, placebo-controlled trial. Clin Ther is tremendous. As an inhaled neuraminidase inhibitor, zanamivir was 29:1579-1590. efficacious in twice daily treatment for 5 days [2], and was also efficacious 12. Mitchell J, Nagel M (2003) Cascade impactors for the size characterization of for the prevention of influenza with self-administration once daily for aerosols from medical inhalers: Their uses and limitations. J Aerosol Med 16: up to 10 days in families [3]. In addition, zanamivir was successful 341-377. in preventing infection with the predominant strains circulating in the 13. Mitchell J, Newman S, Chan HK (2007) In vitro and in vivo aspects of cascade 2000-2001 influenza season in high-risk community-dwelling subjects impactor tests and inhaler performance: A review. AAPS PharmSciTech 8: E1- E12. for up to 28 days [11]. It is reported that LO has substantial efficacy as both a therapeutic and a prophylactic agent against H5N1 influenza 14. Newman S, Wilding IR, Hirst PH (2000) Human lung deposition data: the bridge between in vitro and clinical evaluations for inhaled drug products? Int J Pharm viruses in mice. LO is, therefore, a promising candidate antiviral for 208: 49–60. the prevention and treatment of influenza patients infected with H5N1 15. Neumann G, Noda T, Kawaoka Y (2009) Emergence and pandemic potential of or other subtype viruses [7]. From the current study, it revealed that swine-origin H1N1 influenza virus. Nature 459: 931-939. the plasma half-life of laninamivir, which might reflect the elimination 16. Son YJ, McConville J (2008) Advancements in dry powder delivery to the lung. of drug from retaining tissues, was long enough to prevent infection Drug Dev Ind Pharm 34: 948-959. by a single inhaled LO administration in humans. However, whether 17. Sugaya N, Ohashi Y (2010) Long-acting neuraminidase inhibitor laninamivir laninamivir concentration in target tissues may be enough to prevent octanoate (LO) versus oseltamivir as treatment for children with influenza virus influenza virus infection was not clear. Further clinical investigation to infection. Antimicrob Agents Chemother 54 :2575-2582. evaluate laninamivir concentration in target tissues might be necessary 18. Watanabe A, Chang SC, Kim MJ, Chu DW, Ohashi Y, et al. (2010) Long-acting to consider the appropriate dosage regimens for prevention of influenza neuraminidase inhibitor laninamivir octanoate versus oseltamivir for treatment infection by LO inhalation, especially for highly pathogenic viruses. of influenza : A double-blind, randomized, noninferiority clinical trial. Clin Infect Dis 51: 1167-1175. LO was well tolerated by all subjects following a single inhaled dose 19. Yamashita M, Tomozawa T, Kakuta M, Tokumitsu A, Nasu H, et al. (2009) LO, a using the new easy-to-use inhaler. Similar pharmacokinetic profiles prodrug of the new neuraminidase inhibitor R-125489, shows long-acting anti- between the two inhalers indicate that a single inhaled dose of LO using influenza virus activity. Antimicrob Agents Chemother 53: 186-192.

J Bioequiv Availab ISSN:0975-0851 JBB, an open access journal Volume 3(1): 001-004 (2011) - 004