alenc uiv e & eq B io io B a f v o a i l l a Journal of a b Yoshiba et al. J Bioequiv Availab 2011, 3:1 n r i l i u t y o DOI: 10.4172/jbb.1000048 J ISSN: 0975-0851 Bioequivalence & Bioavailability 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 prodrug of 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; maxC : 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 a 1/2 ( o n n o a 3 days apart from the renal insufficiency. These pharmacokinetic i t t 300 c a r o t r n characteristics suggest the potential for long lasting anti-influenza i e v i c n m activity. o a 200 c n i a n a m L s 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 i o Powder formulation containing 20 mg of LO is directly filled in i v t i 30 a r m t a the dose compartments in the manufacturing process. This inhaler n n e i c n n a becomes ready to use by just pushing the shuttle sideways to align o L 20 c a the dose compartment with the mouthpiece for the first dose, and m s 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 m a new easy-to-use inhaler. ( 4 n e t o i t a e o r n c Materials and Methods a t x 3 c e o y r r i a v i Clinical pharmacokinetic study n i r 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).