Hitoshi Ishizuka

Clinical Pharmacokinetics of Laninamivir, a Novel Long‐Acting Neuraminidase Inhibitor, After Single and Multiple Inhaled Doses of Its Prodrug, CS‐8958, in Healthy Male Volunteers

Phase 1 studies of laninamivir, a novel long‐acting neuraminidase inhibitor, were carried out to assess its safety, tolerability, and pharmacokinetics after inhaled administration of its prodrug, CS‐8958. Healthy male volunteers (total N = 76) participated in double‐blind, randomized, placebo‐controlled trials and received 5, 10, 20, 40, 80, or 120 mg of a single dose or 20 or 40 mg of a twice‐daily dose for 3 days. The clinical and laboratory parameters and plasma and urinary concentrations of CS‐8958 and laninamivir for 144 hours post dosing were measured. There were no adverse events related to the test drug. CS‐8958 disappeared from plasma with a half‐life of about 2 hours, although laninamivir was slowly eliminated from the body, lasting for even up to 144 hours after administration with a half‐life of about 3 days. Area under the curve and maximum concentration increased almost linearly with the dose administered. The cumulative urinary excretion amounts of CS‐8958 and laninamivir were 2.3% to 3.6% and 10.7% to 14.6% of the dose, respectively. The half‐life of the urinary excretion rates of laninamivir at higher single dose is comparable to plasma half‐life. CS‐8958, when inhaled by healthy volunteers, is well tolerated and exhibits a suitable pharmacokinetic profile, suggesting potential for long‐lasting anti‐influenza activity.

Intrapulmonary Distribution and Pharmacokinetics of Laninamivir, a Neuraminidase Inhibitor, after a Single Inhaled Administration of Its Prodrug, Laninamivir Octanoate, in Healthy Volunteers

ABSTRACT A single inhaled dose of laninamivir octanoate (LO), a long-acting neuraminidase inhibitor, exhibits efficacy in treating both adult and pediatric patients with influenza virus infection. The intrapulmonary pharmacokinetics (PK) of LO and laninamivir, a pharmacologically active metabolite, were investigated by a single-center, open-label study of healthy adult volunteers. Subgroups of five subjects each underwent bronchoalveolar lavage (BAL) 4, 8, 24, 48, 72, 168, and 240 h following a single inhaled administration of LO (40 mg). Plasma, BAL fluid, and alveolar macrophages (AM) were analyzed to determine LO and laninamivir concentrations, using validated liquid chromatography-tandem mass spectrometry methods. The concentrations in epithelial lining fluid (ELF) and AM from the first and subsequent BAL fluid samples were determined separately to explore the drug distribution in airways. Mean laninamivir concentrations in ELF, calculated using the first BAL fluids and BAL fluids collected 4 h after inhaled administration, were 8.57 and 2.40 μg/ml, respectively. The laninamivir concentration in ELF decreased with a longer half-life than that in plasma, and it exceeded the 50% inhibitory concentrations for viral neuraminidases at all time points examined for 240 h after the inhalation. Laninamivir exposure in ELF from the first BAL samples was 3.2 times higher than that in ELF from the subsequent BAL fluid samples. ELF concentration profiles of laninamivir support its long-lasting effect for treatment of patients with influenza virus infection by a single inhaled administration.

Contribution of P-glycoprotein to bunitrolol efflux across blood–brain barrier

In this study, we investigated the mechanism of the blood–brain barrier (BBB) transport of bunitrolol (BTL), as a model of β‐blocker, in vivo and in vitro. In order to define the contribution of P‐glycoprotein (P‐gp) to the active efflux of BTL from brain to blood, we examined the in vivo brain distribution of BTL in mdr1a(−/−) mice with a disrupted mdr1a gene. After intravenous administration of BTL to mdr1a(−/−) mice, the brain concentration and Kp value of BTL were significantly increased as compared with those in mdr1a(+/+) mice. Next, the contribution of the mdr1a P‐gp to in vitro uptake of BTL was compared in LV500 cells and L cells (mouse mdr1a‐expressing cells and host cells, respectively). The intracellular accumulations of [3H]vinblastine and BTL by LV500 cells were lower than those by L cells, but were significantly increased by verapamil, a P‐gp inhibitor. Furthermore, the BTL uptake by KB‐VJ300 cells, which express human P‐gp, was also significantly lower than that by KB host cells, and was increased by verapamil. The steady‐state uptake of BTL by LLC‐GA5‐COL300 cells, expressing human P‐gp, was significantly increased in the presence of 20 μM cyclosporin A (another P‐gp inhibitor), which had no effect in the LLC‐PK1 host cells. On the other hand, the steady‐state intracellular accumulation of BTL by MBEC4 cells, which express mdr1b P‐gp instead of mdr1a P‐gp, was not significantly changed in the presence of verapamil. This finding suggested that BTL is not a good substrate for mdr1b P‐gp. In conclusion, our results suggest that BTL is transported from brain to blood by mdr1a P‐gp in mice and by MDR1 in humans, and this presumably accounts for the low brain distribution of BTL. Copyright

Assessment of the Effects of Renal Impairment on the Pharmacokinetic Profile of Laninamivir, a Novel Neuraminidase Inhibitor, After a Single Inhaled Dose of Its Prodrug, CS‐8958

This open‐label, single‐dose study assessed the safety and pharmacokinetics of laninamivir, a new long‐acting neuraminidase inhibitor, after an inhaled 20‐mg dose of its prodrug, CS‐8958, to a total of 20 subjects with normal, mild, moderate, or severe renal impairment. CS‐8958 and laninamivir concentrations were measured in plasma and urine by validated liquid chromatography tandem mass spectrometry methods. The area under the concentration‐time curve extrapolated to infinity (AUC0‐inf), maximum concentration (Cmax), and time to Cmax of CS‐8958 did not change with the degree of renal impairment, whereas the half‐life (t1/2) of CS‐8958 increased with increasing renal insufficiency. The AUC0‐inf and Cmax of laninamivir tended to increase along with the decrease of creatinine clearance. The AUC0‐inf of laninamivir compared with normal subjects increased 1.10‐, 2.03‐, and 4.92‐fold in subjects with mild, moderate, and severe renal impairment, respectively, without changing t1/2 among the subjects. Renal clearance of both CS‐8958 and laninamivir was well correlated with creatinine clearance. These data indicate that the rate‐limiting step for the elimination of laninamivir would not be the renal excretion rate but rather the drug release rate to plasma from the retained tissues. CS‐8958 was well tolerated by all the subjects, although increasing renal dysfunction leads to increasing systemic exposure to laninamivir, particularly in severe renal insufficiency.

Association study of genetic polymorphisms of drug transporters, SLCO1B1, SLCO1B3 and ABCC2, in African-Americans, Hispanics and Caucasians and olmesartan exposure

It has been reported that organic anion-transporting polypeptide (OATP) 1B1, OATP1B3 and multidrug resistance-associated protein 2 are involved in the hepatobiliary transport of olmesartan. We investigated the association of SLCO1B1, SLCO1B3 and ABCC2 polymorphisms with the pharmacokinetics of olmesartan. We sequenced all exons, exon–intron junctions and the 5′ and 3′ flanking regions of the three genes in 115 individuals from African-American, Hispanic and Caucasian populations who had participated in our clinical studies. A total of 348 single-nucleotide polymorphisms (SNPs) were identified with a minor allele frequency of ⩾0.01 in at least one population; 132 SNPs were detected in SLCO1B1, 130 in SLCO1B3 and 86 in ABCC2. We characterized the linkage disequilibrium (LD) and haplotypes shared across the populations and then evaluated the association between the haplotypes and the pharmacokinetics of olmesartan. Seven inter-ethnic LD blocks were observed in SLCO1B1, while three in SLCO1B3 and four in ABCC2. Although extensive variability in the sequences of SLCO1B1, SLCO1B3 and ABCC2 existed across the three populations, there was no remarkable difference in any pharmacokinetic parameters of olmesartan between subjects with and without any major haplotypes in the three transporter genes we tested.

Population Pharmacokinetic Analysis of Panipenem/Betamipron in Patients with Various Degrees of Renal Function

Background: Although plasma concentrations of panipenem were elevated and the risk of adverse events would increase in patients with renal impairment, a precise dosage regimen for patients with renal impairment has not been established. Methods: Population pharmacokinetic analyses were performed with plasma concentrations from 26 healthy volunteers and 41 patients. Optimal dosage regimens for patients with renal impairment were determined based on the bacteriostatic index of C20%T>MIC, the concentration corresponding to the time above MIC of 20% of the dosing interval. Results: The clearance of panipenem and betamipron was correlated with creatinine clearance and the volume of the distribution of panipenem was correlated with body weight. C20%T>MIC for a standard dosage regimen of panipenem was 4.3 µg/ml, and the optimal dosage regimen for the patients was established based on this value. Conclusion: The dosage regimen of panipenem for patients with renal impairment should be reduced when creatinine clearance is lower than 60 ml/min.

Pharmacokinetics and Safety of a Single Oral Dose of Mirogabalin in Japanese Subjects With Varying Degrees of Renal Impairment

Mirogabalin (DS‐5565) is a novel preferentially selective α2δ‐1 ligand being developed for the treatment of diabetic peripheral neuropathic pain and postherpetic neuralgia. The current multicenter open‐label study determined the effect of varying degrees of renal impairment on the pharmacokinetics and safety of a single dose of mirogabalin 5 mg in Japanese subjects. A total of 30 subjects (6 subjects per renal function category [normal, mild, moderate, or severe impairment; and end‐stage renal disease (ESRD)]) were enrolled and completed the study. The AUClast increased with severity of renal impairment; the geometric least‐squares mean ratios of AUClast compared with subjects with normal renal function were 1.3, 1.9, 3.6, and 5.3 for patients with mild, moderate, and severe impairment and ESRD, respectively. In accordance with this AUClast increase, apparent total body clearance (CL/F), renal clearance (CLr), and the cumulative percentage of mirogabalin dose excreted into urine all decreased with severity of renal impairment. There were no deaths and no severe treatment‐related adverse events (TEAEs), serious TEAEs, or TEAEs resulting in study discontinuation. Mirogabalin was well tolerated in Japanese subjects with normal renal function and those with mild to severe renal impairment. It was also tolerated in subjects with ESRD but with a higher incidence of TEAEs. The most frequently reported TEAEs were dizziness (ESRD, n = 3), somnolence (ESRD, n = 2), and vomiting (ESRD, n = 2). Based on these data, a mirogabalin dose adjustment will be considered in Japanese subjects with moderate to severe renal impairment and those with ESRD.

Single-dose evaluation of safety, tolerability and pharmacokinetics of newly formulated hydromorphone immediate-release and hydrophilic matrix extended-release tablets in healthy Japanese subjects without co-administration of an opioid antagonist.

This single dose, open‐label study investigated the safety, tolerability and pharmacokinetics of single oral doses of newly formulated immediate‐release (IR) and hydrophilic matrix extended‐release (ER) hydromorphone tablets in healthy Japanese subjects without co‐administration of an opioid antagonist under fasting and fed conditions. Plasma and urinary concentrations of hydromorphone and metabolites were measured by liquid‐chromatography tandem mass‐spectroscopy. Following administration of the ER tablet, plasma concentrations of hydromorphone slowly increased with a median tmax of 5.0 h and the Cmax decreased to 37% of the IR tablet, while the AUC0‐inf was comparable with that of the IR tablet when administered at the same dose. The degree of fluctuation in the plasma concentration for the ER tablet was much lower than that of the IR tablet and certain levels of plasma concentrations were maintained after 24 h of ER dosing. The AUC0‐inf and Cmax increased with food for both IR and ER tablets. The AUC0‐inf of hydromorphone‐3‐glucoside was one‐tenth of that of hydromorphone‐3‐glucuronide. A single oral administration of the hydromorphone tablets would be well‐tolerated in healthy Japanese subjects despite a lack of co‐administration of an opioid antagonist and the newly developed ER hydromorphone tablets may have the appropriate PK characteristics for once‐daily dosing.

A Randomized, Placebo‐Controlled, Double‐Blind Study of the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single and Repeated Doses of Mirogabalin in Healthy Asian Volunteers

Mirogabalin is a novel, preferentially selective α2δ‐1 ligand under investigation to treat neuropathic pain. The purpose of this study was to evaluate the safety, tolerability, and pharmacokinetics of various doses of mirogabalin in healthy subjects of different ethnicities. This randomized, placebo‐controlled, double‐blind, sequential, ascending‐dose study evaluated single (10‐40 mg) and repeated (10, 15 mg twice a day) doses of mirogabalin in Japanese subjects, and a single dose of mirogabalin in Korean, Chinese, and white subjects. Mirogabalin was rapidly absorbed, with a median time to maximum plasma concentration of 1 hour, and rapidly eliminated, with a mean elimination half‐life of 2 to 3 hours. Single‐dose mirogabalin pharmacokinetic parameters were comparable between Asian and white subjects. Exposure increased proportionally as mirogabalin dose increased in Japanese subjects. Mean mirogabalin steady‐state clearance and volume of distribution values were comparable across dose levels. No accumulation of mirogabalin was observed on repeated dosing in Japanese subjects. Mirogabalin had an acceptable safety and tolerability profile in Asian and white subjects at doses up to 15 mg twice a day for 7 days. The most common treatment‐emergent adverse events (somnolence, headache, and dizziness) were consistent with the known mechanism of action and safety profile of mirogabalin.

Identification of Circulating miRNAs Differentially Regulated by Opioid Treatment

Emerging evidence demonstrates functional contributions of microRNAs (miRNAs) to μ-opioid receptor (MOR) signaling, but the information so far has been mostly limited to their intracellular regulatory mechanisms. The present study aimed to investigate changes in plasma miRNA profiles elicited by opioid treatment in blood samples collected from clinical studies. Healthy male subjects were orally administered with hydromorphone or oxycodone and blood samples were collected at a specified time after the drug treatment. A total of 179 plasma miRNAs were measured using multiplex qRT-PCR. Nine and seventeen miRNAs were commonly upregulated (let-7a-5p, miR-423-3p, miR-199a-3p, miR-146a-5p, miR-23b-3p, miR-24-3p, miR-221-3p, miR-223-3p, and miR-146b-5p) and downregulated (miR-144-3p, miR-215, miR-363-3p, etc.), respectively, following opioid treatment. The MOR signaling-associated miRNAs, namely let-7 family miRNAs (i.e., let-7d-5p, let-7f-5p, let-7c, let-7e-5p), miR-103a-3p, miR-339-3p, miR-146a-5p, miR-23b-3p, miR-23a-3p, and miR-181a-5p, were differentially expressed following drug treatment. These differentially expressed miRNAs are circulating biomarker candidates that can be used to evaluate MOR stimulation and serve as novel clinical diagnostic tools for improving clinical outcomes.