ABSTRACT
Lanabecestat (AZD3293; LY3314814) is an orally active potent inhibitor of human ß-secretase 1 in clinical development for the treatment of Alzheimer disease. In this first Japanese clinical study for an Alzheimer disease intervention to include cerebrospinal fluid (CSF) sampling in Japanese elderly healthy subjects, we report the pharmacokinetics and effects on plasma and CSF amyloid-ß (Aß) peptides of lanabecestat in a phase 1 study involving 40 healthy Japanese subjects (NCT02005211). No safety and tolerability concerns were identified in healthy Japanese subjects exposed to lanabecestat up to the highest doses given, which is consistent with observations in a US phase 1 study of lanabecestat. Exposure to lanabecestat was similar for young and elderly subjects and increased in a dose-dependent manner. For elderly subjects, plasma lanabecestat half-life after multiple dosing was 12 to 17 hours (on days 10 and 14). Robust plasma and CSF Aß peptide reductions were also seen at all doses, with CSF Aß42 concentrations reduced by 63% and 79% in the 15- and 50-mg lanabecestat groups, respectively. CSF soluble amyloid-ß precursor protein ß also decreased following lanabecestat treatment. Suppression of CSF Aß peptides was similar in elderly healthy Japanese subjects and US patients with mild to moderate Alzheimer disease. Lanabecestat is a promising potentially disease-modifying treatment in phase 3 development for patients with early Alzheimer disease.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Amyloid beta-Peptides/metabolism , Aspartic Acid Endopeptidases/antagonists & inhibitors , Cerebrospinal Fluid/metabolism , Imidazoles/therapeutic use , Plasma/metabolism , Spiro Compounds/therapeutic use , Adult , Aged , Alzheimer Disease/drug therapy , Amyloid Precursor Protein Secretases/metabolism , Amyloid beta-Protein Precursor/metabolism , Asian People , Brain/metabolism , Double-Blind Method , Female , Half-Life , Healthy Volunteers , Humans , Male , Middle Aged , Peptide Fragments/metabolism , Young AdultABSTRACT
To predict drug-induced serious adverse events (SAE) in clinical trials, a model using a panel of cells derived from human induced pluripotent stem cells (hiPSCs) of individuals with different susceptibilities could facilitate major advancements in translational research in terms of safety and pharmaco-economics. However, it is unclear whether hiPSC-derived cells can recapitulate interindividual differences in drug-induced SAE susceptibility in populations not having genetic disorders such as healthy subjects. Here, we evaluated individual differences in SAE susceptibility based on an in vitro model using hiPSC-derived cardiomyocytes (hiPSC-CMs) as a pilot study. hiPSCs were generated from blood samples of ten healthy volunteers with different susceptibilities to moxifloxacin (Mox)-induced QT prolongation. Different Mox-induced field potential duration (FPD) prolongation values were observed in the hiPSC-CMs from each individual. Interestingly, the QT interval was significantly positively correlated with FPD at clinically relevant concentrations (r > 0.66) in multiple analyses including concentration-QT analysis. Genomic analysis showed no interindividual significant differences in known target-binding sites for Mox and other drugs such as the hERG channel subunit, and baseline QT ranges were normal. The results suggest that hiPSC-CMs from healthy subjects recapitulate susceptibility to Mox-induced QT prolongation and provide proof of concept for in vitro preclinical trials.
Subject(s)
Electrophysiological Phenomena/drug effects , Induced Pluripotent Stem Cells/cytology , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/physiology , Action Potentials/drug effects , Alleles , Cell Differentiation , ERG1 Potassium Channel/genetics , ERG1 Potassium Channel/metabolism , Electrocardiography , Gene Expression Profiling , Gene Frequency , Healthy Volunteers , Heart Conduction System/drug effects , Humans , Male , Mutation , Myocytes, Cardiac/cytology , Polymorphism, Single NucleotideABSTRACT
INTRODUCTION: Phosphodiesterase type 4 (PDE4) inhibition is a well-known anti-inflammatory mechanism. However, the clinical use of PDE4 inhibitors has been compromised by the occurrence of mechanism-associated adverse reactions, which often limit the maximum tolerated dose. To minimize systemic exposure, a topically active PDE4 inhibitor with low transdermal bioavailability could be clinically useful. The purpose of this study was to evaluate the efficacy of a novel topical PDE4 inhibitor, E6005, in patients with atopic dermatitis. METHODS: This randomized, investigator-blinded, vehicle-controlled, multiple ascending dose study included 40 adult male patients with atopic dermatitis, who were randomly assigned to 10 days of treatment with either E6005 ointment (0.01, 0.03, 0.1 or 0.2%) or vehicle ointment. RESULTS: Of 81 patients screened, 40 who had typical lesions on their posterior trunk were randomized into the study. One patient receiving 0.03% E6005 treatment discontinued because of acute gout and one receiving vehicle treatment discontinued because of progression of atopic dermatitis. The targeted lesion severity scores decreased in a concentration-dependent manner in patients treated with E6005. This drop was significant in the 0.2% E6005 ointment treatment group (mean percent change: -54.30%, p = 0.007). CONCLUSION: E6005 ointment showed anti-inflammatory efficacy in adult patients with atopic dermatitis.
Subject(s)
Dermatitis, Atopic/drug therapy , Phosphodiesterase 4 Inhibitors/administration & dosage , Phthalic Acids/administration & dosage , Quinazolines/administration & dosage , Administration, Cutaneous , Adult , Dose-Response Relationship, Drug , Humans , Male , Ointments/therapeutic use , Phthalic Acids/adverse effects , Quinazolines/adverse effects , Treatment OutcomeABSTRACT
BACKGROUND: DMB-3111 is a biosimilar trastuzumab drug being jointly developed by Meiji Seika Pharma (Japan) and Dong-A Socio Holdings (Korea). We investigated the bioequivalence of DMB-3111 relative to trastuzumab. OBJECTIVES: The aim of this study was to investigate the bioequivalence between DMB-3111 and trastuzumab and the pharmacokinetic, safety, and immunogenicity of both drugs in healthy Japanese adult males. METHODS: Seventy healthy Japanese adult males were randomized 1:1 to receive either DMB-3111 or trastuzumab as a single intravenous infusion (6 mg/kg) over 90 min. Bioequivalence was assessed in terms of the pharmacokinetic parameters of both drugs. Adverse events (AEs) were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Immunogenicity was tested using anti-drug antibody (ADA) assays. RESULTS: The 90% confidence intervals of the treatment differences (DMB-3111 versus trastuzumab) in the mean log-transformed maximum concentration, the area under the concentration-time curves (from 0 min to the last measured value or from 0 min to infinity), mean residence time, and the terminal half-life were within the accepted range for bioequivalence [log(0.80) to log(1.25)]. The frequencies of AEs and adverse drug reactions were similar with both drugs. No ADA reactivity to DMB-3111 or trastuzumab was observed in any subject. CONCLUSIONS: DMB-3111, a trastuzumab biosimilar, was bioequivalent to trastuzumab in terms of its pharmacokinetics and showed similar safety after a single intravenous infusion at 6 mg/kg over 90 min in healthy Japanese adult males. DMB-3111 is likely to show similar efficacy and safety profiles to trastuzumab in cancer patients (ClinicalTrials.gov #NCT02100917).
Subject(s)
Antineoplastic Agents/administration & dosage , Biosimilar Pharmaceuticals/administration & dosage , Trastuzumab/administration & dosage , Adult , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Area Under Curve , Asian People , Biosimilar Pharmaceuticals/adverse effects , Biosimilar Pharmaceuticals/pharmacokinetics , Double-Blind Method , Follow-Up Studies , Half-Life , Humans , Infusions, Intravenous , Male , Therapeutic Equivalency , Trastuzumab/adverse effects , Trastuzumab/metabolism , Young AdultABSTRACT
FSK0808, a biosimilar of filgrastim, is a recombinant human granulocyte colony-stimulating factor developed by Fuji Pharmaceuticals and Mochida Pharmaceutical Co., Ltd. We conducted a double-blind, randomized, crossover study in healthy Japanese men, comparing the number of CD34-positive cells (CD34(+) cells) after repeated subcutaneous administration of either FSK0808 or the reference filgrastim (Gran(®) ). As primary endpoints, we compared the maximum number of CD34(+) cells (CD34(+) Cmax ) and the time to reach CD34(+) Cmax (CD34(+) tmax ). As secondary endpoints, we compared the area under the curve for the number of CD34(+) cells over time at the 410 hours time point (CD34(+) AUC0-410 ), the parameters used to calculate the pharmacodynamic index of the absolute neutrophil count, and the pharmacokinetic parameters. Regarding the CD34(+) Cmax and the CD34(+) AUC0-410 values, the 95% confidence interval (CI) of the differences between the mean values for each drug was within the range of log(0.8)-log(1.25). With respect to the differences in the median values between drugs, the ratio against the reference filgrastim median value in the 95% CI was within the range of ± 0.2 for the CD34(+) tmax value. From these results, we considered that these drugs display equivalent pharmacodynamic and pharmacokinetic properties.
Subject(s)
Biosimilar Pharmaceuticals/administration & dosage , Biosimilar Pharmaceuticals/pharmacokinetics , Filgrastim/administration & dosage , Filgrastim/pharmacokinetics , Granulocyte Colony-Stimulating Factor/administration & dosage , Granulocyte Colony-Stimulating Factor/pharmacokinetics , Adult , Antigens, CD34/blood , Area Under Curve , Asian People , Biomarkers/blood , Biosimilar Pharmaceuticals/adverse effects , Biosimilar Pharmaceuticals/blood , Cross-Over Studies , Double-Blind Method , Filgrastim/adverse effects , Granulocyte Colony-Stimulating Factor/adverse effects , Granulocyte Colony-Stimulating Factor/blood , Healthy Volunteers , Hematopoietic Stem Cells/drug effects , Hematopoietic Stem Cells/metabolism , Humans , Japan , Male , Therapeutic Equivalency , Treatment Outcome , Young AdultABSTRACT
FSK0808 is a recombinant human granulocyte colony-stimulating factor developed by Fuji Pharma Co., Ltd and Mochida Pharmaceutical Co., Ltd. as a biosimilar product of Gran®. We verified the pharmacokinetic/pharmacodynamic equivalence of FSK0808 and commercially available Gran® by a randomized crossover study of single intravenous dose (200 µg/m(2)) and single subcutaneous dose (400 µg/m(2)) in healthy Japanese adult male subjects. According to the bioequivalence guidelines, the area under the blood concentration - time curve by 48 hours after administration (AUC0-48) in a single intravenous drip (IVD) study, and AUC0-48 and maximum blood concentration (Cmax) in a single subcutaneous (SC) dose study were used as primary endpoints, and the pharmacodynamic parameters including absolute neutrophil count (ANC) or number of CD34 positive cells (CD34(+) cells) as secondary endpoints. The safety was evaluated based on the characteristics and incidence of adverse reactions. As a result, the 90% confidence interval (CI) of the difference in mean value for AUC0-48 among drugs ranged from log(0.8) to log(1.25), in the IVD study, and those for Cmax and AUC0-48 were within the range of log(0.8)-log(1.25) in the SC study. Those for secondary endpoints were all within the range of log(0.8)-log(1.25). Thus, the pharmacokinetics/pharmacodynamics of both drugs were considered equivalent for all routes of administration, and the profiles of adverse reactions were also very similar.
Subject(s)
Asian People , Biosimilar Pharmaceuticals/administration & dosage , Biosimilar Pharmaceuticals/pharmacokinetics , Granulocyte Colony-Stimulating Factor/administration & dosage , Granulocyte Colony-Stimulating Factor/pharmacokinetics , Adult , Cross-Over Studies , Double-Blind Method , Healthy Volunteers , Humans , Infusions, Intravenous , Injections, Subcutaneous , Male , Young AdultABSTRACT
Brivaracetam is a high-affinity synaptic vesicle protein 2A ligand, in phase 3 clinical development for epilepsy. A phase 1, single-center, randomized, double-blind, placebo-controlled, single (2.5-100 mg) and multiple (2.5-50 mg twice daily) rising oral dose study (N01209) was conducted to assess the adverse event profile and pharmacokinetics of brivaracetam in healthy Japanese men, and the influence of the cytochrome P450 (CYP) 2C19 genotype. Plasma and urine were collected serially for analysis of brivaracetam and its three main metabolites: acid, hydroxy and hydroxy acid. Overall, 79/80 randomized participants completed the study. Brivaracetam was generally well tolerated. After single- and multiple-dose administration, brivaracetam was rapidly absorbed, with dose-proportional pharmacokinetics over the dose ranges tested. Steady state was reached after 2 days of repeated dosing. Brivaracetam clearance (averaged across the five single dose levels) was reduced from 0.99 mL/min/kg in homozygous extensive metabolizers (EM; n = 10) to 0.81 mL/min/kg (-18%) in heterozygous EM (n = 17) and 0.70 mL/min/kg (-29%) in poor metabolizers (PM; n = 9). Exposure and urinary excretion of hydroxy metabolite were reduced 10-fold in PM participants, compared with EM participants. Results suggest that brivaracetam is hydroxylated by CYP2C19, but this pathway is minor compared with hydrolysis to the acid metabolite.
Subject(s)
Cytochrome P-450 CYP2C19/genetics , Pyrrolidinones/administration & dosage , Pyrrolidinones/pharmacokinetics , Administration, Oral , Adult , Asian People/genetics , Cytochrome P-450 CYP2C19/metabolism , Double-Blind Method , Genotype , Healthy Volunteers , Humans , Japan , Male , Pyrrolidinones/metabolism , Young AdultABSTRACT
To investigate the potential for a QT/QTc study in Japan, a randomized, single-blind, crossover study was conducted using moxifloxacin in 64 healthy Japanese male volunteers. A 12-lead Holter electrocardiogram was used to test a relatively small population at each of 4 incorporated clinical research units to confirm the assay sensitivity and efficiency. Moxifloxacin (400 mg) significantly prolonged QT intervals, as previously reported, with small variations in this study. In addition, the placebo-adjusted mean QTcF changes from predose baseline showed that the lower bounds of the 1-sided 95% confidence interval exceeded 5 milliseconds at all of the clinical research units. The data also indicated statistically significant concentration-QT relationships in 3 of the 4 research units by separate analysis. These findings and the small amount of variability in this study suggest the feasibility of conducting a high-quality QT/QTc study in Japan.
ABSTRACT
We investigated the mechanisms of ritonavir-mediated enhancement effect on the pharmacokinetics of saquinavir using in vivo probes for CYP3A4 (midazolam), p-glycoprotein (fexofenadine), and OATP1B1 (pravastatin) following oral micro/small dosing. A cocktail of the drugs (2 mg of saquinavir, 100 µg of each probe) was administered to eight healthy volunteers (phase 1), and then coadministered with 20 mg (phase 2) and 100 mg (phase 3) of ritonavir. Plasma concentrations of the drugs were measured by validated LC-MS/MS methods. The mean plasma AUC0-24 (pg hour/mL) of saquinavir at phases 1, 2, and 3 was 101, 2 540, and 23 900 (P < .01), respectively. The relative area under the plasma concentration-time curve (AUC)0-24 ratios of midazolam and fexofenadine at phases 1, 2, and 3 were 1:5.9:14.7 (P < .01), and 1:1.4:2.2 (P < .01-.05), respectively. In contrast, there was no difference in the pharmacokinetics of pravastatin. Inhibition of intestinal and hepatic CYP3A-mediated metabolism, and intestinal p-glycoprotein-mediated efflux of saquinavir, but not OATP1B1, is involved in the enhancement mechanism. Micro/small dosing is useful for examining the mechanism of drug interactions without safety concern.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists & inhibitors , Cytochrome P-450 CYP3A Inhibitors , Ritonavir/pharmacology , Saquinavir/pharmacokinetics , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Adult , Area Under Curve , Chromatography, Liquid , Cross-Over Studies , Cytochrome P-450 CYP3A/metabolism , Dose-Response Relationship, Drug , Drug Interactions , HIV Protease Inhibitors/administration & dosage , HIV Protease Inhibitors/pharmacokinetics , HIV Protease Inhibitors/pharmacology , Humans , Intestines/drug effects , Intestines/enzymology , Liver/drug effects , Liver/enzymology , Liver-Specific Organic Anion Transporter 1 , Male , Midazolam/pharmacokinetics , Organic Anion Transporters/drug effects , Organic Anion Transporters/metabolism , Pravastatin/pharmacokinetics , Ritonavir/administration & dosage , Tandem Mass Spectrometry , Terfenadine/analogs & derivatives , Terfenadine/pharmacokinetics , Young AdultABSTRACT
OBJECTIVES: To test whether the multiple phenotype and genotype relationships established using therapeutic dose, can be reproduced following oral microdosing using substrates of CYP2C9 (warfarin and glibenclamide), CYP2C19 (lansoprazole), CYP2D6 (dextromethorphan), and OATPs (glibenclamide). METHODS: A cocktail of test drugs was administered orally under the microdose in liquid or capsule form, and then a therapeutic dose of dextromethorphan was administered to 17 healthy subjects whose genotypes for CYPs and OATPs had been prescreened. Concentrations of the drugs and their metabolites were measured by LC-MS/MS. RESULTS: The AUC and t1/2 of glibenclamide following the microdosing tended to be higher and longer, respectively, in CYP2C9*1/*3 than CYP2C9*1/*1 subjects. In contrast, there were no significant differences in any of the pharmacokinetic parameters for warfarin between the two genotypes. For CYP2D6 following the therapeutic dose, there was good concordance between genotype and phenotype; however, such relationships disappeared after microdosing. For CYP2C19 following the microdosing, there were significant differences between EMs and PMs in the pharmacokinetic parameters of lansoprazole. The relative AUC0-12 ratio of lansoprazole in EMs and PMs was 1:3.3 - 4.3. Among test drugs, phenotypic measurements of lansoprazole accorded well with the CYP2C19 genotype at the microdose as well as therapeutic dose. CONCLUSIONS: The present study suggests that 1) the sampling strategy should be optimized according to pharmacokinetic profiles of the test drugs following oral microdosing, and 2) microdosing can be applied to the pharmacogenomic study of CYP-specific drugs.
Subject(s)
Aryl Hydrocarbon Hydroxylases/genetics , Cytochrome P-450 CYP2D6/genetics , Organic Anion Transporters/genetics , 2-Pyridinylmethylsulfinylbenzimidazoles/pharmacokinetics , Administration, Oral , Adult , Area Under Curve , Cytochrome P-450 CYP2C19 , Cytochrome P-450 CYP2C9 , Dextromethorphan/pharmacology , Genotype , Glyburide/pharmacokinetics , Humans , Lansoprazole , Male , Warfarin/pharmacokinetics , Young AdultABSTRACT
Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, is mainly degraded by dimethylarginine dimethylaminohydrolase (DDAH). It was recently reported that reduced DDAH expression could contribute to ADMA accumulation and subsequent elevation of BP in an experimental model of chronic kidney disease (CKD). ADMA is a strong predictor of the progression of CKD as well. However, a role for the ADMA-DDAH in the pathogenesis of CKD remains to be elucidated. This study investigated the effects of DDAH-elicited ADMA lowering on renal function and pathology in a rat remnant kidney model. Four weeks after five-sixths subtotal nephrectomy (Nx), the rats were given tail-vein injections of recombinant adenovirus vector encoding DDAH-I (Adv-DDAH) or control vector expressing bacterial beta-galactosidase (Adv-LZ) or orally administered 20 mg/kg per d hydralazine (Hyz), which served as a BP control model. In comparison with Adv-LZ or Hyz administration, Adv-DDAH decreased plasma levels of ADMA and inhibited the deterioration of renal dysfunction. Plasma levels of ADMA were associated with decreased number of peritubular capillaries, increased tubulointerstitial fibrosis, and proteinuria levels in Nx rats. These changes were progressed in Adv-LZ-or Hyz-treated Nx rats, which were ameliorated by DDAH overexpression. In addition, semiquantitative reverse transcriptase-PCR and immunohistochemistry for TGF-beta revealed that Adv-DDAH inhibited upregulation of TGF-beta expression in Nx rats. These data suggest that ADMA may be involved in peritubular capillary loss and tubulointerstitial fibrosis, thereby contributing to the progression of CKD. Substitution of DDAH protein or enhancement of its activity may become a novel therapeutic strategy for the treatment of CKD.
Subject(s)
Amidohydrolases/physiology , Kidney Diseases/pathology , Kidney/blood supply , Kidney/physiopathology , Amidohydrolases/genetics , Animals , Arginine/analogs & derivatives , Arginine/blood , Capillaries/pathology , Chronic Disease , Disease Models, Animal , Disease Progression , Fibrosis , Gene Expression Regulation, Enzymologic , Genetic Therapy , Kidney/enzymology , Kidney Diseases/enzymology , Kidney Diseases/genetics , Male , Rats , Rats, Sprague-Dawley , Transforming Growth Factor beta/pharmacologyABSTRACT
Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase. ADMA is generated by protein methyltransferase (PRMT) and is metabolized mainly by dimethylarginine dimethylaminohydrolase (DDAH). ADMA levels are reported to increase in patients with chronic kidney disease (CKD), thereby playing a role in the pathogenesis of accelerated atherosclerosis in this population. However, the precise mechanism underlying ADMA accumulation in these patients is not fully understood. This study investigated the molecular mechanism for the elevation of ADMA levels in CKD, using a rat remnant kidney model that represents progressive CKD. After male Sprague-Dawley rats underwent baseline measurement of BP and renal function, 5/6 subtotal nephrectomy (5/6Nx) and 4/6 nephrectomy were performed. Plasma and urinary levels of ADMA and symmetric dimethylarginine, an inert isomer of ADMA, were measured by HPLC. Expression levels of PRMT genes and DDAH proteins were analyzed by semiquantitative reverse transcription-PCR and Western blotting, respectively. Plasma ADMA levels were elevated in the Nx groups in proportion to the degree of nephrectomy despite marked increases in renal clearance of ADMA. In contrast, renal clearance of symmetric dimethylarginine was decreased and its plasma levels were increased in the Nx groups. Furthermore, both liver and kidney gene expression of PRMT was increased, whereas DDAH protein expression was decreased in the 5/6Nx group. Plasma ADMA levels were correlated with systolic BP levels. Moreover, adenovirus-mediated DDAH gene transfer into the 5/6Nx rats prevented the elevation of BP levels, which was associated with the reduction of plasma and urinary ADMA levels. The results presented here suggest that decreased DDAH levels as well as increased PRMT gene expression could cause the elevation of plasma ADMA levels, thereby eliciting hypertension in CKD. Substitution of DDAH protein or enhancement of its activity may become a novel therapeutic strategy for the treatment of hypertension-related vascular injury in CKD.
Subject(s)
Arginine/analogs & derivatives , Hypertension/physiopathology , Kidney Failure, Chronic/physiopathology , Adenoviridae/genetics , Amidohydrolases/metabolism , Animals , Arginine/biosynthesis , Arginine/blood , Arginine/pharmacokinetics , Arginine/urine , Cholesterol/blood , Hypertension/complications , Kidney/enzymology , Kidney Failure, Chronic/complications , Kinetics , Liver/enzymology , Male , Nephrectomy , Protein-Arginine N-Methyltransferases/genetics , Protein-Arginine N-Methyltransferases/metabolism , Rats , Rats, Sprague-Dawley , Time FactorsABSTRACT
OBJECTIVES: We conducted a randomized, double-blind, placebo-controlled study to evaluate the pharmacokinetics and pharmacodynamics of landiolol hydrochloride in a dose escalation regimen in healthy male volunteers. METHODS: We set two-dose escalation regimen (LM and MH groups) using three different doses [L (low): 0.03 mg/kg/min (1 min) loading-->0.01 mg/kg/min (10 min) continuous, M (medium): 0.06 mg/kg/min (1 min) loading-->0.02 mg/kg/min (10 min) continuous, H (high): 0.125 mg/kg/min (1 min) loading-->0.04 mg/kg/min (10 min) continuous]. Sixteen subjects were allocated randomly to the LM, MH, and placebo groups (n=6, 6, and 4, respectively). RESULTS: In both the LM and MH groups, the blood concentration of landiolol hydrochloride changed within a constant range from 2 minutes after initiation of administration to just before the higher dose escalation. By 2 minutes following the higher dose escalation, the concentration of landiolol hydrochloride reached C(max), and reached almost steady state levels until 6 minutes following administration of the higher dose. The t(1/2) of landiolol hydrochloride was 3.5 minutes. The heart rates and blood pressures of subjects administered landiolol hydrochloride decreased, but there were no adverse events in any subject. CONCLUSIONS: The concentration of landiolol hydrochloride rapidly reached steady state levels, and rapidly dissipated after completion of administration.