Pharmacokinetics, pharmacodynamics, safety and tolerability of multiple ascending doses of ticagrelor in healthy volunteers

AIM

To determine the pharmacokinetics, pharmacodynamics, safety and tolerability of multiple oral doses of ticagrelor, a P2Y₁₂ receptor antagonist, in healthy volunteers.

METHODS

This was a randomized, single-blind, placebo-controlled, ascending dose study. Thirty-two subjects received ticagrelor 50–600 mg once daily or 50–300 mg twice daily or placebo for 5 days at three dose levels in two parallel groups. Another group of 16 subjects received a clopidogrel 300 mg loading dose then 75 mg day⁻¹, or placebo for 14 days.

RESULTS

Ticagrelor was absorbed with median t_max 1.5–3 h, exhibiting predictable pharmacokinetics over the 50–600 mg dose range. Mean C_max and AUC for ticagrelor and its main metabolite, AR-C124910XX, increased approximately dose-proportionately (approximately 2.2- to 2.4-fold with a twofold dose increase) over the dose range. Inhibition of platelet aggregation (IPA) with ticagrelor was greater and better sustained at high levels with ticagrelor twice daily vs. once daily regimens. Throughout dosing, more consistent IPA was observed at doses ≥300 mg once daily and ≥100 mg twice daily compared with clopidogrel. Mean IPA with ticagrelor ≥100 mg twice daily was greater and less variable (93–100%, range 65–100%) than with clopidogrel (77%, range 11–100%) at trough concentrations. No safety or tolerability issues were identified.

CONCLUSIONS

Multiple dosing provided predictable pharmacokinetics of ticagrelor and its metabolite over the dose range of 50–600 mg once daily and 50–300 mg twice daily with C_max and AUC(0,t) increasing approximately dose-proportionally. Greater and more consistent IPA with ticagrelor at doses ≥100 mg twice daily and ≥300 mg once daily were observed than with clopidogrel. Ticagrelor at doses up to 600 mg day⁻¹ was well tolerated.     

Pharmacokinetics and pharmacodynamics of intravenous ilaprazole in healthy subjects after single ascending doses

1.?Ilaprazole is a novel proton pump inhibitor and this is the first study to investigate the pharmacokinetics, pharmacodynamics and safety of intravenous ilaprazole in healthy volunteers.

2.?In this open-label, single-dose, randomized and four-period crossover study, 16 healthy Chinese subjects received ilaprazole 5, 10 or 20?mg intravenously, or 10?mg orally. Serial blood and urine samples were collected and intragastric pH was recorded within 24?h. The percentage time of intragastric pH?>?6 was the major index. Safety was assessed throughout the study.

3.?Plasma exposure of intravenous ilaprazole increased proportionally over the dose of 5–20?mg. Clearance and volume of distribution were independent of dose. Ilaprazole was not eliminated through urine and the absolute bioavailability was 55.2%. For the intravenous dose of 5, 10, 20?mg, and oral dose of 10?mg, the mean percentages time of intragastric pH?>?6 were 47.3%, 52.8%, 68.2% and 47.5%, respectively.

4.?Ilaprazole showed linear pharmacokinetics over the dose of 5–20?mg. Intravenous ilaprazole provided rapid onset of action and the potency of effect were exhibited in a dose-dependent manner. Intravenous ilaprazole was safe and well tolerated except for elevated activated partial thromboplastin time (APTT) and prothrombin time (PT).     

Pharmacokinetics and safety of FFR-rFVIIa after single doses in healthy subjects

FFR-rFVIIa is an antithrombotic agent, which has also proven to have antirestenotic properties in animal models. FFR-rFVIIa is a modified recombinant FVIIa in which the catalytic site is irreversibly inactivated by a synthetic tripeptide covalently bound with the FVIIa molecule. The modified rFVIIa retains its tissue factor (TF) binding capacity but is otherwise enzymatically inactive. A double-blind, placebo-controlled, randomized dose escalation trial was conducted to investigate eight single i.v. doses of FFR-rFVIIa (0.01, 0.02, 0.05, 0.08, 0.12, 0.18, 0.27, or 0.40 mg/kg body weight) in healthy male volunteers (n = 62). Safety, pharmacokinetics, and pharmacodynamics of FFR-rFVIIa were assessed. Mean (SD)AUC0-infinity ranged from 0.35 (0.11) to 28.8 (3.5)microg.h/ml, and mean Cmax ranged from 0.078 (0.019) to 4.8 (0.7) microg/ml. The mean elimination half-life ranged from 3.8 to 5.8 hours. Mean AUC0-infinity increased with increasing dose levels. Cmax appeared to be proportional to the dose level, with the exception of the lowest dose level. A dose-dependent prolongation of the prothrombin time was found, demonstrating that FFR-rFVIIa inhibited coagulation via the TF-dependent pathway FFR-rFVIIa was generally well tolerated at all dose levels studied.     

比伐卢定序贯给药在中国健康受试者中的药代、药效及安全性研究

目的：探讨合理的比伐卢定临床序贯给药方案。方法：筛选健康受试者12名,给予比伐卢定0．75mg／kg静脉推注后,1．75mg·kg^-1·h^-1的速度匀速静滴4h,不同时间点采集血样,测定血药浓度、活性凝血时间（ACT）及凝血功能,计算药代动力学、药效学参数,同时观察试验期间的不良事件。结果：序贯给药期间药-时曲线与时-效曲线吻合良好,ACT稳定在220～240S,药效动力学符合M—Mequation模型。试验期间未出现严重不良事件,凝血功能于停药后24h恢复至正常水平。结论：比伐卢定序贯给药（0．75mg／kg静脉推注后,1．75mg·kg^-1·h^-1静滴）的药效及安全性能够满足临床要求。     

Pharmacokinetics and pharmacodynamics of single and multiple doses of prasugrel in healthy native Chinese subjects

Aim:

To characterize the pharmacokinetics (PKs), pharmacodynamics (PDs), and tolerability of different dose regimens of prasugrel in healthy Chinese subjects.

Methods:

This was a single-centered, open-label, parallel-design study. Subjects received a single loading dose (LD) of prasugrel followed by once-daily maintenance dose (MD) for 10 d. They were enrolled into 3 groups: 60 mg LD/10 mg MD; 30 mg LD/7.5 mg MD; 30 mg LD/5 mg MD. Blood samples were collected after the first and last dose. The serum concentration of the active metabolite of prasugrel was determined using a LC/MS/MS method. Platelet aggregation was assessed using the VerifyNow-P2Y₁₂ assay.

Results:

Thirty-six healthy native Chinese subjects (19 males) aged 18–45 were enrolled; mean age and body weight were similar across the treatment groups (n=12 for each). The metabolite AUC_0–4 and C_max increased dose-proportionally across the dose range of 5 mg to 60 mg. The median T_max was 0.5 h in all groups. The PD parameters, indicated by the inhibition of ADP-induced platelet aggregation, were met more rapidly in the 60 mg group than the 30 mg group after the LD (94%–98%). This high degree of inhibition of platelet aggregation was maintained following the 10 mg MD (87%–90%) and was lower in the 7.5 mg and 5 mg MD groups (79%–83% and 64%–67%, respectively). Prasugrel was well tolerated in healthy Chinese subjects for single doses up to 60 mg and a MD of 10 mg for 10 d.

Conclusion:

The PKs and PDs of the active metabolite of prasugrel were similar to those in Chinese subjects reported by a previous bridging study, which demonstrated that the exposure to the active metabolite in Chinese subjects was higher than in Caucasians.     

Pharmacokinetics, pharmacodynamics, and safety of microencapsulated octreotide acetate in healthy subjects

The pharmacokinetics, pharmacodynamics, and safety of the marketed formulation of microencapsulated octreotide acetate were evaluated in an open-label study in 22 healthy cholecystectomized subjects. Each subject received a single 30 mg dose of microencapsulated octreotide acetate intramuscularly (i.m.). Concentrations of octreotide, growth hormone (GH), insulin-like growth factor binding protein 3 (IGFBP-3), and insulin-like growth factor 1 (IGF-1) as well as clinical safety were evaluated over a period of 112 days (16 weeks). After the injection, mean serum octreotide concentration initially increased rapidly, reached the maximum (Cmax, day 1 = 0.96 +/- 0.25 ng/ml) approximately 1.5 hours after dosing, and declined thereafter until 24 hours postdose (Cmin, 24 h = 0.088 +/- 0.093 ng/ml). The octreotide concentration then increased and started a sustained release from day 7 onward. Plateau concentrations were maintained through day 70 and gradually declined to below the lower limit of quantification (LLOQ) by day 112. The plateau height (Cplateau (2-112d, 60%)) was 1.68 +/- 0.88 ng/ml, and the duration (delta plateau, 60%) was 30.2 +/- 15.7 days. The integrated concentration-time curve, AUC0-112d, was 2819 +/- 782 (ng.h/ml), and the apparent half-life (t1/2) was 169 hours. To assess the variability, the drug concentrations were determined hourly for 8 hours on day 28, and the mean octreotide concentration, Cavg, day 28' was 1.55 +/- 1.26 ng/ml. The suppression of IGF-1 was statistically significant compared to the baseline (p < 0.05) through day 63; however, there were no appreciable changes in GH and IGFBP-3 concentrations after a single injection of microencapsulated octreotide acetate. Simulation of a 28-day dose schedule suggested that steady-state octreotide concentrations would be reached by the third injection with steady-state concentrations about twofold greater than the first injection. There were no serious adverse events or clinically meaningful changes in vital signs, ECGs, or laboratory evaluations observed in this study, indicating that the 30 mg i.m. dose of microencapsulated octreotide acetate was well tolerated in this population.     

Safety, tolerability, pharmacokinetics and pharmacodynamics of ascending single and multiple doses of lecozotan in healthy young and elderly subjects

AIMS

To determine the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of oral immediate release (IR) lecozotan in healthy young and elderly subjects.

METHODS

Three randomized, double-blind, placebo-controlled, sequential, ascending dose Phase I studies of lecozotan were conducted. In a single-dose study, ascending doses of 2, 5 and 10 mg were administered to cohorts of eight young subjects. In the two ascending 14-day multiple-dose studies, 41 young subjects received 0.1, 0.25, 0.5, 1 and 5 mg q12h of lecozotan or placebo and 24 elderly received 0.5 mg and 5 mg q12h of lecozotan or placebo. Assessments included safety evaluations, a complete PK profile and PD.

RESULTS

Lecozotan was safe and well tolerated at steady state up to 5 mg q12. The maximum tolerated dose after multiple doses was >10 mg (5 mg q12). In the single-dose study, the maximum tolerated dose was 10 mg. Dose-limiting mild-to-moderate adverse events included paraesthesia, dizziness and visual disturbances peaking at t_max and disappearing concomitantly with plasma concentrations. No clinically relevant changes in vital signs, ECG intervals or routine laboratory tests occurred. Lecozotan did not significantly change cognitive function, EEG or hormone levels. PK was characterized by rapid absorption, dose proportionality, extensive distribution and rapid elimination. The mean CL/F was approximately 35% lower in the elderly.

CONCLUSIONS

Lecozotan IR was safe and well tolerated after administration of multiple oral doses up to 5 mg q12h in young and elderly subjects. These results support the development of lecozotan in patients with Alzheimer''s disease.     

Pharmacokinetics and pharmacodynamics of single and multiple doses of the MAO-6 inhibitor lazabemide in healthy subjects

Aim The objectives of this study were to assess the tolerability, pharmacokinetics and pharmacodynamics of the reversible monoamine oxidase B (MAO-B) inhibitor, lazabemide, in healthy subjects.
Methods Single and multiple (1 week) twice daily oral doses (100–350 mg) of lazabemide were administered sequentially to five groups of six healthy male subjects in a placebo-controlled, double-blind design. Adverse events, vital signs, and clinical laboratory variables were recorded. Pharmacokinetic parameters of lazabemide were determined after single and multiple doses. Pharmacodynamics were assessed by determination of MAO-B activity in blood platelets and intravenous tyramine potentiation tests.
Results Lazabemide was well tolerated at all dose levels, causing no clinically relevant changes in vital signs or laboratory parameters. Headache was the most frequent adverse event at higher doses. Lazabemide was rapidly absorbed and eliminated by mixed linear and non-linear pathways. Only minor accumulation occurred upon multiple dosing and steady-state plasma concentrations were achieved on the third day. Lazabemide caused a rapid and reversible inhbition of MAO-B activity in platelets. The twice dady dosing regimen resulted in complete inhbition at all dose levels. The duration of complete inhbition was dose-dependent and ranged from 16 h with 100 mg to 36 h with 350 mg. The sensitivity to i.v. tyramine dd not change to a clinically relevant extent following single and multiple doses of lazabemide.
Conclusions The clinical pharmacology characteristics of lazabemide did not differ markedly after single and multiple oral doses. A dose regimen of lazebemide 100 mg twice daily is anticipated because it caused full and continuous MAO-B inhibition.     

Entecavir pharmacokinetics, safety, and tolerability after multiple ascending doses in healthy subjects

A double-blind, placebo-controlled, multiple oral dose escalation study was conducted to investigate the pharmacokinetics, safety, and tolerability of entecavir in healthy subjects. Eight subjects were assigned to each of the 3 dose panels (0.1 mg, 0.5 mg, and 1 mg or matched placebo once daily for 14 days). Blood and urine samples were collected for pharmacokinetic analyses. Entecavir was rapidly absorbed, with peak plasma concentration occurring within 1 hour of dosing. Steady-state plasma concentrations of entecavir were achieved by 10 days following the initial dose. At steady state, the mean area under the plasma concentration-time curve over 1 dosing interval, increased approximately proportional to dose. Entecavir had a mean terminal half-life ranging from 128 to 149 hours and an effective half-life of approximately 24 hours. Elimination was predominantly through renal excretion, with mean urinary recovery ranging from 62% to 73%. Entecavir was safe and well tolerated when administered at doses ranging from 0.1 mg to 1 mg/d for 14 days.     

Pharmacokinetics and safety of single and multiple doses of rasagiline in healthy Japanese and caucasian subjects

As of March 2018, rasagiline is approved for the treatment of Parkinson disease in 55 countries including Japan. The present study evaluated the pharmacokinetics (PK) and safety of rasagiline in healthy Japanese and Caucasian subjects following single and multiple administrations of three rasagiline doses. In this double‐blind, placebo‐controlled study, 64 healthy subjects (32 Japanese and 32 Caucasian) received either rasagiline (0.5, 1.0, or 2.0 mg) or placebo for 10 days with PK sampling for single‐dose administration on day 1 and for multiple administration on day 10. Regardless of administration schedule, rasagiline plasma concentrations and dose‐related increases in exposure parameters were similar between Japanese and Caucasians. Rasagiline accumulation (2‐fold for 0.5 mg and 3‐fold for 1.0 mg and 2.0 mg doses) following multiple administration was similar across the ethnic groups. Geometric mean ratios (GMR) comparing Japanese to Caucasians for AUC_0‐24, C_max and AUC_inf following single administration were 1.38, 1.17 and 1.38 for 0.5 mg; 1.22, 1.20 and 1.22 at 1.0 mg; and 1.02, 1.00 and 1.02 at for 2.0 mg. GMR for AUC_tau and C_max,ss following multiple administration were 1.43 and 1.06 at 0.5 mg, 1.06 and 1.00 at 1.0 mg, and 1.09 and 1.07 at 2.0 mg. Safety measures were unremarkable and similar between Caucasian and Japanese subjects. Comparable systemic exposure and safety parameters were demonstrated for rasagiline administered to healthy Japanese and Caucasian subjects.     

铝镁匹林片单剂量和多剂量人体药动学研究

目的:研究单剂量和多剂量铝镁匹林片(每片含阿司匹林81 mg,甘羟铝11 mg,重质碳酸镁22 mg)的人体药动学特征。方法:27名健康受试者随机等分成81,162和324 mg·d~(-1)三组,每日口服规定剂量的铝镁匹林片,连续7 d。采用HPLC-MS-MS法测定血浆阿司匹林和水杨酸浓度。结果:阿司匹林的T_(max)约30 min,t_(1/2)为17．4～29．8 min;水杨酸的t_(1/2)为3～4 h,T_(max)为30～60 min;各剂量组的C_(max)AUC,T_(max),t_(1/2)和Cl/F在给药后d1和d7均无显著性差异,t_(1/2)和Cl/F在三组间无显著性差异。结论:在本研究剂量范围内,阿司匹林和水杨酸呈线性动力学,连续服药未见体内蓄积。     

Pharmacokinetics,pharmacodynamics, tolerability and safety of single ascending doses of ticagrelor,a reversibly binding oral P2Y<Subscript>12</Subscript> receptor antagonist,in healthy subjects

Purpose  

Ticagrelor (AZD6140) is the first reversibly binding oral P2Y₁₂ receptor antagonist in development for reduction of clinical thrombotic events in patients with acute coronary syndromes. The purpose of our studies was to determine the effect of single-ascending doses of ticagrelor in healthy subjects.     

Clinical pharmacokinetics and tolerability of alpidem in healthy subjects given increasing single doses

Summary In a double-blind, placebo-controlled, crossover experiment in 21 healthy male volunteers, aged 19 to 27 y, the pharmacokinetics and tolerance of the new anxiolytic drug alpidem (SL80.0342) and its three major metabolites were studied after single doses of 25, 50, 100 and 200 mg. Plasma concentrations of alpidem (in 20 subjects) and metabolites (in 6 subjects) were measured by HPLC over a period of 54 h after dosing.C_max, t_max and AUC(0–54) and, when possible, t1/2 were determined for alpidem and metabolites and the dose linearity of the parameters was investigated. The time to peak of alpidem was dose independent in most subjects and was short (1–4 h); the mean values at the four dosing levels were 1.9, 1.7, 1.6 and 1.8 h. The peak concentration increased with the dose, the mean values being 17, 34, 88 and 115 ng · ml^–1, respectively. In 50% of the subjects c_max tended to stabilize between the 100 and 200 mg dose. Dose linearity was also present for the AUC, which plateaued between the 100 and 200 mg dose in only 3 out of 20 subjects; the mean AUC was 119, 281, 669 and 1117 ng · ml^–1 · h, respectively. The apparent half-life of elimination appeared to be dose independent, mean values at the increasing dosing levels being 18.7, 19.9, 18,1 and 17.9 h.A similar relationship between the kinetics parameters and dose of the alpidem was observed for the metabolites SL83.0912, SL80.0522 and SL83.0725. The formation of metabolites was not saturated as their AUCs relative to corresponding alpidem AUCs were not dose related.Thus the kinetics of alpidem and its three major metabolites were linear after doses of 25 to 200 mg.The drug was well tolerated by most of the subjects. Sedation and dizziness occurred mainly after the 100 and 200 mg doses.     

Pharmacokinetics, safety, and tolerability after single and multiple oral doses of varenicline in elderly smokers

Varenicline is a novel selective alpha4beta2 nicotinic acetylcholine partial agonist developed for smoking cessation. This study investigated the single- and multiple-dose pharmacokinetics, safety, and tolerability of varenicline in elderly (> or = 65 years) smokers. Twenty-four elderly smokers with normal renal function for their age (estimated creatinine clearance > or = 70 mL/min) received varenicline 1 mg once daily (n = 8) or placebo (n = 4) for 7 days, or 1 mg twice daily (n = 8) or placebo (n = 4) for 6 days with a single dose on day 7 in a double-blind, parallel group and placebo-controlled design. There was no evidence of concentration- or time-dependent changes in varenicline pharmacokinetics upon repeat dosing. Once- and twice-daily dosing was associated with an approximate 2-fold and 3-fold increase, respectively, in systemic exposure to varenicline. Varenicline was well tolerated; all adverse events reported were mild to moderate in intensity. Thus, no dose adjustment is necessary based on age alone.     

Ibudilast in healthy volunteers: safety,tolerability and pharmacokinetics with single and multiple doses

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Ibudilast is an oral drug approved in Asia for asthma.
• Tolerability of 10-mg regimens has been described previously.
• Published pharmacokinetics (PK) are limited: single or 7-day repeat oral administration of 10 mg in healthy male Asian volunteers.

WHAT THIS STUDY ADDS

• Safety/tolerability and PK of a single 30-mg dose and a 30-mg twice daily (b.i.d.) 2-week regimen in male and female healthy volunteers.
• Higher-dose regimens are relevant for testing in new neurological indications.
• LC-MS/MS analytics for quantification of plasma and urine levels of ibudilast parent and its primary metabolite (6,7-dihydrodiol-ibudilast).

AIMS

To investigate the safety, tolerability and pharmacokinetics (PK) of ibudilast after a single-dose and a multiple-dose regimen.

METHODS

Healthy adult male (n = 9) and female (n = 9) volunteers were evaluated over a 17-day stay in a Phase 1 unit. Subjects were randomized 1 : 3 to either oral placebo or ibudilast at 30-mg single administration followed by 14 days of 30 mg b.i.d. Complete safety analyses were performed and, for PK, plasma and urine samples were analysed for ibudilast and its major metabolite.

RESULTS

Ibudilast was generally well tolerated. No serious adverse events occurred. Treatment-related adverse events included hyperhidrosis, headache and nausea. Two subjects discontinued after a few days at 30 mg b.i.d. because of vomiting. Although samples sizes were too small to rule out a sex difference, PK were similar in men and women. The mean half-life for ibudilast was 19 h and median T_max was 4–6 h. Mean (SD) steady-state plasma C_max and AUC_0–24 were 60 (25) ng ml⁻¹ and 1004 (303) ng h ml⁻¹, respectively. Plasma levels of 6,7- dihydrodiol-ibudilast were approximately 30% of the parent.

CONCLUSIONS

Ibudilast is generally well tolerated in healthy adults when given as a single oral dose of 30 mg followed by 30 mg b.i.d. (60 mg day⁻¹) for 14 days. Plasma PK reached steady state within 2 days of starting the b.i.d. regimen. Exposure to ibudilast was achieved of a magnitude comparable to that associated with efficacy in rat chronic pain models.     

Pharmacokinetics of fluvoxamine maleate after increasing single oral doses in healthy subjects

The pharmacokinetics of fluvoxamine after single oral administration of 25, 50, and 100 mg fluvoxamine maleate was studied in a three-way cross-over study in 12 healthy male subjects. Fluvoxamine was administered orally in a solution. For doseproportionality, AUC, and C_max-dose relationships were evaluated by linear regression. Plasma concentrations increased in a linear dose-dependent manner in the dose range between 25 and 100 mg; t_1/2 and T_max showed no significant differences among treatments. Fluvoxamine was well tolerated.     

Pharmacokinetics, safety, and tolerability of intramuscular ziprasidone in healthy volunteers

Little has been published regarding the pharmacokinetics of the intramuscular (IM) formulation of Ziprasidone. The authors report results from 2 early phase I studies in healthy volunteers: a trial of single 5-, 10-, or 20-mg IM doses of ziprasidone in 24 subjects and an open-label 3-way crossover trial of 5-mg intravenous (IV), 5-mg IM, and 20-mg oral ziprasidone in 12 subjects. Absorption of IM ziprasidone was rapid (Tmax < 1 hour). The IM pharmacokinetic profile was consistent between studies and linear, with dose-related increases in exposure observed. The mean IM elimination t(1/2) was short and approximately 2.5 hours. The mean bioavailability for the 5-mg IM ziprasidone dose was approximately 100%. Adverse events were generally mild to moderate, and no subjects were discontinued from the study. No significant effects on renal function or other laboratory values were noted. These results support the use of IM ziprasidone in treating acutely agitated patients with schizophrenia.     

Pharmacokinetics and safety of single rising doses of ofloxacin in healthy volunteers.

The pharmacokinetics, safety, and disposition of the new antimicrobial fluoroquinolone ofloxacin were evaluated after oral administration in 14 healthy, male volunteers in a double-blind, placebo-controlled study. Ofloxacin was administered as 100-, 300-, and 600-mg doses separated by 1 week. Plasma and urine concentrations after each administration were measured using a sensitive and specific high-performance liquid chromatographic procedure. The distribution of ofloxacin was modeled using a two-compartment open-body model with first-order absorption. Maximum plasma concentrations and area under the plasma concentration versus time curve increased in a linear, dose-proportional manner over the range studied. At all levels, within 36 hours after administration, approximately 70% of the dose was recovered in urine as unchanged ofloxacin and only minimal amounts (less than 4%) as metabolites. No significant changes in the distribution or elimination of the compound were found over the 6-fold dose range. No major laboratory toxicities or clinically significant adverse effects were noted in either the ofloxacin or placebo group.     

Pharmacokinetics and pharmacodynamics of the vasopeptidase inhibitor,omapatrilat in healthy subjects

AIMS: To determine the pharmacokinetics, pharmacodynamics and tolerability of omapatrilat, a vasopeptidase inhibitor, in healthy subjects. METHODS: The effects of oral omapatrilat were evaluated in healthy men in two double-blind, placebo-controlled, dose-escalation trials. In a single-dose study, subjects received omapatrilat in doses of 2.5, 7.5, 25, 50, 125, 250, or 500 mg. In a multiple-dose study, subjects received doses of 10, 25, 50, 75, or 125 mg daily for 10 days. RESULTS: In the multiple-dose study, peak plasma concentrations (Cmax = 10-895 ng ml(-1); tmax = 0.5-2 h) of omapatrilat were attained rapidly. Omapatrilat exhibited a long effective half-life (14-19 h), attaining steady state in 3-4 days. In the single-dose study, Cmax (1-1009 ng ml(-1)) and AUC(0,t) (0.4-1891 ng ml(-1) h) were linear but not dose proportional. In the multiple-dose study, based on weighted least-squares linear regression analyses vs dose, Cmax but not AUC(0,t) was linear at the lower doses on day 10. The lowest dose of omapatrilat (2.5 mg) almost completely inhibited (> 97%) serum angiotensin converting enzyme activity at 2 h after dosing. In the multiple dose study, angiotensin converting enzyme activity was inhibited by more than 80% 24 h after all doses of omapatrilat. Inhibition of neutral endopeptidase activity was shown by increases in the daily urinary excretion of atrial natriuretic peptide and cyclic guanosine monophosphate at doses of more than 7.5 and 25 mg, respectively. In the single dose study, omapatrilat increased the daily urinary excretion of atrial natriuretic peptide dose-dependently from 10.8 +/- 4.1 (+/- SD) ng 24 h(-1) in the placebo group to 60.0 +/- 18.2 ng 24 h(-1) in the 500 mg group. Omapatrilat did not affect sodium and potassium excretion or urinary volume. Compared with placebo, omapatrilat produced a decrease in mean arterial pressure at 3 h after all doses in both the single- and multiple-dose studies. CONCLUSIONS: Omapatrilat was generally well tolerated. The pharmacokinetic and pharmacodynamic effects of omapatrilat are consistent with once-daily dosing.