Browse
Submit Data
Databases
API
Help

Dataset Information

16 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Phase 1 Studies to Define the Safety, Tolerability, and Pharmacokinetic and Pharmacodynamic Profiles of the Nonsteroidal Mineralocorticoid Receptor Antagonist Apararenone in Healthy Volunteers.

ABSTRACT: Apararenone is a long-acting, nonsteroidal mineralocorticoid receptor antagonist (MRA). The safety, tolerability, and pharmacokinetic (PK) and pharmacodynamic (PD) profiles of single- and multiple-dose apararenone were assessed in 3 phase 1 randomized, double-blind studies in 223 healthy adults. Study 1 assessed the PK, safety/tolerability, and PD of single-dose apararenone (3.75-640 mg) and multiple-dose apararenone (10-40 mg/day on days 1-14, 320 mg loading dose on day 1 + 10 mg/day on days 2-14, or 40-320 mg loading dose on day 1 + 2.5-20 mg/day on days 2-14) in Caucasian and Black men and women. Study 2 assessed the PK and safety of single-dose apararenone (5-320 mg) in healthy Japanese men. Study 3 assessed the PK, PD, and safety/tolerability of single-dose apararenone (160 or 640 mg) or eplerenone (200 mg; only for 160 mg of apararenone), each after fludrocortisone challenge in Caucasian men. In studies 1 and 2, an approximately dose-proportional increase was observed in PK parameters over the apararenone dose range of 3.75-40 mg; at higher doses, a less than dose-proportional increase was observed. Food, sex, age, and race had no apparent effect on apararenone PK. A long half-life was seen for apararenone and its principal metabolite; in addition, the exposure of the metabolite was lower than that of apararenone. Apararenone suppressed the decrease in urinary sodium and potassium ion ratio that occurs after loading with fludrocortisone. These studies support the mechanism of action of apararenone as an MRA, and further clinical development is warranted.

SUBMITTER: Nakamura T

PROVIDER: S-EPMC8048531 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Pharmacokinetic, partial pharmacodynamic and initial safety analysis of (-)-epicatechin in healthy volunteers.

Project description:(-)-Epicatechin ((-)-EPI), a naturally occurring flavanol, has emerged as a likely candidate for cocoa-based product reported reductions in cardiometabolic risk. The present study aimed to determine the safety, tolerability, pharmacokinetics and pharmacodynamics of purified (-)-EPI administered to healthy volunteers. In this phase I, open-label, two-part single- and multiple-dose study, subjects received either a single dose (n = 9) of 50, 100 or 200 mg or multiple doses (n = 8) of 50 mg daily (q.d.) or twice daily (b.i.d) for 5 days. Blood was collected at 0, 0.5, 1, 2, 4 and 6 h after (-)-EPI administration in the single and multiple dose groups (blood collection repeated in day 5). Samples were analyzed by HPLC-HR-ESI-MS for EPI and metabolite quantification. In the q.d. and b.i.d. groups, blood samples were analyzed for NO surrogates and follistatin levels as well as, platelet mitochondrial complexes I, V and citrate synthase activity levels. (-)-EPI was well tolerated and readily absorbed with further phase 2 metabolism. On day 5, in the q.d. and b.i.d. groups, there were significant increases in plasma nitrite of 30% and 17%, respectively. In the q.d. group on day 5 vs. day 1, platelet mitochondrial complexes I, IV and citrate synthase activities demonstrated a significant increase of ?92, 62 and 8%, respectively. Average day 5 follistatin AUC levels were ?2.5 fold higher vs. day 1 AUC levels in the b.i.d. group. (-)-EPI was safe to use, with no observed adverse effects, and our findings suggest that increases in NO metabolites, mitochondrial enzyme function and plasma follistatin levels may underlie some of the beneficial effects of cocoa products or (-)-EPI as reported in other studies.

| S-EPMC4357542 | biostudies-literature

Effects of the TRPV1 antagonist ABT-102 on body temperature in healthy volunteers: pharmacokinetic/ pharmacodynamic analysis of three phase 1 trials.

Project description:AimTo characterize quantitatively the relationship between ABT-102, a potent and selective TRPV1 antagonist, exposure and its effects on body temperature in humans using a population pharmacokinetic/pharmacodynamic modelling approach.MethodsSerial pharmacokinetic and body temperature (oral or core) measurements from three double-blind, randomized, placebo-controlled studies [single dose (2, 6, 18, 30 and 40?mg, solution formulation), multiple dose (2, 4 and 8?mg twice daily for 7?days, solution formulation) and multiple-dose (1, 2 and 4?mg twice daily for 7?days, solid dispersion formulation)] were analyzed. NONMEM was used for model development and the model building steps were guided by pre-specified diagnostic and statistical criteria. The final model was qualified using non-parametric bootstrap and visual predictive check.ResultsThe developed body temperature model included additive components of baseline, circadian rhythm (cosine function of time) and ABT-102 effect (Emax function of plasma concentration) with tolerance development (decrease in ABT-102 Emax over time). Type of body temperature measurement (oral vs. core) was included as a fixed effect on baseline, amplitude of circadian rhythm and residual error. The model estimates (95% bootstrap confidence interval) were: baseline oral body temperature, 36.3 (36.3, 36.4)°C; baseline core body temperature, 37.0 (37.0, 37.1)°C; oral circadian amplitude, 0.25 (0.22, 0.28)°C; core circadian amplitude, 0.31 (0.28, 0.34)°C; circadian phase shift, 7.6 (7.3, 7.9) h; ABT-102 Emax , 2.2 (1.9, 2.7)°C; ABT-102 EC50 , 20 (15, 28) ng?ml(-1) ; tolerance T50 , 28 (20, 43) h.ConclusionsAt exposures predicted to exert analgesic activity in humans, the effect of ABT-102 on body temperature is estimated to be 0.6 to 0.8°C. This effect attenuates within 2 to 3?days of dosing.

| S-EPMC3612721 | biostudies-literature

Tolerability and pharmacokinetic evaluation of inhaled dry powder hydroxychloroquine in healthy volunteers.

Project description:RationaleInhaled antimicrobials enable high local concentrations where needed and, compared to orally administration, greatly reduce the potential for systemic side effects. In SARS-CoV-2 infections, hydroxychloroquine sulphate (HCQ) administered as dry powder via inhalation could be safer than oral HCQ allowing higher and therefore more effective pulmonary concentrations without dose limiting toxic effects.ObjectivesTo assess the local tolerability, safety and pharmacokinetic parameters of HCQ inhalations in single ascending doses of 5, 10 and 20 mg using the Cyclops dry powder inhaler.MethodsTwelve healthy volunteers were included in the study. Local tolerability and safety were assessed by pulmonary function tests, electrocardiogram and recording adverse events. To estimate systemic exposure, serum samples were collected before and 0.5, 2 and 3.5 h after inhalation.Results and discussionDry powder HCQ inhalations were well tolerated by the participants, except for transient bitter taste in all participants and minor coughing irritation. There was no significant change in QTc-interval or drop in FEV1 post inhalation. The serum HCQ concentration remained below 10 μg/L in all samples.ConclusionSingle doses of inhaled dry powder HCQ up to 20 mg are safe and well tolerated. Our data support that further studies with inhaled HCQ dry powder to evaluate pulmonary pharmacokinetics and efficacy are warranted.

| S-EPMC9355221 | biostudies-literature

Metformin and daclatasvir: absence of a pharmacokinetic-pharmacodynamic drug interaction in healthy volunteers.

Project description:AIM:The aim of the present study was to evaluate the effect of the proposed organic cation transporter (OCT) inhibitor daclatasvir on the pharmacokinetics and pharmacodynamics of the OCT substrate metformin. METHODS:This was an open-label, two-period, randomized, crossover trial in 20 healthy subjects. Treatment A consisted of metformin and treatment B consisted of metformin + daclatasvir. Pharmacokinetic curves were recorded at steady-state. Geometric mean ratios (GMRs) with 90% confidence intervals (CIs) were calculated for metformin area under the concentration-time curve from 0 h to 12 h (AUC0-12 ), maximum plasma concentration (Cmax ) and final plasma concentration (Clast ). An oral glucose tolerance test was performed, measuring insulin, glucose and lactate levels. RESULTS:The GMRs (90% CI) of metformin AUC0-12 , Cmax and Clast (B vs. A) were 109% (102-116%), 108% (101-116%) and 112% (103-122%). The geometric mean AUC0-2 for insulin, glucose and lactate during treatments A and B were 84 h. mEl-1 and 90 h. mEl-1 , 13.6 h. mmol l-1 and 13.4 h. mmol l-1 , and 3.4 h. mmol l-1 and 3.5 h. mmol l-1 , respectively. CONCLUSIONS:Bioequivalence analysis showed that daclatasvir does not influence the pharmacokinetics of metformin in healthy subjects. Pharmacodynamic parameters were also comparable between treatments.

| S-EPMC5595943 | biostudies-literature

A phase I study to evaluate the safety, tolerability, pharmacodynamic and pharmacokinetic profiles of ocular GLH8NDE in healthy male adults.

Project description:GLH8NDE, a derivative of eupatilin, is currently under development to treat dry eye disease. We conducted a randomized, double-masked, placebo-controlled, single- and multiple-day study to evaluate safety, tolerability, pharmacodynamics, and pharmacokinetics of ocular GLH8NDE in healthy male adults. Subjects randomly received topical ocular dosing of GLH8NDE or its matching placebo for a day, then for 7 consecutive days with a 62-h washout at one of the following daily doses: 9, 18, 36 (Koreans), and 36 mg (Whites). The study drug was administered in divided doses over 10 h with 2- or 5-h intervals. Thirty-nine (97.5%) out of 40 subjects completed the study. A total of 17 subjects experienced 31 treatment-emergent adverse events, all of which were mild in severity and recovered without sequelae. Neither pathological changes in eye compartments nor clinically significant systemic effects were observed. GLH8NDE was rapidly absorbed reaching the peak concentration within 0.25-0.75 h postdose. The systemic exposure as measured by area under the concentration-time curve from time of administration up to the time of the last quantifiable concentration (AUClast ) after single-day administration of the same dose was 109% higher in Koreans than in Whites. In conclusion, GLH8NDE was safe and well-tolerated in healthy Korean and White male adults at 9-36 mg/day after single- and multiple-day administrations.

| S-EPMC8841454 | biostudies-literature

Piperaquine Pharmacokinetic and Pharmacodynamic Profiles in Healthy Volunteers of Papua New Guinea after Administration of Three-Monthly Doses of Dihydroartemisinin-Piperaquine.

Project description:Mass drug administration (MDA) with monthly dihydroartemisinin-piperaquine (DHA-PQP) appears useful in malaria control and elimination strategies. Determining the relationship between consecutive piperaquine phosphate (PQP) exposure and its impact on QT interval prolongation is a key safety consideration for MDA campaigns. Healthy volunteers from Papua New Guinea received a 3-day course of DHA-PQP (2.1/17.1 mg/kg) monthly for 3 consecutive months in a single arm longitudinal study. Plasma PQP concentrations were measured after the third dose of each course (at 52-54 h) and at 0 h of course 3. Twelve-lead electrocardiographic readings were conducted at 0 h, 48 h, 52 h, and day 7 of each course. QT interval corrected by Fridericia's formula (QTcF) was measured at each time point. A pharmacokinetic-pharmacodynamic model using nonlinear mixed effects models was developed to correlate PQP concentrations with QTcF. Ten thousand female and 10,000 male individuals were simulated at each treatment course. Eighty-two participants were included; mean age was 28.3 years (standard deviation [SD] ±12.3 years), and 36 (44%) were female. Pharmacokinetic-pharmacodynamic models were determined with 290 PQP concentrations and 868 QTcF observations. The average baseline QTcF was 392 ms with a between-subject variability SD ±14.4 ms and between-occasion variability SD ±3.64 ms. From the population modeled, only 0.08% of males and 0.45% of females would be at risk of an absolute QTcF of >500 ms. DHA-PQP is safe at standard doses in consecutive months, and the likelihood of severe cardiac events occurring during an MDA campaign is very low. This study has been registered at ClinicalTrials.gov under identifier NCT02605720.

| S-EPMC9380548 | biostudies-literature

Pharmacokinetic/pharmacodynamic modeling and simulation of dotinurad, a novel uricosuric agent, in healthy volunteers.

Project description:This study aimed to investigate the pharmacokinetic and pharmacodynamic (PK/PD) profiles of dotinurad, a novel uricosuric agent, and to construct a PK/PD model to predict serum urate (SUA) levels after dotinurad administration in healthy men. PK/PD model was constructed using single-dose study data considering the physiological features of urate handling. Model validation was performed by comparing the predicted SUA levels with the SUA levels in a multiple-dose study. Dotinurad was absorbed rapidly, and its exposure increased proportionally in the tested dose ranges (0.5-20 mg) after a single-dose administration. The PK model after oral administration was described using a one-compartment model with first-order absorption. Effects on SUA and renal urate excretion of dotinurad increased with dose escalation but were apparently saturable at a dose >5 mg. The simple maximal effect (E max) model was selected as the PD model of dotinurad on renal urate reabsorption, resulting in an estimated E max of 0.51. The plasma concentration at the half-maximal effect of dotinurad was 196 ng/mL. Other PD parameters were calculated from the change in SUA level or urinary excretion of urate before and after dotinurad administration. The predicted SUA levels, using the PK/PD model, were well-fitted with the observed values. The constructed PK/PD model of dotinurad appropriately described the profiles of dotinurad plasma concentrations and SUA level in multiple administration study.

| S-EPMC6880184 | biostudies-literature

Pharmacokinetic/Pharmacodynamic Model of CW002, an Investigational Intermediate Neuromuscular Blocking Agent, in Healthy Volunteers.

Project description:BACKGROUND:CW002 is an investigational nondepolarizing, neuromuscular blocking agent with a rapid onset and intermediate duration of action in animals. This is a single ascending dose, healthy subject study exploring tolerability, pharmacokinetics, and potency. METHODS:Population pharmacokinetic and pharmacokinetic/pharmacodynamic models were developed using plasma drug concentration data from a previously published dose-response study in 28 healthy subjects receiving single doses of CW002 during sevoflurane anesthesia. Subjects included in the models were from five different dose cohorts (cohorts 3, 4, 5, 6, and 8 receiving 0.04, 0.06, 0.08, 0.10, and 0.14?mg/kg, respectively). Serial arterial plasma concentrations and muscle twitch heights were monitored. RESULTS:A four-compartment model was fit to the concentration-time data, whereas a transit compartment with a sigmoid Emax model was fit to the pharmacokinetic/pharmacodynamic data. The population pharmacokinetics of CW002 was linear with very low interindividual variability in clearance (10.8%). Simulations were conducted to predict the onset and offset of effect at 2×, 3×, and 4× ED95. The time to 80% block was predicted to be 1.5, 0.8, and 0.7?min for 2×, 3×, and 4× ED95 doses, respectively. The simulated 25 to 75% recovery index was independent of dose. CONCLUSIONS:CW002 has predictable pharmacokinetics and is likely to have a rapid onset with an intermediate duration of action at 3× ED95. This model provides information to inform critical decisions (e.g., dose, study design) for continued development of CW002.

| S-EPMC5953789 | biostudies-literature

Pharmacokinetics, pharmacodynamics, safety and tolerability of cilofexor, a novel nonsteroidal Farnesoid X receptor agonist, in healthy volunteers.

Project description:Cilofexor is a nonsteroidal farnesoid X receptor (FXR) agonist being evaluated for treatment of nonalcoholic steatohepatitis (NASH) and primary sclerosing cholangitis (PSC). This work characterized the pharmacokinetics, pharmacodynamic, safety, and tolerability of cilofexor in healthy participants. Cilofexor single and multiple once-daily doses (10 to 300 mg fasting or fed and twice-daily doses [15 and 50 mg; fed]; tablet formulation) were evaluated. In each cohort, participants were randomized to active drug or placebo in a 4:1 ratio (planned n = 15/cohort). Multiple dosing was for 14 days. Pharmacokinetic and pharmacodynamic samples were collected and safety and tolerability were assessed. Overall, 120 participants were enrolled in the study and 118 participants received at least one dose of study drug. Cilofexor pharmacokinetics followed bi-exponential disposition and its exposure increased in a less-than-dose-proportional manner over the 10 to 300 mg dose range, with no significant accumulation with repeated dosing. Moderate-fat meal reduced cilofexor area under the plasma concentration versus time curve (AUC) by 21% to 45%. Cilofexor increased plasma levels of fibroblast growth factor19 (FGF19) and reduced the serum bile acid intermediate 7α-hydroxy-4-cholesten-3-one (C4) and bile acids in an exposure-dependent manner. Cilofexor doses >30 mg appeared to achieve the plateau of intestinal FXR activation. Cilofexor was generally well tolerated; all treatment-emergent adverse events (TEAEs) were mild or moderate in severity, with headache being the most frequently observed TEAE. The pharmacokinetics pharmacodynamic safety, and tolerability results from this study supported further evaluations, and informed dose selection, of cilofexor in phase II studies in patients with NASH and PSC.

| S-EPMC10014688 | biostudies-literature

Influence of CYP2D6 Polymorphism on the Pharmacokinetic/Pharmacodynamic Characteristics of Carvedilol in Healthy Korean Volunteers.

Project description:Background:Carvedilol is commonly used to treat hypertension as a ?- and ?1-adrenoreceptor blocker, but it is metabolized by CYP2D6, and CYP2D6*10 allele is dominant in Asian population. The objective of this study was to assess the influence of CYP2D6 polymorphisms on the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of carvedilol in healthy Korean volunteers. Methods:A PK/PD study for a single and multiple dosing of carvedilol were conducted. All volunteers in 3 genotypic groups received single oral dose of carvedilol 12.5 mg for 3 days, then 25 mg QD for 5 days, and 12.5 mg QD for another 3 days. PK parameters for carvedilol and its three metabolites were determined using non-compartmental analysis. For PD properties, blood pressure, heart rate, and the chronotropic dose 25 (CD25) value were obtained. Results:The IM_2 group with two *10 alleles (intermediate metabolizers) exhibited lower clearance of carvedilol as well as higher area under the curve (AUC) for O-desmethyl carvedilol. The ratio of CD25 to baseline at multiple dosing was significantly higher in the combined IM group (IM_1 and IM_2) than in the EM group, however, the ratio of CD25 after single and multiple dosing and the other PD markers were not significantly different between the 3 genotypic groups compared with the baseline. Conclusion:These findings showed that CYP2D6 genotype influenced the PK characteristics of carvedilol and no differences in PD response were observed in Korean healthy volunteers. Registered at the ClinicalTrials.gov, NCT02286934.

| S-EPMC6021360 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data