Effect of hospitalisation on liver enzymes in healthy subjects

Narjes, H.; Nehmiz, Gerhard

doi:10.1007/s002280000142

Cited by 24 publications

(26 citation statements)

References 12 publications

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“…Furthermore, three subjects had elevated alanine aminotransferase levels at screening. Indeed, these elevations may have been the result of the subjects being confined within the trial unit for a prolonged period, an effect that has been observed in placebo recipients in numerous Phase I clinical studies [31, 32]. Similar transient elevations have been observed in other Phase I studies with rivaroxaban [19].…”

Section: Discussionmentioning

confidence: 66%

Safety, pharmacokinetics and pharmacodynamics of single/multiple doses of the oral, direct Factor Xa inhibitor rivaroxaban in healthy Chinese subjects

Zhao

Sun

Zhou

et al. 2009

Brit J Clinical Pharma

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Rivaroxaban is an oral, direct Factor Xa inhibitor in advanced clinical development for the prevention and treatment of thromboembolic disorders.• In single-and multiple-dose Phase I studies in White subjects, rivaroxaban was safe and demonstrated predictable, dose-dependent pharmacokinetics and pharmacodynamics. WHAT THIS STUDY ADDS• The Phase III programme with rivaroxaban is being conducted worldwide.• Therefore, it is necessary to determine whether the pharmacokinetics, pharmacodynamics and tolerability of rivaroxaban are altered in patients of different ethnic origins.• Dose-escalation studies were conducted to determine the safety, pharmacokinetics and pharmacodynamics of single and multiple doses of rivaroxaban in healthy Chinese subjects. AIMSTo investigate the safety, pharmacokinetics and pharmacodynamics of rivaroxaban, an oral, direct Factor Xa (FXa) inhibitor, in healthy, male Chinese subjects. METHODSTwo randomized, single-blind, placebo-controlled, dose-escalation studies were conducted in healthy Chinese men aged 18-45 years. In the single-dose study, subjects received single, oral doses of rivaroxaban 2.5, 5, 10, 20 and 40 mg. In the multiple-dose study, oral rivaroxaban was administered in doses of 5, 10, 20 and 30 mg twice daily for 6 days. RESULTSRivaroxaban, in single and multiple doses up to 60 mg, was well tolerated. Rapid absorption was observed in both studies (time to Cmax 1.25-2.5 h). In the multiple-dose study, rivaroxaban exposure increased dose-proportionally after the first dose and at steady state (for the 5-20-mg doses). The half-life of rivaroxaban was up to 7.9 h in the single-dose study. CONCLUSIONSRivaroxaban demonstrated predictable pharmacokinetics and pharmacodynamics in healthy Chinese subjects, in line with findings observed previously in White subjects. This suggests that fixed doses of rivaroxaban may be administered to all patients, regardless of their ethnic origin.

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Section: Discussionmentioning

confidence: 66%

Safety, pharmacokinetics and pharmacodynamics of single/multiple doses of the oral, direct Factor Xa inhibitor rivaroxaban in healthy Chinese subjects

Zhao

Sun

Zhou

et al. 2009

Brit J Clinical Pharma

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“…Terbogrel was well tolerated and had only minor effects on haemostasis. Liver enzymes were found to be elevated in a small number of subjects in all treatment groups, which may be due to the lack of exercise during their stay in the Human Pharmacological Center [18]. The therapeutic potential of a combined TxA 2 receptor/synthase inhibitor may substantially exceed that obtained by blocking TxA 2 alone.…”

Section: Discussionmentioning

confidence: 94%

Pharmacokinetics and pharmacodynamics of terbogrel, a combined thromboxane A₂ receptor and synthase inhibitor, in healthy subjects

Guth¹,

Narjes

Schubert³

et al. 2004

Brit J Clinical Pharma

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AimsTo characterize the pharmacokinetics of terbogrel, a new combined thromboxane A 2 (TxA 2 ) receptor and synthase inhibitor, in healthy human subjects after single or multiple oral administration. MethodsForty-eight healthy male subjects received a single oral dose (10, 25, 50, 100, 150 or 200 mg) of terbogrel or placebo and 32 different subjects received one of the following treatments twice daily for 7 days: 50, 100 or 150 mg terbogrel, placebo, or once-a-day 330 mg acetylsalicylic acid. ResultsTerbogrel was well tolerated without obvious adverse effects following either a single oral dose or administration over 7 days. Plasma drug concentrations were dose-linear and there was no accumulation over 7 days. There was a dose-dependent blockade of TxA 2 receptors and of inhibition of thromboxane synthase activity with values for I C 50 of 12 ng ml -1 and 6.7 ng ml -1 , respectively. At the highest dose tested (150 mg) there was almost complete inhibition of thomboxane synthase and thromboxane receptor occupancy. Even at trough concentrations, receptor occupancy remained above 80% and thromboxane synthase was still completely inhibited. These two activities were associated with a dose-dependent inhibition of platelet agg regation ( > 80% at the 150 mg dose of terbogrel) and enhanced prostacyclin production. ConclusionsTerbogrel is a potent agent having two distinct, complimentary pharmacodynamic actions, namely inhibition of thromboxane synthase and antagonism of the TxA 2 receptor. The antithrombotic effect of terbogrel was dose-dependent and was associated with enhanced prostacyclin production. Terbogrel is an attractive candidate for long-term antithrombotic therapy.

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“…Studies of ambulatory subjects have consistently reported that the highest observed elevation is less than 3 times the upper limit of normal [3-5,18], while studies of subjects confined to a clinical research facility reported elevations more than 8 times the upper limit of normal [2,6]. While the exact reason for these differences is not clear, there is meta-analytic evidence that subjects on a clinical research unit may increase their aminotransferase activity independent of treatment [19]. This meta-analysis compared the change in ALT for the placebo groups in studies where subjects were admitted to a clinical research unit to the change in ALT for the placebo group in studies where subjects were ambulatory.…”

Section: Discussionmentioning

confidence: 99%

A randomized, placebo-controlled trial to determine the course of aminotransferase elevation during prolonged acetaminophen administration

Heard

Green

Anderson

et al. 2014

BMC Pharmacol Toxicol

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BackgroundAcetaminophen administration for more than 4 days causes aminotransferase elevation in some subjects. The objective of this randomized, placebo-controlled trial is to describe the course of alanine aminotransferase (ALT) elevation in subjects administered 4 g/day of acetaminophen for at least 16 days.MethodsA randomized, placebo controlled trial of acetaminophen (4 g/day) vs placebo. Subjects were healthy volunteers with normal liver enzymes. The primary outcome was the course of ALT during acetaminophen administration. All subjects were treated for a minimum of 16 days. Subjects with ALT elevation at day 16 were continued on treatment until these elevations resolved up to a maximum of 40 days. Subjects were also evaluated for elevation of INR or serum bilirubin as evidence of hepatic dysfunction.Results157/205 (77%) completed acetaminophen subjects had no ALT elevation or transient elevations that resolved by day 16. Of the 48 subjects who had ALT elevations at study day 16, 47 continued on acetaminophen and had resolution by study day 40. One acetaminophen subject did not have resolution by study day 40, and the course of aminotransferase elevation suggests an alternative cause. One placebo subject had an ALT elevation at day 16 that resolved by day 22. The highest observed ALT among all acetaminophen subjects was 191 IU/L. The mean ALT at day 16 was 4.4 IU/L higher for the acetaminophen than for the placebo group. No subject developed liver dysfunction.ConclusionsA minority of subjects treated with 4 g/day of acetaminophen for 16 days will have low-grade aminotransferase elevations that are not accompanied by liver dysfunction and resolve if administration is continued.Trials registrationClintrials.gov NCT00743093 registered August 26, 2008

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Effect of hospitalisation on liver enzymes in healthy subjects

Cited by 24 publications

References 12 publications

Safety, pharmacokinetics and pharmacodynamics of single/multiple doses of the oral, direct Factor Xa inhibitor rivaroxaban in healthy Chinese subjects

Safety, pharmacokinetics and pharmacodynamics of single/multiple doses of the oral, direct Factor Xa inhibitor rivaroxaban in healthy Chinese subjects

Pharmacokinetics and pharmacodynamics of terbogrel, a combined thromboxane A₂ receptor and synthase inhibitor, in healthy subjects

A randomized, placebo-controlled trial to determine the course of aminotransferase elevation during prolonged acetaminophen administration

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Effect of hospitalisation on liver enzymes in healthy subjects

Cited by 24 publications

References 12 publications

Safety, pharmacokinetics and pharmacodynamics of single/multiple doses of the oral, direct Factor Xa inhibitor rivaroxaban in healthy Chinese subjects

Safety, pharmacokinetics and pharmacodynamics of single/multiple doses of the oral, direct Factor Xa inhibitor rivaroxaban in healthy Chinese subjects

Pharmacokinetics and pharmacodynamics of terbogrel, a combined thromboxane A2 receptor and synthase inhibitor, in healthy subjects

A randomized, placebo-controlled trial to determine the course of aminotransferase elevation during prolonged acetaminophen administration

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Pharmacokinetics and pharmacodynamics of terbogrel, a combined thromboxane A₂ receptor and synthase inhibitor, in healthy subjects