Pharmacokinetic and Pharmacodynamic Interaction Between Tolvaptan, a Non-Peptide AVP Antagonist, and Furosemide or Hydrochlorothiazide

Shoaf, Susan E.; Bramer, Steven L.; Bricmont, Patricia; Zimmer, Christopher

doi:10.1097/fjc.0b013e318074f934

Cited by 52 publications

(65 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although these data support a stimulatory role for the vasopressin V 2 receptor in renin release, it has recently been found that renin mRNA is also increased in vasopressin V 2 receptor-deficient mice (759), which exhibit a clear renal phenotype (981). Furthermore, the vasopressin V 2 receptor antagonist tolvaptan did not change the plasma renin activity in rats and humans (800,801,911).…”

Section: Vasopressinmentioning

confidence: 85%

Physiology of Kidney Renin

Castrop

Höcherl

Kurtz

et al. 2010

Physiological Reviews

232

277

View full text Add to dashboard Cite

The protease renin is the key enzyme of the renin-angiotensin-aldosterone cascade, which is relevant under both physiological and pathophysiological settings. The kidney is the only organ capable of releasing enzymatically active renin. Although the characteristic juxtaglomerular position is the best known site of renin generation, renin-producing cells in the kidney can vary in number and localization. (Pro)renin gene transcription in these cells is controlled by a number of transcription factors, among which CREB is the best characterized. Pro-renin is stored in vesicles, activated to renin, and then released upon demand. The release of renin is under the control of the cAMP (stimulatory) and Ca2+(inhibitory) signaling pathways. Meanwhile, a great number of intrarenally generated or systemically acting factors have been identified that control the renin secretion directly at the level of renin-producing cells, by activating either of the signaling pathways mentioned above. The broad spectrum of biological actions of (pro)renin is mediated by receptors for (pro)renin, angiotensin II and angiotensin-( 1 – 7 ).

show abstract

Section: Vasopressinmentioning

confidence: 85%

Physiology of Kidney Renin

Castrop

Höcherl

Kurtz

et al. 2010

Physiological Reviews

232

277

View full text Add to dashboard Cite

show abstract

“…Following co-administration of 30 mg tolvaptan with ketoconazole, 24 h urine volume was only increased 1.3-fold, a much smaller change than the 5.4-fold increase seen in tolvaptan AUC(0,•). Previously, it was reported that a 30 mg dose of tolvaptan produces a maximal increase in urine output for 8 h post dose [19]. Therefore, increased tolvaptan plasma concentrations during this time period would not be expected to increase total urine output due to the saturation of response in urine excretion rate.…”

Section: Tablementioning

confidence: 99%

Effects of CYP3A4 inhibition and induction on the pharmacokinetics and pharmacodynamics of tolvaptan, a non‐peptide AVP antagonist in healthy subjects

Shoaf

Bricmont

Mallikaarjun

2012

Brit J Clinical Pharma

Self Cite

View full text Add to dashboard Cite

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Before these trials were done, the effects of CYP3A4 inhibition and induction on the pharmacokinetics (PK) and pharmacodynamics (PD) of tolvaptan in healthy subjects were unknown. As tolvaptan is a CYP3A4 substrate, knowing the effects of inhibition and induction on CYP3A4-mediated metabolism was important for dosing recommendations. WHAT THIS STUDY ADDS• This paper describes the changes in tolvaptan PK and PD following inhibition or induction of CYP3A4 and explores the mechanisms behind the disparity seen between tolvaptan PK and effects on urine output. It also discusses the concentrations at which tolvaptan produces its maximal response on urine output and the timing of the onset and offset of this response. AIMSIn vitro studies indicated CYP3A4 alone was responsible for tolvaptan metabolism. To determine the effect of a CYP3A4 inhibitor (ketoconazole) and a CYP3A4 inducer (rifampicin) on tolvaptan pharmacokinetics (PK) and pharmacodynamics (PD), two clinical trials were performed. METHODSFor CYP3A4 inhibition, a double-blind, randomized (5:1), placebo-controlled trial was conducted in 24 healthy subjects given either a single 30 mg dose of tolvaptan (n = 19) or matching placebo (n = 5) on day 1 with a 72 h washout followed by a 3 day regimen of 200 mg ketoconazole, once daily with 30 mg tolvaptan or placebo also given on day 5. For CYP3A4 induction, 14 healthy subjects were given a single dose of 240 mg tolvaptan with 48 h washout followed by a 7 day regimen of 600 mg rifampicin, once daily, with 240 mg tolvaptan also given on the seventh day. RESULTSWhen co-administered with ketoconazole, mean Cmax and AUC(0,•) of tolvaptan were increased 3.48-and 5.40-fold, respectively. Twenty-four hour urine volume increased from 5.9 to 7.7 l. Erythromycin breath testing showed no difference following a single dose of tolvaptan. With rifampicin, tolvaptan mean Cmax and AUC were reduced to 0.13-and 0.17-fold of tolvaptan administered alone. Twenty-four hour urine volume decreased from 12.3 to 8.8 l. CONCLUSIONSTolvaptan is a sensitive CYP3A4 substrate with no inhibitory activity. Due to the saturable nature of tolvaptan's effect on urine excretion rate, changes in the pharmacokinetic profile of tolvaptan do not produce proportional changes in urine output.

show abstract

“…Tolvaptan is an oral V2 receptor antagonist which has been shown in healthy individuals to have a greater aquaresis than either frusemide or hydrochlorothiazide, without having a significant natriuresis or kaliuresis (34). The effect of tolvaptan in SIADH was explored in the SALT-1 (conducted in US) and SALT-2 (conducted in US and Europe) trials (35).…”

Section: Future Treatment Options: the Vaptansmentioning

confidence: 99%

The syndrome of inappropriate antidiuretic hormone: current and future management options

Sherlock

Thompson²

2010

European Journal of Endocrinology

View full text Add to dashboard Cite

Hyponatraemia is the commonest electrolyte abnormality, and syndrome of inappropriate antidiuretic hormone (SIADH) is the most frequent underlying pathophysiology. Hyponatraemia is associated with significant morbidity and mortality, and as such appropriate treatment is essential. Treatment options for SIADH include fluid restriction, demeclocycline, urea, frusemide and saline infusion, all of which have their limitations. The introduction of the vasopressin-2 receptor antagonists has allowed clinicians to specifically target the underlying pathophysiology of SIADH. Initial studies have shown good efficacy and safety profiles in the treatment of mild to moderate hyponatraemia. However, studies assessing the efficacy and safety of these agents in acute severe symptomatic hyponatraemia are awaited. Furthermore, the cost of these agents at present may limit their use.European Journal of Endocrinology 162 S13-S18

show abstract

Pharmacokinetic and Pharmacodynamic Interaction Between Tolvaptan, a Non-Peptide AVP Antagonist, and Furosemide or Hydrochlorothiazide

Cited by 52 publications

References 13 publications

Physiology of Kidney Renin

Physiology of Kidney Renin

Effects of CYP3A4 inhibition and induction on the pharmacokinetics and pharmacodynamics of tolvaptan, a non‐peptide AVP antagonist in healthy subjects

The syndrome of inappropriate antidiuretic hormone: current and future management options

Contact Info

Product

Resources

About