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

Abstract

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.

Mechanisms of tolvaptan-induced toxicity in HepG2 cells

“…It is possible that patients who take both tolvaptan and proteasome inhibitors might have a higher risk of developing liver injury. [5]. Although the cytotoxic concentrations of tolvaptan reported here are higher than the plasma concentration in humans, we believe they were reasonable in the present mechanistic study for two reasons.…”

“…For example, co-administration of grapefruit juice [4], which interferes with CYP3A4 activity, or the CYP3A4 inhibitor ketoconazole [5], increased the mean maximal plasma concentration (C max ) and the area-under-the-curve M a n u s c r i p t Page 9 of 9 well plate. The luminescence was normalized to the MTT assay data, and further normalized to the control.…”

Hepatocellular Disposition and Transporter Interactions with Tolvaptan and Metabolites in Sandwich-Cultured Human Hepatocytes

“…After oral administration, tolvaptan was absorbed readily from the gastrointestinal tract with an absolute bioavailability of ;50% after a 30-mg dose, and was metabolized extensively, with ;1% of the dose excreted in the urine unchanged (Shoaf et al, 2007(Shoaf et al, , 2012a. CYP3A is the main enzyme involved in tolvaptan metabolism, primarily forming dehydrogenated and hydroxylated metabolites (Shoaf et al, 2012b). DM-4103 and DM-4107 are two major metabolites of tolvaptan primarily excreted in urine and feces, respectively (Tammara et al, 1999).…”

Bioanalysis of tolvaptan, a novel AVP‐V2 receptor antagonist in human plasma by a novel LC‐ESI‐MS/MS method: a pharmacokinetic application in healthy South Indian male subjects

“…The reported procedures employed PP (Pei et al, 2013) and solid-phase extraction (Shoaf et al, 2007a(Shoaf et al, , 2007b(Shoaf et al, , 2012a(Shoaf et al, , 2012b(Shoaf et al, , 2012cKim et al, 2011;Yi et al, 2012) to extract tolvaptan from human plasma. Based on that, different sample pretreatment methods were investigated.…”

“…As per the literature, several studies (Shoaf et al, 2007a(Shoaf et al, , 2007b(Shoaf et al, , 2012a(Shoaf et al, , 2012b(Shoaf et al, , 2012cKim et al, 2011;Yi et al, 2012;Pei et al, 2013) have investigated the pharmacokinetics of tolvaptan in healthy subjects. Of these, only one report describes the chromatography, method development process and validation details.…”