Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Otsuka Pharmaceutical Netherlands B.V., Herikerbergweg 292, 1101 CT, Amsterdam, Netherlands
Pharmacotherapeutic group: Diuretics, vasopressin antagonists
ATC code: C03XA01
Tolvaptan is a vasopressin antagonist that specifically blocks the binding of arginine vasopressin (AVP) at the V2 receptors of the distal portions of the nephron. Tolvaptan affinity for the human V2 receptor is 1.8 times that of native AVP.
The pharmacodynamic effects of tolvaptan have been determined in healthy subjects and subjects with ADPKD across CKD stages 1 to 4. Effects on free water clearance and urine volume are evident across all CKD stages with smaller absolute effects observed at later stages, consistent with the declining number of fully functioning nephrons. Acute reductions in mean total kidney volume were also observed following 3 weeks of therapy in all CKD stages, ranging from -4.6% for CKD stage 1 to -1.9% for CKD stage 4.
The primary focus of the clinical program for development of tolvaptan tablets for the treatment of ADPKD is a single pivotal, multi-national, phase 3, randomised, placebo-controlled trial in which the long-term safety and efficacy of oral split dose tolvaptan regimens (titrated between 60 mg/day and 120 mg/day) were compared with placebo in 1,445 adult subjects with ADPKD.
In total, 14 clinical trials involving tolvaptan have been completed worldwide in support of the ADPKD indication, including 8 trials in the US, 1 in the Netherlands, 3 in Japan, 1 in Korea, and the multinational phase 3 pivotal trial.
The phase 3 pivotal trial (TEMPO 3:4, 156-04-251) included subjects from 129 centres in the Americas, Japan, Europe and other countries. The primary objective of this trial was to evaluate the long-term efficacy of tolvaptan in ADPKD through rate of total kidney volume (TKV) change (normalised as percentage; %) for tolvaptan-treated compared with placebo-treated subjects. In this trial a total of 1,445 adult patients (age 18 years to 50 years) with evidence of rapidly-progressing, early ADPKD (meeting modified Ravine criteria, TKV ≥750 mL, estimated creatinine clearance ≥60 mL/min) were randomised 2:1 to treatment with tolvaptan or placebo. Patients were treated for up to 3 years.
Tolvaptan (n=961) and placebo (n=484) groups were well matched in terms of gender with an average age of 39 years. The inclusion criteria identified patients who at baseline had evidence of early disease progression. At baseline, patients had average estimated glomerular filtration rate (eGFR) of 82 mL/min/1.73 m² (Chronic Kidney Disease-Epidemiology Collaboration; CKD-EPI) with 79% having hypertension and a mean TKV of 1,692 mL (height adjusted 972 mL/m). Approximately 35% of subjects were CKD stage 1, 48% CKD stage 2, and 17% CKD stage 3 (eGFR CKD-EPI). While these criteria were useful in enriching the study population with patients who were rapidly progressing, subgroup analyses based on stratification criteria (age, TKV, GFR, Albuminuria, Hypertension) indicated the presence of such risk factors at younger ages predicts more rapid disease progression.
The results of the primary endpoint, the rate of change in TKV for subjects randomised to tolvaptan (normalised as percentage, ) to the rate of change for subjects on placebo, were highly statistically significant. The rate of TKV increase over 3 years was significantly less for tolvaptan-treated subjects than for subjects receiving placebo: 2.80 per year versus 5.51% per year, respectively (ratio of geometric mean 0.974; 95% CI 0.969 to 0.980; p<0.0001).
Pre-specified secondary endpoints were tested sequentially. The key secondary composite endpoint (ADPKD progression) was time to multiple clinical progression events of:
The relative rate of ADPKD-related events was decreased by 13.5% in tolvaptan-treated patients, (hazard ratio, 0.87; 95% CI, 0.78 to 0.97; p=0.0095).
The result of the key secondary composite endpoint is primarily attributed to effects on worsening kidney function and medically significant kidney pain. The renal function events were 61.4% less likely for tolvaptan compared with placebo (hazard ratio, 0.39; 95% CI, 0.26 to 0.57; nominal p<0.0001), while renal pain events were 35.8% less likely in tolvaptan-treated patients (hazard ratio, 0.64; 95% CI, 0.47 to 0.89; nominal p=0.007). In contrast, there was no effect of tolvaptan on either progression of hypertension or albuminuria.
TEMPO 4:4 is an open-label extension study that included 871 subjects that completed TEMPO 3:4 from 106 centres across 13 countries. This trial evaluated the effects of tolvaptan on safety, TKV and eGFR in subjects receiving active treatment for 5 years (early-treated), compared with subjects treated with placebo for 3 years, then switched to active treatment for 2 years (delayed-treated).
The primary end point for TKV did not distinguish a difference in change (−1.7%) over the 5-year treatment between early- and delayed-treated subjects at the pre-specified threshold of statistical significance (p=0.3580). Both groups' TKV growth trajectory was slowed, relative to placebo in the first 3 years, suggesting both early- and delayed-tolvaptan treated subjects benefitted to a similar degree.
A secondary endpoint testing the persistence of positive effects on renal function indicated that the preservation of eGFR observed by the end of the TEMPO 3:4 pivotal trial (3.01 to 3.34 mL/min/1.73 m² at follow-up visits 1 and 2) could be preserved during open-label treatment. This difference was maintained in the pre-specified mixed effect model repeat measurement (MMRM) analysis (3.15 mL/min/1.73 m², 95%CI 1.462 to 4.836, p=0.0003) and with sensitivity analyses where baseline eGFR data were carried forward (2.64 mL/min/1.73 m², 95% CI 0.672 to 4.603, p=0.0086). These data suggest that tolvaptan can slow the rate of renal function decline, and that these benefits persist over the duration of therapy.
Longer term data are not currently available to show whether long-term therapy with tolvaptan continues to slow the rate of renal function decline and affect clinical outcomes of ADPKD, including delay in the onset of end-stage renal disease.
Genotyping for PKD1 and PKD2 genes was conducted in a majority of patients entering the open-label extension study (TEMPO 4:4) but the results are not yet known.
Following an additional 2 years of tolvaptan treatment, resulting in a total of 5 years on tolvaptan therapy no new safety signals were identified.
The phase 3, multi-centre, international, randomised-withdrawal, placebo-controlled, double-blind trial 156-13-210 compared the efficacy and safety of tolvaptan (45 mg/day to 120 mg/day) to placebo in patients able to tolerate tolvaptan during a five-week titration and run-in period on tolvaptan. The trial utilised a randomised withdrawal design, to enrich for patients that were able to tolerate tolvaptan for a 5-week, single-blind pre-randomisation period consisting of a 2-week titration period and 3-week run-in period. The design was used to minimise the impact of early discontinuation and missing data on trial endpoints.
A total of 1,370 patients (age 18 years to 65 years) with CKD with an eGFR between 25 and 65 mL/min/1.73 m² if younger than age 56 years; or eGFR between 25 and 44 mL/min/1.73 m², plus eGFR decline >2.0 mL/min/1.73 m²/year if between age 56 years to 65 years were randomised to either tolvaptan (n=683) or placebo (n=687) and were treated for a period of 12 months.
For subjects randomised, the baseline, average eGFR was 41 mL/min/1.73 m² (CKD-EPI) and historical TKV, available in 318 (23%) of subjects, averaged 2,026 mL. Approximately 5%, 75% and 20% had an eGFR 60 mL/min/1.73 m² or greater (CKD stage 2), or less than 60 and greater than 30 mL/min/1.73 m² (CKD stage 3) or less than 30 but greater than 15 mL/min/1.73 m² (CKD stage 4), respectively. The CKD stage 3 can be subdivided further to stage 3a 30%, (eGFR 45 mL/min/1.73 m² to less than 60 mL/min/1.73 m²) and stage 3b 45%, (eGFR between 30 and 45 mL/min/1.73 m²).
The primary endpoint of the trial was the change in eGFR from pre-treatment baseline levels to post- treatment assessment. In patients treated with tolvaptan the reduction in eGFR was significantly less than in patients treated with placebo (p<0.0001). The treatment difference in eGFR change observed in this trial is 1.27 mL/min/1.73 m², representing a 35% reduction in the LS means of change in eGFR of -2.34 mL/min/1.73 m² in tolvaptan group relative to a -3.61 mL/min/1.73 m² in placebo group observed over the course of one year. The key secondary endpoint was a comparison of the efficacy of tolvaptan treatment versus placebo in reducing the decline of annualised eGFR slope across all measured time points in the trial. These data also showed significant benefit from tolvaptan versus placebo (p<0.0001).
Subgroup analysis of the primary and secondary endpoints by CKD stage found similar, consistent treatment effects relative to placebo for subjects in stages 2, 3a, 3b and early stage 4 (eGFR 25 to 29 mL/min/1.73 m²) at baseline.
A pre-specified subgroup analysis suggested that tolvaptan had less of an effect in patients older than 55 years of age, a small subgroup with a notably slower rate of eGFR decline.
The European Medicines Agency has deferred the obligation to submit the results of studies with tolvaptan in one or more subsets of the paediatric population in polycystic kidney disease (see section 4.2 for information on paediatric use).
After oral administration, tolvaptan is rapidly absorbed with peak plasma concentrations occurring about 2 hours after dosing. The absolute bioavailability of tolvaptan is about 56%. Co-administration of tolvaptan with a high-fat meal increased peak concentrations of tolvaptan up to 2-fold but left AUC unchanged. Even though the clinical relevance of this finding is not known, the morning dose should be taken under fasted conditions to minimise the unnecessary risk of increasing the maximal exposure (see section 4.2).
Following single oral doses of ≥300 mg, peak plasma concentrations appear to plateau, possibly due to saturation of absorption. Tolvaptan binds reversibly (98%) to plasma proteins.
Tolvaptan is extensively metabolised in the liver almost exclusively by CYP3A. Tolvaptan is a weak CYP3A4 substrate and does not appear to have any inhibitory activity. In vitro studies indicated that tolvaptan has no inhibitory activity for CYP3A. Fourteen metabolites have been identified in plasma, urine and faeces; all but one were also metabolised by CYP3A. Only the oxobutyric acid metabolite is present at greater than 10% of total plasma radioactivity; all others are present at lower concentrations than tolvaptan. Tolvaptan metabolites have little to no contribution to the pharmacological effect of tolvaptan; all metabolites have no or weak antagonist activity for human V2 receptors when compared with tolvaptan. The terminal elimination half-life is about 8 hours and steady-state concentrations of tolvaptan are obtained after the first dose.
Less than 1% of intact active substance is excreted unchanged in the urine. Radio labelled tolvaptan experiments showed that 40% of the radioactivity was recovered in the urine and 59% was recovered in the faeces, where unchanged tolvaptan accounted for 32% of radioactivity. Tolvaptan is only a minor component in plasma (3%).
Following single oral doses, Cmax values show less than dose proportional increases from 30 mg to 240 mg and then a plateau at doses from 240 mg to 480 mg. AUC increases linearly.
Following multiple once daily dosing of 300 mg, tolvaptan exposure was only increased 6.4-fold when compared to a 30 mg dose. For split-dose regimens of 30 mg/day, 60 mg/day and 120 mg/day in ADPKD patients, tolvaptan exposure (AUC) increases linearly.
Clearance of tolvaptan is not significantly affected by age.
The effect of mildly or moderately impaired hepatic function (Child-Pugh classes A and B) on the pharmacokinetics of tolvaptan was investigated in 87 patients with liver disease of various origins. No clinically significant changes have been seen in clearance for doses ranging from 5 mg to 60 mg. Very limited information is available in patients with severe hepatic impairment (Child-Pugh class C).
In a population pharmacokinetic analysis in patients with hepatic oedema, AUC of tolvaptan in severely (Child-Pugh class C) and mildly or moderately (Child-Pugh classes A and B) hepatic impaired patients were 3.1-times and 2.3-times higher than that in healthy subjects.
In a population pharmacokinetic analysis for patients with ADPKD, tolvaptan concentrations were increased, compared to healthy subjects, as renal function decreased below eGFR of 60 mL/min/1.73 m². An eGFR CKD-EPI decrease from 72.2 to 9.79 (mL/min/1.73 m²) was associated with a 32% reduction in total body clearance.
Non-clinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity or carcinogenic potential. Teratogenicity was noted in rabbits given 1,000 mg/kg/day (7.5 times the exposure from the 120 mg/day human dose on an AUC basis). No teratogenic effects were seen in rabbits at 300 mg/kg/day (about 1.25 to 2.65 times the exposure in humans at the 120 mg/day dose, based on AUC). In a peri- and post-natal study in rats, delayed ossification and reduced pup bodyweight were seen at the high dose of 1,000 mg/kg/day.
Two fertility studies in rats showed effects on the parental generation (decreased food consumption and body weight gain, salivation), but tolvaptan did not affect reproductive performance in males and there were no effects on the foetuses. In females, abnormal oestrus cycles were seen in both studies. The no observed adverse effect level (NOAEL) for effects on reproduction in females (100 mg/kg/day) was about 8-times the maximum human recommended dose of 120 mg/day on a mg/m² basis.
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