Tolvaptan in autosomal dominant polycystic kidney disease: three years' experience

Abstract

Background and objectives: Autosomal dominant polycystic kidney disease (ADPKD), a frequent cause of end-stage renal disease, has no cure. V2-specific vasopressin receptor antagonists delay disease progression in animal models.

Design, setting, participants, and measurements: This is a prospectively designed analysis of annual total kidney volume (TKV) and thrice annual estimated GFR (eGFR) measurements, from two 3-year studies of tolvaptan in 63 ADPKD subjects randomly matched 1:2 to historical controls by gender, hypertension, age, and baseline TKV or eGFR. Prespecified end points were group differences in log-TKV (primary) and eGFR (secondary) slopes for month 36 completers, using linear mixed model (LMM) analysis. Sensitivity analyses of primary and secondary end points included LMM using all subject data and mixed model repeated measures (MMRM) of change from baseline at each year. Pearson correlation tested the association between log-TKV and eGFR changes.

Results: Fifty-one subjects (81%) completed 3 years of tolvaptan therapy; all experienced adverse events (AEs), with AEs accounting for six of 12 withdrawals. Baseline TKV (controls 1422, tolvaptan 1635 ml) and eGFR (both 62 ml/min per 1.73 m(2)) were similar. Control TKV increased 5.8% versus 1.7%/yr for tolvaptan (P < 0.001, estimated ratio of geometric mean 0.96 [95% confidence interval 0.95 to 0.97]). Corresponding annualized eGFR declined: -2.1 versus -0.71 ml/min per 1.73 m(2)/yr (P = 0.01, LMM group difference 1.1 ml/min per 1.73 m(2)/yr [95% confidence interval 0.24 to 1.9]). Sensitivity analyses including withdrawn subjects were similar, whereas MMRM analyses were significant at each year for TKV and nonsignificant for eGFR. Increasing TKV correlated with decreasing eGFR (r = -0.21, P < 0.01).

Conclusion: ADPKD cyst growth progresses more slowly with tolvaptan than in historical controls, but AEs are common.

Trial registration: ClinicalTrials.gov NCT00413777 NCT00841568.

Figure 1.

Tolerability and efficacy during titration phase. In the initial 2 months of the TEMPO₄² study a split-dose regimen of oral tolvaptan (8 a.m./4 p.m.) was up titrated (15/15, 30/15, 45/15, 60/30, 90/30 mg/d) until tolerability was reached. Tolerability was defined as self-reported tolerance of a specific dose regimen by responding yes to the question: “Could you tolerate taking this dose of tolvaptan for the rest of your life?” Efficacy was defined by the capacity to suppress the action of vasopressin on the kidney reflected by sustained urine hypotonicity (Uosm <300 mOsm/kg).

Figure 2.

Subject disposition in TEMPO₄² and 156-05-002 trials. Of 48 eligible subjects for the TEMPO₄² study, 47 entered screening and 46 participated; seven subjects withdrew early (including one of six in the high-dose group who permanently down-titrated), leaving 39 who completed 3 years' therapy. Exposure verified by tolvaptan metabolite levels confirmed compliance in all but one subject in the 45/15-mg/d group. Of 18 eligible subjects for the 156-05-002 study, 17 participated, five withdrew, and 12 completed 3 years' therapy. Subjects completing 36 months were used in the primary analysis; analyses including data from withdrawn subjects who received at least one dose of study drug and who had posttreatment data were also performed.

Figure 3.

Change in total kidney volume and renal function over 3 years of tolvaptan compared with matched control and their correlation for individual subjects. The primary analysis for slope of total kidney volume (TKV) and estimated GFR (eGFR) use each parameter's annualized change and a linear mixed model to test for group differences. Because these data are not easily displayed, subjects completing 3 years of tolvaptan (black circles) and their controls (red triangles) are displayed for TKV (a) and eGFR (b). Control subjects were matched 1:2 by gender, presence of hypertension, age, and either baseline TKV (a) or baseline eGFR (b). Values for change from baseline (as percent TKV or ml/min per 1.73 m² per year) are plotted, and dotted lines representing a linear regression of group trend were drawn. (c) These subjects' annualized change in eGFR (by MDRD formula) and the annualized percent change in TKV were plotted, and the entire data set's correlation (r = −0.21, P < 0.01) was evaluated. Dashed lines marking a zero change in TKV and eGFR parameters are drawn, creating quadrants representing improvement in both parameters (A), improvement in eGFR but worsened TKV (B), worsened eGFR but improved TKV (C), and worsening in both parameters (D) are shown. The data point circled represents the subject in whom compliance with tolvaptan was not supported by tolvaptan metabolite data.