Tolvaptan pharmacokinetics and pharmacodynamics in adolescents with autosomal dominant polycystic kidney disease

Abstract

Tolvaptan, an oral selective antagonist of the vasopressin V2 receptor, is the only medication for autosomal dominant polycystic kidney disease (ADPKD) with disease-modifying properties in adults at risk of rapid progression. The pharmacokinetics (PK) and pharmacodynamics (PD) of tolvaptan have been well characterized in adults with ADPKD, but data are lacking for adolescents. We assessed prespecified PK/PD endpoints from a randomized clinical trial of tolvaptan in adolescents (ages 12–17 years) with ADPKD (NCT02964273). Dense 24-h PK and PD sampling was conducted in a subgroup of 20 trial participants after a minimum of 1 month on treatment. Endpoints included standard PK parameters and PD endpoints of urine volume, fluid intake, fluid balance, and clearance of sodium, creatinine, and free water. The analysis population (12 tolvaptan; 8 placebo) had well-preserved kidney function. Total daily tolvaptan doses ranged from 22.5–60.0 mg dependent on tolerability. All tolvaptan-treated adolescents had a tolvaptan maximum plasma concentration > 100 ng/mL, urine osmolality in each collection interval of < 215 mOsm/kg, and positive 24-h free water clearance values. In the placebo group, median 12- to 24-h urine osmolality was 507 mOsm/kg, and free water clearance values were close to zero. There was wide interindividual variability in response to tolvaptan, with no correlation between exposure and 24-h urine output or free water clearance. Tolvaptan did not affect sodium excretion.

Conclusion: Tolvaptan was associated with large increases in free water clearance and urine output. Similar to adult populations, PD responses to tolvaptan varied considerably among adolescent individuals.

Trial registration: EudraCT number: 2016–000187-42 (6 May 2016). ClinicalTrials.gov identifier: NCT02964273 (10 November 2016).

What is Known: • The pharmacokinetics and pharmacodynamics of tolvaptan have been well characterized in adults with autosomal dominantpolycystic kidney disease (ADPKD) but its effects have not been studied in adolescents with ADPKD. What is New: • This report presents the pharmacokinetics and pharmacodynamic effects of tolvaptan in adolescents with ADPKD and compares the pharmacodynamic effects to untreated adolescents.

Supplementary Information

The online version contains supplementary material available at 10.1007/s00431-025-06689-2.

Introduction

Tolvaptan, an oral selective antagonist of the vasopressin V2 receptor, is the only medication for autosomal dominant polycystic kidney disease (ADPKD) that has demonstrated disease-modifying properties in adults [1, 2]. Tolvaptan is not approved for use in pediatric patients. A trial in children and adolescents (EudraCT number: 2016–000187-42; ClinicalTrials.gov identifier: NCT02964273) was conducted to provide initial data on the use of tolvaptan in children and adolescents with ADPKD at high risk of progression, with focus on safety of use, appropriate dosing, and pharmacodynamic (PD) activity. The pediatric trial investigators reported the study design [3]; primary and key secondary endpoints and safety results following 1 year of randomized, double-blind, placebo-controlled treatment (Phase A) [4]; and secondary endpoints (excluding PD) and safety following 2 years of open-label treatment (Phase B) [5].

As noted by Schaefer et al., required secondary endpoints included PD endpoints of urine volume (including 24-h fluid volume), fluid intake, fluid balance, and clearance of sodium, creatinine, and free water during dense pharmacokinetic (PK) sampling (after at least 1 month on study drug) [3]. Exploratory endpoints included tolvaptan maximum (peak) plasma concentration (C_max), minimum plasma concentration (C_min), time to C_max (t_max), and area under the concentration–time curve from time zero to 24 h (AUC_0–24 h) following dense PK sampling. These endpoints were to be determined during Phase A (double-blind, placebo-controlled treatment) in a subgroup of 20 adolescents (10 on tolvaptan, 10 on placebo) enrolled at selected sites.

This report presents tolvaptan PK and PD endpoints following tolvaptan or placebo treatment in adolescents with ADPKD who had been on treatment for at least 1 month.

Methods

Trial design

Please refer to Schaefer et al. for details on the trial design [3]. Briefly, in Phase A, 60 adolescents (aged 12–17 years) with a diagnosis of ADPKD defined by the presence of family history and/or genetic criteria and with at least 10 kidney cysts (≥ 0.5 cm) confirmed by MRI were to be enrolled in a 1-year, randomized, double-blind, placebo-controlled, multi-center trial conducted in Belgium, Germany, Italy and the United Kingdom. Children (aged 4–11 years) could also be enrolled. Starting doses were based on weight. See Table 1. After 1 week, participants who could tolerate the initial dose were to up-titrate once. Participants could remain on their starting dose or down-titrate at any time so that they could remain on treatment to complete the trial.

Table 1.

Starting and up-titrated tolvaptan doses

Body Weight	Starting Dose	Up-titrated Maximum Dose
≥ 20 kg to < 45 kg	15/7.5 mg	30/15 mg
≥ 45 kg to ≤ 75 kg	30/15 mg	45/15 mg
> 75 kg	45/15 mg	60/30 mg

Down-titration steps are presented in Supplemental Table 1 Mekahli et al. [4]

Per regulatory requirement, dense PK and PD sampling was to be conducted in a subgroup of 20 adolescents, 10 on tolvaptan and 10 on placebo, after a minimum of 1 month on treatment. The minimum treatment duration was to ensure that participants were on a tolerable dose, as PK concentrations reach steady state on Day 2 and PD responses are stable by Day 5 [6]. These assessments required the signing of a separate informed assent by the adolescent and consent from a parent/guardian. An interactive response system tracked how many participants from each treatment signed an assent form and completed the assessments. If a treatment group reached 10 completers and informed assent/consent signing data was entered for a participant in the same treatment group, the system was to indicate that this participant should not participate in dense PK/PD assessments. However, as only 20 participants signed the assent, it was determined that all should participate to meet the goal of 20 participants with assessments.

Participants were typically in-clinic from the evening prior to the scheduled PK sampling and discharged after the 24-h PK/PD sample collection.

Dosing

Each participant was to be dosed with study drug from their dispensed supply. The morning dose was to be administered after a minimum 8-h fast, with no food within 2 h postdose. The afternoon dose was administered 8 h after the morning dose. Each dose was administered with 240 mL still, room temperature water; the total 240 mL could be consumed over a 1-h period following dosing.

For participants taking concomitant medications, the medications were to be dosed 2 h after the morning dose of study drug.

Pharmacokinetic samples and analyses

Blood samples (4 mL) for determination of tolvaptan and metabolite plasma concentrations were taken at predose (within 15 min prior to the morning dose), 1, 2, 4, 8 (within 15 min prior to the afternoon dose), 12, and 24 h post the morning dose.

Tolvaptan plasma concentrations were quantified by validated assay using high-performance liquid chromatography with tandem mass spectrophotometric detection [7]. All samples were analyzed within the known sample stability period (1025 days when stored at –70 °C). Noncompartmental analysis of plasma concentrations was performed using SAS® 9.4 (TS1M4). Values of C_max, C_min and t_max were determined directly from observed data. Values of AUC_0–24 h were determined using the linear trapezoidal rule. Analysis was performed using actual times postdose.

Plasma concentrations and parameters were summarized by total daily dose using descriptive statistics in SAS.

Pharmacodynamic samples and analyses

Sodium and creatinine serum and urine concentrations and serum and urine osmolality were determined by standard clinical chemistry laboratory methods.

Serum samples for determination of sodium, creatinine, and osmolality were taken predose and at 2, 4, 8, 12, and 24 h post the morning dose. Where possible, samples were collected from the same needle stick used to collect the PK sample.

Urine (mL) was collected from 0 to 2, 2 to 4, 4 to 8, 8 to 12, and 12 to 24 h post the morning dose. Urine collection began with participants voiding within 30 min prior to the morning dose. Participants were asked to void prior to the end-time of each collection interval. All voids collected within a collection interval were kept refrigerated and then pooled at the end of each of the collection intervals, at which time the volume (mL) per interval was determined and an aliquot collected for determination of sodium, creatinine, and osmolality. If no urine was excreted in an interval, the volume was recorded as zero.

For determination of sodium, creatinine, and osmole clearance, if no urine was collected during an interval, the clearance for that interval and the next was determined using the urine volume and concentration for the following interval divided by the time for both intervals and using the average serum concentration over both intervals. If the serum concentration at the end of the interval was missing, clearance was not determined. Free water clearance was determined as urine excretion rate minus osmole clearance.

Fluid intake (mL) was recorded for the intervals of 0 to 4, 4 to 8, 8 to 12, and 12 to 24 h. Intake included fluid used for dosing (tolvaptan and any concomitant medication) and food items that included significant amounts of water (e.g., Jello® [including gelatin or jelly dessert], or soup). The fluid for the morning dose administration was included in the 0- to 4-h interval and for the afternoon dose administration in the 8- to 12-h interval.

Fluid balance was determined as fluid intake minus urine output.

Endpoints were calculated using SAS. Endpoints for each urine collection interval and for 0 to 24 h and each serum timepoint were summarized by tolvaptan total daily dose and placebo using descriptive statistics (SAS).

Results

Table 2 presents a summary of demographic and baseline characteristics for the 20 participants who had dense PK/PD assessments.

Table 2.

Demographics and baseline characteristics

	Tolvaptan (n = 12)	Placebo (n = 8)
Age, years	15.5 (1.4) [12–17]	14.6 (1.2) [12–16]
Weight, kg	61.9 (10.8) [33.0–71.2]	60.3 (10.1) [44.0–79.0]
Height, cm	172 (10.8) [150–192]	171 (6.1) [163–181]
Sex, n (%)
Male	7 (58%)	6 (75%)
Female	5 (42%)	2 (25%)
Race, n (%)
White	12 (100%)	8 (100%)
Serum Creatinine, mg/dL	0.83 (0.18) [0.53–1.10]	0.76 (0.13) [0.60–1.02]
eGFR, mL/min/1.73 m2	122 (17) [97–153]	132 (10) [108–141]

Statistics are mean (standard deviation) [minimum–maximum] except where noted

eGFR estimated glomerular filtration rate (Schwartz equation; eGFR = 0.413 × height [or length, cm]/serum creatinine mg/dL)

Most participants were not taking any oral concomitant medications at the time of the dense PK/PD sampling. In the tolvaptan group, participants were taking losartan (n = 1); enalapril, omeprazole and vitamin D (n = 1); levocetirizine (n = 1); cetirizine and dienogest;ethinylestradiol (n = 1); and mesalazine (n = 1). In the placebo group, participants were taking atenolol and ramipril (n = l), enalapril and seretide (n = 1), ramipril (n = 1), and multivitamins (n = 1). None of these medications was expected to affect tolvaptan PK or PD.

Table 3 presents individual weight and dosing at treatment start and during the time of the dense PK/PD assessments for the tolvaptan treatment group. In the tolvaptan group, four participants down-titrated from their starting dose, two remained at the starting dose, and six were able to titrate to a higher dose. In the placebo group, one participant did not attempt up-titration and remained at their starting ‘dose,’ while the other seven performed up-titration and remained at the higher ‘dose.’

Table 3.

Starting dose and dose at time of PK/PD assessments in the tolvaptan treatment group

Weight (kg)	Starting Dose	Attempted Up-titration (Y/N)	Dose for PK/PD Assessment (total daily dose, mg)
71.0	30/15	N	15/7.5 (22.5)
56.7	30/15	N	22.5/15 (37.5)
55.0	30/15	N	22.5/15 (37.5)
61.6	30/15	Y	22.5/15 (37.5)
71.2	30/15	N	30/15 (45)
33.0	15/7.5	Y	30/15 (45)
70.5	30/15	Y	30/15 (45)
68.7	30/15	Y	45/15 (60)
59.8	30/15	Y	45/15 (60)
71.0	30/15	Y	45/15 (60)
63.7	30/15	Y	45/15 (60)
60.2	30/15	Y	45/15 (60)

PD pharmacodynamics, PK pharmacokinetic

Figure 1 presents a composite plot of individual tolvaptan plasma concentrations following tolvaptan split-dose regimens. Table 4 presents a summary of tolvaptan plasma pharmacokinetic parameters following tolvaptan split-dose regimens. Tolvaptan concentrations were highly variable even when concentrations were normalized to a 1 mg/kg dose, as shown in the supplementary figure (Online Resource 1).

Fig. 1.

Individual plots of tolvaptan plasma concentrations following tolvaptan split-dose regimens during dense PK/PD sampling. PD, pharmacodynamic; PK, pharmacokinetic; TDD, total daily dose

Table 4.

Mean (SD) tolvaptan plasma pharmacokinetic parameters following tolvaptan split-dose regimens during dense PK/PD sampling

Parameters	Tolvaptan Total Daily Doses
	22.5 (n = 1)a	37.5 (n = 3)	45 mg (n = 3)	60 mg (n = 5)
Cmax (ng/mL)	166	158 (31.8)	363 (183)	363 (51.1)
tmax (ng/mL)b	1.00	2.02 (1.00–2.17)	2.00 (1.00–2.00)	2.00 (2.00–2.02)
Cmin (ng/mL)	40.0	1.69 (2.92)	16.9 (22.2)	20.5 (21.1)
AUC0–24 h (h∙ng/mL)	2220	1320 (175)c	3190 (1250)	3510 (705)

Split-dose regimes were as follows: 22.5 mg (15/7.5), 37.5 mg (22.5/15), 45 mg (30/15), 60 mg (45/15)

AUC_0–24 h area under the concentration–time curve from time zero to 24 h, C_max maximum plasma concentration, C_min minimum plasma concentration, PD pharmacodynamics, PK pharmacokinetic, SD standard deviation, t_max time to maximum plasma concentration

^aValue for single participant presented

^bValues are median (range)

^cn = 2

Figures 2 and 3 present median urine osmolality and free water clearance by urine collection interval for each tolvaptan dose and placebo, respectively. Free water clearance was increased and urine osmolality was decreased in all tolvaptan-treated participants.

Fig. 2.

Median urine osmolality by collection interval and dose for tolvaptan- and placebo-treated adolescents during dense PK/PD sampling. PD, pharmacodynamic; PK, pharmacokinetic

Fig. 3.

Median free water clearance by collection interval and dose for tolvaptan- and placebo-treated adolescents during dense PK/PD sampling. PD, pharmacodynamic; PK, pharmacokinetic

Figure 4 presents mean (standard deviation [SD]) 24-h fluid intake, urine volume, and fluid balance for tolvaptan- and placebo-treated participants.

Fig. 4.

Mean (SD) fluid intake, urine output and fluid balance for 0 to 24 h for tolvaptan- and placebo-treated adolescents during dense PK/PD sampling. PD, pharmacodynamic; PK, pharmacokinetic; SD, standard deviation

Table 5 presents mean (SD) 24-h urine volume, 24-h free water, sodium, and creatinine clearance and sodium and creatinine excretion by tolvaptan dose and for placebo.

Table 5.

Mean (SD) pharmacodynamic parameters for tolvaptan- and placebo-treated adolescents during dense PK/PD sampling

Parameters	Tolvaptan Total Daily Doses
	22.5 (n = 1)a	37.5 (n = 3)	45 mg (n = 3)	60 mg (n = 5)	Placebo (n = 8)
24-h Urine Volume (mL)	13600	6380 (1680)	6050 (2300)	7040 (2470)	2530 (2160)
24-h Free Water Clearance (mL/min)	ND	2.3 (0.9)	2.6 (0.9)	3.0 (1.2)	0.1 (1.2)
24-h Sodium Excretion (mEq)	ND	166 (59)	134 (65)	172 (61)b	136 (92)c
24-h Sodium Clearance (mL/min)	ND	0.8 (0.3)	0.7 (0.3)	0.9 (0.3)b	0.7 (0.5)c
24-h Creatinine Excretion (mg)	1376	1679 (225)	1068 (253)	1482 (262)b	1129 (578)
24-h Creatinine Clearance (mL/min)	124.6	148.5 (23.4)	95.0 (10.1)	123.7 (23.2)b	105.1 (51.7)

ND, value could not be determined due to missing data; PD, pharmacodynamic; PK, pharmacokinetic; SD, standard deviation

^aValue for single participant presented

^bn = 4

^cn = 7

Discussion

Following tolvaptan dosing to adults with ADPKD, variability in PK parameters was high, with percent coefficient of variation for AUC > 50% [6], and median/mean PK parameter values in participants with well-preserved kidney function (eGFR > 60 mL/min/1.73 m²) were similar to those in healthy adults [8]. Tolvaptan concentrations in adolescents with ADPKD had similar variability, and, when normalized to a 1 mg/kg dose, mean (SD) concentrations were similar to healthy adults (data on file). As a sensitive CYP3A4 substrate, the large interindividual variability in tolvaptan exposure is not unexpected.

In an absolute bioavailability trial of tolvaptan, it was determined that concentrations from 18 to 45 ng/mL were effective in increasing urine volume and decreasing urine osmolality to < 300 mOsm/kg, indicating that the V2 receptor was inhibited [9]. In a drug-drug interaction trial with rifampicin, it was concluded that maximal inhibition (maximal increase in urine volume) was achieved at approximately 100 ng/mL [10]. As reported here, tolvaptan-treated adolescents had a C_max of > 100 ng/mL, urine osmolality in each collection interval of < 215 mOsm/kg, and positive 24-h free water clearance values. However, only four participants had C_min values greater than 20 ng/mL, so measurable V2 receptor inhibition was not being sustained for a full 24 h in most participants.

In the placebo group, participants had baseline eGFR values > 100 mL/min/1.73 m², so it is not surprising that mean 24-h urine volume was about 2500 mL, that free water clearance values were close to zero, and that they were able to concentrate their urine as shown by median 12- to 24-h urine osmolality of 507 mOsm/kg.

As expected, sodium clearance did not appear affected by tolvaptan administration. Mean serum creatinine concentrations were higher and eGFR was lower in the tolvaptan group compared to the placebo group, but intersubject variability was high.

As discussed by Schaefer et al., it was expected that the high renal clearance capacity of the participants enrolled in this trial might make them more sensitive to aquaretic adverse events [3]. Thus, dosing started with weight-adjusted doses no greater than 67% of the maximal weight-adjusted starting dose for adults. At the time of the dense PK/PD sampling, six participants had up-titrated, two remained at the starting dose, and four participants had down-titrated, yet all participants remained in the trial on a tolvaptan dose that was producing inhibition of the V2 receptor for a significant portion of the day.

Although all participants in the tolvaptan group had eGFR > 95 mL/min/1.73 m², there was wide interindividual variability in response to tolvaptan, with no correlation between exposure (either C_max or AUC) and 24-h urine output or free water clearance. The participant with the lowest total daily dose of 22.5 mg actually had the highest 24-h urine volume (13.6 L) and greatest free water clearance value (11.6 mL/min in the 2- to 4-h interval). There was a tolvaptan treatment effect, as mean urine output over 24 h for tolvaptan-treated participants was about 4.6 L higher than placebo-treated participants. As expected, mean 24-h fluid balance was close to zero for tolvaptan-treated participants, as they were taking their tolerated dose and balancing their urine output with adequate fluid intake.

In adolescents with ADPKD, intersubject variability of tolvaptan plasma concentrations was large even after normalization of doses but was similar to adults. Although participants taking tolvaptan were allowed to down-titrate their dose for tolerability, participants stayed on doses that produced large increases in free water clearance and urine output, indicating sustained target engagement (inhibition) at the V2 receptor. Participants appeared to be maintaining their fluid balance, as mean fluid balance for 24 h was close to zero. As expected, excretion of sodium and sodium clearance were not changed by tolvaptan administration.

Supplementary Information

Below is the link to the electronic supplementary material.

Authors’ Contributions

Conceived of or designed study (SES, KS)—Performed research (KS)—Analyzed data (SES)—Wrote the paper (SES)—Reviewed the work critically for important intellectual content (SES, KS) All authors reviewed and approved the final manuscript.

Funding

This study was funded by Otsuka Pharmaceutical Development & Commercialization, Inc., Rockville, MD, United States.

Data availability

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Declarations

Compliance with ethical standards

Compliance with ethical standards in this trial, including the Declaration of Helsinki, was previously reported by Schaefer et al.: Eur J Pediatr 2019;178:1013–21. Written informed consent was obtained from a parent/guardian or legally acceptable representative, and the trial participants provided age-appropriate informed assent. The study was authorized by the Independent Ethics Committee of UZ Leuven (Leuven, Belgium), the institution of the Coordinating Investigator, and by those of the participating institutions at each study site.

Competing interests

SES and KS are employees of Otsuka Pharmaceutical Development & Commercialization, Inc., Rockville, MD, United States.