Tolvaptan for Children and Adolescents with Autosomal Dominant Polycystic Kidney Disease: Randomized Controlled Trial.

BACKGROUND: Tolvaptan slows expansion of kidney volume and kidney function decline in adults with autosomal dominant polycystic kidney disease (ADPKD). Progression during childhood could be treated before irreversible kidney damage occurs, but trial data are lacking. We evaluated the safety and efficacy of tolvaptan in children/adolescents with ADPKD. METHODS: This was the 1-year, randomized, double-blind, portion of a phase 3b, two-part trial being conducted at 20 academic pediatric nephrology centers. Key eligibility criteria were ADPKD and eGFR ≥60 ml/min per 1.73 m2. Participants aged 12-17 years were the target group (group 1, enrollment goal n≥60); participants aged 4-11 years could additionally enroll (group 2, anticipated enrollment approximately 40). Treatments were tolvaptan or placebo titrated by body weight and tolerability. Coprimary end points, change from baseline in spot urine osmolality and specific gravity at week 1, assessed inhibition of antidiuretic hormone activity. The key secondary end point was change in height-adjusted total kidney volume (htTKV) to month 12 in group 1. Additional end points were safety/tolerability and quality of life. Statistical comparisons were exploratory and post hoc. RESULTS: Among the 91 randomized (group 1, n=66; group 2, n=25), least squares (LS) mean reduction (±SEM) in spot urine osmolality at week 1 was greater with tolvaptan (-390 [28] mOsm/kg) than placebo (-90 [29] mOsm/kg; P<0.001), as was LS mean reduction in specific gravity (-0.009 [0.001] versus -0.002 [0.001]; P<0.001). In group 1, the 12-month htTKV increase was 2.6% with tolvaptan and 5.8% with placebo (P>0.05). For tolvaptan and placebo, respectively, 65% and 16% of subjects experienced aquaretic adverse events, and 2% and 0% experienced hypernatremia. There were no elevated transaminases or drug-induced liver injuries. Four participants discontinued tolvaptan, and three discontinued placebo. Quality-of-life assessments remained stable. CONCLUSIONS: Tolvaptan exhibited pharmacodynamic activity in pediatric ADPKD. Aquaretic effects were manageable, with few discontinuations. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Safety, Pharmacokinetics, Tolerability and Efficacy of Tolvaptan in Children and Adolescents With ADPKD (Autosomal Dominant Polycystic Kidney Disease) NCT02964273.

Neurotransmitter transporter occupancy following administration of centanafadine sustained-release tablets: A phase 1 study in healthy male adults.

BACKGROUND: Centanafadine is an inhibitor of reuptake transporters for norepinephrine (NET), dopamine (DAT) and serotonin (SERT). AIMS: This phase 1, adaptive-design positron emission tomography study investigated the occupancy time course of NET, DAT, and SERT and the relationship to centanafadine plasma concentrations. METHODS: Healthy adult males received centanafadine sustained-release 400 mg/day for 4 days (N = 6) or 800 mg in a single day (N = 4). Assessments included safety monitoring; time course of occupancy of NET, DAT, and SERT; and centanafadine plasma concentrations. RESULTS: Transporter occupancy was numerically higher for NET versus DAT or SERT. For NET, estimated (mean ± standard error [SE]) maximal observable target occupancy (TOmax) and concentration at half maximal occupancy (IC50) were 64 ± 7% and 132 ± 65 ng/mL, respectively, for all regions and 82 ± 13% and 135 ± 97 ng/mL after excluding the thalamus, which showed high nonspecific binding. For DAT and SERT, TOmax could not be established and was assumed to be 100%; estimated IC50 (mean ± SE) values were 1580 ± 186 ng/mL and 1,760 ± 309 ng/mL, respectively. For centanafadine, the estimated in vivo affinity ratio was 11.9 ± 6.0 (mean ± SE) for NET/DAT, 13.3 ± 7.0 for NET/SERT, and 1.1 ± 0.2 for DAT/SERT. DAT and SERT occupancies at a plasma concentration of 1400 ng/mL were estimated to be 47 and 44%, respectively. CONCLUSIONS: High occupancy at NET and moderate occupancy at DAT and SERT was observed at peak concentrations achieved following 400 mg total daily doses of centanafadine.

Regulatory guidelines do not accurately predict tolvaptan and metabolite interactions at BCRP, OATP1B1, and OAT3 transporters.

Tolvaptan (TLV) was US Food and Drug Administration (FDA)-approved for the indication to slow kidney function decline in adults at risk of rapidly progressing autosomal dominant polycystic kidney disease in 2018. In vitro, TLV was a breast cancer resistance protein (BCRP) inhibitor, whereas the oxobutyric acid metabolite of TLV (DM-4013) was an inhibitor of organic anion transport polypeptide (OATP)1B1 and organic anion transporter (OAT)3. Based on the 2017 FDA guidance, potential for clinically relevant inhibition at these transporters was indicated for the highest TLV regimen. Consequently, two postmarketing clinical trials in healthy subjects were required. In trial 1, 5 mg rosuvastatin calcium (BCRP and OATP1B1 substrate) was administered alone, with 90 mg TLV or 48 h following 7 days of once daily 300 mg TLV (i.e., in the presence of DM-4103). In trial 2, 40 mg furosemide (OAT3 substrate) was administered alone and in presence of DM-4103. For BCRP, rosuvastatin geometric mean ratios (90% confidence intervals [CIs]) for maximum plasma concentration (Cmax ) were 1.54 (90% CI 1.26-1.88) and for area under the concentration-time curve from time 0 to the time of the last measurable concentration (AUCt ) were 1.69 (90% CI 1.34-2.14), indicating no clinically significant interaction. DM-4103 produced no clinically meaningful changes in rosuvastatin or furosemide concentrations, indicating no inhibition at OATP1B1 or OAT3. The BCRP prediction assumed the drug dose is completely soluble in 250 ml; TLV has solubility of ~0.01 g/250 ml. For OATP1B1/OAT3, if fraction unbound for plasma protein binding (PPB) is less than 1%, then 1% is assumed. DM-4103 has PPB greater than 99.8%. Use of actual drug substance solubility and unbound fraction in plasma would have produced predictions consistent with the clinical results.

A Randomized Trial of Modified-Release Versus Immediate-Release Tolvaptan in ADPKD.

INTRODUCTION: Tolvaptan, for treatment of autosomal dominant polycystic kidney disease (ADPKD), is provided as immediate-release (IR) tablets administered twice daily in split-dose regimens to suppress urine osmolality to <300 mOsm/kg. A modified-release (MR) formulation was developed for once-daily (QD) dosing to increase compliance and mitigate urinary symptom burden. This phase 2, dose-ranging study (NCT01210560) compared pharmacokinetics, pharmacodynamics, and tolerability of several MR regimens with IR in patients with ADPKD. METHODS: This was a multicenter, parallel-arm, randomized, crossover, double-blind, placebo-controlled trial. Each of 2 study arms had 12 subjects and 3 crossover periods. Dose regimens were administered for 7 days; placebo-masked QD versus split-dose treatments. Endpoints included pharmacokinetic parameters, percentage of subjects with urine osmolality <300 mOsm/kg, urine volume, number of daily urine voids, and tolerability. RESULTS: Tolvaptan MR 20 to 120 mg exhibited dose-proportional pharmacokinetics. Percentage of subjects with spot urine osmolality <300 mOsm/kg increased with dose, with tolvaptan MR 120 mg and IR 90+30 mg each suppressing 91.7% of subjects below this level. Urinary burden on the ADPKD Nocturia Quality of Life, ADPKD Urinary Urgency, and ADPKD Urinary Frequency Questionnaires correlated with tolvaptan exposure, with high interindividual variability in responses. Changes in questionnaire scores were sensitive to changes in urine volume but not proportional to volume change, reflecting differences in subject tolerance to increased urine volume. CONCLUSION: Tolvaptan MR exhibited predictable and dose-proportional pharmacokinetics and no improvement in tolerability versus tolvaptan IR. Tolerability of the urinary effects of treatment within the high-dose MR and IR groups exhibited substantial interindividual variability.

The NOCTURNE Randomized Trial Comparing 2 Tolvaptan Formulations.

INTRODUCTION: Tolvaptan, a treatment for autosomal dominant polycystic kidney disease (ADPKD), inhibits vasopressin V2 receptor signaling, which causes aquaretic adverse events (AAEs). The short-term efficacy and tolerability of a once-daily, modified-release (MR) formulation was assessed relative to the twice-daily, immediate-release (IR) formulation. METHODS: This Phase 2 multicenter, randomized (1:1:1:1), placebo-controlled, double-blind, placebo-masked, parallel-group study (NCT01451827) compared tolvaptan MR 50 mg once daily or tolvaptan MR 80 mg once daily with tolvaptan IR 60/30 mg daily split dose and placebo over 8 weeks in 177 subjects. The primary endpoint was percent change from baseline in total kidney volume (TKV) at week 3. Other endpoints included tolerability, assessed by adverse events and quality of life (QOL) measures. RESULTS: Mean percentage decreases in TKV at week 3 were observed for the pooled group of all (MR+IR) tolvaptan-treated subjects (-2.07%), tolvaptan MR 80 mg (-2.55%), and tolvaptan MR 50 mg (-2.46%) versus placebo (0.09%; P < 0.02 for each comparison with placebo), whereas the decrease with tolvaptan IR 60/30 mg (-1.17%; P = 0.24) did not reach significance. All tolvaptan regimens were associated with AAEs, but scores on ADPKD-specific and generic patient-reported outcome assessments showed little impact based on dosage on overall health-related QOL versus placebo. CONCLUSION: Tolvaptan MR and tolvaptan IR demonstrated similar short-term efficacy, tolerability, and safety, with low impact on multiple measures of QOL. Conclusions regarding long-term efficacy are limited by the short duration of follow-up.

A Post Hoc Analysis of Statin Use in Tolvaptan Autosomal Dominant Polycystic Kidney Disease Pivotal Trials.

BACKGROUND AND OBJECTIVES: Tolvaptan is approved to slow kidney function decline in adults with autosomal dominant polycystic kidney disease (ADPKD) at risk of rapid progression. Because in vitro studies indicated that the tolvaptan oxobutyric acid metabolite inhibits organic anion-transporting polypeptide (OATP)1B1 and OATP1B3, United States prescribing information advises avoiding concurrent use with OATP1B1/1B3 substrates, including hepatic hydroxymethyl glutaryl-CoA reductase inhibitors (statins). This post hoc analysis of the pivotal phase 3 tolvaptan trials (Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes [TEMPO] 3:4 trial [NCT00428948] and Replicating Evidence of Preserved Renal Function: an Investigation of Tolvaptan Safety and Efficacy in ADPKD [REPRISE] trial [NCT02160145]) examined the safety of concurrent tolvaptan/statin use. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The trials randomized a combined total of 2815 subjects with early- to late-stage ADPKD to tolvaptan (n=1644) or placebo (n=1171) for 3 years (TEMPO 3:4) and 1 year (REPRISE). Statin use was unrestricted, and 597 subjects (21.2% overall; 332 [20.2%] tolvaptan, 265 [22.6%] placebo) received statins. Statin use (duration, dose change, statin change, permanent discontinuation), incidences of statin-related adverse events, and hepatic transaminase elevations were determined for subjects who received tolvaptan+statin, placebo+statin, tolvaptan alone, and placebo alone. RESULTS: No differences in statin use parameters between tolvaptan- and placebo-treated subjects were observed. No statistically significant increases in commonly reported statin-related adverse events (e.g., musculoskeletal disorders, gastrointestinal symptoms) were seen between subjects receiving tolvaptan+statin and placebo+statin. For example, in TEMPO 3:4, frequencies were 5.4% and 7.8%, respectively, for myalgia (difference -2.4%; 95% confidence interval, -11.2% to 6.4%) and 9.3% and 7.8%, respectively, for abdominal pain (difference 1.5%; -7.9% to 10.9%). In an analysis that excluded participants concurrently using allopurinol, the frequency of alanine transaminase or aspartate transaminase >3× upper limit of normal in the pooled study populations was 3.6% for the tolvaptan+statin group and 2.3% for the placebo+statin group (difference 1.4%; -2.0% to 4.7%). CONCLUSIONS: Tolvaptan has been used safely in combination with statins in clinical trials. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2020_04_06_CJN.08170719.mp3.

Tolvaptan use in children and adolescents with autosomal dominant polycystic kidney disease: rationale and design of a two-part, randomized, double-blind, placebo-controlled trial.

This report describes the rationale and design of a study assessing tolvaptan in children with autosomal dominant polycystic kidney disease (ADPKD). Phase A is a 1-year, randomized, double-blind, placebo-controlled, multicenter trial. Phase B is a 2-year, open-label extension. The target population is at least 60 children aged 12-17 years, diagnosed by family history and/or genetic criteria and the presence of ≥ 10 renal cysts, each ≥ 0.5 cm on magnetic resonance imaging. Subjects will be allocated into 4 groups: females 15-17 years; females 12-14 years; males 15-17 years; and males 12-14 years. Up to 40 subjects aged 4-11 years may also enroll, provided they meet the entry criteria. Weight-adjusted tolvaptan doses, titrated once to achieve a tolerated maintenance dose, and matching placebo will be administered twice-daily. Assessments include spot urine osmolality and specific gravity (co-primary endpoints), height-adjusted total kidney volume, estimated glomerular filtration rate, pharmacodynamic parameters (urine volume, fluid intake and fluid balance, serum sodium, serum creatinine, free water clearance), pharmacokinetic parameters, safety (aquaretic adverse events, changes from baseline in creatinine, vital signs, laboratory values including liver function tests), and generic pediatric quality of life assessments.Conclusion: This will be the first clinical study to evaluate tolvaptan in pediatric ADPKD. What is Known: • Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder causing the development of cysts that impede kidney function over time and eventually induce renal failure • There are few data on the effects of tolvaptan, the only treatment approved for adults to slow disease progression, in pediatric ADPKD patients with early-stage disease What is New: • A phase 3, placebo-controlled study is evaluating tolvaptan over 3 years in children and adolescents with ADPKD • This study is designed to account for challenges of tolvaptan dosing and outcome assessment specific to the pediatric population.

Population Pharmacokinetic Analyses and Model Validation of Tolvaptan in Subjects With Autosomal Dominant Polycystic Kidney Disease.

Tolvaptan is the first approved drug treatment to slow kidney function decline in adults at risk of rapidly progressing autosomal dominant polycystic kidney disease (ADPKD). The objective is to develop (1091 subjects, 7335 observations) and validate (678 subjects, 3012 observations) a population pharmacokinetic model to describe tolvaptan pharmacokinetics in ADPKD subjects. The final model was evaluated with a bootstrapping method. The final model was internally and externally evaluated using visual predictive checks (VPC). Pharmacokinetics was best described by a 1-compartmental model with 0-order absorption, nonlinear relative bioavailability (F1), and first-order elimination. Accounting for changes in F1 significantly improved the model: as the dose increased from 15 mg to 120 mg, F1 decreased by 36%. Population estimates for clearance/F (CL/F), volume of distribution/F (Vd/F), duration of absorption (D1), the highest dose at which F1 is lowest, and the amount of dose at which F1 is 50% were 12.6 L·h-1 , 110 L, 0.58 hour, 182 mg, and 166 mg, respectively. The interindividual variability was 64% in CL/F, 70% in Vd/F, and 238% in D1. Residual variability was described by a combined-error model. The VPC (500 data sets simulated) showed that 76% to 92% of the observed data fell within the 90% prediction intervals. The model stability assessed by a 1000-run bootstrap analysis showed that the mean parameter estimates of data were within 10% of those obtained with the final model. The developed model is robust and stable. Internal and external validation confirmed the model ability to describe the data optimally.

Tolerability of Aquaretic-Related Symptoms Following Tolvaptan for Autosomal Dominant Polycystic Kidney Disease: Results From TEMPO 3:4.

INTRODUCTION: In the randomized placebo-controlled Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and its Outcomes (TEMPO) 3:4 trial, tolvaptan slowed kidney growth and renal function decline in subjects with autosomal dominant polycystic kidney disease (ADPKD). Consistent with its primary pharmacologic activity, tolvaptan use was commonly associated with aquaretic adverse events (AAEs) attributable to excess free water clearance. METHODS: A post hoc analysis of tolvaptan-related discontinuations from the pivotal randomized controlled trial TEMPO 3:4 and its open-label extension TEMPO 4:4. RESULTS: In total, 750 of 961 tolvaptan-treated subjects (78%) in TEMPO 3:4 reported at least one AAE. Of these 750 subjects, 72 (10%) discontinued because of an AAE (aquaretic-discontinued group) and 573 (76%) continued (aquaretic-continued group). The aquaretic-discontinued subjects were younger, had better baseline renal function, and had higher fasting urine osmolality than aquaretic-continued subjects. Of the 750 subjects reporting an AAE, 105 (14%) discontinued for another reason (non-aquaretic-discontinued group). Compared to non-aquaretic-discontinued subjects, aquaretic-discontinued subjects were more commonly male, had better baseline renal function, and discontinued the study drug faster. After 3 years of therapy, 75% of tolvaptan subjects indicated that they could tolerate their current dose for the rest of their lives, compared to 85% of placebo subjects. These findings were corroborated by results in the open-label extension trial TEMPO 4:4. DISCUSSION: In this study, AAEs were common but well tolerated in ADPKD patients on tolvaptan. ADPKD patients in earlier stages of disease progression may be more sensitive to aquaretic symptoms, which may help in guiding tolvaptan dosing and titration decisions in the future.

Low-dose tolvaptan PK/PD: comparison of patients with hyponatremia due to syndrome of inappropriate antidiuretic hormone secretion to healthy adults.

PURPOSE: Tolvaptan (TLV) is indicated to treat hyponatremia due to syndrome of inappropriate diuretic hormone (SIADH) in Europe. Treatment is to be initiated at 15 mg QD but post-approval reporting indicates increasing use of 7.5 mg as the starting dose. Physicians believe 7.5 mg is effective and has a lower incidence of overly rapid correction of serum sodium. METHODS: Single TLV doses of 3.75, 7.5, and 15 mg were administered to 14 healthy adults in a crossover design and to 29 subjects ≥18 years with SIADH and serum sodium between 120 and 133 mmol/L in a parallel-group design. Pharmacodynamics and TLV plasma concentrations were assessed for 24 h post-dose. RESULTS: In SIADH subjects, corrections of serum sodium (Δ of ≥8 mmol/L in the first 8 h or ≥12 mmol/L in the first 24 h) were observed in one, one, and two subjects in the 3.75-, 7.5-, and 15-mg dose groups. Fluid balance (FB) for 0-6 h post-dose was correlated (r 2 = 0.37) with maximum increases in serum sodium; subjects with large corrections had large (~1 L) negative FB. Compared to healthy adults, subjects with SIADH did not drink in response to their negative FB and had larger increases in serum sodium at 24 h. Median time of maximum increase in healthy adults was 6 h, with no rapid corrections, and FB was near 0 mL by 24 h. CONCLUSION: Starting titration with 7.5 mg TLV will not eliminate the risk of rapid corrections in serum sodium. Monitoring FB may indicate that a subject is at risk for over correction.

Pharmacokinetics and Pharmacodynamics of Tolvaptan in Autosomal Dominant Polycystic Kidney Disease: Phase 2 Trials for Dose Selection in the Pivotal Phase 3 Trial.

In the pivotal TEMPO 3:4 trial, the arginine vasopressin V2-receptor antagonist tolvaptan reduced the rate of kidney growth in patients with autosomal dominant polycystic kidney disease. Tolvaptan was initiated as daily morning/afternoon doses of 45/15 mg, and uptitrated weekly to 60/30 mg and 90/30 mg according to patient-reported tolerability. The current report describes 3 phase 2 trials in adult autosomal dominant polycystic kidney disease subjects that were the basis for the titrated split-dose regimen: a single ascending-dose trial (tolvaptan 15 to 120 mg; n = 11), a multiple split-dose trial (tolvaptan 15/15 mg, 30/0 mg, 30/15 mg, and 30/30 mg; n = 37), and an 8-week open-label safety and efficacy trial in 46 of the 48 subjects who participated in the prior 2 trials (tolvaptan 30/15 mg, 45/15 mg, 60/30 mg, and 90/30 mg). Urine osmolality (Uosm ) was chosen as the biomarker of V2 receptor inhibition. Two tolvaptan doses per day were necessary to suppress Uosm to <300 mOsm/kg for 24 hours. The 45/15-mg regimen was well tolerated and effective in suppressing Uosm in >50% of subjects. Therefore, this regimen was selected as the starting regimen for the TEMPO 3:4 trial. The 90/30-mg regimen suppressed Uosm in 85% of subjects tested; however, only 28/46 subjects agreed to uptitrate to 90/30 mg due to tolerability. Higher concentrations of tolvaptan were less well tolerated, resulting in adverse events of pollakiuria, thirst, polyuria, nocturia, and a higher number of times out of bed to urinate. Subjects who agreed to uptitrate to 90/30 mg had lower eGFR than those who did not uptitrate.

Application of a Mechanistic Model to Evaluate Putative Mechanisms of Tolvaptan Drug-Induced Liver Injury and Identify Patient Susceptibility Factors.

Tolvaptan is a selective vasopressin V2 receptor antagonist, approved in several countries for the treatment of hyponatremia and autosomal dominant polycystic kidney disease (ADPKD). No liver injury has been observed with tolvaptan treatment in healthy subjects and in non-ADPKD indications, but ADPKD clinical trials showed evidence of drug-induced liver injury (DILI). Although all DILI events resolved, additional monitoring in tolvaptan-treated ADPKD patients is required. In vitro assays identified alterations in bile acid disposition and inhibition of mitochondrial respiration as potential mechanisms underlying tolvaptan hepatotoxicity. This report details the application of DILIsym software to determine whether these mechanisms could account for the liver safety profile of tolvaptan observed in ADPKD clinical trials. DILIsym simulations included physiologically based pharmacokinetic estimates of hepatic exposure for tolvaptan and2 metabolites, and their effects on hepatocyte bile acid transporters and mitochondrial respiration. The frequency of predicted alanine aminotransferase (ALT) elevations, following simulated 90/30 mg split daily dosing, was 7.9% compared with clinical observations of 4.4% in ADPKD trials. Toxicity was multifactorial as inhibition of bile acid transporters and mitochondrial respiration contributed to the simulated DILI. Furthermore, simulation analysis identified both pre-treatment risk factors and on-treatment biomarkers predictive of simulated DILI. The simulations demonstrated that in vivo hepatic exposure to tolvaptan and the DM-4103 metabolite, combined with these 2 mechanisms of toxicity, were sufficient to account for the initiation of tolvaptan-mediated DILI. Identification of putative risk-factors and potential novel biomarkers provided insight for the development of mechanism-based tolvaptan risk-mitigation strategies.

Delamanid Coadministered with Antiretroviral Drugs or Antituberculosis Drugs Shows No Clinically Relevant Drug-Drug Interactions in Healthy Subjects.

Delamanid is a medicinal product approved for treatment of multidrug-resistant tuberculosis. Three studies were conducted to evaluate the potential drug-drug interactions between delamanid and antiretroviral drugs, including ritonavir, a strong inhibitor of CYP3A4, and selected anti-TB drugs, including rifampin, a strong inducer of cytochrome P450 (CYP) isozymes. Multiple-dose studies were conducted in parallel groups of healthy subjects. Plasma samples were analyzed for delamanid, delamanid metabolite, and coadministered drug concentrations, and pharmacokinetic (PK) parameters were determined. The magnitude of the interaction was assessed by the ratio of the geometric means and 90% confidence intervals. Coadministration of delamanid with tenofovir or efavirenz did not affect the PK characteristics of delamanid. Coadministration of Kaletra (lopinavir/ritonavir) with delamanid resulted in an approximately 25% higher delamanid area under the concentration-time curve from time 0 to the end of the dosing interval (AUCτ). Tenofovir, efavirenz, lopinavir, and ritonavir exposure were not affected by delamanid. Coadministration of delamanid with the TB drugs (ethambutol plus Rifater [rifampin, pyrazinamide, and isoniazid]) resulted in lower delamanid exposures (47 and 42% for the AUCτ and Cmax [maximum concentration of a drug in plasma] values, respectively), as well as decreased exposure of three primary metabolites (approximately 30 to 50% lower AUCτ values). Delamanid did not affect rifampin, pyrazinamide, and isoniazid exposure; the ethambutol AUCτ and Cmax values were about 25% higher with delamanid coadministration. The lack of clinically significant drug-drug interactions between delamanid and selected antiretroviral agents (including the strong CYP inhibitor ritonavir) and a combination of anti-TB drugs was demonstrated. Although there was a decrease in the delamanid concentrations when coadministered with ethambutol plus Rifater, this is likely related to decreased delamanid absorption and not to CYP induction.

Pharmacokinetics and pharmacodynamics of oral tolvaptan in patients with varying degrees of renal function.

The selective vasopressin V2-receptor antagonist tolvaptan is eliminated almost exclusively by non-renal mechanisms. As renal impairment can influence the pharmacokinetics of drugs even when eliminated by non-renal mechanisms, we evaluated the effect of renal insufficiency on the pharmacokinetics/pharmacodynamics of tolvaptan. Thirty-seven patients were grouped by a 24-h creatinine clearance (CrCL) and evaluated for 48 h after a single 60 mg oral dose in the fasting state. Mean tolvaptan exposure was 90% higher in the under 30-ml/min group compared with the over 60-ml/min group with individual values significantly but negatively correlated with increasing baseline CrCL. There was a greater and more rapid increase in urine output and free water clearance in the over 60-ml/min compared with the renal impaired groups, but they returned to baseline more quickly. Serum sodium increased more rapidly in the over 60 as opposed to the under 30-ml/min group, but overall maximum increases were similar across groups. Small decreases in mean CrCL and small increases in mean serum creatinine/potassium were independent of baseline CrCL. The percent fractional free water clearance with respect to CrCL was significantly but negatively correlated with increasing baseline CrCL. No unexpected adverse events were reported. Thus, renal impairment attenuated the increase in 24-h urine volume and free water clearance caused by tolvaptan, consistent with decreased nephron function in renal impairment. The delay in serum sodium increase was consistent with the longer duration needed to excrete sufficient water to cause the increase.

Population-based meta-analysis of furosemide pharmacokinetics.

Furosemide is a loop diuretic frequently used to treat fluid overload conditions such as hepatic cirrhosis and congestive heart failure (CHF). A population-based meta-analysis approach in NONMEM® was used to develop a PK model characterizing the time-course of furosemide in plasma and excretion into the urine for healthy subjects and fluid overload patients. Furosemide PK data from healthy subjects receiving 80 mg of oral furosemide were supplemented with additional individual and aggregate plasma concentration and urinary excretion versus time data from the literature after intravenous (i.v.) or oral furosemide administration (10-500 mg) to healthy subjects or fluid overload patients. A three-compartment model with zero-order input following i.v. administration (or first-order absorption using a Weibull function after oral administration) and first-order elimination best described furosemide PK. A covariate analysis identified creatinine clearance (CL(CR)) as a statistically significant predictor of renal clearance (CL(R)), with a population mean CL(R) of 4.67, 3.11, 1.95 and 1.17 l/h for a subject with normal renal function (CL(CR) = 120 ml/min) or mild (CL(CR) = 80 ml/min), moderate (CL(CR) = 50 ml/min) or severe (CLCR = 30 ml/min) renal impairment. Oral bioavailability was 59.1% and non-renal clearance was 2.02 l/h. A PC-VPC and other model diagnostics demonstrated that the population PK model can reasonably predict the rate of urinary furosemide excretion over time using dosing history and commonly available demographic data, allowing for convenient assessment of PK-PD relationships for furosemide when given alone or in combination with other agents used to treat fluid overload conditions.

Population-based meta-analysis of hydrochlorothiazide pharmacokinetics.

Hydrochlorothiazide (HCTZ) is a thiazide diuretic used for the treatment of hypertension and edema associated with fluid overload conditions such as congestive heart failure (CHF). A population-based meta-analysis approach in NONMEM® was used to develop a PK model to characterize the time-course of HCTZ concentrations in plasma and excretion into the urine for healthy subjects and CHF patients. Data from healthy subjects receiving 100 mg of oral HCTZ were supplemented with additional plasma concentration and urinary excretion versus time data published in the literature following administration of oral HCTZ doses ranging from 10 to 500 mg to healthy subjects or patients with renal failure, CHF or hypertension. A two-compartment model with first-order oral absorption, using a Weibull function, and first-order elimination best described HCTZ PK. Creatinine clearance (CLCR ) was a statistically significant predictor of renal clearance (CLR ). Non-renal clearance was estimated to be 2.44 l/h, CLR was 18.3 l/h and T1/2,α was 1.6 h and T1/2,ß was 14.8 h for a typical individual with normal renal function (CLCR = 120 ml/min). However, CLR was reduced to 10.5, 5.47 and 2.70 l/h in mild (CLCR = 80 ml/min), moderate (CLCR = 50 ml/min) and severe (CLCR = 30 ml/min) renal impairment, respectively. Model diagnostics helped to demonstrate that the population PK model reasonably predicts the rate of urinary HCTZ excretion over time using dosing history and estimated CLCR , allowing for the convenient assessment of PK-PD relationships for HCTZ when given alone or in combination with other agents used to treat fluid overload conditions.

Short-term renal hemodynamic effects of tolvaptan in subjects with autosomal dominant polycystic kidney disease at various stages of chronic kidney disease.

Vasopressin V2-receptor antagonists may delay disease progression in ADPKD. Trials with V2-receptor antagonists have been performed predominantly in patients with an estimated creatinine clearance of 60 ml/min or more. Here we determined renal hemodynamic effects of the V2-receptor antagonist tolvaptan in 27 patients with ADPKD at various stages of chronic kidney disease: group A: >60, group B: 30-60, and group C: <30 ml/min per 1.73 m(2). Measurements were performed before, after 3 weeks of tolvaptan (up titration to 90/30 mg/day, split dose), and 3 weeks after the last dose of tolvaptan. With tolvaptan, a minor, reversible decrease in GFR ((125)I-iothalamate clearance) was found that reached significance in groups A and B: -7.8 (interquartile range -13.7 to -1.3) and -4.3 (-9.7 to -0.9) ml/min per 1.73 m(2), respectively, but not in group C (GFR decrease -0.7 (-1.1 to 1.5) ml/min/1.73 m(2)). The percentage change in GFR, ERPF ((131)I-hippuran clearance), and filtration fraction with tolvaptan did not differ between the three study groups. No differences between the three study groups were found in other main efficacy variables, besides smaller increases in urine volume in group C during tolvaptan treatment. Tolvaptan was well tolerated, with only two patients withdrawing. Thus, doses of tolvaptan typically used in patients with ADPKD do not produce a difference in renal hemodynamic profile in chronic kidney disease stages 1 through 4, but minor GFR drops may be observed in individual patients.

Population pharmacokinetics of tolvaptan in healthy subjects and patients with hyponatremia secondary to congestive heart failure or hepatic cirrhosis.

Tolvaptan is a selective V2 -receptor antagonist used to treat hypervolemic and euvolemic hyponatremia. A population pharmacokinetic (PK) analysis was performed for tolvaptan in NONMEM® based upon data obtained from three trials conducted in 93 healthy subjects and six trials conducted in 628 congestive heart failure (CHF) patients or 24 hepatic cirrhosis patients receiving oral tolvaptan (5 to 240 mg). A two-compartment model with first-order absorption and elimination best described tolvaptan PK. Relative oral bioavailability was modeled relative to 100% for a 30 mg dose and ranged from 79.4% to 122%. Body weight and the impact of CHF or hepatic cirrhosis relative to healthy subjects were statistically significant (p < 0.001) predictors of both the apparent oral clearance (CL/F) and apparent central volume of distribution (Vc /F). The CL/F was reduced to 58.2% for New York Heart Association (NYHA) Class 1 or 2 CHF, 45.5% for NYHA Class 3 or 4 CHF, and 58.0% for hepatic cirrhosis relative to healthy subjects. Vc /F was reduced to 59.9% for NYHA Class 1 or 2 CHF and 51.3% for NYHA Class 3 or 4 CHF, and was 64.8% larger for severe hepatic cirrhosis (Child-Pugh score ≥ 10) relative to healthy subjects. A slight additional decrease in CL/F of 18.3% was also detected for patients with moderate hyponatremia (serum sodium of 115-130 mEq/l) after adjusting for CHF or cirrhosis (p < 0.001). This population PK model enabled assessment of tolvaptan PK with varying degrees of CHF and hepatic cirrhosis with fluid overload and may be used to explore PK-PD relationships with respect to fluid and electrolyte balance.

Pharmacokinetics and pharmacodynamics of single-dose oral tolvaptan in fasted and non-fasted states in healthy Caucasian and Japanese male subjects.

PURPOSE: To compare the pharmacokinetics and pharmacodynamics of tolvaptan in Caucasian and Japanese healthy male subjects under fasting and non-fasting conditions. METHODS: This was a single-center, parallel-group, randomized, open-label, three-period crossover trial of single oral doses of tolvaptan 30 mg under fasting and non-fasting [a high-fat, high-calorie meal (HFM) or Japanese standard meal] conditions in 25 healthy male Caucasian subjects and 24 healthy male Japanese subjects. Pharmacodynamic endpoints were urine volume and fluid balance for 0 to 24 h postdose. RESULTS: In the fasted state, the plasma tolvaptan C(max) and AUC(∞) geometric mean ratios (90 % confidence interval) were 1.105 (0.845-1.444) and 1.145 (0.843-1.554) for Japanese compared to Caucasian subjects. A HFM increased the C(max) and AUC(∞) values by about 1.15-fold in both Japanese and Caucasian subjects.. Twenty-four-hour urine volumes paralleled pharmacokinetic changes, but the increases were not clinically significant. Fluid balance in the Japanese men was 1.4- to 2.0-fold more negative than that in the Caucasian men. CONCLUSION: Tolvaptan pharmacokinetics is not clinically significantly affected by race. Body weight is a factor that affects exposure. Tolvaptan can be administered with or without food.