Review of Tolvaptan for Autosomal Dominant Polycystic Kidney Disease Brian P. Baur and Calvin J. Meaney* University at Buffalo School of Pharmacy and Pharmaceutical Sciences, Buffalo, New York
Autosomal dominant polycystic kidney disease (ADPKD) is characterized by bilateral renal cysts, kidney pain, hypertension, and progressive loss of renal function. It is a leading cause of end-stage renal disease and the most common inherited kidney disease in the United States. Despite its prevalence, disease-modifying treatment options do not currently exist. Tolvaptan is an orally active, selective arginine vasopressin V2 receptor antagonist already in use for hyponatremia. Tolvaptan exhibits dose-proportional pharmacokinetics with a half-life of ~12 hours. Metabolism occurs through the cytochrome P450 3A4 isoenzyme, and tolvaptan is a substrate for P-glycoprotein, resulting in numerous drug interactions. Recent research has highlighted the beneficial effect of tolvaptan on delaying the progression of ADPKD, which is the focus of this review. Pharmacologic, preclinical, and phase II and III clinical trial studies have demonstrated that tolvaptan is an effective treatment option that targets underlying pathogenic mechanisms of ADPKD. Tolvaptan delays the increase in total kidney volume (surrogate marker for disease progression), slows the decline in renal function, and reduces kidney pain. However, tolvaptan has significant adverse effects including aquaretic effects (polyuria, nocturia, polydipsia) and elevation of aminotransferase enzyme concentrations with the potential for acute liver failure. Appropriate patient selection is critical to optimize long-term benefits while minimizing adverse effects and hepatotoxic risk factors. Overall, tolvaptan is the first pharmacotherapeutic intervention to demonstrate significant benefit in the treatment of ADPKD, but practitioners and regulatory agencies must carefully weigh the risks versus benefits. Additional research should focus on incidence and risk factors of liver injury, cost-effectiveness, clinical management of drug–drug interactions, and long-term disease outcomes. KEY WORDS Tolvaptan, polycystic kidney disease, vasopressin. (Pharmacotherapy 2014;34(6):605–616) doi: 10.1002/phar.1421
Autosomal dominant polycystic kidney disease (ADPKD) is a monogenic disease characterized by renal cysts associated with pain, hypertension, and a progressive loss of renal function over time.1, 2 The estimated prevalence of ADPKD is between 1 in 400 to 1 in 1000 people with 5000–6000 new cases diagnosed annually in the United States.3, 4 It is the fourth leading cause of end-stage renal disease (ESRD) in the Disclosures: None. *Address for correspondence: Calvin J. Meaney, University at Buffalo School of Pharmacy and Pharmaceutical Sciences, 201 Kapoor Hall, Buffalo, NY 14214; e-mail: [email protected]. Ó 2014 Pharmacotherapy Publications, Inc.
United States and the most frequent inherited kidney disease.1, 2, 5 In 2010, 32.9 patients per million Americans initiated dialysis because of cystic kidney disease.5 Currently, ~10% of patients undergoing dialysis developed ESRD as a result of ADPKD.5, 6 Annual ESRD expenditures in the United States exceed $47 billion.5 Therefore, it is imperative to patients, practitioners, the health care system, and society to identify therapeutic interventions that slow or halt the progression of ADPKD. Tolvaptan is a selective arginine vasopressin V2 receptor antagonist that has demonstrated initial efficacy in slowing the progression of ADPKD.7, 8 It was approved by the Food and Drug Administration (FDA) in 2009 for the
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treatment of euvolemic and hypervolemic hyponatremia associated with heart failure, cirrhosis, and syndrome of inappropriate antidiuretic hormone.9 The manufacturer of tolvaptan (Otsuka Pharmaceutical Co. Inc, Tokyo, Japan) submitted a new drug application to the FDA and received priority-review status.10 Tolvaptan offers a novel treatment modality for ADPKD and is the focus of this review that presents data on the use of tolvaptan in ADPKD from pharmacologic and preclinical studies as well as recent phase II and III clinical trials. An exhaustive literature search was completed with the terms tolvaptan and polycystic kidney disease in Medline and Embase databases from inception to January 2, 2014, in addition to review of references from selected articles. Critical appraisal of available evidence with emphasis on risk-benefit ratio and patient selection is provided. Presentation and Pathophysiology of ADPKD Diagnosis is based on family history and radiologic evidence of renal cysts.11, 12 Neither gender nor ethnicity are risk factors for ADPKD.1, 2 Mutations in plasma membrane-spanning polycystin 1 and 2 (PKD1 and PKD2) genes, which are inherited in a dominant fashion, are the primary risk factor for ADPKD.1, 2 The offspring of a parent with ADPKD has a 50% chance of inheriting the disease. However, spontaneous mutations may occur in up to 5% of cases. PKD1 mutations are more common than PKD2 mutations and associated with more renal cysts and faster progression of renal disease.1 Genetic testing for ADPKD is possible, but detection rates are 50–85% with genetic linkage analysis or direct sequencing because of numerous mutations in PKD1, many with unknown pathogenicity.2 Mutations in PKD1 or PKD2 alone are not sufficient to cause ADPKD. A second mutation occurring at an unknown time point prior to manifestation of ADPKD stimulates monoclonal differentiation of tubular cells and development of cysts.13 This is hypothesized to occur through a somatic mutation in the PKD gene on the chromosome opposite the inherited PKD mutation.14 The second mutation is necessary to decrease the expression and/or function of the polycystin proteins below a threshold that allows for clinically evident cyst development. Polycystin proteins functionally interact to regulate tubular and vascular development in the kidneys and other organs via regulation of
calcium transport.2 An initial bulge in the tubule wall is potentiated by adenosine-30 , 50 -cyclic monophosphate (cAMP), epidermal growth factor, and insulinlike growth factor. The proliferative state is regulated by extracellular signal-regulated kinase (ERK) and mammalian target of rapamycin (mTOR) pathways.15, 16 The cyst size increases as surrounding epithelial cells proliferate and fluid accumulates, both of which are processes largely regulated by cAMP.1, 2 Plasma vasopressin concentrations increase, likely due to altered medullary architecture, which contributes to cyst development and enlargement.2, 17–19 Fibrosis can occur through macrophage and fibroblast infiltration of the interstitium. Cysts eventually disengage from the tubule and become autonomous units. The rate of disease progression is highly variable, with increases in total kidney volume (TKV) ranging from 1–10% per year.1 Radiologically assessed change in kidney volume is currently the best method of measuring disease progression.11, 20–22 Renal function assessments, such as serum creatinine and glomerular filtration rate (GFR), are poor markers in early disease because hyperfiltration in remaining nephrons maintains normal ranges for each. Markers of renal function decline are observed once damage to the kidney reaches a critical threshold, which is patient specific.4 Nearly all adults with progressive disease develop arterial hypertension (blood pressure higher than 140/90 mm Hg).23 Other renal manifestations are hematuria, albuminuria, urinary tract infections, and, most commonly, kidney pain, although these are not specific markers of disease progression.1, 2 Nephrolithiasis is twice as common in ADPKD than in the general population.24 Lower urine pH predisposes patients to uric acid stone formation, which is more common than calcium oxalate stones.24 Liver cysts and intracranial aneurysms are severe extrarenal manifestations that contribute to morbidity and mortality.1, 2 Approximately 50% of patients with ADPKD develop ESRD, usual during the fourth to sixth decades of life. Pharmacology Arginine vasopressin, also called antidiuretic hormone, is a neuropeptide hormone produced in the hypothalamus and released into systemic circulation from the posterior pituitary gland. Three primary vasopressin receptors, V1A, V1B,
TOLVAPTAN FOR ADPKD Baur and Meaney and V2, account for a variety of functions including vasoconstriction, platelet aggregation, glycogenolysis, adrenocorticotropic hormone release, osmoregulation, and body fluid regulation.25 The V2 receptors are located in the renal collecting ducts that, when bound by arginine vasopressin, promote free-water reabsorption via increased cAMP and upregulation of aquaporin2 channels.26 Tolvaptan is an orally active, selective arginine vasopressin V2 receptor antagonist with 1.8 times the affinity of the V2 receptor than native arginine vasopressin and 29 times the affinity of the V2 compared with the V1A receptor.25 Antagonism of the V2 receptors in the renal collecting ducts causes free-water excretion (aquaresis), net fluid loss, reduced urine osmolality, and an increase in serum sodium concentration.25 Additionally, decreases in the secondary messenger cAMP resulting in decreased kidney cyst cell proliferation and fluid secretion occur due to V2 antagonism.17, 19, 27, 28 Tolvaptan undergoes rapid absorption with ~40% oral bioavailability.9, 29 Bioavailability as assessed by maximum concentration (Cmax) and area under the concentration-time curve (AUC) is minimally affected by food.30 Although the fed state results in slightly higher exposure, it does not translate to differences in urine output. Dose-dependent increases in Cmax and AUC are linear for doses up to 300 mg. Doses greater than or equal to 300 mg result in a plateau of Cmax with a nonproportional increase in AUC. This suggests a nonlinear process, such as saturable absorption, at these high doses.29, 31 However, the clinical relevance of this nonlinearity is likely minimal because doses of tolvaptan do not exceed 180 mg/day in clinical trials. There is marked interpatient variability in Cmax and AUC with coefficients of variation ranging from 30–60%.9 Tolvaptan is highly bound (99%) to plasma proteins.9, 29 Metabolism occurs primarily through hepatic cytochrome P450 isoenzyme 3A4.29, 31 Excretion is via the fecal route with an elimination half-life of ~12 hours.29, 31 Based on data from patients with hyponatremia, dosage adjustments are not necessary for renal or hepatic dysfunction. However, tolvaptan is not recommended if creatinine clearance (Clcr) is less than 10 ml/minute or if the patient does not respond to tolvaptan and is anuric. With the substantial loss of nephron mass that occurs in advanced renal disease, there is limited capacity in terms of the site of effect for tolvaptan. This has been
607
demonstrated by reductions in urine excretion rate and free-water clearance in patients with renal impairment.32 Cmax and AUC nearly doubled in patients with severe renal impairment compared with controls after a single 60-mg dose of tolvaptan.9, 32 The effect of renal dysfunction on tolvaptan pharmacokinetics and pharmacodynamics in patients with ADPKD and varying degrees of renal dysfunction requires further study. The benefit of tolvaptan in ADPKD exceeds its effects on osmoregulation and may slow disease progression in patients with later stage disease. Therefore, pharmacokinetic changes in these patients are critical to understand for proper drug dosing and monitoring. Limited data are available about tolvaptan pharmacokinetics in patients with ADPKD because most studies were conducted in healthy volunteers or patients with hyponatremia.33 Pharmacokinetic comparison of Caucasian and Japanese subjects is critical because large clinical trials group these ethnicities in analysis and results.30 Geometric mean ratios for Japanese compared with Caucasian subjects in a fasting state were 1.11 (90% confidence interval [CI] 0.85–1.44) for Cmax and 1.15 (90% CI 0.84–1.55) for AUC. Higher exposure in Japanese subjects was likely due to lower weight (mean 12.2 kg less than Caucasian subjects). No difference in pharmacodynamic measures between ethnicities was noted. Tolvaptan is associated with clinically relevant drug-drug interactions related to CYP3A4 and P-glycoprotein (P-gp).34–36 Tolvaptan does not inhibit CYP3A4, but appears to be a sensitive substrate. However, tolvaptan is both a substrate and competitive inhibitor of P-gp.35 Tolvaptan is contraindicated for use with strong CYP3A4 inhibitors, and it is recommended to avoid use with moderate CYP3A4 inhibitors.9, 34 Use is cautioned with P-gp inhibitors, and the dose of tolvaptan should be based on clinical response.9 Preclinical Studies A plethora of data from basic research and translational studies supports the rapid clinical development of tolvaptan and other diseasemodifying treatments for ADPKD. Animal models of PKD provide a well-controlled environment by which pathogenic disease mechanisms and treatments can be investigated. In a rat model of PKD, a vasopressin V2 receptor agonist (1-deamino-8-D-arginine vasopressin) was shown to increase renal cAMP and cystogenesis.28
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The findings from this study, which demonstrate that arginine vasopressin agonism promotes PKD progression, provided the rationale for the investigation of vasopressin V2 receptor antagonists in polycystic kidney disease (PKD). The specific V2 receptor antagonist OPC-31260 ameliorated cystic enlargement and azotemia in a mouse model of PKD.37 Overexpression of the V2 receptor appears to cause progression of PKD because a specific antagonist prevented renal enlargement. A follow-up study using OPC-31260 in a similar mouse model demonstrated that vasopressin V2 receptor antagonism was effective against early or established PKD.17 Mechanistic investigations revealed reductions in renal cAMP and cystogenesis by V2 receptor antagonism. In another mouse model of ADPKD, OPC-31260 administration reduced renal cAMP levels, prevented renal enlargement, markedly inhibited cystogenesis, and protected renal function.19 However, initiation of V2 receptor antagonism later in the disease progression model (at experimental week 3 vs week 0) did not reduce cyst formation, suggesting that early initiation of tolvaptan is most effective at decreasing disease progression.38 The effects of tolvaptan (OPC-41061) were compared with OPC-31260 in a rat model of PKD.39 Tolvaptan was developed through structural modifications to its predecessor, OPC-31260, and exhibits increased potency and V2 receptor selectivity. Decreased renal cAMP and protection from PKD progression were observed for tolvaptan compared with baseline as demonstrated by a reduction in kidney weight, cyst volume, and fibrosis volume and improvement in markers of mitosis and apoptosis. These outcomes were achieved using the lowest dose, which caused only modest aquaresis compared with the higher dose regimens. Tolvaptan inhibited vasopressin-induced cAMP production and demonstrated higher affinity for the V2 receptor than OPC-31260.40 Oral administration of tolvaptan in this rat model produced dose-dependent aquaresis causing hemoconcentration 4 hours after the dose without changes in serum osmolality, sodium, creatinine, or urea nitrogen concentrations at 24 hours after the dose. An in vitro study examined the effect of tolvaptan on intracellular cAMP, ERK activity, cell proliferation, and transcellular chloride anion secretion using human ADPKD cyst epithelial cells.27 Tolvaptan caused concentration-dependent inhibition of arginine vasopressin-induced cAMP production, arginine vasopressin-induced ERK signaling, cell proliferation, and chloride anion secretion. These effects significantly contributed to
a decrease in vitro cyst growth (p
Autosomal dominant polycystic kidney disease (ADPKD) is characterized by bilateral renal cysts, kidney pain, hypertension, and progressive loss of renal function. It is a leading cause of end-stage renal disease and the most common inherited kidney disease in the United States. Despite its prevalence, disease-modifying treatment options do not currently exist. Tolvaptan is an orally active, selective arginine vasopressin V2 receptor antagonist already in use for hyponatremia. Tolvaptan exhibits dose-proportional pharmacokinetics with a half-life of ~12 hours. Metabolism occurs through the cytochrome P450 3A4 isoenzyme, and tolvaptan is a substrate for P-glycoprotein, resulting in numerous drug interactions. Recent research has highlighted the beneficial effect of tolvaptan on delaying the progression of ADPKD, which is the focus of this review. Pharmacologic, preclinical, and phase II and III clinical trial studies have demonstrated that tolvaptan is an effective treatment option that targets underlying pathogenic mechanisms of ADPKD. Tolvaptan delays the increase in total kidney volume (surrogate marker for disease progression), slows the decline in renal function, and reduces kidney pain. However, tolvaptan has significant adverse effects including aquaretic effects (polyuria, nocturia, polydipsia) and elevation of aminotransferase enzyme concentrations with the potential for acute liver failure. Appropriate patient selection is critical to optimize long-term benefits while minimizing adverse effects and hepatotoxic risk factors. Overall, tolvaptan is the first pharmacotherapeutic intervention to demonstrate significant benefit in the treatment of ADPKD, but practitioners and regulatory agencies must carefully weigh the risks versus benefits. Additional research should focus on incidence and risk factors of liver injury, cost-effectiveness, clinical management of drug–drug interactions, and long-term disease outcomes. KEY WORDS Tolvaptan, polycystic kidney disease, vasopressin. (Pharmacotherapy 2014;34(6):605–616) doi: 10.1002/phar.1421
Autosomal dominant polycystic kidney disease (ADPKD) is a monogenic disease characterized by renal cysts associated with pain, hypertension, and a progressive loss of renal function over time.1, 2 The estimated prevalence of ADPKD is between 1 in 400 to 1 in 1000 people with 5000–6000 new cases diagnosed annually in the United States.3, 4 It is the fourth leading cause of end-stage renal disease (ESRD) in the Disclosures: None. *Address for correspondence: Calvin J. Meaney, University at Buffalo School of Pharmacy and Pharmaceutical Sciences, 201 Kapoor Hall, Buffalo, NY 14214; e-mail: [email protected]. Ó 2014 Pharmacotherapy Publications, Inc.
United States and the most frequent inherited kidney disease.1, 2, 5 In 2010, 32.9 patients per million Americans initiated dialysis because of cystic kidney disease.5 Currently, ~10% of patients undergoing dialysis developed ESRD as a result of ADPKD.5, 6 Annual ESRD expenditures in the United States exceed $47 billion.5 Therefore, it is imperative to patients, practitioners, the health care system, and society to identify therapeutic interventions that slow or halt the progression of ADPKD. Tolvaptan is a selective arginine vasopressin V2 receptor antagonist that has demonstrated initial efficacy in slowing the progression of ADPKD.7, 8 It was approved by the Food and Drug Administration (FDA) in 2009 for the
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treatment of euvolemic and hypervolemic hyponatremia associated with heart failure, cirrhosis, and syndrome of inappropriate antidiuretic hormone.9 The manufacturer of tolvaptan (Otsuka Pharmaceutical Co. Inc, Tokyo, Japan) submitted a new drug application to the FDA and received priority-review status.10 Tolvaptan offers a novel treatment modality for ADPKD and is the focus of this review that presents data on the use of tolvaptan in ADPKD from pharmacologic and preclinical studies as well as recent phase II and III clinical trials. An exhaustive literature search was completed with the terms tolvaptan and polycystic kidney disease in Medline and Embase databases from inception to January 2, 2014, in addition to review of references from selected articles. Critical appraisal of available evidence with emphasis on risk-benefit ratio and patient selection is provided. Presentation and Pathophysiology of ADPKD Diagnosis is based on family history and radiologic evidence of renal cysts.11, 12 Neither gender nor ethnicity are risk factors for ADPKD.1, 2 Mutations in plasma membrane-spanning polycystin 1 and 2 (PKD1 and PKD2) genes, which are inherited in a dominant fashion, are the primary risk factor for ADPKD.1, 2 The offspring of a parent with ADPKD has a 50% chance of inheriting the disease. However, spontaneous mutations may occur in up to 5% of cases. PKD1 mutations are more common than PKD2 mutations and associated with more renal cysts and faster progression of renal disease.1 Genetic testing for ADPKD is possible, but detection rates are 50–85% with genetic linkage analysis or direct sequencing because of numerous mutations in PKD1, many with unknown pathogenicity.2 Mutations in PKD1 or PKD2 alone are not sufficient to cause ADPKD. A second mutation occurring at an unknown time point prior to manifestation of ADPKD stimulates monoclonal differentiation of tubular cells and development of cysts.13 This is hypothesized to occur through a somatic mutation in the PKD gene on the chromosome opposite the inherited PKD mutation.14 The second mutation is necessary to decrease the expression and/or function of the polycystin proteins below a threshold that allows for clinically evident cyst development. Polycystin proteins functionally interact to regulate tubular and vascular development in the kidneys and other organs via regulation of
calcium transport.2 An initial bulge in the tubule wall is potentiated by adenosine-30 , 50 -cyclic monophosphate (cAMP), epidermal growth factor, and insulinlike growth factor. The proliferative state is regulated by extracellular signal-regulated kinase (ERK) and mammalian target of rapamycin (mTOR) pathways.15, 16 The cyst size increases as surrounding epithelial cells proliferate and fluid accumulates, both of which are processes largely regulated by cAMP.1, 2 Plasma vasopressin concentrations increase, likely due to altered medullary architecture, which contributes to cyst development and enlargement.2, 17–19 Fibrosis can occur through macrophage and fibroblast infiltration of the interstitium. Cysts eventually disengage from the tubule and become autonomous units. The rate of disease progression is highly variable, with increases in total kidney volume (TKV) ranging from 1–10% per year.1 Radiologically assessed change in kidney volume is currently the best method of measuring disease progression.11, 20–22 Renal function assessments, such as serum creatinine and glomerular filtration rate (GFR), are poor markers in early disease because hyperfiltration in remaining nephrons maintains normal ranges for each. Markers of renal function decline are observed once damage to the kidney reaches a critical threshold, which is patient specific.4 Nearly all adults with progressive disease develop arterial hypertension (blood pressure higher than 140/90 mm Hg).23 Other renal manifestations are hematuria, albuminuria, urinary tract infections, and, most commonly, kidney pain, although these are not specific markers of disease progression.1, 2 Nephrolithiasis is twice as common in ADPKD than in the general population.24 Lower urine pH predisposes patients to uric acid stone formation, which is more common than calcium oxalate stones.24 Liver cysts and intracranial aneurysms are severe extrarenal manifestations that contribute to morbidity and mortality.1, 2 Approximately 50% of patients with ADPKD develop ESRD, usual during the fourth to sixth decades of life. Pharmacology Arginine vasopressin, also called antidiuretic hormone, is a neuropeptide hormone produced in the hypothalamus and released into systemic circulation from the posterior pituitary gland. Three primary vasopressin receptors, V1A, V1B,
TOLVAPTAN FOR ADPKD Baur and Meaney and V2, account for a variety of functions including vasoconstriction, platelet aggregation, glycogenolysis, adrenocorticotropic hormone release, osmoregulation, and body fluid regulation.25 The V2 receptors are located in the renal collecting ducts that, when bound by arginine vasopressin, promote free-water reabsorption via increased cAMP and upregulation of aquaporin2 channels.26 Tolvaptan is an orally active, selective arginine vasopressin V2 receptor antagonist with 1.8 times the affinity of the V2 receptor than native arginine vasopressin and 29 times the affinity of the V2 compared with the V1A receptor.25 Antagonism of the V2 receptors in the renal collecting ducts causes free-water excretion (aquaresis), net fluid loss, reduced urine osmolality, and an increase in serum sodium concentration.25 Additionally, decreases in the secondary messenger cAMP resulting in decreased kidney cyst cell proliferation and fluid secretion occur due to V2 antagonism.17, 19, 27, 28 Tolvaptan undergoes rapid absorption with ~40% oral bioavailability.9, 29 Bioavailability as assessed by maximum concentration (Cmax) and area under the concentration-time curve (AUC) is minimally affected by food.30 Although the fed state results in slightly higher exposure, it does not translate to differences in urine output. Dose-dependent increases in Cmax and AUC are linear for doses up to 300 mg. Doses greater than or equal to 300 mg result in a plateau of Cmax with a nonproportional increase in AUC. This suggests a nonlinear process, such as saturable absorption, at these high doses.29, 31 However, the clinical relevance of this nonlinearity is likely minimal because doses of tolvaptan do not exceed 180 mg/day in clinical trials. There is marked interpatient variability in Cmax and AUC with coefficients of variation ranging from 30–60%.9 Tolvaptan is highly bound (99%) to plasma proteins.9, 29 Metabolism occurs primarily through hepatic cytochrome P450 isoenzyme 3A4.29, 31 Excretion is via the fecal route with an elimination half-life of ~12 hours.29, 31 Based on data from patients with hyponatremia, dosage adjustments are not necessary for renal or hepatic dysfunction. However, tolvaptan is not recommended if creatinine clearance (Clcr) is less than 10 ml/minute or if the patient does not respond to tolvaptan and is anuric. With the substantial loss of nephron mass that occurs in advanced renal disease, there is limited capacity in terms of the site of effect for tolvaptan. This has been
607
demonstrated by reductions in urine excretion rate and free-water clearance in patients with renal impairment.32 Cmax and AUC nearly doubled in patients with severe renal impairment compared with controls after a single 60-mg dose of tolvaptan.9, 32 The effect of renal dysfunction on tolvaptan pharmacokinetics and pharmacodynamics in patients with ADPKD and varying degrees of renal dysfunction requires further study. The benefit of tolvaptan in ADPKD exceeds its effects on osmoregulation and may slow disease progression in patients with later stage disease. Therefore, pharmacokinetic changes in these patients are critical to understand for proper drug dosing and monitoring. Limited data are available about tolvaptan pharmacokinetics in patients with ADPKD because most studies were conducted in healthy volunteers or patients with hyponatremia.33 Pharmacokinetic comparison of Caucasian and Japanese subjects is critical because large clinical trials group these ethnicities in analysis and results.30 Geometric mean ratios for Japanese compared with Caucasian subjects in a fasting state were 1.11 (90% confidence interval [CI] 0.85–1.44) for Cmax and 1.15 (90% CI 0.84–1.55) for AUC. Higher exposure in Japanese subjects was likely due to lower weight (mean 12.2 kg less than Caucasian subjects). No difference in pharmacodynamic measures between ethnicities was noted. Tolvaptan is associated with clinically relevant drug-drug interactions related to CYP3A4 and P-glycoprotein (P-gp).34–36 Tolvaptan does not inhibit CYP3A4, but appears to be a sensitive substrate. However, tolvaptan is both a substrate and competitive inhibitor of P-gp.35 Tolvaptan is contraindicated for use with strong CYP3A4 inhibitors, and it is recommended to avoid use with moderate CYP3A4 inhibitors.9, 34 Use is cautioned with P-gp inhibitors, and the dose of tolvaptan should be based on clinical response.9 Preclinical Studies A plethora of data from basic research and translational studies supports the rapid clinical development of tolvaptan and other diseasemodifying treatments for ADPKD. Animal models of PKD provide a well-controlled environment by which pathogenic disease mechanisms and treatments can be investigated. In a rat model of PKD, a vasopressin V2 receptor agonist (1-deamino-8-D-arginine vasopressin) was shown to increase renal cAMP and cystogenesis.28
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The findings from this study, which demonstrate that arginine vasopressin agonism promotes PKD progression, provided the rationale for the investigation of vasopressin V2 receptor antagonists in polycystic kidney disease (PKD). The specific V2 receptor antagonist OPC-31260 ameliorated cystic enlargement and azotemia in a mouse model of PKD.37 Overexpression of the V2 receptor appears to cause progression of PKD because a specific antagonist prevented renal enlargement. A follow-up study using OPC-31260 in a similar mouse model demonstrated that vasopressin V2 receptor antagonism was effective against early or established PKD.17 Mechanistic investigations revealed reductions in renal cAMP and cystogenesis by V2 receptor antagonism. In another mouse model of ADPKD, OPC-31260 administration reduced renal cAMP levels, prevented renal enlargement, markedly inhibited cystogenesis, and protected renal function.19 However, initiation of V2 receptor antagonism later in the disease progression model (at experimental week 3 vs week 0) did not reduce cyst formation, suggesting that early initiation of tolvaptan is most effective at decreasing disease progression.38 The effects of tolvaptan (OPC-41061) were compared with OPC-31260 in a rat model of PKD.39 Tolvaptan was developed through structural modifications to its predecessor, OPC-31260, and exhibits increased potency and V2 receptor selectivity. Decreased renal cAMP and protection from PKD progression were observed for tolvaptan compared with baseline as demonstrated by a reduction in kidney weight, cyst volume, and fibrosis volume and improvement in markers of mitosis and apoptosis. These outcomes were achieved using the lowest dose, which caused only modest aquaresis compared with the higher dose regimens. Tolvaptan inhibited vasopressin-induced cAMP production and demonstrated higher affinity for the V2 receptor than OPC-31260.40 Oral administration of tolvaptan in this rat model produced dose-dependent aquaresis causing hemoconcentration 4 hours after the dose without changes in serum osmolality, sodium, creatinine, or urea nitrogen concentrations at 24 hours after the dose. An in vitro study examined the effect of tolvaptan on intracellular cAMP, ERK activity, cell proliferation, and transcellular chloride anion secretion using human ADPKD cyst epithelial cells.27 Tolvaptan caused concentration-dependent inhibition of arginine vasopressin-induced cAMP production, arginine vasopressin-induced ERK signaling, cell proliferation, and chloride anion secretion. These effects significantly contributed to
a decrease in vitro cyst growth (p
