Comprehensive Monograph: Ivacaftor (VX-770)

Executive Summary

Ivacaftor, marketed as Kalydeco® and also known as VX-770, represents a landmark achievement in the field of precision medicine and a paradigm shift in the therapeutic management of cystic fibrosis (CF). As the first-in-class Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) potentiator, Ivacaftor was the first approved therapy to target the underlying molecular defect of CF rather than merely managing its downstream symptoms.[1] Its mechanism of action involves binding directly to specific mutant CFTR protein channels on the epithelial cell surface, where it increases the probability of the channel being open, thereby enhancing chloride ion transport.[2] This restoration of channel function is indicated for patients with specific

CFTR gene mutations that result in defective channel gating.

Clinically, treatment with Ivacaftor leads to rapid and significant improvements in key disease markers, including substantial reductions in sweat chloride concentration, a direct measure of restored CFTR activity. These pharmacodynamic effects translate into meaningful clinical benefits, such as improved lung function as measured by the percent predicted forced expiratory volume in one second (FEV1​), increased body weight, and a reduced rate of pulmonary exacerbations.[1]

The pharmacokinetic profile of Ivacaftor is characterized by its high lipophilicity and poor aqueous solubility, which mandates oral administration with fat-containing food to ensure adequate absorption.[1] It is extensively metabolized in the liver by the cytochrome P450 3A (CYP3A) enzyme system, a characteristic that makes it highly susceptible to clinically significant drug-drug interactions with CYP3A inhibitors and inducers, necessitating careful management and dose adjustments.[7] Key safety considerations include the risk of elevated liver transaminases, requiring routine monitoring, and the development of cataracts in pediatric patients.[9] While Ivacaftor monotherapy has transformed care for a small subset of the CF population, its most profound impact has been as the essential potentiator component in highly effective combination therapies, such as Trikafta®, which have extended the benefits of CFTR modulation to the majority of individuals living with cystic fibrosis.[11]

Introduction: A Paradigm Shift in Cystic Fibrosis Therapeutics

Pathophysiology of Cystic Fibrosis (CF)

Cystic fibrosis is a life-shortening, autosomal recessive genetic disorder that arises from mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.[1] This gene provides the instructions for making the CFTR protein, which is a member of the ATP-binding cassette (ABC) transporter superfamily, specifically ABCC7.[11] Uniquely among ABC transporters, CFTR functions as an ion channel, regulating the transport of chloride and bicarbonate ions across the apical membrane of epithelial cells in multiple organs, including the lungs, pancreas, liver, intestines, and reproductive tract.[1]

In healthy individuals, the CFTR channel plays a crucial role in maintaining ion and fluid homeostasis. Its dysfunction due to genetic mutations disrupts this balance, leading to the production of abnormally thick, viscous mucus and other secretions.[4] In the lungs, this thick mucus obstructs airways, impairs mucociliary clearance, and creates a favorable environment for chronic bacterial infections and persistent inflammation, culminating in progressive bronchiectasis and respiratory failure.[1] In the pancreas, clogged ducts prevent the release of digestive enzymes, leading to pancreatic insufficiency, malabsorption, and malnutrition in the majority of patients.[1]

Classification of CFTR Mutations

More than 2,000 mutations in the CFTR gene have been identified, though a smaller number account for most cases of CF.[4] These mutations are categorized into functional classes based on their impact on the CFTR protein's lifecycle, a classification system that has become fundamental to guiding therapeutic strategies.[3]

• Class I (Production Mutations): These mutations, often nonsense or frameshift mutations, lead to a premature stop codon, resulting in the production of a truncated, non-functional protein or no protein at all.
• Class II (Processing/Trafficking Mutations): These mutations cause the CFTR protein to misfold within the endoplasmic reticulum. The cell's quality control machinery recognizes the misfolded protein and targets it for premature degradation, preventing it from reaching the cell surface. The most common CF mutation, F508del (a deletion of phenylalanine at position 508), belongs to this class and is present in approximately 90% of people with CF.[1]
• Class III (Gating Mutations): In this class, the CFTR protein is produced and correctly trafficked to the cell surface in sufficient quantity, but its function is impaired due to a defect in channel opening, or "gating." The channel remains predominantly closed, severely limiting ion transport. The G551D mutation is the archetypal Class III defect.[3]
• Class IV (Conductance Mutations): The CFTR protein is present at the cell surface and gates properly, but the flow of ions through its open pore is reduced.
• Class V (Splicing/Quantity Mutations): These mutations affect the splicing of CFTR mRNA, leading to a reduced amount of normal, functional CFTR protein being produced and trafficked to the cell surface.[3]

Historical Treatment Landscape

Prior to the development of CFTR modulators, the management of CF was entirely supportive and symptomatic. The therapeutic focus was on mitigating the downstream consequences of CFTR dysfunction rather than correcting the root cause.[3] Standard care involved a burdensome regimen of therapies, including mucoactive agents like dornase alfa and hypertonic saline to help clear mucus, inhaled and systemic antibiotics to treat chronic lung infections, bronchodilators to open airways, pancreatic enzyme replacement therapy to address malabsorption, and aggressive nutritional support.[3] While these interventions significantly improved survival over decades, they did not halt the underlying disease progression.

Emergence of Ivacaftor

The development of Ivacaftor by Vertex Pharmaceuticals, in a pioneering collaboration with the Cystic Fibrosis Foundation, marked a turning point in the history of CF treatment.[2] Approved by the U.S. Food and Drug Administration (FDA) in 2012, Ivacaftor was the first medication to address the underlying molecular defect of the disease.[1] It heralded the era of precision medicine for CF, where treatment is tailored to a patient's specific genetic makeup.

The success of Ivacaftor was predicated on targeting a precise functional defect. Its mechanism as a "potentiator" is designed to enhance the function of CFTR channels that are already present at the cell surface.[1] This directly addresses the defect in Class III gating mutations like G551D, where the protein is correctly located but cannot open. Conversely, this mechanism explains its ineffectiveness as a monotherapy for Class II mutations like F508del, where the primary problem is a lack of protein at the cell surface.[1] This direct causal link between mutation class and drug mechanism not only defined Ivacaftor's initial, narrow indication but also laid the scientific groundwork for the development of "corrector" molecules needed to address the more common trafficking defects.

Physicochemical and Molecular Profile of Ivacaftor

A thorough understanding of the physicochemical properties of Ivacaftor is essential, as these characteristics fundamentally influence its formulation, pharmacokinetics, and clinical administration.

Chemical Structure and Classification

Chemically, Ivacaftor is classified as an aromatic amide, a quinolone, and a member of the phenol family.[15] Its structure is derived from the formal condensation of the carboxy group of 4-oxo-1,4-dihydroquinoline-3-carboxylic acid with the amino group of 5-amino-2,4-di-tert-butylphenol.[15] This specific chemical architecture is responsible for its biological activity as a CFTR potentiator.

Nomenclature and Identifiers

The molecule is identified by a standardized set of names and codes across scientific and regulatory databases.

• IUPAC Name: N-(2,4-ditert-butyl-5-hydroxyphenyl)-4-oxo-1H-quinoline-3-carboxamide.[15] An alternative chemical name is N--1,4-dihydro-4-oxo-3-quinolinecarboxamide.[21]
• Synonyms: The most common synonyms are its development code, VX-770 (or VX770), and its primary brand name, Kalydeco®.[1]
• Database Identifiers: Key identifiers include DrugBank ID DB08820, CAS Number 873054-44-5, and PubChem CID 16220172.[1]

Molecular and Physical Properties

Ivacaftor's molecular formula is C24​H28​N2​O3​.[2] It is a white to off-white or light brown crystalline solid or powder.[20] Its key physical characteristics, which are critical for drug development and clinical use, are summarized in Table 1.

The molecule's high lipophilicity (XLogP of 6.93) and its practical insolubility in water are its most defining physicochemical traits.[20] These properties are not merely abstract data points; they are the primary determinants of its pharmacokinetic behavior and clinical administration guidelines. The poor aqueous solubility presents a significant challenge for absorption from the gastrointestinal tract's aqueous environment. This directly necessitates the mandatory clinical instruction to administer Ivacaftor with fat-containing food, which aids in its solubilization via micelle formation and increases systemic exposure by a factor of 2 to 4.[1] This requirement is a cornerstone of its FDA-approved labeling and patient counseling information.[9] Furthermore, the high lipophilicity suggests a propensity for absorption into the intestinal lymphatic system, a pathway that bypasses first-pass metabolism in the liver and may contribute to its overall bioavailability.[27] These properties also dictate the need for advanced pharmaceutical formulations, such as the use of copolymers and surfactants in its tablet and granule forms, to ensure consistent and reliable drug delivery.[31]

Table 1: Chemical and Physical Identifiers of Ivacaftor

Property	Value	Source(s)
DrugBank ID	DB08820	1
Type	Small Molecule	1
CAS Number	873054-44-5	2
IUPAC Name	N-(2,4-ditert-butyl-5-hydroxyphenyl)-4-oxo-1H-quinoline-3-carboxamide	2
Common Synonyms	Kalydeco, VX-770	1
Molecular Formula	C24​H28​N2​O3​	2
Molecular Weight	392.49 g/mol	6
Appearance	White to off-white crystalline solid/powder	20
Solubility (Water)	Practically insoluble (<0.05 µg/mL)	20
Solubility (Organic)	Soluble in DMSO; slightly soluble in methanol, ethyl acetate	20
Melting Point	212-215°C	20
pKa (Predicted)	11.08	20
XLogP	6.93	26
SMILES	CC(C)(C)C1=CC(=C(C=C1NC(=O)C2=CNC3=CC=CC=C3C2=O)O)C(C)(C)C	2
InChIKey	PURKAOJPTOLRMP-UHFFFAOYSA-N	15

Pharmacological Profile: Mechanism of Action and Pharmacodynamics

Mechanism as a CFTR Potentiator

Ivacaftor is the first-in-class CFTR potentiator, a type of modulator designed to restore the function of defective CFTR protein that has successfully reached the apical membrane of epithelial cells.[1] Its mechanism of action is highly specific: it binds directly to the CFTR protein itself.[1] This binding event allosterically modulates the protein's conformation to increase its channel open probability (Po), a process also referred to as potentiating its gating.[1] By forcing the channel's "gate" to stay open for longer periods, Ivacaftor facilitates increased transport of chloride and bicarbonate ions across the cell membrane, thereby addressing the fundamental ion transport defect in responsive forms of CF.

The action of Ivacaftor is nuanced. It enhances the channel's gating activity in a manner that is dependent on the protein being phosphorylated by protein kinase A (PKA), a prerequisite for normal CFTR activation.[14] However, once the protein is phosphorylated, Ivacaftor's potentiation effect is independent of ATP binding and hydrolysis at the nucleotide-binding domains (NBDs).[14] This suggests that Ivacaftor effectively decouples the channel's gating cycle from its normal ATP-driven engine, inducing a non-conventional open state that bypasses the defect in certain mutant proteins.[14]

This mechanism exhibits state-dependent binding, a classic characteristic of allosteric modulators, where the drug demonstrates a higher affinity for the open state of the CFTR channel compared to the closed state.[14] By preferentially binding to and stabilizing the open conformation, Ivacaftor shifts the equilibrium of the channel population towards being open, thus potentiating its function. This sophisticated biophysical model provides a more nuanced understanding than simply stating the drug "opens the channel." It explains the observed variability in response across different mutations, as the drug's apparent potency is linked to the baseline open probability of the specific mutant channel; a channel with a lower baseline activity requires a higher concentration of Ivacaftor to achieve a maximal effect.[14]

Mutation-Specific Efficacy

The efficacy of Ivacaftor is intrinsically linked to the underlying CFTR mutation. It is highly effective as a monotherapy for patients with Class III "gating" mutations, which account for approximately 4–5% of the CF population.[2] The archetypal gating mutation is G551D, where the CFTR protein is present on the cell surface but fails to open properly in response to cellular signals.[3] Ivacaftor directly remedies this defect. In vitro studies have demonstrated its potent activity, with half-maximal effective concentration (

EC50​) values of 100 nM for G551D-CFTR and, interestingly, 25 nM for F508del-CFTR, though the latter is not clinically relevant for monotherapy.[22]

The overall level of Ivacaftor-mediated chloride transport is dependent on two factors: the amount of CFTR protein present at the cell surface and the responsiveness of that specific mutant protein to Ivacaftor's potentiation.[1] This is why Ivacaftor monotherapy is not effective for patients homozygous for the F508del mutation (a Class II defect). In these patients, the protein is misfolded and degraded, resulting in an insufficient quantity of CFTR at the cell surface to serve as a target for the drug.[1]

Pharmacodynamic Effects

The potentiation of CFTR function by Ivacaftor translates into clear and measurable pharmacodynamic effects that serve as biomarkers of its activity.

• Sweat Chloride Reduction: The most direct and dramatic pharmacodynamic effect is a rapid and substantial reduction in the concentration of chloride in sweat, which is pathognomonically elevated in CF. Clinical trials have consistently reported mean decreases from baseline of over 50 mmol/L (e.g., -53.8 mmol/L and -55.5 mmol/L), often bringing levels into the normal or indeterminate range and providing definitive in-vivo proof of restored CFTR activity.[1]
• Clinical Improvements: This restoration of ion transport at the cellular level leads to significant and clinically meaningful improvements. Pivotal trials have demonstrated marked improvements in respiratory function (as measured by FEV1​), significant weight gain, and a reduced frequency of pulmonary exacerbations requiring antibiotic treatment.[1]
• Physiological Mechanisms: Further studies have provided insight into the physiological mechanisms underlying these clinical benefits. Ivacaftor has been shown to improve mucociliary clearance in the airways and normalize gastrointestinal pH, directly linking the restored CFTR function to improvements in lung and digestive health.[4]

Clinical Pharmacokinetics and Metabolism (ADME)

The absorption, distribution, metabolism, and excretion (ADME) profile of Ivacaftor dictates its dosing regimen, administration requirements, and potential for drug interactions.

Absorption

Ivacaftor is administered orally and is well-absorbed from the gastrointestinal tract, but its absorption is critically dependent on the presence of fat.[1]

• Food Effect: Administration with fat-containing food is essential, as it increases the total systemic exposure (Area Under the Curve, or AUC) by approximately 2- to 4-fold compared to administration in a fasted state. This is a direct consequence of the drug's high lipophilicity and poor aqueous solubility.[6]
• Pharmacokinetic Parameters: Following a single 150 mg oral dose given to healthy subjects with a meal, the peak plasma concentration (Cmax​) of 768 ng/mL is reached at a median time (Tmax​) of approximately 4 hours.[6] With twice-daily dosing, plasma concentrations reach a steady state within 3 to 5 days.[6]

Distribution

Once absorbed into the systemic circulation, Ivacaftor distributes extensively throughout the body.

• Plasma Protein Binding: It is highly bound (approximately 99%) to plasma proteins, primarily to alpha 1-acid glycoprotein and, to a lesser extent, albumin. It does not bind to human red blood cells.[2]
• Volume of Distribution: The apparent volume of distribution (Vd​/F) is large, with a mean of 353 L, indicating that the drug distributes extensively into tissues beyond the plasma compartment.[1]

Metabolism

Ivacaftor undergoes extensive metabolism, primarily in the liver.

• Metabolic Pathway: The primary pathway for metabolism is through the cytochrome P450 system, specifically the CYP3A isoforms (CYP3A4 and CYP3A5).[2] This heavy reliance on a single enzyme system is the key determinant of its drug-drug interaction profile.
• Metabolites: Two major metabolites have been identified in humans: M1 (hydroxymethyl-ivacaftor) and M6 (ivacaftor-carboxylate).[6]
• M1 is pharmacologically active, possessing approximately one-sixth the potency of the parent compound, Ivacaftor.[2]
• M6 has less than one-fiftieth the potency of Ivacaftor and is considered pharmacologically inactive.[2]
• Disproportionate Human Metabolites: In human plasma, the concentrations of M1 and M6 are significantly higher than that of the parent drug. This makes them "disproportionate human metabolites" compared to the levels observed in preclinical animal models, a finding that required specific regulatory consideration during its development to ensure the safety of these high-exposure metabolites was adequately covered by toxicology studies.[35]

Excretion

Ivacaftor and its metabolites are eliminated from the body almost entirely via the feces.

• Route of Elimination: Following oral administration, the majority of the dose (87.8%) is excreted in the feces after metabolic conversion.[1]
• Metabolite Contribution: The major metabolites, M1 and M6, account for approximately 65% of the total eliminated dose (22% as M1 and 43% as M6).[2]
• Urinary Excretion: Urinary excretion of unchanged Ivacaftor is negligible.[2]
• Half-Life and Clearance: The apparent terminal half-life (t1/2​) is approximately 12 to 14 hours following a single dose in the fed state.[2] The apparent clearance (CL/F) was determined to be 17.3 L/h in healthy subjects.[2]

Table 2: Key Pharmacokinetic Parameters of Ivacaftor

Parameter	Value	Clinical Implication/Comment	Source(s)
Tmax​ (fed state)	~4 hours	Time to reach peak concentration after oral dose with food.	1
Cmax​ (150 mg dose)	768 ng/mL	Peak plasma concentration achieved with a standard dose.	6
AUC (150 mg dose)	10,600 ng*hr/mL	Total drug exposure after a single standard dose.	6
Food Effect	2- to 4-fold increase in AUC	Administration with fat-containing food is mandatory for absorption.	6
Protein Binding	~99%	Highly bound, primarily to alpha 1-acid glycoprotein and albumin.	2
Apparent Volume of Distribution (Vd​/F)	353 L	Indicates extensive distribution into body tissues.	1
Metabolism Pathway	Primarily CYP3A4/5	High potential for drug-drug interactions.	1
Active Metabolite	M1 (hydroxymethyl-ivacaftor)	~1/6th the potency of parent drug; contributes to overall effect.	2
Inactive Metabolite	M6 (ivacaftor-carboxylate)	<1/50th the potency of parent drug; not considered active.	2
Primary Route of Elimination	Feces (~88%)	Primarily eliminated as metabolites; negligible renal excretion.	1
Terminal Half-life (t1/2​)	~12-14 hours	Supports twice-daily (every 12 hours) dosing regimen.	2
Apparent Clearance (CL/F)	17.3 L/h	Rate of drug removal from the body.	2

Clinical Efficacy, Approved Indications, and Off-Label Use

Clinical Trial Evidence

The clinical development program for Ivacaftor has robustly demonstrated its efficacy and safety across various