Ripretinib, an inhibitor of multiple receptor tyrosine kinases, including platelet-derived growth factor receptor alpha (PDGFR-α) and c-Kit, is an antineoplastic agent.1, 4, 6, 7, 8, 9
Gastrointestinal Stromal Tumor
Ripretinib is used for the treatment of adults with advanced gastrointestinal stromal tumor (GIST) previously treated with at least 3 tyrosine kinase inhibitors, including imatinib.1, 3 Ripretinib has been designated an orphan drug by FDA for the treatment of this cancer.2 Ripretinib has also been evaluated as a second-line treatment for GIST†.10002
Advanced GIST Previously Treated with 3 Tyrosine Kinase Inhibitors, Including Imatinib
The current indication for ripretinib in the treatment of GIST is based principally on the results of a randomized, double-blind, placebo-controlled, phase 3 study (INVICTUS) in adults with locally advanced, unresectable, or metastatic GIST previously treated with imatinib, sunitinib, and regorafenib.1, 3 In the INVICTUS study, 129 patients were randomized (stratified by prior lines of therapy and Eastern Cooperative Oncology Group [ECOG] performance status) in a 2:1 ratio to receive either ripretinib 150 mg orally once daily or placebo until disease progression or unacceptable toxicity occurred.1, 3 The mean duration of ripretinib therapy was 24.4 weeks.4 The primary measure of efficacy was progression-free survival as evaluated by a blinded independent review committee according to modified Response Evaluation Criteria in Solid Tumors (RECIST 1.1), in which lymph nodes and bone lesions were not target lesions and a progressively growing new tumor nodule within a preexisting tumor mass was considered progression if specific criteria were met; additional outcome measures were objective response rate and overall survival.1, 3 The median age of patients was 60 years (range: 29-83 years); 75% were white, 57% were male, 92% had an ECOG performance status of 0 or 1, 63% received 3 prior therapies, and 37% received 4 or more prior therapies.1 The majority (66%) of patients randomized to placebo crossed over to ripretinib after disease progression.1
Data analysis revealed a median progression-free survival of 6.3 months in patients receiving ripretinib compared with 1 month in patients receiving placebo (hazard ratio of 0.15; 95% confidence interval: 0.09-0.25).1, 3 The objective response rate in patients receiving ripretinib was 9% compared with 0% in patients receiving placebo.1 The median overall survival was 15.1 months in patients receiving ripretinib compared with 6.6 months in patients receiving placebo (hazard ratio of 0.36; 95% confidence interval: 0.21-0.62).1
Second-line Treatment for GIST
For advanced GIST, tyrosine kinase inhibitors (TKIs) are the cornerstone of treatment since the majority of GISTs (80 to 90%) are driven by activating genomic alterations in KIT or platelet-derived growth factor α (PDGFRA).10001, 10002 Imatinib is the first-line TKI in the advanced GIST setting for most patients; however, nearly all patients experience disease progression with continued treatment.10001, 10002 Sunitinib is the preferred second-line TKI for those with progressive disease on imatinib.10001 Ripretinib may be another second-line option for patients with advanced GIST†; ripretinib was compared to sunitinib in the open-label, multicenter, randomized, phase 3, INTRIGUE study.10002
Adult patients (≥18 years of age) with histologically confirmed GIST and at least 1 measurable lesion within 21 days prior to study drug administration were eligible for study enrollment.10002 Enrolled patients also experienced disease progression on or an intolerance to first-line imatinib therapy and an Eastern Cooperative Oncology Group (ECOG) score of 0 to 2.10002 Patients were initially stratified by mutational status and imatinib intolerance and subsequently randomized to ripretinib 150 mg orally once daily on a continuous basis or sunitinib 50 mg orally once daily for 4 weeks followed by 2 weeks without taking the drug.10002 Ripretinib dose reduction to 100 or 50 mg once daily was allowed; sunitinib dose modifications occurred per the approved prescribing information or institutional guidelines.10002 If a patient required therapy interruption for >28 consecutive days, treatment was discontinued.10002
Of the 541 patients assessed for eligibility, 453 were randomized to ripretinib (n=226) or sunitinib (n=227).10002 Of all enrolled patients, 62% were male, 66.2% were White, and the median age was 60 years (range, 18 to 88 years).10002 Most patients (99.1%) enrolled in the study had a baseline ECOG performance status of ≤1.10002 Regarding mutation status, 327 patients had a primary KIT exon 11 mutation, 60 had a primary KIT exon 9 mutation, 33 were KIT/PDGFRA wild type, and 33 had a primary mutation in another KIT exon or a PDGFRA mutation.10002 Imatinib intolerance was reported in 9.9% of patients.10002 The primary end point was progression-free survival (PFS), defined as time from randomization to initial disease progression or death from any cause (whichever occurred first), as determined by independent radiologic review using mRECIST v1.1.10002 Imaging assessments of the tumor were conducted at screening, day 1 of cycles 2 to 7, every other cycle thereafter, and at the end-of-treatment visit.10002 Key secondary end points included objective response rate (ORR) and overall survival (OS).10002 The primary and key secondary end points were analyzed in 2 intention-to-treat populations: KIT exon 11 patients and the overall study population.10002
Results revealed that ripretinib therapy was not associated with a significant improvement in PFS over sunitinib in either the overall ITT population (median 8.0 versus 8.3 months, respectively; hazard ratio [HR]: 1.05; 95% confidence interval [CI], 0.82 to 1.33) or the KIT exon 11 ITT population (median 8.3 versus 7.0 months, respectively; HR: 0.88; 95% CI, 0.66 to 1.16).10002 The ORR was significantly improved with ripretinib in the KIT exon 11 ITT population (23.9% vs. 14.6%), but not in the overall ITT population (21.7% vs. 17.6%).10002 Median duration of response for ripretinib and sunitinib in both populations was 16.7 and 20.1 months, respectively.10002 Data for OS were highly immature and the median OS was not reached in either arm during this study.10002 The most common adverse events of any grade severity with ripretinib included alopecia (64.1%), fatigue (37.7%), myalgia (36.3%), and constipation (35%).10002 The most common adverse events of any grade severity with sunitinib were hand-foot syndrome (51.1%), diarrhea (48%), hypertension (47.1%), and stomatitis (36.2%).10002 A more favorable safety profile, fewer grade 3/4 treatment-emergent adverse events (41.3% vs. 65.6%) and improved scores on patient-reported tolerability outcome measures were observed with ripretinib as compared to sunitinib.10002
Based on current evidence, ripretinib as a second-line treatment for adult patients with advanced GIST has Level 2 (moderate strength/quality) evidence supporting its use.10002 Ripretinib demonstrated similar clinical activity with a more favorable safety profile as compared to sunitinib for patients with advanced GIST previously treated with imatinib, especially for those with KIT exon 11.10002 Clinicians may consider preferential use of ripretinib over sunitinib in patients who are frail or have severe cardiovascular complications or uncontrolled hypertension.
Ripretinib is administered orally once daily without regard to meals at the same time each day.1 The tablets should be swallowed whole.1
If a dose of ripretinib is missed by <8 hours, administer missed dose as soon as possible.1 If a dose is missed by >8 hours or if a dose is vomited, skip the missed or vomited dose and take the next dose at the regularly scheduled time.1
Gastrointestinal Stromal Tumor
For the treatment of advanced gastrointestinal stromal tumor (GIST) in adult patients previously treated with at least 3 tyrosine kinase inhibitors, the recommended dosage of ripretinib is 150 mg once daily.1 Therapy should be continued until disease progression or unacceptable toxicity occurs.1
When ripretinib is used for the second-line treatment of advanced GIST†, the usual dosage administered is 150 mg orally once daily.10002 In the double-blind, randomized, placebo-controlled, phase 3, INVICTUS trial that compared ripretinib to placebo in patients with previously treated, advanced GIST, dose escalation of ripretinib to 150 mg twice daily was permitted upon further disease progression.10003 In INVICTUS, ripretinib 150 mg twice daily doses were well tolerated without clinically meaningful dose-limiting adverse reactions.10003
Dosage Modification for Toxicity
When dosage modification is necessary, the dosage of ripretinib should be reduced to 100 mg once daily; however, if a dosage of 100 mg once daily is not tolerated, ripretinib should be permanently discontinued.1
Palmar-plantar Erythrodysesthesia Syndrome
If grade 2 palmar-plantar erythrodysesthesia syndrome occurs, ripretinib should be withheld until resolution to grade 1 or less or to baseline.1 If resolution occurs within 7 days, ripretinib therapy may be resumed at the same dosage (150 mg once daily).1 If resolution occurs in 7 days or more, therapy may be resumed at a reduced dosage (100 mg once daily).1 If resolution of palmar-plantar erythrodysesthesia syndrome is maintained for at least 28 days on a reduced dosage of 100 mg once daily, ripretinib therapy may be increased to 150 mg once daily.1 If grade 2 palmar-plantar erythrodysesthesia syndrome recurs on a dosage of 150 mg once daily, ripretinib should be withheld until resolution or improvement to grade 1 or less occurs, and then resumed at a reduced dosage.1
If grade 3 palmar-plantar erythrodysesthesia syndrome occurs, ripretinib therapy should be withheld for at least 7 days or until resolution or improvement to grade 1 or less occurs (maximum of 28 days).1 If resolution occurs, ripretinib therapy may be resumed at a reduced dosage (100 mg once daily).1 If resolution of palmar-plantar erythrodysesthesia syndrome is maintained for at least 28 days on a reduced dosage of 100 mg once daily, ripretinib therapy may be increased to 150 mg once daily.1
If symptomatic grade 3 hypertension occurs, ripretinib therapy should be withheld until symptoms have resolved and blood pressure is controlled.1 If hypertension resolves or improves to grade 1 or less, ripretinib therapy may be resumed at the same dosage (150 mg once daily).1 If hypertension does not resolve or improve to grade 1 or less, ripretinib therapy may be resumed at a reduced dosage (100 mg once daily).1 If grade 3 hypertension recurs, ripretinib should be withheld until symptoms have resolved and blood pressure is controlled; following recovery, therapy may be resumed at a reduced dosage.1
If grade 4 hypertension occurs, ripretinib therapy should be permanently discontinued.1
If grade 3 or 4 left ventricular systolic dysfunction occurs, ripretinib therapy should be permanently discontinued.1
If grade 2 arthralgia or myalgia occurs, ripretinib should be withheld until resolution or improvement to grade 1 or less occurs.1 If recovery occurs within 7 days, ripretinib therapy may be resumed at the same dosage (150 mg once daily).1 If grade 2 arthralgia or myalgia does not resolve within 7 days, ripretinib therapy may be resumed at a reduced dosage (100 mg once daily).1 If resolution of arthralgia or myalgia is maintained for at least 28 days on a reduced dosage of 100 mg once daily, ripretinib therapy may be increased to 150 mg once daily.1 If grade 2 arthralgia or myalgia recurs on a dosage of 150 mg once daily, ripretinib should be withheld until resolution or improvement to grade 1 or less occurs, and then resumed at a reduced dosage regardless of the time to improvement.1
If grade 3 arthralgia or myalgia occurs, ripretinib therapy should be withheld for at least 7 days or until resolution or improvement to grade 1 or less (maximum of 28 days).1 If recovery occurs within 28 days, ripretinib therapy may be resumed at a reduced dosage.1 If recovery or improvement to grade 1 or less is maintained for at least 28 days on a reduced dosage of 100 mg once daily, ripretinib therapy may be increased to 150 mg once daily.1
Development of New Primary Cutaneous Malignancies
No dosage adjustment is necessary in patients who develop new primary cutaneous malignancies.1
If other grade 3 or 4 adverse reactions occur, ripretinib therapy should be withheld until recovery or improvement to grade 1 or less.1 If resolution occurs, ripretinib therapy may be resumed at a reduced dosage (100 mg once daily).1 If resolution does not occur within 28 days, permanently discontinue ripretinib therapy.1 If recovery to grade 1 or less or to baseline is maintained for at least 28 days on a reduced dosage of 100 mg once daily, ripretinib therapy may be increased to 150 mg once daily.1 If grade 3 or 4 adverse reaction recurs, permanently discontinue ripretinib therapy.1
Concomitant Use with Moderate CYP3A Inducers
Concomitant use of ripretinib with moderate CYP3A inducers (e.g., efavirenz) should be avoided.1 If concomitant use of a moderate CYP3A inducer cannot be avoided, the manufacturer recommends increasing the dosage of ripretinib from 150 mg once daily to 150 mg twice daily .1 Patients should be monitored for clinical response and tolerability of the drug.1 If concomitant use of a moderate CYP3A inducer is discontinued, the ripretinib dosage should be returned to 150 mg once daily 14 days after discontinuation of the moderate CYP3A inducer.1
For patients concomitantly using a moderate CYP3A inducer with ripretinib (twice daily) who missed a dose:
No dosage adjustment is necessary in patients with mild, moderate, or severe hepatic impairment (Child-Pugh class A, B, or C).1
The manufacturer makes no specific dosage recommendations in patients with renal impairment.1
The manufacturer makes no specific dosage recommendations for geriatric patients.1
Palmar-plantar Erythrodysesthesia Syndrome
In the INVICTUS study, palmar-plantar erythrodysesthesia syndrome (PPES) occurred in 21% of 85 ripretinib-treated patients.1 In patients experiencing palmar-plantar erythrodysesthesia syndrome, temporary interruption of ripretinib therapy or dosage reduction was necessary in 2.4 or 1.2% of patients, respectively; discontinuance of ripretinib therapy was necessary in 1.2% of patients.1
Temporary interruption of therapy followed by dosage adjustment may be necessary depending on the severity of the palmar-plantar erythrodysesthesia.1
Development of New Primary Cutaneous Malignancies
In the INVICTUS study, cutaneous squamous cell carcinoma or melanoma were reported in 4.7 or 2.4% of 85 ripretinib-treated patients, respectively.1 The median time to development of cutaneous squamous cell carcinoma was 4.6 months (range: 3.8-6 months).1 In a pooled safety population, cutaneous squamous cell carcinoma, keratoacanthoma, or melanoma was reported in 7, 1.9, or 0.9% of 351 patients receiving ripretinib, respectively.1
A dermatologic evaluation should be performed prior to initiating ripretinib therapy and routinely during therapy.1 Suspicious cutaneous lesions should be treated as appropriate and excised for pathologic evaluation; no dosage adjustment is necessary.1
In the INVICTUS study, hypertension was reported in 14% of 85 ripretinib-treated patients compared with 4.7% of those receiving placebo.1 Grade 3 or 4 hypertension occurred in 7% of ripretinib-treated patients compared with none of those receiving placebo.1
Ripretinib should not be initiated in patients with uncontrolled hypertension.1 Blood pressure must be adequately controlled prior to initiation of ripretinib therapy.1 Blood pressure should be monitored as clinically indicated during ripretinib therapy and antihypertensive therapy should be initiated or adjusted as appropriate.1 Temporary interruption followed by dosage adjustment or permanent discontinuance of ripretinib may be necessary depending on the severity of the hypertension.1
In the INVICTUS study, cardiac failure was reported in 1.2% of patients receiving ripretinib.1 Grade 3 decreased ejection fraction occurred in 2.6% of 77 patients receiving ripretinib who were assessed by echocardiogram at baseline and at least once after initiation of therapy.1 Permanent discontinuance of ripretinib therapy was necessary in 1.2% of 85 patients who developed cardiac dysfunction.1
In a pooled safety population, cardiac dysfunction (i.e., cardiac failure, acute left ventricular failure, diastolic dysfunction, ventricular hypertrophy) was reported in 1.7% of 351 (grade 3 in 1.1%) patients receiving ripretinib.1 Grade 3 decreased ejection fraction occurred in 3.4% of 263 patients receiving ripretinib who were assessed by echocardiogram at baseline and at least once after initiation of therapy.1
The safety of ripretinib has not been evaluated in patients with a baseline left ventricular ejection fraction (LVEF) less than 50%.1
LVEF should be assessed (e.g., echocardiogram, MUGA scan) prior to initiation of therapy, during therapy, and as clinically indicated.1 Ripretinib should be permanently discontinued in patients who develop grade 3 or 4 left ventricular systolic dysfunction.1
Surgery and Wound Healing Complications
Because inhibitors of vascular endothelial growth factor receptor (VEGFR), including ripretinib, may impair wound healing, ripretinib should be withheld at least 1 week prior to elective surgery.1 The drug should not be resumed until at least 2 weeks following major surgery and after the surgical incision has adequately healed.1 The safety of resuming ripretinib therapy postoperatively after resolution of wound healing complications has not been established.1
Ripretinib may cause photosensitivity; 0.6% of patients in clinical trials experienced photosensitivity reactions.1 Patients should limit direct ultraviolet exposure during therapy and for at least 1 week following discontinuation of ripretinib.1
Based on its mechanism of action, ripretinib may cause fetal harm if administered to pregnant females.1 In animal reproduction studies, embryofetal toxicity (i.e., decreased fetal body weight, postimplantation loss) and teratogenic effects (i.e., cardiovascular and skeletal malformations) were observed when the drug was administered to pregnant rats and rabbits receiving ripretinib at exposure levels of approximately 0.5 times the human exposure at the recommended 150 mg once daily dose.1
Pregnancy should be avoided during therapy.1 The manufacturer states that a pregnancy test should be performed prior to initiation of ripretinib in females of reproductive potential and that such females should use adequate methods of contraception while receiving the drug and for at least 1 week after the last dose.1 In addition, males who are partners of females of reproductive potential should use effective contraceptive methods during and for at least 1 week after the last dose.1 If ripretinib is used during pregnancy or if the patient or their partner becomes pregnant during therapy, the patient should be apprised of the potential fetal hazard.1
Ripretinib may cause fetal harm if administered to pregnant females based on its mechanism of action.1
It is not known whether ripretinib or its metabolites are distributed into human milk.1 The effects of the drug on breast-fed infants or on the production of milk are unknown.1
Because of the potential for serious adverse reactions to ripretinib in breast-fed infants, females should be advised not to breast-feed while receiving the drug and for at least 1 week after the last dose.1
Females and Males of Reproductive Potential
A pregnancy test should be performed prior to initiation of ripretinib in females of reproductive potential and such females should use adequate methods of contraception while receiving the drug and for at least 1 week after the last dose.1 In addition, males who are partners of females of reproductive potential should use effective contraceptive methods during and for at least 1 week after the last dose.1
Based on animal studies, ripretinib may impair male fertility.1 The effect of the drug on fertility in humans is not known.1 In repeat-dose toxicity studies, degeneration of the testes and cellular debris of the epididymis were observed in male animals receiving ripretinib at exposure levels approximately 0.5 times the human exposure at the recommended 150 mg once daily dosage.1, 4
Safety and efficacy of ripretinib have not been established in pediatric patients.1 In animal toxicology studies, ripretinib has been associated with changes in growing teeth (missing or discolored teeth accompanied by dose-dependent incisor degeneration) and bones (decreased trabeculae of the femur, increased osteoblastic surface).1
In the INVICTUS study, 24% of patients receiving ripretinib were 65 years of age or older, while 9% were 75 years of age or older.1 The manufacturer states that insufficient data are available to determine whether geriatric patients respond differently than younger adults.1
Population pharmacokinetic analysis suggests that age (range: 19-87 years) does not have a clinically important effect on the pharmacokinetics of ripretinib.1
Population pharmacokinetic analysis suggests that the observed magnitude of increase in ripretinib exposure in patients with hepatic impairment is unlikely to be clinically relevant.1
Population pharmacokinetic analysis suggests that the pharmacokinetics of ripretinib are not substantially altered in patients with mild or moderate renal impairment (creatinine clearance 30 to less than 90 mL/minute).1
The effect of severe renal impairment (creatinine clearance 15-29 mL/minute) on the pharmacokinetics of ripretinib has not been established.1
Adverse effects reported in at least 20% of patients receiving ripretinib for the treatment of GI stromal tumor (GIST) include alopecia, fatigue, nausea, abdominal pain, constipation, myalgia, diarrhea, decreased appetite, palmar-plantar erythrodysesthesia syndrome, and vomiting.1 The most common grade 3 or 4 laboratory abnormalities (≥4%) were increased lipase and decreased phosphate.1
Ripretinib is metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A4 and, to a lesser extent, by CYP2C8 and CYP2D6 to its equally active metabolite DP-5439.1 DP-5439 is metabolized principally by CYP3A4 and, to a lesser extent, by CYP isoenzymes 2C8, 2E1, and 2D6.1
In vitro, ripretinib and DP-5439 inhibit CYP2C8, but do not induce CYP isoenzymes 1A2, 2B6, or 3A4.1
In vitro, ripretinib is an inhibitor of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP).1 DP-5439 inhibits BCRP and multidrug and toxic compound extrusion protein (MATE) 1 and is a substrate of P-gp and BCRP.1
Drugs Affecting Hepatic Microsomal Enzymes
Concomitant use of ripretinib with potent inhibitors of CYP3A may result in increased systemic exposure to ripretinib and DP-5439 and increase the risk of ripretinib toxicity.1 When the potent CYP3A inhibitor itraconazole was administered concomitantly with ripretinib, peak plasma concentration and AUC of ripretinib were increased by 36 and 99%, respectively; peak plasma concentration and AUC of DP-5439 were increased by 0 and 99%, respectively.1, 4
The manufacturer states that patients receiving ripretinib concomitantly with potent CYP3A4 inhibitors (e.g., itraconazole) should be monitored frequently for signs of ripretinib toxicity.1
Concomitant use of ripretinib with potent inducers of CYP3A may result in decreased systemic exposure to ripretinib and DP-5439, and reduced ripretinib efficacy.1 When the potent CYP3A inducer rifampin was administered concomitantly with ripretinib, peak plasma concentration and AUC of ripretinib were decreased by 18 and 61%, respectively; AUC of DP-5439 was decreased by 57% and peak plasma concentration of DP-5439 increased by 37%.1
Concomitant use of ripretinib with potent CYP3A inducers should be avoided.1
Concomitant use of ripretinib with moderate inducers of CYP3A is predicted to decrease systemic exposure to ripretinib and DP-5439, and reduced ripretinib efficacy.1 Concomitant administration of ripretinib with the moderate CYP3A inducer efavirenz is predicted to decrease peak plasma concentration and AUC of ripretinib by 24 and 56%, respectively.1
Concomitant use of ripretinib with moderate CYP3A inducers (e.g., efavirenz) should be avoided.1 If concomitant use of a moderate CYP3A inducer cannot be avoided, the manufacturer recommends increasing the dosage of ripretinib from 150 mg once daily to 150 mg twice daily .1 Patients should be monitored for clinical response and tolerability of the drug.1 If concomitant use of a moderate CYP3A inducer is discontinued, the ripretinib dosage should be returned to 150 mg once daily .1
Concomitant administration of ripretinib and the proton-pump inhibitor pantoprazole had no clinically important effect on systemic exposure to ripretinib or DP-5439.1
Ripretinib, a potent inhibitor of receptor tyrosine kinases, including platelet-derived growth factor receptor alpha (PDGFR-α) and c-Kit, is an antineoplastic agent.1, 3, 4, 6, 7, 8, 9 Ripretinib is a type II tyrosine switch control inhibitor with broad activity against c-KIT and PDGFR-α, including wild-type and primary and secondary mutations associated with resistance to other tyrosine kinase inhibitors.1, 6, 8, 9 c-KIT and PDGFR-α are dual switch kinases containing both an inhibitory and activation loop switch which regulate kinase activity by binding to the kinase switch pocket.6, 8 Oncogenic kinase mutations, such as activating mutations in the c-KIT receptor tyrosine kinase gene (present in approximately 80% of patients with gastrointestinal stromal tumor [GIST]), result in dysregulated switch control and constitutive activation of c-KIT and PDGFR-α, leading to abnormal cell growth and survival.6, 9 In vitro, ripretinib also inhibits PDGF-β, tyrosine kinase with immunoglobulin and epidermal growth factor homology (TIE-2), vascular endothelial growth factor (VEGF)-2, and b-Raf serine-threonine kinase (BRAF).1
Ripretinib is metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A4 and, to a lesser extent, by CYP2C8 and CYP2D6.1 The main circulating metabolite, DP-5439, has been shown to be equipotent and has similar activity as ripretinib in vitro and in pharmacokinetic studies in humans.1, 4, 6, 8 When ripretinib is administered over a dose range of 20-250 mg in patients with advanced malignancies, systemic exposure or ripretinib increases in a dose proportional manner and peak plasma concentration increases in a less than a dose-proportional manner; systemic exposure and peak plasma concentration of DP-5439 increase in a less than a dose-proportional manner.1 Following oral administration of a single dose, the median time to peak plasma concentrations of ripretinib and DP-5439 are 4 and 15.6 hours, respectively.1 Steady-state concentrations of ripretinib and DP-5439 are reached within 14 days of once-daily dosing.1 No clinically significant differences in peak plasma concentrations and area under the concentration-time curve (AUC) were observed between administration of ripretinib with a high-fat meal and under fasted conditions.1 Ripretinib and DP-5439 are highly bound (more than 99%) to plasma proteins (mainly albumin and α1-acid glycoprotein).1 Following oral administration of a single 150-mg dose of ripretinib, 34% of the dose was recovered in feces as unchanged drug and to a lesser extent, as DP-5439 (6%); less than 0.1% of the dose is eliminated in urine.1 The mean elimination half-life of ripretinib and DP-5439 are 14.8 and 17.8 hours, respectively.1
The pharmacokinetics of ripretinib and DP-5439 do not appear to be affected substantially by age (19-87 years), sex, race, and body weight (39-138 kg).1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Ripretinib can only be obtained through a limited network of specialty pharmacies and distributors.5 Contact manufacturer for specific ordering and availability information.5
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets | 50 mg | Deciphera |
1. Deciphera Pharmaceuticals, LLC. Qinlock® (ripretinib) tablets prescribing information. Waltham, MA; 2023 Oct. [Web]
2. US Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed 2024 Jun 4. [Web]
3. Blay JY, Serrano, C, Heinrich MC et al. Ripretinib in patients with advanced gastrointestinal stromal tumours (INVICTUS): a double-blind, randomised, placebo-controlled, phase 3 trial . Lancet Oncol . 2020; 21:923-34. [PubMed 32511981]
4. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 213973Orig1s000: Multi-discipline review. From FDA website. [Web]
5. Deciphera Pharmaceuticals.Qinlock® Support and Resources. 2024 Jun. From Qinlock® for Healthcare Professionals website. [Web]
6. Nemunaitis J, , Bauer S, Blay JY et al. Intrigue: Phase III study of ripretinib versus sunitinib in advanced gastrointestinal stromal tumor after imatinib . Future Oncol . 2020; 16:4251-264. [PubMed 31755321]
7. Smith BD, Kaufman MD, Wei-Ping, L et al. Ripretinib (DCC-2618) Is a Switch Control Kinase Inhibitor of a Broad Spectrum of Oncogenic and Drug-Resistant KIT and PDGFRA Variants. Cancer Cell . 2019; 35:738-51. [PubMed 31085175]
8. Lostrd-Bardaji MJ, Garcia-Illescas D, Valverde C et al. Ripretinib in gastrointestinal stromal tumor: the long-awaited step forward. Ther Adv Med Oncol . 2021; 13:1-12. [PubMed 33473249]
9. Dhillon, S. Ripretinib: First Approval . Drugs . 2020; 80:1133-8. [PubMed 32578014]
10001. Zalcberg JR. Ripretinib for the treatment of advanced gastrointestinal stromal tumor. Ther Adv Gastroenterol. 2021;14:1-12.
10002. Bauer S, Jones RL, Blay JY, et al. Ripretinib versus sunitinib in patients with advanced gastrointestinal stromal tumor after treatment with imatinib (INTRIGUE): a randomized, open-label, phase III trial. J Clin Oncol. 2022;40:3918-28.
10003. Blay JY, Serrano C, Heinrich MC, et al. Ripretinib in patients with advanced gastrointestinal stromal tumours (INVICTUS): a double-blind, randomized, placebo-controlled, phase 3 trial. Lancet Oncol. 20220;21(7):923-934.