QINLOCK
Clinical safety rating: caution
Comprehensive clinical and safety monograph for QINLOCK (QINLOCK).
Ripretinib is a switch-control tyrosine kinase inhibitor that inhibits KIT proto-oncogene receptor tyrosine kinase (KIT) and platelet-derived growth factor receptor alpha (PDGFRA) kinase signaling. It binds to both the switch pocket and the activation loop of KIT and PDGFRA, preventing kinase activation and inhibiting downstream signaling pathways involved in tumor cell proliferation and survival.
| Metabolism | Primarily metabolized by CYP3A4, with minor contributions from CYP2C8 and CYP2D6. |
| Excretion | Primarily hepatic metabolism, with <1% excreted unchanged in urine. Fecal excretion accounts for approximately 80% of the administered dose, with renal excretion of unchanged drug being minimal (<1%). |
| Half-life | Terminal elimination half-life is approximately 15 hours (range 11–20 hours) in patients with advanced GIST. This supports twice-daily dosing. |
| Protein binding | Approximately 94% bound to plasma proteins, primarily albumin. |
| Volume of Distribution | Apparent volume of distribution (Vd/F) is approximately 2,100 L (range 1,400–3,100 L), indicating extensive tissue distribution. |
| Bioavailability | Oral bioavailability is approximately 70% (range 50–90%) under fasting conditions. Absorption is reduced by high-fat meals (AUC decreased by about 30%). |
| Onset of Action | Clinical response (e.g., symptom improvement, tumor response) may be observed within 2–4 weeks of initiating therapy at the recommended dose. |
| Duration of Action | Continuous therapy is required to maintain disease control. Treatment duration is variable and based on individual patient tolerability and clinical response; median treatment duration in clinical trials was approximately 6 months. |
150 mg orally once daily with food, until disease progression or unacceptable toxicity.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment (CrCl ≥30 mL/min). Not studied in severe renal impairment (CrCl <30 mL/min) or end-stage renal disease. |
| Liver impairment | Mild hepatic impairment (Child-Pugh A): no adjustment. Moderate (Child-Pugh B): reduce dose to 100 mg orally once daily. Severe (Child-Pugh C): not recommended. |
| Pediatric use | Safety and efficacy not established in pediatric patients. |
| Geriatric use | No specific dose adjustment; no overall differences in safety or efficacy observed in patients aged ≥65 years compared to younger adults. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for QINLOCK (QINLOCK).
| Breastfeeding | There are no data on the presence of ripretinib in human milk, its effects on the breastfed infant, or its effects on milk production. Because of the potential for serious adverse reactions in breastfed infants from ripretinib, advise women not to breastfeed during treatment and for 1 week after the last dose. M/P ratio is unknown. |
| Teratogenic Risk | QINLOCK (ripretinib) is a kinase inhibitor. Based on its mechanism of action and animal studies, it may cause fetal harm when administered to pregnant women. There are no adequate and well-controlled studies in pregnant women. In animal reproduction studies, ripretinib caused embryo-fetal toxicity including reduced fetal body weights and skeletal abnormalities at maternal exposures below the recommended human dose. Therefore, it is contraindicated in pregnancy. Women of childbearing potential should use effective contraception during treatment and for at least 2 weeks after the last dose. |
■ FDA Black Box Warning
None.
| Serious Effects |
None.
| Precautions | ["Palmar-plantar erythrodysesthesia (hand-foot skin reaction)","Hypertension","Cardiac dysfunction (including left ventricular ejection fraction reduction)","Hemorrhage and gastrointestinal perforation","Wound healing complications","Hepatotoxicity","Embryo-fetal toxicity"] |
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| Fetal Monitoring | Monitor pregnant women exposed to QINLOCK for fetal toxicity. Perform pregnancy testing prior to initiation of therapy in women of childbearing potential. Use effective contraception during treatment and for at least 2 weeks post-treatment. No specific fetal monitoring guidelines established; consider ultrasound and fetal assessment if exposure occurs. |
| Fertility Effects | Based on animal studies, ripretinib may impair fertility in males and females of reproductive potential. In female rats, ripretinib caused decreased fertility and early embryo loss at clinically relevant exposures. In male rats, impaired spermatogenesis and reduced testicular weight were observed. The reversibility of these effects is unknown. |