Effects of Renal Function on Crizotinib Pharmacokinetics: Dose Recommendations for Patients with ALK-Positive Non-Small Cell Lung Cancer

Tan, Weiwei; Yamazaki, Shinji; Johnson, Theodore R.; Wang, Rong; O'Gorman, Melissa; Kirkovsky, Leonid; Boutros, Tanya; Brega, Nicoletta; Bello, Akintunde

doi:10.1007/s40261-016-0490-z

Cited by 19 publications

(10 citation statements)

References 14 publications

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“…moderate RI did not significantly affect the PK of crizotinib (78). Due to the small size of the increases in crizotinib exposure (5-15%), dose adjustment is not required for patients with mild to moderate RI (24, 25,77,78). However, patients with severe RI exhibited increases in crizotinib AUC and C max of 79 and 34%, respectively, compared to subjects with NRF (77).…”

Section: Cabozantinibmentioning

confidence: 94%

“…Due to the small size of the increases in crizotinib exposure (5-15%), dose adjustment is not required for patients with mild to moderate RI (24, 25,77,78). However, patients with severe RI exhibited increases in crizotinib AUC and C max of 79 and 34%, respectively, compared to subjects with NRF (77). Thus, crizotinib at a dose of 250 mg once daily is recommended for patients with severe RI (24, 25,77).…”

Section: Cabozantinibmentioning

confidence: 99%

“…However, patients with severe RI exhibited increases in crizotinib AUC and C max of 79 and 34%, respectively, compared to subjects with NRF (77). Thus, crizotinib at a dose of 250 mg once daily is recommended for patients with severe RI (24, 25,77). A case report demonstrated that crizotinib 250 mg once daily was tolerated and effective for a patient with ESRD not undergoing HD (79).…”

Section: Cabozantinibmentioning

confidence: 99%

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Dose adjustment for tyrosine kinase inhibitors in non‑small cell lung cancer patients with hepatic or renal function impairment (Review)

Zhao¹,

Chen²,

Long³

et al. 2020

Oncol Rep

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In recent years, a number of tyrosine kinase inhibitors (TKIs) have been approved for the treatment of non-small cell lung cancer. These novel treatments exhibit improved efficacy and toxicity when compared to conventional chemotherapy agents. TKIs are administered orally, which has the advantages of improved flexibility and convenience for the patients. However, challenges have arisen in the use of these novel agents. Prescribing drugs for patients with hepatic or renal function impairment poses a challenge for clinicians due to the large pharmacokinetic variability in each individual patient. Moreover, several TKIs have been shown to cause laboratory test abnormalities normally associated with hepatic or renal injury. The aim of the present review was to discuss the effects of hepatic and renal function impairment on the pharmacokinetic variability of 17 TKIs and their potential hepatotoxicity and nephrotoxicity, and to recommend dose adjustment for patients with hepatic or renal impairment.

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Section: Cabozantinibmentioning

confidence: 94%

Section: Cabozantinibmentioning

confidence: 99%

Section: Cabozantinibmentioning

confidence: 99%

See 1 more Smart Citation

Dose adjustment for tyrosine kinase inhibitors in non‑small cell lung cancer patients with hepatic or renal function impairment (Review)

Zhao¹,

Chen²,

Long³

et al. 2020

Oncol Rep

View full text Add to dashboard Cite

show abstract

Section: Methodsmentioning

confidence: 99%

“…In keeping with the EMA and FDA guidelines and common study designs in Phase I renal drug studies, 22,23 a 2‐stage method was used here. In the first stage, the value of CL is estimated using a noncompartmental approach 22,23 . In this work, we sampled CL values directly from an assumed distribution (details in Appendix 1) rather than simulating concentration data for individuals to estimate the value of CL using noncompartmental analysis.…”

Section: Methodsmentioning

confidence: 99%

Evaluation of designs for renal drug studies based on the European Medicines Agency and Food and Drug Administration guidelines for drugs that are predominantly secreted

Pradhan

Wright

Duffull

2020

Brit J Clinical Pharma

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Aims Dose adjustment for drugs eliminated by the kidneys generally assume a linear relationship between renal drug clearance (CLR) and glomerular filtration rate (GFR). This assumption may not hold for drugs that undergo extensive tubular secretion where nonlinearity in drug handling is expected. The aim of this study is to determine if renal drug study designs recommended by the European Medicines Agency (EMA) and Food and Drug Administration (FDA) could distinguish linear from nonlinear renal drug handling. Methods In this simulation and estimation study, the study designs based on the EMA and FDA guidelines for Phase I renal drug studies were evaluated for their ability to discriminate a linear from a nonlinear relationship between CLR and GFR. The number of subjects for each simulated study ranged from 4 to 960. Power, relative standard error and bias were calculated. Results Study designs under the EMA and FDA guidelines required ≥8 and ≥48 subjects, respectively, to achieve ≥80% power to discriminate a linear from nonlinear relationship between CLR and GFR. The relative standard error of estimated parameters were 13–37 and 17–44% for the designs with 24 subjects under the EMA and FDA guidelines, respectively. The bias in parameter estimates under the EMA designs were not evident, however, they were biased (13–21%) under the FDA designs. Conclusion The EMA design was found to require fewer subjects (n = 8) compared to the FDA (n = 48) to discriminate linear from nonlinear drug renal handling at ≥80% study power while both the designs perform poorly for the parameter precision.

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Use of Modeling and Simulation to Predict the Influence of Triazole Antifungal Agents on the Pharmacokinetics of Crizotinib

Chen

2022

Clinical Pharm in Drug Dev

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Crizotinib is used for the treatment of c-ros oncogene 1-positive advanced non-small-cell lung cancer. Triazole antifungal agents are widely used for invasive fungal infections in clinical practice. To predict the potential influence of different triazoles (voriconazole, fluconazole, and itraconazole) on the pharmacokinetics of crizotinib by modeling and simulation the physiologically based pharmacokinetic models were established and validated in virtual cancer subjects through Simcyp software based on the essential physicochemical properties and pharmacokinetic data collected. The validated physiologically based pharmacokinetic models were applied to predict the drug-drug interactions between crizotinib and different triazoles (voriconazole, fluconazole, or itraconazole) in patients with cancer. Crizotinib and triazole antifungal agents were administered orally. The predicted plasma concentration vs time profiles of crizotinib, voriconazole, fluconazole, and itraconazole showed good agreement with observed, respectively. The geometric mean area under the plasma concentration-time curve (AUC) of crizotinib was increased by 84%, 58%, and 79% when coadministered with voriconazole, fluconazole, or itraconazole at multiple doses, respectively. The drug-drug interaction results showed increased pharmacokinetic exposure (maximum plasma concentration and area under the plasma concentration-time curve) of crizotinib when coadministrated with different triazoles (voriconazole > itraconazole > fluconazole). Among the 3 triazoles, voriconazole exhibited the most significant influence on the pharmacokinetic exposure of crizotinib. In clinic, adverse drug reactions and toxicity related to crizotinib should be carefully monitored, and therapeutic drug monitoring for crizotinib is recommended to guide dosing and optimize treatment when coadministered with voriconazole, fluconazole, or itraconazole.

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Effects of Renal Function on Crizotinib Pharmacokinetics: Dose Recommendations for Patients with ALK-Positive Non-Small Cell Lung Cancer

Abstract: These results suggest no dose adjustment for patients with mild or moderate renal impairment. The recommended crizotinib dose for patients with severe renal impairment not requiring dialysis is 250 mg once daily.

Cited by 19 publications

References 14 publications

Dose adjustment for tyrosine kinase inhibitors in non‑small cell lung cancer patients with hepatic or renal function impairment (Review)

Dose adjustment for tyrosine kinase inhibitors in non‑small cell lung cancer patients with hepatic or renal function impairment (Review)

Evaluation of designs for renal drug studies based on the European Medicines Agency and Food and Drug Administration guidelines for drugs that are predominantly secreted

Use of Modeling and Simulation to Predict the Influence of Triazole Antifungal Agents on the Pharmacokinetics of Crizotinib

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