The Effect of a High‐Fat Meal on the Pharmacokinetics of Brigatinib, an Oral Anaplastic Lymphoma Kinase Inhibitor, in Healthy Volunteers

Tugnait, Meera; Gupta, Neeraj; Hanley, Michael; Venkatakrishnan, Karthik; Sonnichsen, Daryl; Kerstein, David; Dorer, David J.; Narasimhan, Narayana I.

doi:10.1002/cpdd.641

Cited by 20 publications

(35 citation statements)

References 24 publications

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“…34 During food-effect studies, the brigatinib AUC and C max were reduced by 2% and 13%, respectively, in healthy subjects when administered with a high-fat meal (920 calories, 58 grams carbohydrate, 59 grams fat and 40 grams protein). 43 Therefore, patients were instructed to take brigatinib without regard to meals. 20…”

Section: Brigatinibmentioning

confidence: 99%

<p>Pharmacokinetic-Based Drug–Drug Interactions with Anaplastic Lymphoma Kinase Inhibitors: A Review</p>

Zhao¹,

Chen²,

Chu

et al. 2020

DDDT

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Anaplastic lymphoma kinase (ALK) inhibitors are important treatment options for non-small-cell lung cancer (NSCLC), associated with ALK gene rearrangement. Patients with ALK gene rearrangement show sensitivity to and benefit clinically from treatment with ALK tyrosine kinase inhibitors (ALK-TKIs). To date, crizotinib, ceritinib, alectinib, brigatinib, lorlatinib, and entrectinib have received approval from the US Food and Drug Administration and/or the European Medicines Agency for use during the treatment of ALKgene-rearrangement forms of NSCLC. Although the oral route of administration is convenient and results in good compliance among patients, oral administration can be affected by many factors, such as food, intragastric pH, cytochrome P450 enzymes, transporters, and p-glycoprotein. These factors can result in increased risks for serious adverse events or can lead to reduced therapeutic effects of ALK-TKIs. This review characterizes and summarizes the pharmacokinetic parameters and drug-drug interactions associated with ALK-TKIs to provide specific recommendations for oncologists and clinical pharmacists when prescribing ALK-TKIs.

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Section: Brigatinibmentioning

confidence: 99%

<p>Pharmacokinetic-Based Drug–Drug Interactions with Anaplastic Lymphoma Kinase Inhibitors: A Review</p>

Zhao¹,

Chen²,

Chu

et al. 2020

DDDT

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“…2 The recommended dose of brigatinib is 90 mg orally once daily for the first 7 days of treatment, which, if tolerated, is followed by escalation to 180 mg once daily. 5 Therefore, brigatinib can be administered with or without food. 3 After administration of 180 mg brigatinib once daily in patients with cancer, the mean plasma elimination half-life was 25 hours, with a corresponding steady-state apparent oral clearance (CL/F) of 12.7 L/h.…”

mentioning

confidence: 99%

“…Brigatinib single-and repeat-dose systemic exposures increased dose-proportionally following administration in patients with cancer across the dose range of 60-240 mg once daily. 5 Following administration of a single 180-mg oral dose of [ 14 C]-brigatinib to healthy volunteers, 65% and 25% of the administered dose were recovered in feces and urine, respectively. 3,4 A study in healthy volunteers demonstrated that consumption of a high-fat meal decreased brigatinib peak concentration (C max ) by 13% and delayed median time to C max (t max ) from 2 hours to 5 hours compared with fasted-state administration, but it had no impact on total systemic exposure.…”

mentioning

confidence: 99%

“…3,4 A study in healthy volunteers demonstrated that consumption of a high-fat meal decreased brigatinib peak concentration (C max ) by 13% and delayed median time to C max (t max ) from 2 hours to 5 hours compared with fasted-state administration, but it had no impact on total systemic exposure. 5 Therefore, brigatinib can be administered with or without food. 5 Following administration of a single 180-mg oral dose of [ 14 C]-brigatinib to healthy volunteers, 65% and 25% of the administered dose were recovered in feces and urine, respectively.…”

mentioning

confidence: 99%

“…5 Therefore, brigatinib can be administered with or without food. 5 Following administration of a single 180-mg oral dose of [ 14 C]-brigatinib to healthy volunteers, 65% and 25% of the administered dose were recovered in feces and urine, respectively. 4 Metabolic clearance of brigatinib was primarily via N-demethylation (to Ndesmethyl brigatinib) and cysteine conjugation.…”

mentioning

confidence: 99%

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Effects of Strong CYP2C8 or CYP3A Inhibition and CYP3A Induction on the Pharmacokinetics of Brigatinib, an Oral Anaplastic Lymphoma Kinase Inhibitor, in Healthy Volunteers

Tugnait

Gupta

Hanley

et al. 2019

Clinical Pharm in Drug Dev

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In vitro data support involvement of cytochrome P450 (CYP)2C8 and CYP3A4 in the metabolism of the anaplastic lymphoma kinase inhibitor brigatinib. A 3-arm, open-label, randomized, single-dose, fixed-sequence crossover study was conducted to characterize the effects of the strong inhibitors gemfibrozil (of CYP2C8) and itraconazole (of CYP3A) and the strong inducer rifampin (of CYP3A) on the single-dose pharmacokinetics of brigatinib. Healthy subjects (n = 20 per arm) were administered a single dose of brigatinib (90 mg, arms 1 and 2; 180 mg, arm 3) alone in treatment period 1 and coadministered with multiple doses of gemfibrozil 600 mg twice daily (BID; arm 1), itraconazole 200 mg BID (arm 2), or rifampin 600 mg daily (QD; arm 3) in period 2. Compared with brigatinib alone, coadministration of gemfibrozil with brigatinib did not meaningfully affect brigatinib area under the plasma concentration-time curve (AUC 0-inf ; geometric least-squares mean [LSM] ratio [90%CI], 0.88 [0.83-0.94]). Coadministration of itraconazole with brigatinib increased AUC 0-inf (geometric LSM ratio [90%CI], 2.01 [1.84-2.20]). Coadministration of rifampin with brigatinib substantially reduced AUC 0-inf (geometric LSM ratio [90%CI], 0.20 [0.18-0.21]) compared with brigatinib alone. The treatments were generally tolerated. Based on these results, strong CYP3A inhibitors and inducers should be avoided during brigatinib treatment. If concomitant use of a strong CYP3A inhibitor is unavoidable, the results of this study support a dose reduction of brigatinib by approximately 50%. Furthermore, CYP2C8 is not a meaningful determinant of brigatinib clearance, and no dose modifications are needed during coadministration of brigatinib with CYP2C8 inhibitors.

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A Phase 1 Drug‐Drug Interaction Study Between Brigatinib and the CYP3A Substrate Midazolam in Patients With ALK‐Positive or ROS1‐Positive Solid Tumors

Hanley

D’Arcangelo

Felip

et al. 2023

The Journal of Clinical Pharma

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Brigatinib is a next‐generation anaplastic lymphoma kinase (ALK) inhibitor approved for the treatment of patients with ALK‐positive (ALK+) non–small cell lung cancer (NSCLC). A phase 1 drug‐drug interaction study was conducted to evaluate the effect of multiple‐dose administration of brigatinib on the single‐dose pharmacokinetics of midazolam, a sensitive cytochrome P450 3A substrate. In cycle 1, patients with ALK+ or ROS1+ solid tumors, including NSCLC, received a single 3‐mg dose of midazolam as an oral solution alone on day 1 and then coadministered with brigatinib on day 21 (brigatinib 90 mg once daily on days 2‐8; 180 mg once daily on days 9‐28). After cycle 1, patients could continue to receive brigatinib in 28‐day treatment cycles. The primary study objective was to characterize the effect of brigatinib 180 mg once daily on midazolam pharmacokinetics. The secondary objective was to assess safety. Exploratory efficacy endpoints included objective response rate and progression‐free survival. Brigatinib was generally well tolerated, and safety data were consistent with the known safety profile. Among the 10 patients with ALK+ NSCLC, the confirmed objective response rate was 30% and median progression‐free survival was 7.2 months. Coadministration of brigatinib reduced midazolam maximum observed plasma concentration by ≈16% (geometric least‐squares mean ratio, 0.836 [90%CI, 0.662‐1.056]) and area under the plasma concentration–time curve from time 0 to infinity by ≈26% (geometric least‐squares mean ratio, 0.741 [90%CI, 0.600‐0.915]). Thus, brigatinib is a weak inducer of cytochrome P450 3A in vivo.

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The Effect of a High‐Fat Meal on the Pharmacokinetics of Brigatinib, an Oral Anaplastic Lymphoma Kinase Inhibitor, in Healthy Volunteers

Cited by 20 publications

References 24 publications

<p>Pharmacokinetic-Based Drug–Drug Interactions with Anaplastic Lymphoma Kinase Inhibitors: A Review</p>

<p>Pharmacokinetic-Based Drug–Drug Interactions with Anaplastic Lymphoma Kinase Inhibitors: A Review</p>

Effects of Strong CYP2C8 or CYP3A Inhibition and CYP3A Induction on the Pharmacokinetics of Brigatinib, an Oral Anaplastic Lymphoma Kinase Inhibitor, in Healthy Volunteers

A Phase 1 Drug‐Drug Interaction Study Between Brigatinib and the CYP3A Substrate Midazolam in Patients With ALK‐Positive or ROS1‐Positive Solid Tumors

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