Clinical Pharmacology of Brigatinib: A Next-Generation Anaplastic Lymphoma Kinase Inhibitor

Abstract

Brigatinib, a next-generation anaplastic lymphoma kinase (ALK) inhibitor designed to overcome mechanisms of resistance associated with crizotinib, is approved for the treatment of ALK-positive advanced or metastatic non-small cell lung cancer. After oral administration of single doses of brigatinib 30-240 mg, the median time to reach maximum plasma concentration ranged from 1 to 4 h. In patients with advanced malignancies, brigatinib showed dose linearity over the dose range of 60-240 mg once daily. A high-fat meal had no clinically meaningful effect on systemic exposures of brigatinib (area under the plasma concentration-time curve); thus, brigatinib can be administered with or without food. In a population pharmacokinetic analysis, a three-compartment pharmacokinetic model with transit absorption compartments was found to adequately describe brigatinib pharmacokinetics. In addition, the population pharmacokinetic analyses showed that no dose adjustment is required based on body weight, age, race, sex, total bilirubin (< 1.5× upper limit of normal), and mild-to-moderate renal impairment. Data from dedicated phase I trials have indicated that no dose adjustment is required for patients with mild or moderate hepatic impairment, while a dose reduction of approximately 40% (e.g., from 180 to 120 mg) is recommended for patients with severe hepatic impairment, and a reduction of approximately 50% (e.g., from 180 to 90 mg) is recommended when administering brigatinib to patients with severe renal impairment. Brigatinib is primarily metabolized by cytochrome P450 (CYP) 3A, and results of clinical drug-drug interaction studies and physiologically based pharmacokinetic analyses have demonstrated that coadministration of strong or moderate CYP3A inhibitors or inducers with brigatinib should be avoided. If coadministration with a strong or moderate CYP3A inhibitor cannot be avoided, the dose of brigatinib should be reduced by approximately 50% (strong CYP3A inhibitor) or approximately 40% (moderate CYP3A inhibitor), respectively. Brigatinib is a weak inducer of CYP3A in vivo; data from a phase I drug-drug interaction study showed that coadministration of brigatinib 180 mg once daily reduced the oral midazolam area under the plasma concentration-time curve from time zero to infinity by approximately 26%. Brigatinib did not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6 at clinically relevant concentrations in vitro. Exposure-response analyses based on data from the ALTA (ALK in Lung Cancer Trial of AP26113) and ALTA-1L pivotal trials of brigatinib confirm the favorable benefit versus risk profile of the approved titration dosing regimen of 180 mg once daily (after a 7-day lead-in at 90 mg once daily).

Fig. 1

Chemical structure of brigatinib

Fig. 2

Simulated average drug concentration at steady state (C_av) for brigatinib 90 and 180 mg (black circles and lines) versus 50% inhibitory concentration (IC₅₀) and 90% inhibitory concentration (IC₉₀) values for native EML4-ALK (blue lines) and the G1202R mutant (red lines). In vitro potency estimates were adjusted upward by a factor of two to account for the observed in vitro potency shift in the presence of plasma proteins [24]. Reprinted from Gupta et al. [24] (with permission indicated by the Creative Commons License Deed; CC BY-NC 4.0)

Fig. 3

Linear regression plot of apparent oral clearance (CL/F) versus renal clearance (CL_R) based on data from healthy volunteers with normal renal function in the dedicated renal impairment study [34]

Fig. 4

In vivo metabolic pathways of brigatinib after administration of a single oral 180-mg dose of [¹⁴C]-brigatinib to healthy male volunteers

Fig. 5

Predicted brigatinib exposure for the 180-mg dose based on the final population pharmacokinetic model stratified by covariates of interest using data from the phase I/II and phase II ALTA (ALK in Lung Cancer Trial of AP26113) studies. The vertical dashed lines represent the median and 5th and 95th percentiles of predicted area under the plasma concentration–time curve (AUC) in a typical patient with a baseline albumin level of 38 g/dL. For categorical covariates, the ratio of exposure for the category versus the reference category is shown whereas the ratio of exposure for the 95th and 5th percentiles of the covariate versus the medians is shown for continuous covariates. The black shaded bar represents the 5th–95th percentile exposure range across the entire population. The blue shaded bar represents the influence of baseline albumin on exposure. ALT alanine aminotransferase, AST aspartate aminotransferase, AUC_SS area under the plasma concentration–time curve at steady state, CI confidence interval, eGFR estimated glomerular filtration rate. ^aCategories for eGFR: normal, ≥ 90 mL/min/1.73 m²; mild impairment, 60 to < 90 mL/min/1.73 m²; moderate impairment, 30 to < 60 mL/min/1.73 m² [24]. Adapted or reprinted from Gupta et al. [24]

Fig. 6

Mean (± standard deviation) unbound brigatinib plasma concentration–time profiles from a 0 to 24 h postdose, linear scale and b from 0 to 168 h post-dose, log-linear scale in patients with normal renal function versus severe renal impairment, and c from 0 to 24 h post-dose, linear scale, and d from 0 to 192 h postdose, log-linear scale in patients with normal hepatic function versus chronic hepatic impairment [34, 41, 48]. Figure 5a, b are reprinted from Gupta et al. [34]. Figure 5c, d are adapted from Hanley et al. [48]

Fig. 7

Log-linear plots of mean (± standard deviation [SD]) plasma brigatinib concentration–time profiles with and without coadministration of a the strong cytochrome P450 (CYP) 2C8 inhibitor gemfibrozil, b the strong CYP3A inhibitor itraconazole, and c the strong CYP3A inducer rifampin [31]. Adapted from Tugnait et al. [31]

Fig. 8

Scatterplots of a the QT interval corrected using Fridericia’s formula (QTcF) [23], b the PR interval, and c heart rate (HR) responses versus brigatinib concentrations with model-predicted typical responses and a 90% confidence interval. Dots represent brigatinib concentrations, and in each graph, the line and gray area represent the model-predicted typical responses and 90% confidence intervals. Error bars show the response at 1452 ng/mL (i.e., geometric mean steady-state maximum plasma concentration at 180 mg once daily) and 2904 ng/mL (i.e., maximum plasma concentration for patients with impaired elimination, corresponding to twice the geometric mean steady-state maximum plasma concentration). Adapted from Gupta et al. [23]

Fig. 9

Parametric time-to-event final model for progression-free survival (PFS): a visual predictive check of the final model by the ALTA (ALK in Lung Cancer Trial of AP26113) treatment arm, and b median PFS under different brigatinib dosing regimens (N = 10,000 simulated patients) [23]. In panel a, the blue shaded area represents the spread (5th–95th percentiles) of the simulated Kaplan–Meier curve based on the 500 simulated replicates from the final model; the blue solid line represents the median of the values of the simulated Kaplan–Meier curves. The gray solid lines represent the actual Kaplan–Meier curves, with the gray dashed lines representing the corresponding 95% confidence interval (CI). The visual predictive check evaluated the model by taking the individual survival function values, $S(t_j,x_i)$, at the time ($t_j$) of all events and predicting PFS status for each patient by timepoint based on the final model estimates and each patient’s daily exposure [51]. A survival time ($T$) for patient $i$ was generated by the inverse cumulative distribution function method [–54]. Survival times were randomly simulated based on survival probabilities on a grid of timepoints using the algorithm of Rich et al. [54]. In panel b, the red line represents the median survival with the tan shaded area representing the 95% CI for the median PFS. Adapted from Gupta et al. [23]

Fig. 10

Visual predictive check of a logistic regression model for a grade ≥ 2 rash and b grade ≥ 2 amylase increase based on time-averaged brigatinib exposure. Open blue circles reflect the observed events. The filled black symbols are the observed probability of an event, and the error bars are standard error [sqrt (P*(1 − P)/N)] for quantiles at (100 × 1/5th) percentiles (vertical dotted lines) of exposures (plotted at the median value within each quantile). The blue dashed lines are the predicted probabilities based on the final models. The blue shaded areas represent the 95% confidence band based on 1000 bootstrap samples [23]. AUC area under the plasma concentration–time curve. Adapted from Gupta et al. [23]

Fig. 11

Exposure–efficacy analyses. a Kaplan–Meier probability of progression-free survival (PFS) by simulated brigatinib exposure quartiles. To evaluate the relationship between brigatinib exposure and PFS, a static exposure metric of time‐averaged area under the plasma concentration–time curve (AUC) between the last two disease assessment scans preceding progression or censoring was used. Progression-free survival Kaplan–Meier estimates plotted by exposure quartiles suggested that patients with higher exposure had a faster onset and a higher incidence of disease progression than those with lower exposure. Values for the crizotinib arm of the study are superimposed; however, no exposure values were available for crizotinib. For median PFS values, NA indicates that the probability of having no disease progression or death has not yet gone beyond 0.50 and hence the median survival time cannot be determined. ^aSimulated exposure metric is time‐averaged AUC between the last two disease assessment scans preceding progression for PFS or censoring. Observed (Obs) incidence and model‐predicted probability of b objective response rate (ORR) and c intracranial objective response rate (iORR) as a function of brigatinib exposure. The relationships between ORR and iORR and brigatinib exposure were analyzed using the static exposure metric of time‐averaged AUC between the last two disease assessment scans preceding best confirmed response. The probability of response was plotted against predicted exposure values, and probabilities were calculated by observed exposure quartiles or tertiles. Exposure–clinical response relationships were characterized by logistic regression models, which did not show a significant relationship between the probability of achieving ORR and time‐averaged brigatinib AUC between the last two disease assessment scans preceding the best confirmed objective response. In contrast, time‐averaged brigatinib AUC between the last two disease assessment scans preceding best confirmed intracranial response was a statistically significant predictor of iORR in patients with brain metastases at baseline. Dotted curves represent the 95% confidence interval (CI) of the logistic regression model prediction. The horizontal black line separated by vertical black solid lines denotes the brigatinib exposure range in each quartile (ORR) and tertile (iORR). Black dots (vertical lines) represent the observed proportion of patients (95% CI) in each quartile (ORR) and tertile (iORR). n/N is the number of patients with events/total number of patients in each quartile (ORR) and tertile (iORR). Gray open circles represent observed individual data [25]. NA not available. Reprinted from Gupta et al. [25]

Fig. 12

Exposure–safety analyses. Observed (Obs) incidence and predicted probability of a grade ≥ 3 lipase increase and b grade ≥ 2 amylase increase as a function of brigatinib exposure. The relationship between time‐averaged area under the plasma concentration–time curve (AUC) across days 8–14 of cycle 1 and adverse event probability was examined using logistic regression models. The analysis demonstrated a statistically significant relationship between exposure and grade ≥ 3 lipase increase and grade ≥ 2 amylase increase. c Kaplan–Meier estimates for the time to first brigatinib dose reduction stratified by time‐averaged AUC quartiles. To explore the relationship between brigatinib exposure and dose reductions, Kaplan–Meier plots of the time to first brigatinib dose reduction were generated for brigatinib exposure (time‐averaged AUC to the first occurrence of a dose reduction) quartiles. No discernible effect of brigatinib exposure on the time to first brigatinib dose reduction was noted. Values for the crizotinib arm of the study are superimposed; however, no exposure values were available for crizotinib. Dotted curves represent the 95% confidence interval (CI) of the logistic regression model prediction. The horizontal black line separated by vertical black solid lines denotes the brigatinib exposure range in each quartile. Black dots (vertical lines) represent the observed proportion of patients (95% CI) in each quartile. n/N is the number of patients with events/total number of patients in each quartile. Gray open circles represent observed individual data [25]. Reprinted from Gupta et al. [25]