Population pharmacokinetics of mobocertinib in healthy volunteers and patients with non-small cell lung cancer

Abstract

Mobocertinib is an oral tyrosine kinase inhibitor approved for treatment of patients with locally advanced or metastatic non-small cell lung cancer (mNSCLC) with epidermal growth factor receptor gene (EGFR) exon 20 insertion mutations whose disease has progressed on or after platinum-based chemotherapy. This population pharmacokinetic (PK) analysis describes the PK of mobocertinib and its active metabolites, AP32960, and AP32914, using data from two phase I studies in healthy volunteers (n = 110) and two phase I/II studies in patients with mNSCLC (n = 317), including the pivotal phase I/II study. The plasma PK of mobocertinib, AP32960, and AP32914 were well-characterized by a joint semimechanistic model that included two compartments for mobocertinib with absorption via three transit compartments, two compartments for AP32960, and one compartment for AP32914. The observed time-dependency in PK was described by an enzyme compartment with drug and metabolite concentration-dependent stimulation of enzyme production, resulting in the enzyme increasing the apparent clearance of mobocertinib, AP32960, and AP32914. Effects of healthy volunteer status (vs. patients with mNSCLC) on apparent oral clearance of all three moieties and on apparent central volume of distribution for mobocertinib were included as structural covariates in the final model. No clinically meaningful differences in mobocertinib PK were observed based on age (18-86 years), race, sex, body weight (37.3-132 kg), mild-to-moderate renal impairment (estimated glomerular filtration rate 30-89 ml/min/1.73 m² by modification of diet in renal disease equation), or mild-to-moderate hepatic impairment, suggesting that no dose adjustment is required based on these covariates in patients with mNSCLC.

FIGURE 1

Structural model describing the PK of mobocertinib and its active metabolites, AP32960 and AP32914. The enzyme compartment impacted all three elimination pathways from the central compartment for mobocertinib; however, only one dashed arrow is shown for visual simplicity. CL/F, apparent oral clearance; F, bioavailability; f _m, fraction metabolized; K _a, absorption rate constant; K _tr, transit rate constant; mobo, mobocertinib; PK, pharmacokinetic; Q/F, intercompartmental clearance; Vc/F, apparent central volume of distribution; Vp/F, apparent peripheral volume of distribution

FIGURE 2

Observed concentrations of mobocertinib, AP32960, and AP32914 versus (a) population‐predicted concentrations and (b) individual‐predicted concentrations from the final population pharmacokinetic (PK) model. Conditional weighted residuals (CWRES) versus (c) time after first dose and (d) population‐predicted values from the final population PK model. Dots represent individual data points, solid blue lines represent linear regression lines, and gray lines represent lines of identity

FIGURE 3

Prediction‐corrected visual predictive checks of the final population PK model showing mobocertinib plasma concentrations in patients with mNSCLC in (a) the global phase I/II study and (b) in the Japanese phase I/II study, and showing molar sum plasma concentrations of mobocertinib, AP32960, and AP32914 in patients with mNSCLC in (c) the global phase I/II study and (d) in the Japanese phase I/II study. The top graphs in each panel show data for mobocertinib doses greater than or equal to 120 mg and the bottom graphs show data for the 160‐mg dose. The red solid line represents the observed median; green and blue solid lines represent observed 5th and 95th percentiles. The red area represents the 95% CI of the simulated median, and green and blue areas represent the 95% CIs of the simulated 5th and 95th percentiles. Only bins with more than four observations greater than the lower limit of quantification are displayed. CI, confidence interval; mNSCLC, metastatic non‐small cell lung cancer; NSCLC, non‐small cell lung cancer; PK, pharmacokinetic

FIGURE 4

(a) Individual‐predicted molar sum exposure (AUC_24 h) after administration of mobocertinib 160 mg once daily (cycle 2, day 1) stratified by patient status. Red and blue dots represent means. Numbers (brackets) at the top of plots show the percentage change in mean AUC_24 h (with 95% CI) in the healthy volunteer category relative to the patient category, whereas numbers at the bottom of the plots show the number of individuals in each category. (b) Individual‐predicted relative molar sum exposure following daily dosing of mobocertinib 160 mg in the patient population based on the final population PK model stratified by covariates of interest. For categorical covariates, the ratio of exposure for the category versus the reference category is shown. For continuous covariates, the ratios of exposure for the 5th and 95th percentiles of the covariate versus the median are shown. The blue bar illustrates the 5th to 95th percentile exposure range across the entire patient population. ALT, alanine aminotransferase; AST, aspartate aminotransferase; AUC_24 h, area under the concentration‐time curve from time 0 to 24 h postdose; CI, confidence interval; eGFR, estimated glomerular filtration rate calculated using the modification of diet in renal disease (MDRD) formula; PK, pharmacokinetic