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 m 2 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. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?Mobocertinib is a first-in-class, oral, irreversible tyrosine kinase inhibitor that demonstrated a favorable benefit-risk profile in patients with metastatic nonsmall cell lung cancer (mNSCLC) with epidermal growth factor receptor gene

Discovery of mobocertinib, a new irreversible tyrosine kinase inhibitor indicated for the treatment of non-small-cell lung cancer harboring EGFR exon 20 insertion mutations

“…It is believed that these two active metabolites do contribute to the observed efficacy of mobocertinib in patients [ 40 ]. Additionally, co-administration of mobocertinib with a strong CYP3A inhibitor increased its AUC by 527% while co-administration with a strong CYP3A inducer decreased its AUC by 95% [ 73 ]. Repeated dosing of mobocertinib was associated with lower-than-expected accumulation due to possible auto-induction of its metabolism via the CYP3A enzymes [ 74 ].…”

“…After a single oral dose of radiolabeled mobocertinib (160 mg), about 76% of the radioactivity was recovered in feces with ~6% as unchanged mobocertinib while about 4% was recovered in urine with ~1% as unchanged mobocertinib [ 72 , 73 ]. The amount of metabolites recovered in urine was low or below the limit of detection, suggesting that renal excretion is a minor pathway for its elimination [ 71 , 73 ].…”

Mobocertinib Dose Rationale in Patients with Metastatic NSCLC with EGFR Exon 20 Insertions: Exposure–Response Analyses of a Pivotal Phase I/II Study

“…Modelbased simulations demonstrated that age, body weight, race, sex, creatinine clearance, estimated glomerular filtration rate, alanine aminotransferase, aspartate aminotransferase, bilirubin, and albumin did not have clinically meaningful effects on the systemic exposures of mobocertinib, AP32960, and AP32914 in patients with mNSCLC, suggesting that dose adjustment is not required based on these covariates. 7 The objective of this exposure-response analysis was to assess potential relationships between exposure to mobocertinib and its active metabolites (AP32960 and AP32914) with clinical ORRs, rates of selected AEs, and time to first dose reduction in patients with EGFRex20inspositive mNSCLC previously treated with platinum-based chemotherapy who received mobocertinib 160 mg q.d. utilizing data from the phase I/II study.…”

“…An enzyme compartment with drug‐dependent stimulation of enzyme production (i.e., auto‐induction) was included to describe the observed nonlinear PK of the three moieties. Model‐based simulations demonstrated that age, body weight, race, sex, creatinine clearance, estimated glomerular filtration rate, alanine aminotransferase, aspartate aminotransferase, bilirubin, and albumin did not have clinically meaningful effects on the systemic exposures of mobocertinib, AP32960, and AP32914 in patients with mNSCLC, suggesting that dose adjustment is not required based on these covariates 7 …”

“…A population pharmacokinetic (PK) model for plasma concentrations of mobocertinib, AP32960, and AP32914 was developed based on data from two phase I studies in healthy adults and two phase I/II studies in patients with mNSCLC, including the dose‐escalation, expansion, and extension parts of the phase I/II study. The PK of mobocertinib, AP32960, and AP32914 was well‐characterized by a joint model, which described the PK of mobocertinib, AP32960, and AP32914 7 . The PK of mobocertinib and the PK of AP32960 were described by a two‐compartment PK model, whereas a one‐compartment model was used to describe the PK of AP32914.…”