Effects of Itraconazole and Rifampin on the Pharmacokinetics of Mobocertinib (TAK‐788), an Oral Epidermal Growth Factor Receptor Inhibitor, in Healthy Volunteers

Abstract

is an investigational oral tyrosine kinase inhibitor targeting epidermal growth factor receptor and human epidermal growth factor 2. A phase 1 open-label, 2-period, fixed-sequence, 2-part study (NCT03928327) characterized effects of a strong CYP3A4 inhibitor (itraconazole) and inducer (rifampin) on the pharmacokinetics (PK) of mobocertinib and its active metabolites, AP32960 and AP32914. Healthy volunteers (n = 12 per part) received a single dose of mobocertinib alone (20 mg, part 1; 160 mg, part 2) and with multiple doses of itraconazole 200 mg once daily (part 1) or rifampin 600 mg once daily (part 2). Coadministration of itraconazole with mobocertinib increased the combined molar area under the plasma concentration-time curve from time 0 to infinity (AUC 0-∞ ) of mobocertinib, AP32960, and AP32914 by 527% (geometric least-squares mean [LSM] ratio, 6.27; 90% confidence interval [CI],. Coadministration of rifampin with mobocertinib decreased the combined molar AUC 0-∞ of mobocertinib, AP32960, and AP32914 by 95% (geometric LSM ratio, 0.05; 90%CI, 0.04-0.07). Based on these results, the strong CYP3A inhibitor itraconazole and inducer rifampin significantly influenced the PK of mobocertinib and its active metabolites. Coadministration of mobocertinib with moderate and strong CYP3A inhibitors or inducers is not recommended in ongoing clinical trials.

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

“…Initially, a joint linear model was constructed in which oral mobocertinib was absorbed into the parent central compartment and parent drug was either eliminated or metabolized to AP32960 or AP32914, with each metabolite characterized by one‐compartment models with linear elimination from the system. Based on available clinical data, the fraction of parent mobocertinib metabolized to AP32960 and AP32914 was set to 62% and 8%, respectively 16 . Two‐ and three‐compartmental models with first‐order intercompartmental clearances, as well as more complex models, including transit compartment, and parallel linear and nonlinear elimination mechanisms, were subsequently considered.…”

“…Two‐ and three‐compartmental models with first‐order intercompartmental clearances, as well as more complex models, including transit compartment, and parallel linear and nonlinear elimination mechanisms, were subsequently considered. Mobocertinib and its metabolites were expected to exhibit nonlinear PK due to auto‐induction of metabolism via CYP3A 16 . Therefore, the initial linear joint model was extended to include an additional enzyme compartment where the concentration of enzyme increased as plasma concentrations of mobocertinib and/or its metabolites increased.…”

“…on its plasma elimination half-life and the 24-h dosing interval. 16 These observations suggest auto-induction of metabolism by mobocertinib, likely via induction of CYP3A. 16 Co-administration of mobocertinib with a strong CYP3A inhibitor (itraconazole) increased the molar sum AUC from time zero to infinity (AUC 0-∞ ) of mobocertinib, AP32960, and AP32914 by 527%, whereas coadministration with a strong CYP3A inducer (rifampin) decreased the molar sum of AUC 0-∞ by 95%.…”

Discovery, Development, Inventions, and Patent Trends on Mobocertinib Succinate: The First-in-Class Oral Treatment for NSCLC with EGFR Exon 20 Insertions

“…Mobocertinib (Other names: AP-32788, TAK 788, TAK-788, TAK788; CAS registry number: 1847461-43-1; Molecular Formula: C 32 H 39 N 7 O 4 ; Molecular weight: 585.70), chemically, is 5-Pyrimidinecarboxylic acid, 2-[[4-[[2-(dimethylamino)ethyl]methylamino]-2-methoxy-5-[(1-oxo-2-propen-1-yl)amino]phenyl]amino]-4-(1-methyl-1H-indol-3-yl)-,1-methylethyl ester ( Figure 1 ) [ 24 , 25 , 26 , 27 ]. The chemical structure of this non-chiral molecule was first disclosed in 2015 [ 28 ].…”

“…Mobocertinib, discovered by Ariad Pharmaceuticals and developed by Takeda Pharmaceuticals, is an irreversible tyrosine kinase inhibitor (TKI) that forms a covalent bond with cysteine 797 in EGFR, leading to the inhibition of EGFR signaling, and stops EGFR exon 20 insertion mutations. It was approved by the USFDA, on 15 September 2021, to treat NSCLC with epidermal growth factor receptor (EGFR) exon 20 exon insertion mutations [ 24 ]. This is the first approval of an oral targeted therapy for patients with EGFR exon 20 insertion mutation-positive NSCLC.…”