Browse
Submit Data
Databases
API
Help

Dataset Information

10 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Single-Dose Pharmacokinetics and Tolerability of the Oral Epidermal Growth Factor Receptor Inhibitor Mobocertinib (TAK-788) in Healthy Volunteers: Low-Fat Meal Effect and Relative Bioavailability of 2 Capsule Products.

ABSTRACT: Mobocertinib (TAK-788) is a tyrosine kinase inhibitor under investigation for treatment of non-small cell lung cancer with activating EGFR exon 20 insertions. This study examined the safety; tolerability; pharmacokinetics (PK), including food effects; and bioavailability of mobocertinib in healthy volunteers. In part 1, fasted volunteers were randomized to placebo or mobocertinib in single-ascending-dose cohorts (20-160 mg). In part 2, mobocertinib (120/160 mg) was administered on day 1 of periods 1 and 2 under fasted or low-fat meal conditions (2-period, 2-sequence crossover design). In part 3, fasted volunteers received mobocertinib 160 mg in 1 of 2 capsule products on day 1 of periods 1 and 2 with 7-day washout. Safety and PK parameters were assessed. Sixty-nine volunteers were enrolled (mean age, 29 years; 75% male). The most common adverse events (AEs; ≥10% of volunteers) were gastrointestinal AEs (25%-50%) and headache (8%-31%). No serious AEs were reported. A low-fat meal did not affect the PK of mobocertinib or its active metabolites. The geometric mean terminal disposition phase half-life (20 hours) supported once-daily dosing. The 2 capsule products were bioequivalent. These data guided dosing and supported administration of mobocertinib without regard to low-fat meal intake in ongoing and planned clinical studies.

SUBMITTER: Zhang S

PROVIDER: S-EPMC8453943 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Spotlight on Mobocertinib (TAK-788) in NSCLC with <i>EGFR</i> Exon 20 Insertion Mutations.

Project description:The EGFR exon 20 insertion (EGFRex20ins) mutations are the third most common EGFR mutations seen in non-small cell lung cancer (NSCLC). More than 50 variants of EGFRex20ins mutations have been identified with A767_V769dupASV being the most common variant across multiple surveys. Treatment with currently available EGFR tyrosine kinase inhibitors (TKIs) including osimertinib is generally ineffective. Amivantamab (JNJ-372), a bispecific monoclonal antibody against EGFR and MET, has recently been approved by the US FDA for patients with advanced or metastatic NSCLC harboring EGFRex20ins mutations after disease progression on platinum-based chemotherapy. Among all the TKIs in clinical development, mobocertinib (TAK-788) has been granted priority review by the FDA for the same indication as amivantamab. Here, we provide a concise review on mobocertinib, with a focus on its chemical structure, preclinical data, and phase 1/2 trial results. Future directions will likely focus on combination approach such as TKI plus chemotherapy in the first-line setting, designing drugs with CNS activity, and exploring disease characteristics of various EGFRex20ins mutation variants and how they may affect treatment response.

| S-EPMC8286072 | biostudies-literature

Activity and Safety of Mobocertinib (TAK-788) in Previously Treated Non-Small Cell Lung Cancer with <i>EGFR</i> Exon 20 Insertion Mutations from a Phase I/II Trial.

Project description:Mobocertinib, an oral epidermal growth factor receptor (EGFR) inhibitor targeting EGFR gene mutations, including exon 20 insertions (EGFRex20ins), in non-small cell lung cancer, was evaluated in a phase I/II dose-escalation/expansion trial (ClinicalTrials.gov NCT02716116). Dose escalation identified 160 mg/d as the recommended phase 2 dose and maximum tolerated dose. Among 136 patients treated with 160 mg/d, the most common any-grade treatment-related adverse events (TRAE; >25%) were diarrhea (83%), nausea (43%), rash (33%), and vomiting (26%), with diarrhea (21%) the only grade ≥3 TRAE >5%. Among 28 EGFRex20ins patients treated at 160 mg/d, the investigator-assessed confirmed response rate was 43% (12/28; 95% confidence interval, 24%-63%) with median duration of response of 14 months (5.0-not reached) and median progression-free survival of 7.3 months (4.4-15.6). Mobocertinib demonstrated antitumor activity in patients with diverse EGFRex20ins variants with a safety profile consistent with other EGFR inhibitors. SIGNIFICANCE: No oral EGFR-targeted therapies are currently approved for patients with EGFRex20ins NSCLC. Mobocertinib demonstrated antitumor activity with manageable toxicity in patients with advanced EGFRex20ins NSCLC in this study, supporting additional development of mobocertinib in this patient population.See related commentary by Pacheco, p. 1617.This article is highlighted in the In This Issue feature, p. 1601.

| S-EPMC8295177 | biostudies-literature

Relative Bioavailability and Food Effect of GSK3640254 Tablet and Capsule Formulations in Healthy Participants.

Project description:GSK3640254 is a next-generation maturation inhibitor with demonstrated potency across HIV-1 subtypes and a high barrier to emergent resistance. This phase I, 2-part, randomized, open-label study (ClinicalTrials.gov identifier, NCT04263142) in healthy participants assessed the relative bioavailability of a single dose of GSK3640254 200 mg in tablet and capsule formulations (part 1) and the effect of food on the pharmacokinetic profile of the tablet formulation (part 2). Overall, 39 participants were randomized to treatment (part 1, n = 18; part 2, n = 21). All participants in part 1 completed the study; 2 participants in part 2 withdrew before study completion (adverse event, n = 1; physician decision, n = 1). In part 1, plasma exposures of the GSK3640254 tablet formulation were not meaningfully different from those of the capsule formulation when administered in the presence of a moderate-fat meal. In part 2, GSK3640254 plasma exposures increased by ≈3- to 4-fold under high- and moderate-fat conditions, respectively, compared with fasted conditions. No major safety or tolerability findings were observed. The highest incidence of adverse events (24%) was reported under high-fat conditions. Taken together, these data support the use of the tablet formulation coadministered with food in the clinical development of GSK3640254 for treatment of HIV-1.

| S-EPMC9306620 | biostudies-literature

Relative bioavailability of ultrafine sodium selenite for broilers fed a conventional corn-soybean meal diet.

Project description:The particle size of selenium (Se) sources could affect Se absorption and utilization, and thus it is hypothesized that the Se bioavailability might be higher in ultrafine sodium selenite (USSe) than in sodium selenite (SSe) for broilers because of USSe's smaller particle size. An experiment was conducted to investigate the relative bioavailability of Se as USSe relative to SSe for broiler chicks fed a conventional corn-soybean meal diet. A total of 504 one-d-old Arbor Acres commercial male broilers were randomly allotted to 1 of 7 treatments with 6 replicates per treatment in a completely randomized design involving in a 2 (Se sources) × 3 (added Se levels) factorial arrangement of treatments plus a Se-unsupplemented control diet containing 0.05 mg Se/kg by analysis for 21 d. The 2 Se sources were USSe and SSe, and the 3 added Se levels were 0.15, 0.30, or 0.45 mg Se/kg. The Se concentrations, glutathione peroxidase (GSH-Px) activities, and mRNA relative abundances in plasma, liver, or pancreas of broilers on day 14 and 21 were determined. The results showed that Se concentrations, GSH-Px activities in plasma, liver, and pancreas, and mRNA relative abundances in the liver and pancreas of broilers on day 14 and 21 increased linearly (P < 0.05) as the added Se-level increased. Furthermore, a difference (P < 0.05) between USSe and SSe was detected for GSH-Px mRNA relative abundance in the pancreas of broilers on day 14. On the basis of the slope ratios from the multiple linear regression of the pancreatic GSH-Px mRNA relative abundance of broilers at 14 d of age on daily dietary analyzed Se intake, the Se bioavailability of USSe relative to SSe (100%) was 158% (P < 0.05). The results from this study indicated that the Se from USSe was more available to broilers than the Se from SSe in enhancing the pancreatic GSH-Px mRNA expression.

| S-EPMC6247847 | biostudies-literature

Relative bioavailability of a pediatric dispersible tablet and adult film-coated tablet of macitentan in healthy volunteers.

Project description:To compare the pharmacokinetic (PK) properties of the pediatric dispersible tablet formulation of macitentan and the adult film-coated tablet formulation of macitentan in healthy subjects. A randomized, open-label, single-dose, two-sequence, two-period, crossover, Phase 1 study was conducted in 12 healthy adults. Subjects were randomized to one of the two possible treatment sequences A/B or B/A on Day 1 under fasted conditions. Treatment A was a single 10 mg dose of macitentan (film-coated adult formulation) and Treatment B was a single 10 mg dose of macitentan, consisting of two 5 mg dispersible tablets (pediatric formulation). PK sampling over 216 hours was conducted, and PK parameters were derived using non-compartmental methods. For macitentan, geometric means ratio of peak plasma concentrations (Cmax ), plasma concentration-time curve from zero to the time of the last quantifiable concentration (AUC0- t ), and plasma concentration-time curve from zero to infinity (AUC0-? ) were 1.140, 0.974, and 0.974, respectively. The corresponding 90% confidence intervals fell entirely within the referenced range of 0.8000 to 1.2500, which is used for evaluation of bioequivalence. These results indicate no significant differences between the pediatric dispersible tablet and the adult film-coated tablet. Both formulations were well tolerated. The pediatric dispersible tablet is biocomparable to the adult film-coated tablet formulation.

| S-EPMC7164404 | biostudies-literature

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

Project description: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.

| S-EPMC9197538 | biostudies-literature

Relative bioavailability and food effect study of an oral suspension of alectinib in healthy volunteers using venipuncture and capillary microsampling.

Project description:Alectinib, approved as 150 mg capsules for the treatment of adults with advanced ALK-positive non-small cell lung cancer, is being assessed in children with ALK-positive solid and central nervous system tumors. An ad hoc pediatric-friendly suspension of alectinib, prepared from capsule contents, is under investigation as an alternative formulation for children who cannot swallow capsules. This randomized, crossover, relative bioavailability, and food effect study evaluated alectinib administered as an oral suspension versus capsule formulation following conventional venipuncture and capillary microsampling. A total of 28 healthy adult subjects received a 600 mg single dose of alectinib in two groups: fasted (n = 14) and mixed fed (n = 14; seven receiving high-fat meal and seven receiving low-fat meal). Combined alectinib + M4 (active metabolite) exposure was higher for suspension versus capsule, with geometric mean ratio (GMR) of 2.6 for area under the concentration-time curve extrapolated to infinity (AUC0-∞ ) and 3.0 for maximum observed concentration (Cmax ) under fasted conditions, and 1.7 for both parameters for mixed fed. The suspension showed increased alectinib + M4 AUC0-∞ following a high-fat meal versus fasted conditions (GMR 1.7 [90% confidence interval 1.4-2.2]). Alectinib AUC0-∞ and Cmax measured in venous and capillary samples were generally similar for the suspension and capsule. Single oral doses of 600 mg alectinib suspension and capsule were well tolerated, with no safety concerns. Based on these findings, the oral suspension of alectinib appears suitable for use in pediatric studies after appropriate dose adjustment relative to the capsule.

| S-EPMC10264912 | biostudies-literature

Safety, tolerability, pharmacokinetics and pharmacodynamics of the anti-CD38 cytolytic antibody TAK-079 in healthy subjects.

Project description:AimsThis investigation characterised tolerability, pharmacokinetics and pharmacodynamics of the anti-CD38 antibody TAK-079.MethodsA randomised, double-blind, placebo-controlled trial of a single intravenous (i.v.) infusion or subcutaneous (s.c.) injection of TAK-079 at escalating doses in healthy subjects (n = 74), who were followed for 92 days postexposure.ResultsTAK-079 was well tolerated. All adverse events were mild or moderate. There were no withdrawals, infusion, or injection site reactions over the tested i.v. and s.c. doses up to 0.06 and 0.6 mg kg-1 , respectively. At higher doses, transient cytokine level increases, following i.v. administration, coincided with reduction in CD38-expressing cells; clinical symptoms included mild pyrexia, headache, and postural hypotension. Following an i.v. infusion of 0.06 mg kg-1 TAK-079, maximum observed serum concentration (Cmax ) was 100.4 (%CV: 52) ng mL-1 , time to Cmax was the end of infusion and natural killer (NK_ cells were reduced 93.8 (±8.5) % from baseline levels. Following a s.c. injection of 0.6 mg kg-1 TAK-079, Cmax was 23.0 (%CV: 67) ng mL-1 with time to Cmax of 24 (range 7.98-96.02) hours, and plasmablasts were subsequently reduced 93.4 (±8.8) % from predose levels. Serum immunoglobulin (Ig)M, IgA and IgG levels were reduced by 15-60% and had not returned to baseline levels within 78 days after administration at ≥0.3 mg kg-1 s.c. Reductions in NK cells at 0.6 mg kg-1 s.c. were approximately 2-3 times more durable than at 0.06 mg kg-1 i.v.ConclusionsTAK-079 was well tolerated and s.c. administration elicited more durable reductions in plasmablasts and NK cells. This plasmacytolytic profile could be useful for treating disorders caused by plasma or NK cells, malignant counterparts, and/or pathogenic antibodies.

| S-EPMC7319013 | biostudies-literature

Bioavailability study of dronabinol oral solution versus dronabinol capsules in healthy volunteers.

Project description:BACKGROUND:Dronabinol, a pharmaceutical ?-9-tetrahydrocannabinol, was originally developed as an oral capsule. This study evaluated the bioavailability of a new formulation, dronabinol oral solution, versus a dronabinol capsule formulation. METHODS:In an open-label, four-period, single-dose, crossover study, healthy volunteers were randomly assigned to one of two treatment sequences (T-R-T-R and R-T-R-T; T = dronabinol 4.25 mg oral solution and R = dronabinol 5 mg capsule) under fasted conditions, with a minimum 7-day washout period between doses. Analyses were performed on venous blood samples drawn 15 minutes to 48 hours postdose, and dronabinol concentrations were assayed by liquid chromatography-tandem mass spectrometry. RESULTS:Fifty-one of 52 individuals had pharmacokinetic data for analysis. The 90% confidence interval of the geometric mean ratio (oral solution/capsule) for dronabinol was within the 80%-125% bioequivalence range for area under the plasma concentration-time curve (AUC) from time zero to last measurable concentration (AUC0-t) and AUC from time zero to infinity (AUC0-?). Maximum plasma concentration was also bioequivalent for the two dronabinol formulations. Intraindividual variability in AUC0-? was >60% lower for dronabinol oral solution 4.25 mg versus dronabinol capsule 5 mg. Plasma dronabinol concentrations were detected within 15 minutes postdose in 100% of patients when receiving oral solution and in <25% of patients when receiving capsules. CONCLUSION:Single-dose dronabinol oral solution 4.25 mg was bioequivalent to dronabinol capsule 5 mg under fasted conditions. Dronabinol oral solution formulation may provide an easy-to-swallow administration option with lower intraindividual variability as well as more rapid absorption versus dronabinol capsules.

| S-EPMC5066862 | biostudies-literature

A Performance and Bioavailability Study of Entrectinib in Healthy Volunteers.

Project description:This study will evaluate the bioavailability, palatability, safety and tolerability of entrectinib in healthy volunteers. Part 1 of the study will explore the performance of entrectinib multi-particle formulation. Part 2 will evaluate the effect of drug substance particle size on entrectinib bioavailability.

| 2306412 | ecrin-mdr-crc

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data