An open-label drug-drug interaction study to evaluate the effects of pralsetinib (Gavreto) on the pharmacokinetics of a CYP450 probe substrate cocktail and, in female participants, a hormonal probe substrate, in participants with rearranged during transfection (RET) fusion- or mutation-positive solid tumors
Must be willing and able to participate and comply with all study requirements and to provide signed and dated written informed consent
Adult male or female ≥ 18 years of age at the time of signing the informed consent form.
Must have a body mass index (BMI) ≥ 18 and ≤ 32 kg/m² and a minimum body weight of 50 kg at screening.
Must have an Eastern Cooperative Oncology Group performance status ≤ 2.
Clinically relevant abnormal medical history, abnormal findings on physical examination, vital signs, electrocardiogram (ECG), or laboratory tests at screening that, in the investigator's judgment, are likely to interfere with the objectives of the trial or the safety of the patient.
Surgery (e.g., gastric bypass) or medical condition that may significantly affect absorption of study medications, as judged by the investigator.
History of pneumonitis within the last 12 months.
History of active or latent tuberculosis (TB), regardless of treatment history, or a positive screening test for latent Mycobacterium tuberculosis infection by QuantiFERON® TB Gold. Indeterminate results may be confirmed by repeat testing or by a purified protein derivative (PPD) skin test.
Single group
Pralsetinib
DrugPralsetinib 400mg orally (PO) once daily (QD) from Day 4 to Day 10, with an option to continue up to Day 33
CYP3A4, CYP2C8, and CYP2C9 substrates, and hormonal contraceptive
DrugMidazolam, repaglinide, and losartan (CYP probe substrates) and, for female participants, estradiol/norethisterone acetate (hormonal probe substrate), administered orally (PO) once on Day 1 and once on Day 9.
Area Under the Plasma Concentration-Time Curve from zero to infinity (AUC0-inf)
To evaluate the effect of pralsetinib on the overall exposure of CYP3A4, CYP2C8, and CYP2C9, probe substrates, and hormonal contraceptive by measuring AUC0-inf for each probe substrate and its relevant metabolites.
Area under the plasma concentration-time curve from time zero to time of last measurable concentration (AUClast)
To evaluate the effect of pralsetinib on the overall exposure of CYP3A4, CYP2C8, and CYP2C9 probe substrates, and hormonal contraceptive by measuring AUClast for each probe substrate and its relevant metabolites.
Maximum Peak Plasma Concentration (Cmax)
To evaluate how pralsetinib affects the peak levels of probe substrates, and hormonal contraceptive, in the blood after they are taken alone and again after treatment with pralsetinib
Time to Maximum Plasma Concentration (tmax)
Venous whole blood samples will be collected for activity-based pharmacokinetics characterization to assess how pralsetinib affects the time required to reach peak plasma concentration for each probe drug.
Terminal Half-Life (t½)
Venous whole blood samples will be collected for activity-based pharmacokinetics characterization To evaluate the effect of pralsetinib on the terminal half-life of each probe drug
Percent of Area Under the plasma concentration-time curve obtained at extrapolation (%AUCex)
Venous whole blood samples will be collected for activity-based pharmacokinetics characterization to determine the proportion of the AUC that is extrapolated, providing insight into pralsetinib's effect on drug elimination
Mean residence time (MRT)
Venous whole blood samples will be collected for activity-based pharmacokinetics characterization to assess how pralsetinib affects the average time each probe drug remains in the body
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