Chemical formula: C₂₉H₃₁N₇O₃ Molecular mass: 525.613 g/mol
Selpercatinib is an inhibitor of the rearranged during transfection (RET) receptor tyrosine kinase. Selpercatinib inhibited wild-type RET and multiple mutated RET isoforms as well as VEGFR1 and VEGFR3 with IC50 values ranging from 0.92 nM to 67.8 nM. In other enzyme assays, selpercatinib also inhibited FGFR 1, 2, and 3 at higher concentrations that were still clinically achievable. In a binding assay at the concentration of 1 µM selpercatinib, significant antagonist binding activity (>50%) was observed for the 5-HT (serotonin) transporter (70.2% antagonist) and α2C adrenoreceptor (51.7% antagonist). The concentration of 1 µM is approximately 7-fold higher than the maximum unbound plasma concentration of at the efficacious dose of selpercatinib.
Certain point mutations in RET or chromosomal rearrangements involving in-frame fusions of RET with various partners can result in constitutively activated chimeric RET fusion proteins that can act as oncogenic drivers by promoting cell proliferation of tumor cell lines. In in vitro and in vivo tumor models, selpercatinib demonstrated anti-tumor activity in cells harboring constitutive activation of RET protein resulting from gene fusions and mutations, including CCDC6-RET, KIF5B-RET, RET V804M, and RET M918T. In addition, selpercatinib showed anti-tumor activity in mice intracranially implanted with a patient-derived RET fusion-positive tumor.
In a thorough QT study with positive control in 32 healthy subjects, no large change (that is, >20 ms) in the QTcF interval was detected at selpercatinib concentrations similar to those observed with a therapeutic dosing schedule. An exposure-response analysis indicated that supra therapeutic concentrations, could lead to an increase in QTc >20 ms.
In patients receiving selpercatinib, QT interval prolongation was reported. Therefore, dose interruption or modification may be required in patients.
The pharmacokinetics of selpercatinib were evaluated in patients with locally advanced or metastatic solid tumors administered 160 mg twice daily unless otherwise specified. Steady-state selpercatinib AUC and Cmax increased in a linear to supra-dose proportional manner over the dose range of 20 mg once daily to 240 mg twice daily.
Steady-state was reached by approximately 7 days and the median accumulation ratio after administration of 160 mg twice daily was 3.4-fold. Mean steady-state selpercatinib [coefficient of variation (CV%)] Cmax was 2,980 (53%) ng/mL and AUC0-24h was 51,600 (58%) ng*h/mL.
In vivo studies indicate that selpercatinib is a mild inhibitor of P-gp.
In vitro studies indicate that selpercatinib does not inhibit or induce CYP1A2, CYP2B6, CYP2C9, CYP2C19, or CYP2D6 at clinically relevant concentrations.
In vitro studies indicate that selpercatinib inhibits MATE1, and BCRP, but does not inhibit OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, BSEP, and MATE2-K at clinically relevant concentrations. Selpercatinib may increase serum creatinine by decreasing renal tubular secretion of creatinine via inhibition of MATE1.
After an oral dose of 160 mg, selpercatinib was rapidly absorbed, with Tmax of approximately 2 hours. Geometric mean absolute oral bioavailability was 73.2% (range: 60.2-81.5%).
Compared to selpercatinib AUC and Cmax in the fasted state, selpercatinib AUC was increased by 9% and Cmax was reduced by 14% after oral administration of a single 160 mg dose to healthy subjects taken with a high-fat meal. These changes were not considered to be clinically relevant. Therefore, selpercatinib can be taken with or without food.
Selpercatinib mean (CV%) volume of distribution (Vss/F), estimated by Population PK analysis, is 191 (69%) L following oral administration of selpercatinib in adult patients. Selpercatinib is 96% bound to human plasma proteins in vitro and binding is independent of concentration. The blood-to-plasma concentration ratio is 0.7.
Selpercatinib is metabolized predominantly by CYP3A4. Following oral administration of a single [14C] radiolabeled 160 mg dose of selpercatinib to healthy subjects, unchanged selpercatinib constituted 86% of the measured radioactive components in plasma.
The mean (CV%) clearance (CL/F) of selpercatinib is 6.0 (49%) L/h and the half-life is 22 hours following oral administration of selpercatinib in adult patients. Following oral administration of a single [14C] radiolabeled 160 mg dose of selpercatinib to healthy subjects, 69% (14% unchanged) of the administered radioactivity was recovered in faeces and 24% (11.5% unchanged) was recovered in urine.
Age (range: 15 years to 90 years) or gender had no clinically meaningful effect on the pharmacokinetics of selpercatinib. Patients with a body weight <50 kg should start selpercatinib treatment with a dose of 120 mg twice daily, while patients ≥50 kg should start selpercatinib treatment with a dose of 160 mg twice daily.
Selpercatinib AUC0-∞ increased by 7% in subjects with mild, 32% in subjects with moderate Child-Pugh classification. Thus, selpercatinib exposure (AUC) in subjects with mild and moderate hepatic impairment (Child-Pugh class A and B) is comparable to exposure in healthy subjects when a dose of 160 mg is administered.
Selpercatinib AUC0-∞ increased by 77% in subjects with severe hepatic impairment (Child-Pugh class C). There is limited clinical data on the safety of selpercatinib in patients with severe hepatic impairment. Therefore, dose modification is recommended for patients with severe hepatic impairment (section 4.2).
In a clinical pharmacology study using single dose selpercatinib 160 mg, exposure (AUC) was unchanged in subjects with mild, moderate, or severe renal impairment. End stage renal disease (eGFR <15 ml/min) and dialysis patients have not been studied.
Based on limited pharmacokinetic data, the Cmax and AUC was similar in adolescent patients, 12-18 years of age, and in adults.
Repeat-dose studies were conducted in juvenile and adolescent/adult rats and adolescent/adult minipigs to characterize toxicity. Target organs of toxicity common to the rat and minipig were hematopoietic system, lymphoid tissues, tongue, pancreas, gastro-intestinal tract, epiphyseal growth plate, and male reproductive tissues. In general, toxicities in these organs were reversible; the exceptions were the testicular toxicity in adolescent/adult and juvenile animals, and changes in growth plates in juvenile rats. Reversible toxicity was observed in the ovaries in minipigs only. At high doses, gastrointestinal toxicity caused morbidity at exposures in minipigs that were generally lower than exposures determined in humans at the recommended dose. In one minipig study, females exhibited a slight, reversible increase in QTc prolongation of approximately 12% compared to controls and 7% compared to pre-dose values. Target organs of toxicity observed only in rats were incisor tooth, liver, vagina, lungs, Brunner’s gland, and multi-tissue mineralization associated with hyperphosphatemia. These toxicities only occurring in these organs in rats were reversible.
Selpercatinib exposure approximately 0.5-2 times the exposure in adult humans caused mortality in rats younger than 21 days old. Comparable exposure was tolerated in rats aged 21 days and older.
Juvenile and adolescent/adult rats and adolescent/adult minipigs with open growth plates administered selpercatinib exhibited microscopic changes of hypertrophy, hyperplasia, and dysplasia of growth plate cartilage (physis). In juvenile rats, the dysplasia at the growth plates was irreversible and associated with decreased femur length and reductions in bone mineral density. Skeletal changes were observed at exposure levels equivalent to those seen in adult patients taking the recommended dose of 160 mg BID.
Juvenile male rats administered selpercatinib and allowed to reach reproductive age after cessation of administration, exhibited decreased reproductive performance when mated with untreated female rats. Decreased fertility and copulation indices, increased pre- and post-implantation losses, and decreased number of viable embryos, were observed at an exposure approximately 3.4 times the efficacious exposure in adults.
Selpercatinib is not genotoxic at therapeutic doses. In an in vivo micronucleus assay in rats, selpercatinib was positive at concentrations >7 times the Cmax at the human dose of 160 mg twice daily. In an in vitro micronucleus assay in human peripheral blood lymphocytes, an equivocal response was observed at a concentration approximately 485 times the Cmax at the human dose.
Selpercatinib did not cause mutations in a bacterial mutagenicity assay. Carcinogenesis Long-term studies to assess the carcinogenic potential of selpercatinib have not been performed.
Based on data from animal reproduction studies and its mechanism of action, selpercatinib can cause foetal harm when administered to a pregnant woman. Administration of selpercatinib to pregnant rats during organogenesis at maternal exposures that were approximately equal to those observed at the recommended human dose of 160 mg twice daily resulted in embryolethality and malformations.
Results of studies conducted in rats and minipigs suggest that selpercatinib could impair fertility in males and females.
In a fertility study in male rats, dose-dependent germ cell depletion and spermatid retention were observed at subclinical AUC-based exposure levels (0.2 times the clinical exposure at the recommended human dose). These effects were associated with reduced organ weights, reduced sperm motility, and an increase in the number of abnormal sperm at AUC-based exposure levels approximately twice the clinical exposure at the recommended human dose. Microscopic findings in the fertility study in male rats were consistent with effects in repeat dose studies in rats and minipigs, in which dose-dependent, non-reversible testicular degeneration was associated with reduced luminal sperm in the epididymis at subclinical AUC-based exposure levels (0.1 to 0.4 times the clinical exposure at the recommended human dose).
In a fertility and early embryonic study in female rats, a reduction in the number of estrous cycles as well as embryolethality were observed at AUC-based exposure levels approximately equal to clinical exposure at the recommended human dose. In repeat-dose studies in rats, reversible vaginal mucification with individual cell cornification and altered estrous cycles were noted at clinically relevant AUC-based exposure levels. In minipigs, decreased corpora lutea and/or corpora luteal cysts were observed at subclinical AUC-based clinical exposure levels (0.07 to 0.3 times the clinical exposure at the recommended human dose).
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