Chemical formula: C₁₉H₁₄Cl₂N₂O₃S Molecular mass: 421.297 g/mol PubChem compound: 24776445
Vismodegib is an orally available small-molecule inhibitor of the Hedgehog pathway. Hedgehog pathway signalling through the Smoothened transmembrane protein (SMO) leads to the activation and nuclear localisation of Glioma-Associated Oncogene (GLI) transcription factors and induction of Hedgehog target genes. Many of these genes are involved in proliferation, survival, and differentiation. Vismodegib binds to and inhibits the SMO protein thereby blocking Hedgehog signal transduction.
Vismodegib is a highly permeable compound with low aqueous solubility (BCS Class 2). The single dose mean (CV %) absolute bioavailability of vismodegib is 31.8 (14.5) %. Absorption is saturable as evidenced by the lack of dose proportional increase in exposure after a single dose of 270 mg and 540 mg vismodegib. Under clinically relevant conditions (steady state), the PK of vismodegib is not affected by food. Therefore, vismodegib may be taken without regard to meals.
The volume of distribution for vismodegib is low, ranging from 16.4 to 26.6 L. In vitro binding of vismodegib to human plasma proteins is high (97%) at clinically relevant concentrations. Vismodegib binds to both human serum albumin and alpha-1-acid glycoprotein (AAG). In vitro binding to AAG is saturable at clinically relevant concentrations. Ex vivo plasma protein binding in human patients is >99%. Vismodegib concentrations are strongly correlated with AAG levels, showing parallel fluctuations of AAG and total vismodegib over time and consistently low unbound vismodegib levels.
Vismodegib is slowly eliminated by a combination of metabolism and excretion of parent drug substance. Vismodegib is predominant in plasma, with concentrations representing greater than 98% of the total circulating concentrations (including associated metabolites). Metabolic pathways of vismodegib in humans include oxidation, glucuronidation, and an uncommon pyridine ring cleavage. CYP2C9 appears to contribute in part to vismodegib metabolism in vivo.
After oral administration of a radiolabelled dose, vismodegib is absorbed and slowly eliminated by a combination of metabolism and excretion of parent drug substance, the majority of which is recovered in the faeces (82% of the administered dose), with 4.4% of the administered dose recovered in urine.
Vismodegib and associated metabolic products are eliminated primarily by the hepatic route. After continuous once-daily dosing, the pharmacokinetics of vismodegib appears to be nonlinear due to saturable absorption and saturable protein binding. After a single oral dose, vismodegib has a terminal half-life of ca. 12 days.
The apparent half-life of vismodegib at steady-state is estimated to be 4 days with continuous daily dosing. Upon continuous daily dosing, there is a 3 fold accumulation of vismodegib total plasma concentrations.
Vismodegib inhibits UGT2B7 in vitro and it may not be excluded that inhibition can take place in vivo in the intestine.
There are limited data in older people. In clinical trials with aBCC, approximately 40% of patients were of geriatric age (≥65 years). Population pharmacokinetic analyses suggest that age did not have a clinically significant impact on steady-state concentration of vismodegib.
Based on population pharmacokinetic analysis of combined data from 121 males and 104 females, gender did not appear to affect the pharmacokinetics of vismodegib.
There are limited data in non-Caucasian patients. Since the number of subjects who were not Caucasian comprised only <3% of the total population (6 Black, 219 Caucasian), race was not evaluated as a covariate in the population pharmacokinetic analysis.
Renal excretion of orally administered vismodegib is low. Therefore, mild and moderate renal impairment is unlikely to have a clinically significant effect on the pharmacokinetics of vismodegib. Based on a population PK analysis in patients with mild (BSA-indexed CrCl 50 to 80 mL/min, n=58) and moderate (BSA-indexed CrCl 30 to 50 mL/min, n=16) renal impairment, mild and moderate impaired renal function had no clinically significant effect on the pharmacokinetics of vismodegib. Very limited data is available in patients with severe renal impairments.
The major elimination pathways of vismodegib involve hepatic metabolism and biliary/intestinal secretion. In a clinical study in patients with hepatic impairment (degree of impairment based on subject’s AST and total bilirubin levels) following multiple doses of vismodegib, it was shown that in patients with mild (NCI-ODWG criteria, n=8), moderate (NCI-ODWG criteria, n=6), and severe (NCI-ODWG criteria, n=3) hepatic impairment, the pharmacokinetic profile of vismodegib was comparable to that of subjects with normal hepatic function (n=9).
There are insufficient pharmacokinetic data in paediatric patients.
The preclinical safety profile of vismodegib was assessed in mice, rats, and dogs.
In general, the tolerability of vismodegib in repeat-dose toxicity studies in rats and dogs was limited by nonspecific manifestations of toxicity including decreased body weight gain and food consumption. Additional findings at clinically relevant exposures included faecal changes; skeletal muscle twitching or tremors; alopecia; swelling, follicular hyperkeratosis, and inflammation in paw pads; and increased LDL and HDL cholesterol. Decreased haematocrit or platelet count were observed in some dogs at clinically relevant exposures; however, there was no evidence of a primary effect on bone marrow in affected animals.
Carcinogenicity studies were performed in mice and rats. Carcinogenic potential was identified in rats only and was limited to benign hair follicle tumors, including pilomatricomas and keratoacanthomas respectively at ≥0.1-fold and ≥0.6-fold of the steady-state AUC of the recommended human dose. No malignant tumors were identified in either species tested. Benign hair follicle tumors have not been reported in clinical trials with vismodegib, and the relevance of this finding to humans is uncertain.
There was no evidence of genotoxicity in in vitro assays (reverse bacterial mutagenesis [Ames] and human lymphocyte chromosome aberration assays) or in the in vivo rat bone marrow micronucleus assay.
In the dedicated 26-week vismodegib rat fertility study, significantly increased absolute weights of seminal vesicles and reduced absolute weights of prostate were observed. In addition, the ratio of organ weight to terminal body weight was significantly increased for epididymis, cauda epididymis, testes and seminal vesicles. In the same study there were no histopathological findings in male reproductive organs and no effects on male fertility endpoints, including percent motile sperm, observed at 100 mg/kg/day at the end of dosing or recovery phase (corresponding to 1.3-fold of the steady-state AUC0-24h at the recommended human dose). In addition, in the vismodegib general toxicity studies up to 26-week in sexually mature rats and dogs, no effects on male reproductive organs were observed. Increased number of degenerating germ cells and hypospermia in sexually immature dogs observed at ≥50 mg/kg/day in the 4-week general toxicity study was of undetermined relationship to vismodegib.
In the dedicated 26-week vismodegib rat fertility study, vismodegib-related effects on female reproductive organs were observed at 100 mg/kg/day immediately after treatment discontinuation, including decreased implantations, increased percent preimplantation loss, and decreased number of dams with viable embryos. Similar findings were not observed after a 16 week recovery period. No correlative histopathologic changes were observed. The exposure in female rats at 100 mg/kg corresponds to 1.2-fold of the steady-state AUC0-24h at the recommended human dose. In addition, in the vismodegib general 26-week toxicity study, decreased number of corpora lutea was observed at 100 mg/kg/day; the effect was not reversed by the end of an 8 week recovery period.
In an embryo-foetal development study in which pregnant rats were administered vismodegib daily during organogenesis, vismodegib crossed the placenta and was severely toxic to the conceptus. Malformations, including craniofacial anomalies, open perineum, and absent and/or fused digits, were observed in foetuses of dams at a dose which corresponded to 20% of the typical steady-state exposure in patients, and a 100% incidence of embryolethality was observed at higher doses.
Dedicated studies to assess the potential of vismodegib to affect post-natal development have not been performed. However, irreversible defects in growing teeth and premature closure of the femoral epiphyseal plate, observed in rat toxicity studies at clinically relevant exposures, represent risks to post-natal development.
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