Pharmacokinetics and pharmacodynamics of Hedgehog pathway inhibitors used in the treatment of advanced or treatment-refractory basal cell carcinoma

AbstractIntroduction Sonidegib and vismodegib are currently the only US Food and Drug Administration and European Medicines Agency-approved small-molecule Hedgehog pathway inhibitors (HHIs), for treating adults with advanced or refractory basal cell carcinoma (BCC) that is not amenable to conventional surgery or radiotherapy. At this time, there are no head-to-head clinical trials comparing these two HHIs for efficacy and safety to assist clinicians with determining which HHI may be best suited for their patients.Areas covered This review briefly describes the pathogenesis of BCC, provides a detailed overview of the key pharmacokinetic profile differences between sonidegib and vismodegib, explains their pharmacodynamics, and highlights the therapeutic considerations when either HHI is used to treat special patient populations.Expert opinion Although both HHIs act at the same molecular target in the Hedgehog pathway, there are significant differences in their pharmacokinetic profiles that may play a potential role in their efficacy and safety. Evidence-based recommendations serve to inform clinicians until direct comparative clinical trials of sonidegib versus vismodegib are conducted to determine the clinical relevance of the reported differences in their pharmacokinetic properties.KEYWORDS: Hedgehog pathway inhibitorssonidegibvismodegibpharmacokineticspharmacodynamicsbasal cell carcinomaDisclaimerAs a service to authors and researchers we are providing this version of an accepted manuscript (AM). Copyediting, typesetting, and review of the resulting proofs will be undertaken on this manuscript before final publication of the Version of Record (VoR). During production and pre-press, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal relate to these versions also. Article Highlights:The small-molecule inhibitors sonidegib and vismodegib, are currently the only approved Hedgehog pathway inhibitors (HHIs) for the treatment of advanced basal cell carcinoma (BCC) that is not amenable to conventional surgery or radiotherapy.However, currently there are no head-to-head clinical trials comparing these two HHIs that would provide evidence-based guidance for treating clinicians.Despite similar indications, the pharmacokinetic profiles of sonidegib and vismodegib are notably different, including their volumes of distribution and elimination half-lives.Until comparative studies are conducted to determine the clinical relevance of the reported differences in their pharmacokinetic properties, evidence-based recommendations using available preclinical and clinical data must be utilized to bridge this gap.Declaration of InterestJT Lear has received personal fees from Sun Pharma. LD Lewis has received funding support via his institution for clinical trials involving sonidegib and vismodegib from Sun Pharma and Genentech, respectively and is a paid consultant to G1 Therapeutics and 7 Hills Pharm LLC. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.Reviewer disclosuresPeer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.AcknowledgementsThe authors thank Alexander S. Milliken, Alpha BioCom,a Red Nucleus company, for their medical writing and editorial support.Figure 1. Schematic of the HH signaling pathwayDisplay full size(A) Under physiologic conditions, binding of the Hedgehog (HH) ligand to patched homolog 1 (PTCH1), a negative regulator of Smoothened (SMO), triggers SMO activation. SMO initiates an intracellular signaling cascade that causes glioma-associated oncogene homolog 1 and 2 (GLI1 and GLI2) activation and nuclear translocation. GLI1 and GLI2 are transcription factors that facilitate the induction of HH target gene expression. (B) PTCH1 loss-of-function mutations and/or SMO activating mutations cause aberrant HH pathway signaling that drives unregulated transcription and uncontrolled basal cell carcinoma (BCC) proliferation. Sonidegib and vismodegib are SMO antagonists, while other inhibitors are (i) HH/PTCH1 inhibitors (Robotnikinin, 7_3d3, 5E1 monoclonal antibody therapy, and RU-SKI 43) or (ii) GLI inhibitors (GANT-58, GANT-61, and arsenic trioxide). Created with BioRender.com.The stability of sonidegib and vismodegib were assessed under the various conditions as defined by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. Stability of the drug under the listed condition is represented by a check mark (✓).aAccelerated = ≤6 months under 40°C and 75% room humidity.bIntermediate = ≤24 months under 30°C and 75% room humidity for sonidegib.cLong-term = ≤24 months under 25°C and 60% room humidity.BCS = Biopharmaceutics Classification System; NA, not available.Reported values are for single doses of clinically recommended standard daily sonidegib (200 mg) and vismodegib (150 mg) doses determined in healthy individuals unless otherwise specified.aValue determined in patients with locally advanced or metastatic tumors.bValue determined by population pharmacokinetic modeling.AUClast = area under the plasma concentration curve from the time of dosing to the last measurable concentration, CL/F = apparent oral clearance, CYP = cytochrome P450, Cmax = maximum observed concentration, Css = maximum concentration at steady state, QD = once daily, Tmax = median time-to-maximum concentration, Tss = time until steady state, T1/2 = elimination half-life, Vd/F = apparent volume of distribution.Additional informationFundingMedical writing and editorial support for this paper was funded by Sun Pharma.