Development of an integrated multi-species and multi-dose route PBPK model for volatile methyl siloxanes - D4 and D5.

There are currently seven published physiologically based pharmacokinetic (PBPK) models describing aspects of the pharmacokinetics of octamethylcyclotetrasiloxane (D4) and decamethylcyclopentasiloxane (D5) for various exposure routes in rat and human. Each model addressed the biological and physico-chemical properties of D4 and D5 (highly lipophilic coupled with low blood: air partition coefficient and high liver clearance) that result in unique kinetic behaviors as well differences between D4 and D5. However, the proliferation of these models resulted in challenges for various risk assessment applications when needing to determine the optimum model for estimating dose metrics. To enhance the utility of these PBPK models for risk assessment, we integrated the suite of structures into one coherent model capable of simulating the entire set of existing data equally well as older more limited scope models. In this paper, we describe the steps required to develop this integrated model, the choice of physiological, partitioning and biochemical parameters for the model, and the concordance of the model behavior across key data sets. This integrated model is sufficiently robust to derive relevant dose metrics following individual or combined dermal and inhalation exposures of workers, consumer or the general population to D4 and D5 for route-to-route, interspecies and high to low dose extrapolations for risk assessment.

FDA Approval Summary: Pemigatinib for Previously Treated, Unresectable Locally Advanced or Metastatic Cholangiocarcinoma with FGFR2 Fusion or Other Rearrangement.

On April 17, 2020, the FDA granted accelerated approval to pemigatinib (PEMAZYRE, Incyte Corporation) for the treatment of adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with an FGFR2 fusion or other rearrangement as detected by an FDA-approved test. Approval was based on FIGHT-202 (NCT02924376), a multicenter open-label single-arm trial. Efficacy was based on 107 patients with locally advanced unresectable or metastatic cholangiocarcinoma whose disease had progressed on or after at least one prior therapy and had an FGFR2 gene fusion or rearrangement. Patients received pemigatinib, 13.5 mg orally, once daily for 14 consecutive days, followed by 7 days off therapy. Safety was based on a total of 466 patients, 146 of whom had cholangiocarcinoma and received the recommended dose. Efficacy endpoints were overall response rate (ORR) and duration of response (DOR) determined by an independent review committee using RECIST 1.1. ORR was 36% (95% confidence interval: 27-45). Median DOR was 9.1 months. The most common adverse reactions were hyperphosphatemia, alopecia, diarrhea, nail toxicity, fatigue, dysgeusia, nausea, constipation, stomatitis, dry eye, dry mouth, decreased appetite, vomiting, arthralgia, abdominal pain, hypophosphatemia, back pain, and dry skin. Ocular toxicity and hyperphosphatemia are important risks of pemigatinib. The recommended dosage is 13.5 mg orally once daily for 14 consecutive days followed by 7 days off therapy in 21-day cycles. FDA also approved the FoundationOne CDX (Foundation Medicine, Inc.) as a companion diagnostic for patient selection.