Pharmacokinetics and pharmacodynamics of new drugs for pancreatic cancer

ABSTRACT

Introduction: Pancreatic cancer (PC) remains a disease with a dismal prognosis. Despite accounting for only 3% of cancer diagnosis, 7% of all cancer deaths in the United States are from PC. This is explained by many being diagnosed with late-stage disease and the cancer’s resistance to chemotherapy. Since 1996 there have only been two upfront regimens found to be superior to gemcitabine, FOLFIRINOX (5-fluorouracil/leucovorin and oxaliplatin) and gemcitabine plus nab-paclitaxel.

Areas covered: Clinical pharmacology of newer agents that are either approved or being investigated in the management of PC. Knowledge of their pharmacokinetics, pharmacodynamics, and pharmacogenetics can be used to predict outcomes for specific patient populations. Drugs discussed include nanoliposomal irinotecan, pegvorhyaluronidase alfa, poly (ADP-ribose) polymerase enzyme inhibitors, larotrectinib, and napabucasin.

Expert opinion: PC is a heterogeneous disease and outcomes are likely to improve as better predictive models of an individual’s response to different therapies are developed. This may be best accomplished through phase 0 studies and the use of tumor organoid models grown from initial biopsies or resected tissue. The genetic and physical makeup of the tumor as well as the functional characterization in patient-derived organoids (PDOs), can help guide which agents may be most efficacious or toxic.

KEYWORDS:

• Chemotherapy
• genomic profile
• genomics
• molecular pancreatic pathogenesis
• pancreatic cancer pharmacogenomics
• pancreatic exocrine cancer
• targeted therapy
• pharmacokinetics
• pharmacodynamics
• metabolism
• metabolites

Article highlights

• Nanoliposomal irinotecan, in combination with 5-flurouracil and leucovorin, is FDA approved for second line use in metastatic pancreatic cancer after first line gemcitabine-based therapy. Prior to use the patient should be screened for mutations in UGT1A1 with a dose reduction of 20 mg/m² if there is homozygosity for the *28 genotype. Caution should be used if heterozygote for the UGT1A1*6 genotype.

• All newly diagnosed metastatic pancreatic adenocarcinoma patients should be germline tested for BRCA mutation as it impacts their management. Olaparib should be considered in advanced pancreatic cancer for patients who are germline BRCA mutated who have completed platinum-based first line therapy with stable disease.

• We review the pharmacodynamics, pharmacokinetics and pharmacogenetics of pegvorhyaluronidase alfa, napabucasin and larotrectinib. However, at the time of publication the use of these drugs in management of pancreatic cancer remains investigational.

• Pancreatic cancer patient-derived organoids (PDOs) can be generated with a high success rate from resected tissue or initial biopsy specimen. PDOs are being investigated as a predictive tool, with the goal of improving precision oncology.

• Clinical biomarkers are a useful tool in pancreatic cancer to predict efficacy and toxicity of commonly used drugs. We review the currently available, as well as the investigational biomarkers, in the management of pancreatic cancer.

Declaration of interest

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.