Pharmacokinetics and pharmacodynamics of new drugs for pancreatic cancer

1. Introduction

Pancreatic cancer (PC) is the third leading cause of cancer- related deaths in the United States surpassing breast cancer. It is estimated that 56,770 Americans will be diagnosed with pancreatic cancer in the US and more than 45,750 will die of the disease in 2019 [1]. Median age at diagnosis is 70 years and median age at death is 72 years. It has the highest mortality rate of all major cancers, survival rates have not improved substantially for more than 40 years, and is expected to become the second leading cause of cancer- related deaths in the US by the year 2020 [1]. According to Surveillance, Epidemiology, and End Results (SEER) database including patients in the US from years 2008 to 2014, 52% of patients had metastatic disease (MPC), 29% had regional lymph node involvement, 10% had localized disease, and 9% had an unknown stage. 5-year overall survival rate was 8.5% [2]. Surgery remains the only potentially curative treatment but unfortunately, only 5–10% of patients are candidates for pancreatectomy, and even then, 5-year survival following resection is only 10%. Therefore, it is important to review and learn from current treatments and develop novel agents in treatment of pancreatic cancer.

Gemcitabine became the standard of care for patients with PC in 1996 based on a randomized trial that showed significant improvement in the median overall survival (OS) as com- pared with fluorouracil administered as an intravenous bolus [3]. However, there have been no improvements in survival since its introduction. Then, in 2007, the Food and Drug Administration (FDA) approved erlotinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor based on a study by National Cancer Institute of Canada (NCIC) that showed a survival benefit with the combination of gemcitabine plus erlotinib [4]. Although the study was statistically significant with median OS of 6.24 months with gemcitabine plus erlotinib versus 5.91 months with gemcitabine alone, clinical benefit seems limited. Based on these results, erlotinib was not widely accepted and is rarely used. Continuing with EGFR targeted treatments; cetuximab in combination with gemcitabine was tested in a 2010 Southwest Oncology Group (SWOG) study which showed no improvement in out- comes with the combination [5]. Bevacizumab, anti-vascular endothelial growth factor (VEGF), in combination with gemcitabine showed promising results in a phase-II trial, however, did not show any survival benefit in a phase III trial conducted by Cancer and Leukemia Group B (CALGB) in patients with advanced PC [6]. Therefore, anti-EGFR and anti-VEGF therapies have shown disappointing results in advanced PC.

Two chemotherapy combination regimens have shown superiority in patients with MPC since 1996: FOLFIRINOX (PRODIGE/ACCORD trial) [7] in 2010 and nab-paclitaxel plus gemcitabine (MPACT study) in 2013 [8,9]. The PRODIGE/ ACCORD trial showed an unprecedented median OS of 11.1 months for FOLFIRINOX (5-fluorouracil/leucovorin, irinotecan, oxaliplatin) versus 6.8 months for gemcitabine. Additionally, progression-free-survival (PFS) was also better in the FOLFIRINOX arm. In the MPACT study, median OS was 8.5 months with nab-paclitaxel plus gemcitabine compared to months with gemcitabine alone. PFS benefit was also seen with nab-paclitaxel plus gemcitabine [9]. Based on these trials, FOLFIRINOX and gemcitabine plus nab-paclitaxel have become the standard of care in patients with MPC. Despite promising results from PRODIGE/ACCORD trial and MPACT study, there is still a dire need to develop newer agents and improve outcomes in this deadly disease.

Advancements in the technology to grow patient-derived cancer cells in vitro has led to the development of PC patient- derived organoids (PDOs) [10,11]. PDOs are organ-like 3D cell models that self-assemble and resemble many aspects of the derived tissue [12]. PC PDOs can be generated with a high success rate of ~75% from resected tissue, fine needle aspirates or fine needle biopsies and resemble the hallmarks of PC. Moreover, organoids can help to get deeper insights into the genomics space as they are composed of 100% neoplastic cells and can be potentially used as a tool predictive model for precision oncology. This enables deep genomic analyses that are very difficult in the tumor tissue itself due to the desmoplastic nature of PC. For example, in the group of KRAS wild-type PC, several potentially druggable genes such as ERBB2 [11] or NRG1 fusions have been discovered with potential targeted therapies for these patients [13]. The opportunity of PC PDOs is in their cellular properties that seem to match the corresponding patient. The functional characterization of PDOs may help to guide clinical decisions in the future to stratify patients towards the most effective therapy. Already now a predictive signature for sensitivity that could be retro- spectively validated in the COMPASS trial was derived from PC PDOs [11,14]. Their predictive value, however, has to be pro- ven in a clinical trial.

To make progress in the treatment of PC, it is important to grasp the biology of the tumor, perhaps best done through the development of organoids. A cell’s phenotype is estab- lished based on the set of observable characteristics resulting

2. New drugs for pancreatic cancer

Pancreatic cancer is a tough nut to crack, and investigators are undertaking various and new approaches to find novel and better treatment options for these patients. These efforts have led to the development of many new agents; few of them have entered the clinical trials and while others being tested. In this article, we will review the pharmacokinetics and phar- macodynamics of new drugs for pancreatic cancer and give our expert opinion.

2.1. Nanoliposomal irinotecan

2.1.1. Chemistry

Nanoliposomal irinotecan (MM-398, PEP-02, Onivyde®) is a liposomal-encapsulated form of irinotecan, with around 80,000 molecules of irinotecan contained within each lipo- some [16]. The liposome allows for longer circulation of irino- tecan with less peripheral conversion to its active metabolite, minimizing its exposure in normal tissue and maximizing the exposure in tumor tissue. Irinotecan is hydrolyzed to its active metabolite, SN-38, via cellular carboxylesterases. SN-38 is inac- tivated by glucuronidation via uridine diphosphate glucurono- syltransferase 1A1 (UGT1A1) and excreted through the biliary and renal systems via ATP-binding cassette transporters [17– 19]. The chemical structure of nanoliposomal irinotecan.

2.1.2. Mode of action

Irinotecan, a camptothecin analog, is a cytotoxic alkaloid agent that is converted to its active metabolite, SN-38, via cellular carboxylesterases. SN-38 reversibly inhibits topoisome- rase I-DNA complexes, preventing ligation of cleaved DNA strands. The accumulation of double-strand DNA breaks leads to S-phase cell cycle arrest and cell death [16,20].

2.1.3. Pre-clinical data

It has been determined that 95% of nanoliposomal irinotecan remains encapsulated within the liposome in circulation, and the ratio between total and encapsulated forms remained constant from 0 to 169.5 h post dose. One rat model showed the nanoliposomal formulation increased the half-life 39.6 times that of free irinotecan, and the area under the curve was 344 times greater than the free form [21].

2.1.4. Clinical data

A phase I trial of 11 patients with metastatic refractory solid tumor malignancy treated with single-agent nanoliposomal irinotecan determined a recommended phase II dose (R2PD) of 120 mg/m2 intravenous, given two of four patients dosed at 180 mg/m2 experienced grade 4 diarrhea and a third patient expired from toxicity. A post hoc analysis revealed the expired patient was heterozygote for UGTIA1*6/*28 genotype [22].

A non-randomized multinational phase II trial accrued 40 patients with MPC that had progressed after prior gemcita- bine-based therapy, to treatment with single agent nanolipo- somal irinotecan dosed at 120 mg/m2 intravenous every 3 weeks. The trial had a 75% 3-month overall survival (OS), meeting its primary endpoint goal of 40%. Of note, 65% of patients experienced a grade 3 toxicity or higher, most com- mon were diarrhea and neutropenia, and three patients died of severe neutropenia [23].

NAPOLI-1, an international phase III, randomized 1:1:1 (5-fluorouracil/leucovorin: nanoliposomal irinotecan 120 mg/ m2: nanoliposomal irinotecan 80 mg/m2, 5-fluorouracil/leucov- orin), open-label trial enrolled 417 patients. The primary end- point of OS was met in the combination nanoliposomal irinotecan arm compared to 5-fluorouracil/leucovorin (6.2 months versus 4.2 months; p = 0.012), but a statistical OS benefit was not met in the monotherapy nanoliposomal irino- tecan arm [24].

2.1.5. Toxicity

Fatal neutropenic sepsis occurs in 0.8% of patients receiving nanoliposomal irinotecan, with severe neutropenic fever occurring in 3%. Around 20% of patients receiving nanolipo- somal irinotecan in combination with 5-fluorouracil and leu- covorin experience severe or life-threatening neutropenia. It is recommended to hold nanoliposomal irinotecan for an abso- lute neutrophil count below 1,500/mm3 and to resume at a lower dose of 50 mg/m2 when grade 3 or 4 neutropenia resolves. On a second occurrence, the dose may be lowered to 43 mg/m2. If there is a third occurrence, it is recommended to discontinue. 13% of patients receiving nanoliposomal irinotecan in combi- nation with 5-fluorouracil and leucovorin experience severe diarrhea. Do not administer nanoliposomal irinotecan for patients with bowel obstruction and hold nanoliposomal irino- tecan for patients with grade 2 to 4 diarrhea. If no contraindica- tion atropine should be used to treat early diarrhea. Loperamide may be used to treat late diarrhea. Nanoliposomal irinotecan should be permanently discontinued if a patient develops inter- stitial lung disease or has a severe hypersensitivity reaction [16].

2.1.6. PK (Reference Table 1)

Total irinotecan and SN-38 pharmacokinetics were studied following the administration of nanoliposomal irinotecan 70 mg/m2. Compared to conventional irinotecan, the half-lives of total irinotecan (25.8 versus 12 h) and SN-38 (67.8 versus 20 h) were much longer in the nanoliposomal formulation. Age, gender and mild-moderate kidney dysfunction did not signifi- cantly effect on pharmacokinetics. However, patients with base- line bilirubin 1–2 mg/dL had a 37% increase in the SN-38 average steady-state concentration. This increase in SN-38 con- centrations was not seen in patients with elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT) con- centrations. Asian patients had a 56% lower total irinotecan average steady-state concentration and 8% higher SN-38 con- centration than Caucasian patients [16].

3. Expert opinion

The antimetabolites were the most recognized chemothera- peutic agents to have schedule-dependence administration activity, such as cytosine arabinoside was shown to be inactive unless given as a prolonged infusion or on a multiple-day administration schedule [67], methotrexate’s toxicity is asso- ciated with the duration of time a plasma concentration ade- quate to inhibit dihydrofolate reductase is maintained, 5-fluorouracil’s toxicity also depends on its administration schedule, with weekly bolus doses producing more myelosup- pression and prolonged infusions resulting in higher incidence of gastrointestinal toxicity [68,69]. Interestingly, paclitaxel and etoposide, which are not classical antimetabolites, have cyto- toxicity dependent on the schedule of drug administration [70,71]. These data really underlined the significance of under- standing and determining the pharmacokinetics and pharma- codynamics of cytotoxic agents both for toxicity as well as efficacy.

Pancreatic adenocarcinoma cancer is currently categorized as the third-leading cause of cancer-related mortality in the USA and is projected to be the second by 2020. The statistics remain very alarming. Approximately 56,770 individuals are expected to be diagnosed with pancreatic adenocarcinoma in the USA this year and 45,750 will die of it [1]. Hardly, 8.5% of people diagnosed with pancreatic cancer survive for five years [2]. It is notoriously difficult to treat pancreatic cancer not only because of its late-stage presentation at the time of diagnosis but also only few agents are effective which showed a clinically meaningful survival benefit with manageable toxi- cities. Two combination regimens, nab-paclitaxel and gemcitabine, and FOLFIRINOX remain the most active treatment options but not appropriate for all patients based on performance status, liver function and comorbid conditions. Though few metabolic as well as pharmacogenetics markers have been studied for these agents but none have been validated to identify which patients may benefit more from one regimen or another. However, pharmacogenetics syndromes such as dihydropyrimidine dehydrogenase (DPD) is well recognized to increase toxicity following 5-FU [72]. Efforts have been continued from overcoming Kras mutation in pancreatic cancer dating back to 1990s [73].

It is a fact that FOLFIRINOX poses significant adverse effects leading to empirical dose reduction and discontinuation of treat- ment. Deyme et al. studied a model-based FOLFIRINOX regimen optimization by performing population pharmacokinetics of FOLFIRINOX with an objective to improve patients’ outcome. They found that gender and body size were the only covariates found in the literature. They concluded that their review will provide a basis for further development of pharmacokinetics– pharmacodynamics–toxicity models for optimization of FOLFIRINOX in order to assess the best benefit-to-risk ratio [75]. Simply, pancreatic cancer remains a fatal disease in the majority of patients and it is of utmost significance to perform, analyze and incorporate pharmacokinetic and pharmacody- namic data to customize treatment in patients with a very short interval of time to treat and who already are heavily symptomatic due to the cancer-related complications. Historically, the lack of effective treatment options made the concept of predictive biomarkers moot, but with recent improvements in therapy, there is now a need. As we and others published previously, there are a host of potential treatment paradigm for patients whose tumors are found to be ‘high’-HA expressers prior to treatment. Historically, this cohort of patients has performed worse than low expressers. However, the ‘high’-HA expressers had a better PFS than low expressers when PEGPH20 was added to chemotherapy up front. Pancreatic cancer remains a ‘black box’ disease with a poor prognosis. Though surgical resec- tion offers potentially the best odds of survival, unfortu- nately, most of these patients succumb to development of metastases and die. Currently, there are no particular early- screening tests, although many researchers worldwide are investigating many tools such as circulating tumor cells or RNA markers in the blood.

Therefore, we must undertake different and novel approaches to find a better therapy for these patients.

One such approach is to perform phase 0 studies to speed up and streamline the process of development and approval of drug. These are the studies that could help us to determine drug delivery to the tumor cells, pharmacokinetics and phar- macodynamics with the use of bio-specimens at much earlier stage of drug development and guide us in further stages of development. Hence, if a phase 0 study showed a red flag or disapprove the concept, it can then help the researchers about the next step and prevent the delay and expense of finding out years later in phase II or even phase III clinical trials.

We recommend strongly that PK/PD strategies should be implemented in early research phases of drug discovery pro- jects that may lead to successful transition to drug develop- ment. Effective PK/PD study design, analysis, and interpretation can help investigators understand the relation- ship between PK and PD and the mode of drug action. Moreover, by identifying PK properties earlier would improve and potentially optimize further drug design, such as in vitro compound potency to the in vivo setting, reduce the number of in vivo animal studies, and improve translation of findings from preclinical species into the clinical setting.

This is said to be the era of personalized oncology in which therapy can be targeted at individuals who would most likely have a favorable response, making it more efficacious and cost effective. Unfortunately, pancreatic cancer lags behind this approach at present and there is much that needs to be done in this field. Future efforts should be directed at identifying sensitive or non-responding genotypes or phenotypes both in preclinical models and in the clinical trials and such profiles should then be validated in order to be used for the appropriate patient enrollment into subsequent prospective studies. Napabucasin With the availability of validated genetic/phenotypic platforms, we can select the treatment based on potential chemosensitivity and/or toxicity, thereby provide a guide tool in selecting more effective and rationally based tailored therapy for each patient with pancreatic cancer.