Stefanie D. Krens

Aims: The study aims to predict and improve the absorption of tyrosine kinase inhibitors (TKIs) in patients with malabsorption issues, particularly those who have undergone bariatric surgery or are using proton‐pump inhibitors. The research involves 2 main components: the development of an artificial intelligence (AI) model to identify TKIs that are susceptible to reduced absorption in these patients, and the application of case‐specific absorption enhancements based on 2 clinical scenarios. Methods: A fully connected neural network was applied using pH‐dependent solubility data from 137 785 compounds to identify TKIs at risk of reduced bioavailability when bypassing the stomach. The clinical impact of gastric acid suppressants on the bioavailability of 71 approved TKIs was evaluated by correlating the AI solubility estimates with the effect of proton‐pump inhibitors on clinical exposure. Furthermore, absorption enhancement was applied in 2 clinical scenarios, with therapeutic drug monitoring assessing the effectiveness of the enhancement. Results: Two AI models were developed to predict the difference in molecular aqueous solubility between acid and neutral pH and to capture the concentration available for intestinal absorption in healthy and in patients with malabsorption issues. The AI model capturing the solubility difference between acidic and neutral pH demonstrated predictive capabilities, with a Pearson correlation coefficient of .95 and a coefficient of determination of .90. It predicted that the solubility difference, between acidic and neutral pH, was associated with clinical bioavailability ( P < .001). Nilotinib, lapatinib and dacomitinib were ranked as TKIs with the highest risk of malabsorption in case of increased stomach pH. Conclusion: We developed an AI‐based model that predicts TKIs that are at risk of malabsorption when bypassing the stomach or used with gastric acid suppressants. Drugs with a high malabsorption risk can be enhanced by various methods to improve bioavailability.

Aim: In the registration trial, cabozantinib exposure ≥ 750 ng/mL correlated to improved tumor size reduction, response rate and progression free survival (PFS) in patients with metastatic renal cell cancer (mRCC). Because patients in routine care often differ from patients in clinical trials, we explored the cabozantinib exposure–response relationship in patients with mRCC treated in routine care.Methods: Cabozantinib trough concentrations (C_min) were collected and average exposure was calculated per individual. Exposure–response analyses were performed using the earlier identified target of C_min > 750 ng/mL and median C_min. In addition, the effect of dose reductions on response was explored. PFS was used as measure of response.Results: In total, 59 patients were included:10% were classified as favourable, 61% as intermediate and 29% as poor IMDC risk group, respectively. Median number of prior treatment lines was 2 (0–5). Starting dose was 60 mg in 46%, 40 mg in 42% and 20 mg in 12% of patients. Dose reductions were needed in 58% of patients. Median C_minwas 572 ng/mL (IQR: 496–701). Only 17% of patients had an average C_min ≥ 750 ng/mL. Median PFS was 52 weeks (95% CI: 40–64). No improved PFS was observed for patients with C_min ≥ 750 ng/mL or ≥ 572 ng/ml. A longer PFS was observed for patients with a dose reduction vs. those without (65 vs. 31 weeks,p = .001). After incorporating known covariates (IMDC risk group and prior treatment lines (< 2 vs. ≥ 2)) in the multivariable analysis, the need for dose reduction remained significantly associated with improved PFS (HR 0.32, 95% CI:0.14–0.70,p = .004).Conclusion: In these explorative analyses, no clear relationship between increased cabozantinib exposure and improved PFS was observed. Average cabozantinib exposure was below the previously proposed target in 83% of patients. Future studies should focus on validating the cabozantinib exposure required for long term efficacy.

Background Pazopanib and sunitinib are oral tyrosine kinase inhibitors (TKI) approved for the treatment of renal cell carcinoma. For both oncolytics, a clear target trough concentration level in plasma has been defined above which improved clinical efficacy can be expected. However, many factors can alter TKI exposure, including disease characteristics. Case A 79-year old male with metastatic papillary renal cell carcinoma and malignant ascites was treated with pazopanib. Initially, treatment with pazopanib at adequate trough concentrations resulted in regression of ascites. After a 6-month puncture-free interval, paracenteses were again required and the plasma trough concentration of pazopanib had decreased to 5 mg/L without any dose adjustments. Despite a dose increase, pazopanib levels remained subtherapeutic and could not prevent new paracenteses. Pazopanib concentrations in the drained ascites fluid were comparable to plasma concentrations and remained high also after treatment discontinuation. This observation suggests that the ascites compartment may act as a third space in which pazopanib accumulates. During subsequent treatment with sunitinib, a similar distribution over ascites fluid was observed. Conclusion Presence of ascites or pleural effusion in patients treated with TKIs may lead to subtherapeutic plasma exposure, which may hamper treatment efficacy. Measuring TKIs plasma concentrations regularly during treatment is essential to identify patients with subtherapeutic exposure.

Cabozantinib is registered in fixed 60 mg dose. However, 46-62% of patients in the registration studies needed a dose reduction due to toxicity. Improved clinical efficacy has been observed in renal cell carcinoma patients (RCC) with a cabozantinib exposure >750 μg/L. In this study we explored the cabozantinib exposure in patients with different tumour types. We included RCC patients from routine care and salivary gland carcinoma (SGC) patients from a phase II study with ≥1 measured C_min at steady-state. The geometric mean (GM) C_min at the starting dose, at 40 mg and at best tolerated dose (BTD) were compared between both tumour types. Forty-seven patients were included. All SGC patients (n = 22) started with 60 mg, while 52% of RCC patients started with 40 mg. GM C_min at the start dose was 1456 μg/L(95%CI:1185-1789) vs 682 μg/L(95%CI:572-812)(P < .001) for SGC and RCC patients, respectively. When dose-normalized to 40 mg, SGC patients had a significantly higher cabozantinib exposure compared to RCC patients(C_min 971 μg/L(95%CI:790-1193) vs 669 μg/L(95%CI:568-788)(P = .005). Dose reductions due to toxicity were needed in 91% and 60% of SGC and RCC patients, respectively. Median BTD was ~20-30 mg for SGC and 40 mg for RCC patients. GM C_min at BTD were comparable between the SGC and the RCC group, 694 μg/L(95%CI:584-824) vs 583 μg/L(95%CI:496-671)(P = .1). The observed cabozantinib exposure at BTD of ~600 μg/L is below the previously proposed target. Surprisingly, a comparable exposure at BTD was reached at different dosages of cabozantinib for SGC patients compared to RCC patients Further research is warranted to identify the optimal exposure and starting dose to balance efficacy and toxicity.

Co‐treatment with gastric acid suppressants (GAS) in patients taking anticancer drugs that exhibit pH‐dependant absorption may lead to decreased drug exposure and may hamper drug efficacy. In our study, we investigated whether a 1‐hour time interval between subsequent intake of pazopanib and GAS could mitigate this negative effect on drug exposure. We performed an observational study in which we collected the first steady‐state pazopanib trough concentration (C_min) levels from patients treated with pazopanib 800 mg once daily (OD) taken fasted or pazopanib 600 mg OD taken with food. All patients were advised to take GAS 1 hour after pazopanib. Patients were grouped based on the use of GAS and the geometric (GM) C_min levels were compared between groups for each dose regimen. Additionally, the percentage of patients with exposure below the target threshold of 20.5 mg/L and the effect of the type of PPI was explored. The GM C_min levels were lower in GAS users vs non‐GAS users for both the 800 and 600 mg cohorts (23.7 mg/L [95% confidence interval [CI]: 21.1‐26.7] vs 28.2 mg/L [95% CI: 25.9‐30.5], P = .015 and 26.0 mg/L [95% CI: 22.4‐30.3] vs 33.5 mg/L [95% CI: 30.3‐37.1], P = .006). Subtherapeutic exposure was more prevalent in GAS users vs non‐GAS users (33.3% vs 19.5% and 29.6% vs 14%). Sub‐analysis showed lower GM pazopanib C_min in patients who received omeprazole, while minimal difference was observed in those receiving pantoprazole compared to non‐users. Our research showed that a 1‐hour time interval between intake of pazopanib and GAS did not mitigate the negative effect of GAS on pazopanib exposure and may hamper pazopanib efficacy.

A sensitive and selective ultra‐high performance liquid chromatography–tandem mass spectrometry (UPLC–MS/MS) method for the simultaneous determination of seven oral oncolytics (two PARP inhibitors, i.e. olaparib and niraparib, and five tyrosine kinase inhibitors, i.e. cobimetinib, cabozantinib, dabrafenib, vemurafenib and regorafenib, plus its active metabolite regorafenib M2) in EDTA plasma was developed and validated. Stable isotope‐labelled internal standards were used for each analyte. A simple protein precipitation method was performed with acetonitrile. The LC–MS/MS system consisted of an Acquity H‐Class UPLC system, coupled to a Xevo TQ‐S micro tandem mass spectrometer. The compounds were separated on a Waters CORTECS UPLC C18 column (2.1 × 50 mm, 1.6 μm particle size) and eluted with a gradient elution system. The ions were detected in the multiple reaction monitoring mode. The method was validated for cobimetinib, cabozantinib, dabrafenib, niraparib, olaparib, vemurafenib, regorafenib and regorafenib M2 over the ranges 6–1000, 100–5000, 10–4000, 200–2000, 200–20,000, 5000–100,000, 500–10,000 and 500–10,000 μg/L, respectively. Within‐day accuracy values for all analytes ranged from 86.8 to 115.0% with a precision of %. The developed method was successfully used for guiding therapy with therapeutic drug monitoring in cancer patients and clinical research programs in our laboratory.