Loek A. W. de Jong

Purpose: Etoposide, together with cisplatin, is a cornerstone in the treatment of metastatic testicular cancer, but dosing can be challenging in patients with organ dysfunction and/or polypharmacy. We report a patient with cystic fibrosis, liver cirrhosis and preexisting pancytopenia grade 1, requiring multiple concomitant medications inhibiting CYP3A4 and P-gp, who presented with metastatic seminoma. Method and results: Due to potential drug-drug interactions and liver cirrhosis, the initial etoposide dose was reduced to 50% of standard. Monitoring of etoposide plasma concentrations showed that total exposure was not enhanced. The subsequent dose was increased to 100% and further adjusted based on tolerability. After a dose reduction from cycle 2 due to pancytopenia grade 4, the patient successfully completed the chemotherapy regimen and had a complete response on first evaluation. Conclusion: This case shows that monitoring of etoposide plasma concentrations can be beneficial in complex clinical scenarios involving organ dysfunction and/or potential drug-drug interactions. This is especially important in curative treatment to avoid under dosing. Patient summary: This case report highlights the challenges of dosing etoposide in a patient with cystic fibrosis and liver cirrhosis who is taking multiple drugs that may interact with etoposide. The patient should be monitored closely on how the treatment is tolerated and the dose should be adjusted accordingly.

Mitotane is an adrenolytic drug with cytotoxic effects, registered for the treatment of advanced adrenocortical carcinoma (ACC), a rare but aggressive tumour type with a poor prognosis despite treatment. Recently, the oral multi‐kinase inhibitor cabozantinib has shown promising results as a potential second‐line treatment option. Unfortunately, first‐line mitotane therapy complicates subsequent treatments due to its strong and long‐lasting inducing effects on drug‐metabolizing enzymes resulting in persistent subtherapeutic concentrations. This is also relevant for subsequent cabozantinib treatment, and therefore only patients with mitotane concentration ≤2 mg/L were eligible to enter the cabozantinib study. However, ACC is often too aggressive to await mitotane effects to diminish. In this case report, we describe different pharmacokinetic interventions to potentiate cabozantinib efficacy in a patient with rapidly progressive ACC who had persistent subtherapeutic cabozantinib concentrations after previous mitotane treatment. First, we recommended co‐administration with a high‐fat meal and grapefruit juice to increase cabozantinib absorption. Second, we aimed to reduce cabozantinib clearance through co‐administration of the CYP3A4 inhibitor cobicistat (150 mg once daily). Pharmacokinetic sampling revealed that cobicistat enhanced cabozantinib absorption, but had insufficient impact on metabolic enzymes and thereby failed to normalize the mitotane‐induced clearance of cabozantinib. Therefore, doubling the dose is deemed necessary in order to reach therapeutic cabozantinib concentrations. Our findings suggest that an aggressive approach, combining pharmacokinetic boosting, dose escalation and frequent pharmacokinetic monitoring is required to prevent undertreatment and toxicity. By mitigating mitotane‐induced subtherapeutic concentrations, this pharmacokinetic strategy may facilitate more effective use and earlier initiation of cabozantinib as second‐line treatment in ACC.

All patients treated with anticancer agents should receive the most effective anti‐emetic regimen. Anti‐emetic guidelines provide recommendations but do not take into account possible drug–drug interactions between anti‐emetics and anticancer drugs. This study determines the clinical relevance of the potential drug–drug interaction of the neurokinin‐1 receptor antagonist, aprepitant, on the pharmacokinetics of etoposide. Aprepitant is a moderate CYP3A4 inhibitor and may increase the systemic exposure of etoposide which is partly metabolized by cytochrome P450 enzyme 3A4 (CYP3A4). In this prospective observational study, the pharmacokinetics of etoposide with and without concomitant use of aprepitant was determined in 12 patients receiving first‐line chemotherapy for testicular cancer. The geometric mean (95% confidence interval (CI)) area under the plasma concentration‐time curve 0–24 hour (AUC_0–24h) of etoposide with aprepitant was 86.2 (79.7–93.2) mg/L*hour vs. 83.7 (75.8–92.4) mg/L*hour without aprepitant. Geometric mean ratios (90% CIs) of AUC_0–24h and maximum plasma concentration (C_max) for etoposide with and without aprepitant were 1.03 (0.96–1.10) and 0.96 (0.89–1.03), respectively. This study confirms the absence of a clinically relevant interaction between etoposide and aprepitant. Both drugs can be safely combined without affecting etoposide exposure.

Imatinib plasma trough concentrations are associated with efficacy for patients treated for advanced or metastatic KIT-positive gastrointestinal stromal tumours (GISTs). This relationship has not been studied for patients treated in the neoadjuvant setting, let alone its correlation with tumour drug concentrations. In this exploratory study we aimed to determine the correlation between plasma and tumour imatinib concentrations in the neoadjuvant setting, investigate tumour imatinib distribution patterns within GISTs, and analyse its correlation with pathological response. Imatinib concentrations were measured in both plasma and in three regions of the resected primary tumour: the core, middle part, and periphery. Twenty-four tumour samples derived from the primary tumours of eight patients were included in the analyses. Imatinib tumour concentrations were higher compared to plasma concentrations. No correlation was observed between plasma and tumour concentrations. Interpatient variability in tumour concentrations was high compared to interindividual variability in plasma concentrations. Although imatinib accumulates in tumour tissue, no distribution pattern of imatinib in tumour tissue could be identified. There was no correlation between imatinib concentrations in tumour tissue and pathological treatment response.

Purpose: To determine the systemic exposure to cisplatin and paclitaxel after adjuvant intraperitoneal administration in patients with advanced ovarian cancer who underwent primary debulking surgery. This could provide an explanation for the high incidence of systemic adverse events associated with this treatment regimen. Methods: This is a prospective pharmacokinetic study in patients with newly diagnosed advanced ovarian cancer who were treated with intraperitoneal administered cisplatin and paclitaxel. Plasma and peritoneal fluid samples were obtained during the first treatment cycle. The systemic exposure to cisplatin and paclitaxel was determined and compared to previously published exposure data after intravenous administration. An exploratory analysis was performed to investigate the relation between systemic exposure to cisplatin and the occurrence of adverse events. Results: Pharmacokinetics of ultrafiltered cisplatin were studied in eleven evaluable patients. The geometric mean [range] peak plasma concentration (C_max) and area under the plasma-concentration time curve (AUC_0–24 h) for cisplatin was 2.2 [1.8–2.7] mg/L and 10.1 [9.0–12.6] mg h/L, with a coefficient of variation (CV%) of 14 and 13.0%, respectively. The geometric mean [range] observed plasma concentration of paclitaxel was 0.06 [0.04–0.08] mg/L. No correlation was found between systemic exposure to ultrafiltered cisplatin and adverse events. Conclusion: Systemic exposure to ultrafiltered cisplatin after intraperitoneal administration is high. In addition to a local effect, this provides a pharmacological explanation for high incidence of adverse events seen after intraperitoneal administration of high-dose cisplatin. The study was registered at ClinicalTrials.gov under registration number NCT02861872.

Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is an innovative drug delivery technique invented to be used for the treatment of peritoneal metastasis. Its application gained popularity over the past years. Several prospective clinical trials are being conducted to determine efficacy and safety. At this moment, there remain many challenges to overcome before PIPAC can be widely adopted in clinical practice. See related article by Kim et al., p. 1875

Purpose: In this exploratory study, the effect of postprocedural flushing with crystalloids after oxaliplatin-based hyperthermic intraperitoneal chemotherapy (HIPEC) on platinum concentrations in peritoneal tissue, blood, and drain fluid was studied. Interpatient variability in oxaliplatin pharmacokinetics and the relation between platinum concentration in peritoneal fluid and platinum exposure in tissue and blood was explored. Methods: Ten patients with peritoneal carcinomatosis of colorectal origin were treated with HIPEC including postprocedural flushing, followed by ten patients without flushing afterwards. Tissue, peritoneal fluid, blood, and drain fluid samples were collected for measurement of total and ultrafiltered platinum concentrations. Results: Peritoneal tissue concentration and systemic ultrafiltered platinum exposure showed large inter individual variability, ranging from 65 to 1640 µg/g dry weight and 10.5 to 28.0 µg*h/ml, respectively. No effect of flushing was found on geometric mean platinum concentration in peritoneal tissue (348 vs. 356 µg/g dry weight), blood (14.8 vs. 18.1 µg*h/ml), or drain fluid (day 1: 7.6 vs. 7.7 µg/ml; day 2: 1.7 vs. 1.9 µg/ml). The platinum concentration in peritoneal fluid at the start of HIPEC differed twofold between patients and was positively correlated with systemic exposure (p = .04) and peak plasma concentration (p = .04). Conclusion: In this exploratory study, no effect was found for postprocedural flushing on platinum concentrations in peritoneal tissue, blood, or drain fluid. BSA-based HIPEC procedure leads to large interpatient variability in platinum exposure in all compartments. The study was registered at ClinicalTrials.gov on 7 December 2017 under registration number NCT03364907.