A real or apparent decrease in glomerular filtration rate in patients using olaparib?

PURPOSE: Olaparib is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated for ovarian and metastatic breast cancer. Increased serum creatinine levels have been observed in patients taking olaparib, but the underlying mechanism is unknown. This study aimed to investigate if patients receiving olaparib have increased creatinine levels during olaparib treatment and whether this actually relates to a declined glomerular filtration rate (GFR). METHODS: We retrospectively identified patients using olaparib at the Netherlands Cancer Institute - Antoni van Leeuwenhoek (NKI-AVL) from 2012 until 2020. Patients with at least one plasma or serum sample available at baseline/off treatment and during olaparib treatment were included. Cystatin C levels were measured, creatinine levels were available and renal function was determined by calculating the estimated glomerular filtration rate (eGFR) using the Creatinine Equation (CKD-EPI 2009) and the Cystatin C Equation (CKD-EPI 2012). RESULTS: In total, 66 patients were included. Olaparib treatment was associated with a 14% increase in median creatinine from 72 (inter quartile range (IQR): 22) µmol/L before/off treatment to 82 (IQR: 20) µmol/L during treatment (p < 0.001) and a 13% decrease in median creatinine-derived eGFR from 86 (IQR: 26) mL/min/1.73 m2 before/off treatment to 75 (IQR: 29) mL/min/1.73 m2 during treatment (p < 0.001). Olaparib treatment had no significant effect on median cystatin C levels (p = 0.520) and the median cystatin C-derived eGFR (p = 0.918). CONCLUSIONS: This study demonstrates that olaparib likely causes inhibition of renal transporters leading to a reversible and dose-dependent increase in creatinine and does not affect GFR, since the median cystatin C-derived eGFR was comparable before/off treatment and during treatment of olaparib. Using the creatinine-derived eGFR can give an underestimation of GFR in patients taking olaparib. Therefore, an alternative renal marker such as cystatin C should be used to accurately calculate eGFR in patients taking olaparib.

Radiosensitisation by olaparib through focused ultrasound delivery in a diffuse midline glioma model.

BACKGROUND AND PURPOSE: Diffuse midline glioma H3K27-altered (DMG) is an aggressive, inoperable, predominantly paediatric brain tumour. Treatment strategies are limited, resulting in a median survival of only 11 months. Currently, radiotherapy (RT), often combined with temozolomide, is considered the standard of care but remains palliative, highlighting the urgency for new therapies. Radiosensitisation by olaparib, an inhibitor of PARP1 and subsequently PAR-synthesis, is a promising treatment option. We assessed whether PARP1 inhibition enhances radiosensitivity in vitro and in vivo following focused ultrasound mediated blood-brain barrier opening (FUS-BBBO). METHODS: Effects of PARP1 inhibition were evaluated in vitro using viability, clonogenic, and neurosphere assays. In vivo olaparib extravasation and pharmacokinetic profiling following FUS-BBBO was measured by LC-MS/MS. Survival benefit of FUS-BBBO combined with olaparib and RT was assessed using a patient-derived xenograft (PDX) DMG mouse model. RESULTS: Treatment with olaparib in combination with radiation delayed tumour cell proliferation in vitro through the reduction of PAR. Prolonged exposure of low olaparib concentration was more efficient in delaying cell growth than short exposure of high concentration. FUS-BBBO increased olaparib bioavailability in the pons by 5.36-fold without observable adverse effects. A Cmax of 54.09 µM in blood and 1.39 µM in the pontine region was achieved following administration of 100 mg/kg olaparib. Although RT combined with FUS-BBBO mediated olaparib extravasation delayed local tumour growth, survival benefits were not observed in an in vivo DMG PDX model. CONCLUSIONS: Olaparib effectively radiosensitises DMG cells in vitro and reduces primary tumour growth in vivo when combined with RT. Further studies are needed to investigate the therapeutic benefit of olaparib in suitable preclinical PDX models.

Development and validation of an integrated LC-MS/MS assay for therapeutic drug monitoring of five PARP-inhibitors.

An liquid chromatography-mass spectrometry (LC-MS/MS) assay was developed for the combined analysis of the five poly (ADP-ribose) polymerase (PARP) inhibitors niraparib, olaparib, rucaparib talazoparib and veliparib. A simple and fast sample pre-treatment method was used by protein precipitating of plasma samples with acetonitrile and dilution of the supernatant with formic acid (0.1% v/v in water). This was followed by chromatographic separation on a reversed-phase UPLC BEH C18 column and detection with a triple quadrupole mass spectrometer operating in the positive mode. A simplified validation procedure specifically designed for bioanalytical methods for clinical therapeutic drug monitoring (TDM) purposes, was applied. This included assessment of the calibration model, accuracy and precision, lower limit of quantification (LLOQ), specificity and selectivity, carry-over and stability. The validated range was 30-3000 ng/mL for niraparib, 100-10,000 ng/mL for olaparib, 50-5000 ng/mL for rucaparib, 0.5-50 ng/mL for talazoparib and 50-5000 for veliparib. All results were within the criteria of the US Food and Drug Administration (FDA) guidance and European Medicines Agency (EMA) guidelines on method validation. The assay has been successfully implemented in our laboratory.

Development and validation of an LC-MS/MS method with a broad linear dynamic range for the quantification of tivozanib in human and mouse plasma, mouse tissue homogenates, and culture medium.

The first bioanalytical assay for tivozanib in human and mouse plasma, mouse tissue homogenates and culture medium was developed and validated over a linear dynamic range from 0.5 to 5000 ng/mL. The extended concentration range will cover the quantification of tivozanib in the majority of study samples, reducing the need for reanalysis which is often not possible due to limited amount of sample in preclinical studies. A simple and fast pretreatment method was used consisting of protein precipitation with acetonitrile followed by dilution of the supernatant. The final extract was injected onto an Ultra-Performance Liquid Chromatography (UPLC) BEH C18 column with gradient elution of formic acid in water and formic acid in acetonitrile mobile phase. Chromatographic separation was followed by detection with a triple-quadrupole mass spectrometer operating in the positive ion-mode. By simultaneously monitoring the sensitive conventional [M + H]+ isotopologue- product transition for quantification of low concentrations and a less abundant [M + H]++1 isotopologue- product transition to reduce the sensitivity for quantification of high concentrations, we were able to extend the overall linear dynamic range up to 0.5-5000 ng/mL. A full validation was performed in human plasma and a partial validation was executed for the other matrices. All results were within the acceptance criteria of the European Medicines Agency (EMA) guidelines and the US Food and Drug Administration (FDA) guidance, except for the carry-over. This was solved by the analysis of extra matrix blanks and by grouping study samples containing a high tivozanib concentration in the sample sequence. In this way carry-over did not impact the data integrity. We demonstrated that by measuring two multiple reaction monitoring (MRM) transitions for tivozanib, the linear dynamic range could be extended from two to four decades. The assay was successfully applied in pharmacokinetic studies in mice and a transport assay.