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

Bruin, Michiel de; Korse, Catharina M.; Wijnen, B van; Jong, Vincent M T de; Linn, SC; Triest, B. van; Rosing, Hilde; Beijnen, Jos H.; Broek, Daan van den; Huitema, Alwin D. R.

doi:10.1007/s00228-020-03070-0

Cited by 32 publications

(32 citation statements)

References 16 publications

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“…Studies have shown that olaparib likely causes inhibition of renal transporters leading to a reversible, dose-dependent increase in creatinine. 25 Consistently, strong signal strength of blood creatinine increased (PT: 10005483) has also been reported in our analysis. However, some unexpected and significant safety signals related to olaparib on renal function such as glomerular filtration rate decreased (PT: 10018358), renal impairment (PT: 10062237) and hydronephrosis (PT: 10020524) were shown simultaneously based on our results of FAERS data.…”

Section: Discussionsupporting

confidence: 91%

A Real-World Disproportionality Analysis of Olaparib: Data Mining of the Public Version of FDA Adverse Event Reporting System

Shu¹,

He²,

Liu³

et al. 2022

CLEP

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Background: Olaparib, the world's first poly ADP-ribose polymerase (PARP) inhibitor (PARPi), has been approved for treatment of ovarian cancer, breast cancer, pancreatic cancer and prostate cancer by FDA. The current study was to assess olaparib-related adverse events (AEs) of real-world through data mining of the US Food and Drug Administration Adverse Event Reporting System (FAERS). Methods: Disproportionality analyses, including the reporting odds ratio (ROR), the proportional reporting ratio (PRR), the Bayesian confidence propagation neural network (BCPNN) and the multi-item gamma Poisson shrinker (MGPS) algorithms were employed to quantify the signals of olaparib-associated AEs. Results: Out of 8,450,009 reports collected from the FAERS database, 6402 reports of olaparib-associated AEs were identified. A total of 118 significant disproportionality preferred terms (PTs) conforming to the four algorithms simultaneously were retained. The most common AEs included anemia, thrombocytopenia, nausea, decreased appetite, blood creatinine increased and dermatomyositis, which were corresponding to those reported in the specification and clinical trials. Unexpected significant AEs as interstitial lung disease, Pneumocystis jirovecii pneumonia, folate deficiency, renal impairment and intestinal obstruction might also occur. The median onset time of olaparib-related AEs was 61 days (interquartile range [IQR] 14-182 days), and most of the cases occurred within the first 1 month after olaparib initiation. Conclusion: Results of our study were consistent with clinical observations, and we also found potential new and unexpected AEs signals for olaparib, suggesting prospective clinical studies were needed to confirm these results and illustrate their relationship. Our results could provide valuable evidence for further safety studies of olaparib.

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Section: Discussionsupporting

confidence: 91%

A Real-World Disproportionality Analysis of Olaparib: Data Mining of the Public Version of FDA Adverse Event Reporting System

Shu¹,

He²,

Liu³

et al. 2022

CLEP

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“…22,23 One explanation for this observation is that olaparib likely inhibits renal transporters, leading to a reversible and dose-dependent increase in creatinine, and does not affect glomerular filtration rate. 23 One patient on this trial developed AML 3 months after discontinuing olaparib. The incidence of myelodysplastic syndrome (MDS)/AML in patients treated in clinical trials with olaparib monotherapy was 3.0%.…”

Section: Discussionmentioning

confidence: 99%

First phase 1 clinical study of olaparib in pediatric patients with refractory solid tumors

Takagi

Ogawa

Iehara

et al. 2022

Cancer

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BACKGROUND:The survival of patients with high-risk, refractory, relapsed, or metastatic solid tumors remains dismal. A poly(ADP-ribose) polymerase (PARP) inhibitor could be effective for the treatment of pediatric solid tumors with defective homologous recombination. METHODS:This open-label, multicenter phase 1 clinical trial evaluated the safety, tolerability, and efficacy of olaparib, a PARP inhibitor, in pediatric patients with refractory solid tumors to recommend a dose for Phase 2 trials. Olaparib (62.5, 125, and 187.5 mg/m 2 twice daily) was administered orally every day (1 cycle = 28 days) using a standard 3 + 3 dose-escalation design. Patients aged 3-18 years with recurrent pediatric solid tumors were eligible. Pharmacokinetic and pharmacodynamic analyses were performed. RESULTS: Fifteen patients were enrolled and received olaparib monotherapy, which was well tolerated. The recommended phase 2 dose for daily administration was 187.5 mg/m 2 twice daily. Pharmacokinetics were dose proportional. The area under the concentration-time curve from 0 to 12 h and the peak plasma concentration for 187.5 mg/m 2 twice daily in children were comparable to previous data obtained in a 200-mg, twice-daily cohort and lower than those in the 300-mg twice-daily cohort in adults. Pharmacodynamic studies demonstrated substantial inhibition of PARP activity. Two partial responses were observed in patients with Wilms tumor and neuroblastoma. CONCLUSIONS: This report is the first clinical trial to describe the use of a PARP inhibitor as monotherapy in children. Olaparib was well tolerated, with preliminary antitumor responses observed in DNA damage response-defective pediatric tumors.

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“…Elevated levels of serum creatinine have been documented in about 10–15% of patients receiving PARP inhibitors ( Table 2 ). These drugs can interfere with several renal transporters, such as MATE1, MATE2-K, OCT1 and OCT-2, determining an increase in serum creatinine without actually affecting kidney function [ 71 , 72 ]. Hence, alternative ways to assess renal function (e.g., radionuclide renal scan) should be considered in case of creatinine elevation before reducing the dose of PARP inhibitor [ 26 , 71 ].…”

Section: Safety Profile Of Ddr-targeting Agentsmentioning

confidence: 99%

Everything Comes with a Price: The Toxicity Profile of DNA-Damage Response Targeting Agents

Martorana

Silva

Sessa

et al. 2022

Cancers

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Targeting the inherent vulnerability of cancer cells with an impaired DNA Damage Repair (DDR) machinery, Poly-ADP-Ribose-Polymerase (PARP) inhibitors have yielded significant results in several tumor types, eventually entering clinical practice for the treatment of ovarian, breast, pancreatic and prostate cancer. More recently, inhibitors of other key components of DNA repair, such as ATR, CHK1 and WEE1, have been developed and are currently under investigation in clinical trials. The inhibition of DDR inevitably induces on-target and off-target adverse events. Hematological and gastrointestinal toxicities as well as fatigue are common with all DDR-targeting agents, while other adverse events are drug specific, such as hypertension with niraparib and transaminase elevation with rucaparib. Cases of pneumonitis and secondary hematological malignancies have been reported with PARP inhibitors and, despite being overly rare, they deserve particular attention due to their severity. Safety also represents a crucial issue for the development of combination regimens incorporating DDR-targeting agents with other treatments, such as chemotherapy, anti-angiogenics or immunotherapy. As such, overlapping and cumulative toxicities should be considered, especially when more than two classes of drugs are combined. Here, we review the safety profile of DDR-targeting agents when used as single agents or in combination and we provide principles of toxicity management.

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

Cited by 32 publications

References 16 publications

A Real-World Disproportionality Analysis of Olaparib: Data Mining of the Public Version of FDA Adverse Event Reporting System

A Real-World Disproportionality Analysis of Olaparib: Data Mining of the Public Version of FDA Adverse Event Reporting System

First phase 1 clinical study of olaparib in pediatric patients with refractory solid tumors

Everything Comes with a Price: The Toxicity Profile of DNA-Damage Response Targeting Agents

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