Evaluation of Drug–Drug Interactions of Rucaparib and <scp>CYP</scp>1A2, <scp>CYP</scp>2C9, <scp>CYP</scp>2C19, <scp>CYP</scp>3A, and P‐gp Substrates in Patients With an Advanced Solid Tumor

Xiao, Jim; Nowak, Dorota; Tomaszewska-Kiecana, Monika; Wysocki, Piotr J.; Isaacson, Jeff; Beltman, Jeri; Nash, Eileen; Kaczanowski, Robert; Arold, Gerhard; Watkins, Simon P.

doi:10.1111/cts.12600

Cited by 18 publications

(35 citation statements)

References 26 publications

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“…Seville oranges and grapefruit should be avoided in those patients taking olaparib, since they are CYP3A inhibitors, 12 while rucaparib may increase the effects of caffeine. 17 PARP Inhibitor as Single Agent: Maintenance and Treatment Monotherapy First-line maintenance randomized trials have shown a robust disease-free survival/progression-free survival improvement with PARPi treatment in ovarian cancer; overall survival data remain immature to date. [18][19][20] Two placebo-controlled phase III trials have assessed switch-maintenance PARPi treatment in patients that respond to front-line platinum; SOLO1 (NCT01844986) assessed olaparib in patients with ovarian cancer harboring somatic and germline BRCAm, 18 and PRIMA/ENGOT-Ov26 (NCT02655016) assessed niraparib in the overall population (non-restricted to BRCAm carriers).…”

Section: Reviewmentioning

confidence: 99%

“…Treatment with rucaparib may increase the effect of omeprazole. 17 Dysgeusia has been reported in ~10%-40% of patients, more commonly with rucaparib ( Table 3). Ensuring that patients maintain adequate oral hygiene care may also be helpful for dysgeusia management.…”

Section: Gastrointestinal Disordersmentioning

confidence: 99%

“…Seville oranges and grapefruit should be avoided in those patients taking olaparib, since they are CYP3A inhibitors, 12 while rucaparib may increase the effects of caffeine. 17 …”

Section: Introductionmentioning

confidence: 99%

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Manage wisely: poly (ADP-ribose) polymerase inhibitor (PARPi) treatment and adverse events

Madariaga

Bowering

Ahrari

et al. 2020

Int J Gynecol Cancer

100

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Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) have transformed the treatment landscape in front-line and recurrent high-grade serous ovarian cancer. Maintenance strategies with PARPi have been assessed in randomized phase III trials in ovarian cancer; switch maintenance in the case of olaparib, niraparib, and rucaparib; and concurrent followed by continuation maintenance with veliparib. These studies have shown progression-free survival advantage with PARPi maintenance, with no major adverse changes in the quality of life; however, overall survival data remain immature to date. PARPi have also been incorporated in clinical practice as a single-agent treatment strategy in high-grade serous ovarian cancer, mainly in women who harbor alterations in the BRCA1/2 genes or have alterations in the homologous recombination deficiency (HRD) pathway. Contemporary studies are looking into potentially synergistic combination strategies with anti-angiogenics and immune checkpoint inhibitors, among others. The expansion of PARPi treatment has not been limited to ovarian cancer; talazoparib is licensed in patients with HER2-negative breast cancer with germline BRCA mutations (BRCAm), and front-line olaparib maintenance in patients with pancreatic cancer with germline BRCAm. Numerous studies assessing PARPi either in monotherapy or in combination with other agents are ongoing in multiple tumors, including prostate, endometrial, brain, and gastric cancers. Many patients are being treated with PARPi, some for prolonged periods of time. As a result, a thorough knowledge of the potential short- and long-term adverse events and their management is warranted to improve patient safety, treatment efficacy, and towards maintaining an appropriate dose intensity.

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Section: Reviewmentioning

confidence: 99%

Section: Gastrointestinal Disordersmentioning

confidence: 99%

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Manage wisely: poly (ADP-ribose) polymerase inhibitor (PARPi) treatment and adverse events

Madariaga

Bowering

Ahrari

et al. 2020

Int J Gynecol Cancer

100

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“…Midazolam is a short-acting benzodiazepine (used for sedation [11]) and is metabolized by CYP3A4 in the liver to 1′-hydroxy-midazolam (1′-OH midazolam) [12,13]. Midazolam has been validated as a probe in other studies investigating CYP3A4 activity [14][15][16][17].…”

Section: Pharmacokinetics and Safety Assessmentsmentioning

confidence: 99%

An Open-Label Phase 1 Study to Determine the Effect of Lenvatinib on the Pharmacokinetics of Midazolam, a CYP3A4 Substrate, in Patients with Advanced Solid Tumors

Shumaker

Ren

Aluri

et al. 2020

Eur J Drug Metab Pharmacokinet

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Background and Objective Lenvatinib is a multikinase inhibitor that inhibits enzyme activity but induces gene expression of cytochrome P450 3A4 (CYP3A4), an important enzyme for drug metabolism. We evaluated the impact of lenvatinib on CYP3A4 using midazolam as a probe substrate in patients with advanced solid tumors. The primary objective was to determine the pharmacokinetic effects of lenvatinib on midazolam, and the secondary objective was to assess the safety of lenvatinib. Methods This multicenter, open-label, nonrandomized, phase 1 study involved patients with advanced cancer that progressed after treatment with approved therapies or for which no standard therapies were available. Results Compared with baseline, coadministration of lenvatinib decreased the geometric mean ratio of the area under the concentration-time curve for midazolam on day 1 to 0.914 (90% confidence interval [CI] 0.850-0.983) but increased it on day 14 to 1.148 (90% CI 0.938-1.404). Coadministration of lenvatinib also decreased the geometric mean ratio of the maximum observed concentration for midazolam on day 1 to 0.862 (90% CI 0.753-0.988) but increased it on day 14 to 1.027 (90% CI 0.852-1.238). There was little change in the terminal elimination phase half-life of midazolam when administered with lenvatinib. The most common treatment-related adverse events were hypertension (20.0%), fatigue (16.7%), and diarrhea (10.0%). Conclusions Coadministration of lenvatinib had no clinically relevant effect on the pharmacokinetics of midazolam, a CYP3A4 substrate. The adverse events were consistent with the known safety profile of lenvatinib, and no new safety concerns were identified. ClinicalTrials.Gov Identifier NCT02686164.

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“…Breastfeeding is contraindicated during treatment with rucaparib . Coadministration of rucaparib can increase systemic exposure of cytochrome P450 (CYP) 1A2, CYP3A, CYP2C9, or CYP2C19 substrates . If clinically indicated, dose adjustments may be considered for substrates of CYP1A2, CYP3A, and CYP2C9, particularly those with a narrow therapeutic index (e.g., tizanidine, cyclosporine, and warfarin, respectively).…”

Section: Management Of Rucaparib Toxicitymentioning

confidence: 99%

Real-World Delivery of Rucaparib to Patients with Ovarian Cancer: Recommendations Based on an Integrated Safety Analysis of ARIEL2 and Study 10

et al. 2019

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Treatment options for women with recurrent ovarian cancer who have received two or more prior lines of chemotherapy have recently expanded with the U.S. Food and Drug Administration (FDA) and European Commission (EC) approvals of the poly(ADP‐ribose) polymerase (PARP) inhibitor rucaparib. As more oncologists begin to use rucaparib and other PARP inhibitors as part of routine clinical practice, awareness of possible side effects and how to adequately manage toxicities is crucial. In this review, we summarize the safety and tolerability of rucaparib reported in an integrated safety analysis that supported the FDA's initial approval of rucaparib in the treatment setting. Additionally, drawing on clinical data and our personal experience with rucaparib, we provide our recommendations on the management of common side effects observed with rucaparib, including anemia, blood creatinine elevations, alanine aminotransferase and aspartate aminotransferase elevations, thrombocytopenia, gastrointestinal‐related events (e.g., nausea, vomiting), and asthenia and fatigue. These side effects, many of which appear to be class effects of PARP inhibitors, are often self‐limiting and can be managed with adequate interventions such as treatment interruption and/or dose reduction and the use of supportive therapies. Supportive therapies may include blood transfusions for patients with anemia, prophylactic medications to prevent nausea and vomiting, or behavioral interventions to mitigate fatigue. Understanding and appropriate management of potential side effects associated with rucaparib may allow patients with ovarian cancer to continue to benefit from rucaparib treatment. Implications for Practice Rucaparib was recently approved in the U.S. and European Union for use as treatment or maintenance for recurrent ovarian cancer. This review focuses on the safety and tolerability of rucaparib in the treatment setting. Similar side effects are observed in the maintenance setting. Drawing on the authors’ clinical experience with rucaparib, rucaparib prescribing information, and published supportive cancer care guidelines, this review discusses how to optimally manage common rucaparib‐associated side effects in patients with advanced ovarian cancer in the real‐world oncology setting. Adequate management of such side effects is crucial for allowing patients with ovarian cancer to remain on treatment to receive optimal efficacy benefit.

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Evaluation of Drug–Drug Interactions of Rucaparib and CYP1A2, CYP2C9, CYP2C19, CYP3A, and P‐gp Substrates in Patients With an Advanced Solid Tumor

Cited by 18 publications

References 26 publications

Manage wisely: poly (ADP-ribose) polymerase inhibitor (PARPi) treatment and adverse events

Manage wisely: poly (ADP-ribose) polymerase inhibitor (PARPi) treatment and adverse events

An Open-Label Phase 1 Study to Determine the Effect of Lenvatinib on the Pharmacokinetics of Midazolam, a CYP3A4 Substrate, in Patients with Advanced Solid Tumors

Real-World Delivery of Rucaparib to Patients with Ovarian Cancer: Recommendations Based on an Integrated Safety Analysis of ARIEL2 and Study 10

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