Effect of multiple‐dose osimertinib on the pharmacokinetics of simvastatin and rosuvastatin

Harvey, R. Donald; Aransay, N. Reguart; Isambert, Nicolás; Lee, Jong Seok; Arkenau, Tobias; Vansteenkiste, Johan; Dickinson, Paul; Bui, Khanh; Weilert, Doris; So, Karen; Thomas, Karen; Vishwanathan, Karthick

doi:10.1111/bcp.13753

Cited by 25 publications

(43 citation statements)

References 38 publications

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“…The presence of liver metastases was not an exclusion criterion; therefore, the patients had been enrolled correctly. Baseline demographics and disease characteristics ( Table ) were consistent with the overall study population . Nine other patients had minor liver metastases but normal hepatic biochemistry parameters.…”

Section: Resultssupporting

confidence: 52%

“…A phase I, open‐label, single‐arm study in patients with EGFRm NSCLC investigated the impact of multiple doses of osimertinib on the PK of simvastatin and simvastatin acid to identify the potential for DDIs. Trial methods have been previously published . Briefly, on day (D) 1 (period 1), patients received oral simvastatin 40 mg (single dose), underwent clinic‐based PK and safety assessments over the course of 32–34 hours, then received osimertinib 80 mg orally once‐daily for 28 days (period 2; D3–30) with weekly clinic‐based PK assessments.…”

Section: Methodsmentioning

confidence: 99%

“…Patients with hepatic metastases and with aspartate aminotransferase or alanine aminotransferase > 5 times the upper limit of normal were excluded; therefore, this was not a protocol deviation. A detailed description of the bioanalysis and PK methods utilized has been previously reported …”

Section: Methodsmentioning

confidence: 99%

“…Hence, a DDI study (NCT02197234) was conducted assessing the impact of multiple doses of osimertinib on the PK of simvastatin (a sensitive CYP3A4 substrate) in patients with NSCLC. The study showed that osimertinib is unlikely to produce clinically relevant interactions with CYP3A4 substrates …”

mentioning

confidence: 99%

“…Osimertinib exhibits linear PK across the 20–240 mg dose range and once‐daily administration leads to a threefold accumulation within 15 days . In vitro , osimertinib has potential to inhibit intestinal CYP3A4 and pregnane × receptor‐mediated induction of CYP3A enzymes but not inhibit OATP1B1/OATP1B3 transporters …”

mentioning

confidence: 99%

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Impact of Disease and Treatment Response in Drug–Drug Interaction Studies: Osimertinib and Simvastatin in Advanced Non‐Small Cell Lung Cancer

Vishwanathan

Cantarini

et al. 2019

Clinical Translational Sci

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A phase I, open‐label study (NCT02197234) assessed the effects of osimertinib on simvastatin exposure in patients with advanced epidermal growth factor receptor (EGFR)‐mutated non‐small cell lung cancer and disease progression post‐EGFR tyrosine kinase inhibitor treatment. Here, we report on a retrospective analysis of two patients (patients 1 and 2) who had liver metastases and high simvastatin exposure prior to osimertinib treatment, which changed following treatment. Patients received single oral doses of simvastatin 40 mg on day (D) 1 and D31, and osimertinib 80 mg once daily on D3–32. At baseline, both patients had abnormal liver function tests (LFTs; Child‐Pugh scores of 6 and 8, respectively), significant liver metastasis, and, after a single simvastatin dose, had higher (~ 10‐fold) exposure compared with all other patients. Following 31 days of continuous osimertinib treatment, simvastatin exposures (area under the plasma concentration‐time curve from zero to infinity (AUC) and maximum plasma concentration (Cmax)) and LFTs, such as alanine transaminase, aspartate aminotransferase, and bilirubin normalized to population mean values. Additionally, ~ 50% and ~ 80% reductions in liver metastases were observed on computed tomography scans in patients 1 and 2, respectively. High simvastatin exposure on D1 likely resulted from impairment of hepatic first pass metabolism due to liver metastases. Reduction in hepatic disease burden due to osimertinib treatment likely resulted in liver function returning to normal levels.

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Section: Resultssupporting

confidence: 52%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Impact of Disease and Treatment Response in Drug–Drug Interaction Studies: Osimertinib and Simvastatin in Advanced Non‐Small Cell Lung Cancer

Vishwanathan

Cantarini

et al. 2019

Clinical Translational Sci

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Metabolism and pharmacokinetic study of deuterated osimertinib

Zhan

Bao

et al. 2023

Biopharm & Drug Disp

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Osimertinib is a highly selective third‐generation irreversible inhibitor of epidermal growth factor receptor mutant, which can be utilized to treat non‐small cell lung cancer. As the substrate of cytochrome P450 enzyme, it is mainly metabolized by the CYP3A enzyme in humans. Among the metabolites produced by osimertinib, AZ5104, and AZ7550, which are demethylated that is most vital. Nowadays, deuteration is a new design approach for several drugs. This popular strategy is deemed to improve the pharmacokinetic characteristics of the original drugs. Therefore, in this study the metabolism profiles of osimertinib and its deuterated compound (osimertinib‐d3) in liver microsomes and human recombinant cytochrome P450 isoenzymes and the pharmacokinetics in rats and humans were compared. After deuteration, its kinetic isotope effect greatly inhibited the metabolic pathway that produces AZ5104. The plasma concentration of the key metabolite AZ5104 of osimertinib‐d3 in rats and humans decreased significantly compared with that of the osimertinib. This phenomenon was consistent with the results of the metabolism studies in vitro. In addition, the in vivo results indicated that osimertinib‐d3 had higher systemic exposure (AUC) and peak concentration (Cmax) compared with the osimertinib in rats and human body.

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Assessment of the Effect of Filgotinib on the Pharmacokinetics of Atorvastatin, Pravastatin, and Rosuvastatin in Healthy Adult Participants

Anderson

Nelson

Gong

et al. 2021

Clinical Pharm in Drug Dev

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Filgotinib, an oral Janus kinase-1 preferential inhibitor, is approved in Europe and Japan for adults with rheumatoid arthritis. Patients with rheumatoid arthritis are at higher risk of cardiovascular morbidity/mortality; thus, it is important to understand potential drug-drug interactions of filgotinib with lipid-lowering agents. This open-label, randomized, 2-way crossover study evaluated the pharmacokinetics of atorvastatin, pravastatin, and rosuvastatin with and without filgotinib coadministration. Healthy participants (N = 27) received single doses of atorvastatin (40 mg) and of a pravastatin (40 mg)/rosuvastatin (10 mg) cocktail-alone or with filgotinib (200 mg once daily for 11 days)-on 2 different occasions with washout in between.Serial pharmacokinetic blood samples were collected,and safety was assessed.Pharmacokinetic parameters were evaluated using 90% confidence intervals (CI) of the geometric least-squares mean (GLSM) ratio of the test treatment (statin coadministration with filgotinib) vs statin alone,with prespecified lack-of-interaction bounds of 0.70 to 1.43. Coadministration of filgotinib did not affect atorvastatin area under the plasma concentration-time curve extrapolated to infinity (AUC inf ; [GLSM ratios (90% CI): 0.91 (0.84-0.99)]), but maximum concentration [C max ] was slightly lower [0.82 (0.69-0.99)]. The exposure of 2-hydroxy-atorvastatin was unaffected (GLSM ratios [90% CI], 0.98 [0.81-1.19] for C max ; 1.11 [1.02-1.22] for AUC inf ). Pravastatin AUC inf was also unaffected (GLSM ratios,], but C max was slightly higher 1.25 [1.01-1.54]). Rosuvastatin exposure was moderately higher with filgotinib coadministration-GLSM ratios (90% CI), 1.68 (1.43-1.97) for C max ; 1.42 (1.30-1.57) for AUC inf -but this was not considered clinically relevant. These results indicate that filgotinib has no clinically meaningful effect on exposure of atorvastatin, pravastatin, or rosuvastatin.

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Effect of multiple‐dose osimertinib on the pharmacokinetics of simvastatin and rosuvastatin

Abstract: Osimertinib is unlikely to have any clinically relevant interaction with CYP3A substrates and has a weak inhibitory effect on BCRP. No new safety concerns were identified in either study.

Cited by 25 publications

References 38 publications

Impact of Disease and Treatment Response in Drug–Drug Interaction Studies: Osimertinib and Simvastatin in Advanced Non‐Small Cell Lung Cancer

Impact of Disease and Treatment Response in Drug–Drug Interaction Studies: Osimertinib and Simvastatin in Advanced Non‐Small Cell Lung Cancer

Metabolism and pharmacokinetic study of deuterated osimertinib

Assessment of the Effect of Filgotinib on the Pharmacokinetics of Atorvastatin, Pravastatin, and Rosuvastatin in Healthy Adult Participants

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