Pharmacokinetic boosting of osimertinib with cobicistat in patients with non-small cell lung cancer: The OSIBOOST trial

Veelen, Ard van; Gulikers, J.T.M.; Hendriks, L.; Dursun, Safiye; Ippel, Juanita; Smit, Egbert F.; Dingemans, Anne‐Marie C.; Geel, Robin M.J.M. van; Croes, Sander

doi:10.1016/j.lungcan.2022.07.012

Cited by 9 publications

(14 citation statements)

References 27 publications

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“…The FLAURA study established osimertinib as rst-line treatment in NSCLC due to its bene ts in PFS and OS (7,8). However, the presence of a TP53 mutation can impede the e cacy of osimertinib (21,22). In Choudhury's study, the median PFS was signi cantly reduced by 5 months, from 18.8 months in the wild-type patient group to 13.3 months in the group with the combined mutation (p = 0.002), in patients receiving osimertinib as a rst-line treatment (23).…”

Section: Discussionmentioning

confidence: 99%

“…On one hand, the disparate outcome observed in this study can be attributed to the heterogeneity of TP53 mutations and the admission bias among patients. Previous studies have mainly concentrated on missense mutations primarily found between codons 100 and 300 and frequently located within the DNA-binding domain of the p53 protein (10,21,25). Several hotspot mutations occurred inside the DNA-binding domain and account for only about 30% of the total mutated cases (27).…”

Section: Discussionmentioning

confidence: 99%

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Osimertinib plus Chemotherapy versus Osimertinib for Patients with Advanced NSCLC Concomitant EGFR and TP53 Mutations: A Prospective Cohort Study

Li,

Zhan,

Shao

et al. 2024

Preprint

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Background Osimertinib is the standard first-line options for patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC). Co-mutations in TP53 results in poor survival for patients. However, the studies on treatment options and clinical outcomes of patients with EGFR-TP53 co- mutation are limited. Methods Patients with EGFR mutation-positive locally advanced or metastatic NSCLC carrying TP53 mutations were recruited from two institutions and allocated into two groups, either receiving osimertinib plus chemotherapy (Osi + Chemo group) or osimertinib monotherapy (Osi group). The progression-free survival (PFS) was evaluated as the primary endpoint and the response was also assessed. Results Between January 2020 and August 2023, Ninety-eight patients were enrolled with 47 and 51 patients receiving combination therapy and the monotherapy. After a median follow-up of 19.2 months, overall response rate (ORR) was 80.0% versus 71.7% (p = 0.36), favoring Osi + Chemo group, as well as in disease control rate (DCR) (91.4% vs. 80.4%, p = 0.45). The median PFS in the Osi + Chemo group was 26.0 months versus 20.7 months in the Osi group, but without significant difference (p = 0.34). The subgroup analysis indicated that for patients with L858R mutation, Osi + Chemo therapy significantly prolonged the median PFS (not reached [NR] versus 17.1 months, p = 0.03), but not in patients with 19Del (20.6 months versus NR, p = 0.31). Conclusion Osimertinib plus chemotherapy have a tendency to increase ORR and prolong PFS in NSCLC with EGFR and TP53 co-mutations, particularly in patients with L858R mutation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Osimertinib plus Chemotherapy versus Osimertinib for Patients with Advanced NSCLC Concomitant EGFR and TP53 Mutations: A Prospective Cohort Study

Li,

Zhan,

Shao

et al. 2024

Preprint

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“…There was no evidence to suggest that the current concentration was subtherapeutic. A higher cobicistat dose of 150 mg (twice daily) has been used to boost axitinib and osimertinib, 5 , 6 so an increase in the dose to 150 mg twice daily might increase CYP3A inhibition, thereby increasing ponatinib exposure.…”

Section: Tdm Consultantmentioning

confidence: 99%

Cobicistat as a Potential Booster of Ponatinib and Dasatinib Exposure in a CML Patient: A Case Study

Hofman

Touw

Span

et al. 2023

Therapeutic Drug Monitoring

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:The authors present a case of a 57-year-old patient with chronic myeloid leukemia who was treated with ponatinib and subsequently treated with dasatinib. The patient showed a major molecular response; however, the BCR-ABL1 signal increased with low ponatinib and dasatinib trough concentrations. Cobicistat was used as a pharmacokinetic booster to increase ponatinib and dasatinib exposure, as opposed to increasing the dose. However, ponatinib exposure was not sufficiently increased by cobicistat. The peak dasatinib concentration was successfully increased with cobicistat treatment. Dasatinib and cobicistat cotreatment induced a response in BCR-ABL1 PCR signal, was well tolerated, and led to a substantial reduction in drug costs.

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“…Precedent exists for concomitant administration of a drug with another agent that inhibits or induces certain aspect(s) of its disposition pathway to improve systemic exposure, a strategy known as pharmacokinetic boosting. This has been applied to drugs used in the treatment of different diseases such as HIV and cancer [26][27][28][29][30]. Interaction between nitazoxanide and atazanavir/ritonavir has not been reported.…”

Section: Introductionmentioning

confidence: 99%

Atazanavir/Ritonavir Increased Tizoxanide Exposure from Oral Nitazoxanide through Pharmacokinetic Interaction in Healthy Volunteers

Akinloye,

Oyedeji,

Eniayewu

et al. 2024

Future Pharmacology

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Nitazoxanide use is limited by gastrointestinal side effects associated with increasing dose. In this drug repurposing study, we investigated the possibility of enhancing the exposure of its active metabolite, tizoxanide, through pharmacokinetic interaction with atazanavir/ritonavir. In this crossover drug–drug interaction study, 18 healthy participants received a single dose of 1000 mg of nitazoxanide alone and in combination with 300/100 mg atazanavir/ritonavir in period 1 and 2 respectively. On both days, blood samples for intensive pharmacokinetic analyses were collected at 0–12 h post-dose. To explore the utility of dried blood spots (DBS) as an alternative to plasma for tizoxanide quantification, 50 µL of blood from some participants was spotted on DBS cards and correlated with plasma concentrations. Pharmacokinetic parameters were derived by non-compartmental analysis and compared between both periods. Co-administration of nitazoxanide with atazanavir/ritonavir resulted in a significant increase in tizoxanide plasma exposure [GMR (90% CI) of AUC0–12h, Cmax and C12h being 1.872 (1.870–1.875), 2.029 (1.99–2.07) and 3.14 (2.268–4.352), respectively]. DBS concentration (%CV) was 46.3% (5.6%) lower than plasma concentrations, and there was strong correlation (R = 0.95, p < 0.001) between DBS-derived plasma concentration and plasma concentrations. Co-administration with atazanavir/ritonavir enhanced tizoxanide exposure with no report of adverse events in healthy volunteers.

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Pharmacokinetic boosting of osimertinib with cobicistat in patients with non-small cell lung cancer: The OSIBOOST trial

Cited by 9 publications

References 27 publications

Osimertinib plus Chemotherapy versus Osimertinib for Patients with Advanced NSCLC Concomitant EGFR and TP53 Mutations: A Prospective Cohort Study

Osimertinib plus Chemotherapy versus Osimertinib for Patients with Advanced NSCLC Concomitant EGFR and TP53 Mutations: A Prospective Cohort Study

Cobicistat as a Potential Booster of Ponatinib and Dasatinib Exposure in a CML Patient: A Case Study

Atazanavir/Ritonavir Increased Tizoxanide Exposure from Oral Nitazoxanide through Pharmacokinetic Interaction in Healthy Volunteers

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