Exploring In Silico Prediction of the Unbound Brain-to-Plasma Drug Concentration Ratio: Model Validation, Renewal, and Interpretation

Varadharajan, Srinidhi; Winiwarter, Susanne; Carlsson, Lars; Engkvist, Ola; Anantha, Ajay; Kogej, Thierry; Fridén, Markus; Stålring, Jonna; Chen, Hongming

doi:10.1002/jps.24301

Cited by 39 publications

(37 citation statements)

References 40 publications

(77 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…K puu, brain is well established as a good predictor of BBB permeability, and values >0.3 indicate good diffusion across the BBB. 21 Therefore, from this research, we conclude that osimertinib played an important role in the treatment of our patient.…”

Section: Discussionmentioning

confidence: 55%

Non-small cell lung cancer leptomeningeal metastases treated with intrathecal therapy plus osimertinib and temozolomide and whole-brain radiation therapy: a case report

Wang¹,

Wei²,

Yan³

et al. 2018

OTT

View full text Add to dashboard Cite

RationaleLeptomeningeal metastasis (LM) is an important cause of mortality in patients with non-small cell lung cancer (NSCLC). As the symptoms of LM and its early clinical manifestations are nonspecific, early diagnosis of LM is difficult. However, there are few treatment options for LM, which leads to a poor prognosis; thus, increased clinical attention is necessary. The effects of most systemic chemotherapies on metastatic brain tumors (brain metastases and LMs) are limited as they cannot pass the blood–brain barrier; therefore, whole-brain radiation therapy is a therapeutic option. Osimertinib is a potent and irreversible third-generation oral epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). It binds to EGFR with high affinity when the EGFR T790M mutation is present together with sensitizing mutations. The clinical efficacy of osimertinib in NSCLC patients carrying the T790M mutation has been demonstrated in clinical trial NCT02468661. Intrathecal injection of chemotherapeutic drugs can be directed to a specific lesion. Temozolomide is one such drug, and its effect has been confirmed.Patient and interventionsWe treated a 38-year-old patient with NSCLC who carried the EGFR L858R mutation. We administered a combination of oral osimertinib and oral temozolomide plus an intrathecal injection of cytarabine and whole-brain radiation therapy for symptomatic multiple brain metastases.OutcomesThe patient showed a marked response to this combination therapy. To date (after ~18 months), no recurrence or new lesions have been observed and he is asymptomatic. His disease-free survival surpasses that achieved with any monotherapy for LM.LessonsThis is the first report to demonstrate the response to combination therapy in an NSCLC patient with LM. These findings indicate the potential utility of chemotherapy combined with radiotherapy combined with targeted therapy combined with local treatment, as each treatment acts via a different mechanism, enhancing their therapeutic effects.

show abstract

Section: Discussionmentioning

confidence: 55%

Non-small cell lung cancer leptomeningeal metastases treated with intrathecal therapy plus osimertinib and temozolomide and whole-brain radiation therapy: a case report

Wang¹,

Wei²,

Yan³

et al. 2018

OTT

View full text Add to dashboard Cite

show abstract

“…Kp uu,brain is well established as a good predictor of BBB permeability, with values greater than 0.3 indicative of good diffusion across the BBB (38). Osimertinib was shown to have a good Kp uu,brain value (0.39) compared with other currently available TKIs and rociletinib, suggesting it has the potential to achieve good brain exposure.…”

Section: Discussionmentioning

confidence: 99%

Preclinical Comparison of Osimertinib with Other EGFR-TKIs in EGFR-Mutant NSCLC Brain Metastases Models, and Early Evidence of Clinical Brain Metastases Activity

Ballard

Yates

Yang³

et al. 2016

Clinical Cancer Research

572

460

View full text Add to dashboard Cite

Purpose: Approximately one-third of patients with non-small cell lung cancer (NSCLC) harboring tumors with EGFR-tyrosine kinase inhibitor (TKI)-sensitizing mutations (EGFRm) experience disease progression during treatment due to brain metastases. Despite anecdotal reports of EGFR-TKIs providing benefit in some patients with EGFRm NSCLC brain metastases, there is a clinical need for novel EGFR-TKIs with improved efficacy against brain lesions.Experimental Design: We performed preclinical assessments of brain penetration and activity of osimertinib (AZD9291), an oral, potent, irreversible EGFR-TKI selective for EGFRm and T790M resistance mutations, and other EGFR-TKIs in various animal models of EGFR-mutant NSCLC brain metastases. We also present case reports of previously treated patients with EGFRm-advanced NSCLC and brain metastases who received osimertinib in the phase I/II AURA study (NCT01802632).Results: Osimertinib demonstrated greater penetration of the mouse blood-brain barrier than gefitinib, rociletinib (CO-1686), or afatinib, and at clinically relevant doses induced sustained tumor regression in an EGFRm PC9 mouse brain metastases model; rociletinib did not achieve tumor regression. Under positron emission tomography micro-dosing conditions, [11 C]osimertinib showed markedly greater exposure in the cynomolgus monkey brain than [11 C]rociletinib and [ 11 C]gefitinib. Early clinical evidence of osimertinib activity in previously treated patients with EGFRm-advanced NSCLC and brain metastases is also reported.Conclusions: Osimertinib may represent a clinically significant treatment option for patients with EGFRm NSCLC and brain metastases. Further investigation of osimertinib in this patient population is ongoing.

show abstract

“…[ 14 , 15 ] Ballard and coworkers [ 15 ] reported that osimertinib showed a good Kp uu,brain value of 0.39 greater than other available EGFR-TKIs; Kp uu,brain is well established as a good predictor of BBB permeability, with values greater than 0.3 indicative of good diffusion across the BBB. [ 28 ]…”

Section: Discussionmentioning

confidence: 99%

Rapid intracranial response to osimertinib, without radiotherapy, in nonsmall cell lung cancer patients harboring the EGFR T790M mutation

Koba

Kijima²,

Takimoto³

et al. 2017

Medicine

View full text Add to dashboard Cite

Rationale:Most of nonsmall cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR) activating mutations eventually acquire resistance to the first EGFR-tyrosine kinase inhibitors (TKIs) therapy after varying periods of treatment. Of note, approximately one-third of those patients develop brain metastases, which deteriorate their quality of life and survival. The effect of systemic chemotherapy on brain metastases after acquisition of EGFR-TKI resistance is limited, and thus far, whole-brain radiation therapy, which may cause the harmful effect on neurocognitive functions, has been the only established therapeutic option for especially symptomatic brain metastases. Osimertinib is a third-generation oral, potent, and irreversible EGFR-TKI. It can bind to EGFRs with high affinity even when the EGFR T790M mutation exists in addition to the sensitizing mutations. Its clinical efficacy for NSCLC patients harboring the T790M mutation has already been shown; however, the evidence of osimertinib on brain metastases has not been documented well, especially in terms of the appropriate timing for treatment and its response evaluation.Patient concerns, Diagnoses, and Interventions:We experienced 2 NSCLC patients with the EGFR T790M mutation; a 67-year-old woman with symptomatic multiple brain metastases administered osimertinib as seventh-line chemotherapy, and a 76-year old man with an asymptomatic single brain metastasis administered osimertinib as fifth-line chemotherapy.Outcomes:These patients showed great response to osimertinib within 2 weeks without radiation therapy.Lessons:These are the first reports to reveal the rapid response of the brain metastases to osimertinib within 2 weeks. These cases suggest the possibility that preemptive administration of osimertinib may help patients to postpone or avoid radiation exposures. In addition, rapid reassessment of the effect of osimertinib on brain metastases could prevent patients from being too late to receive essential radiotherapy.

show abstract

Exploring In Silico Prediction of the Unbound Brain-to-Plasma Drug Concentration Ratio: Model Validation, Renewal, and Interpretation

Cited by 39 publications

References 40 publications

Non-small cell lung cancer leptomeningeal metastases treated with intrathecal therapy plus osimertinib and temozolomide and whole-brain radiation therapy: a case report

Non-small cell lung cancer leptomeningeal metastases treated with intrathecal therapy plus osimertinib and temozolomide and whole-brain radiation therapy: a case report

Preclinical Comparison of Osimertinib with Other EGFR-TKIs in EGFR-Mutant NSCLC Brain Metastases Models, and Early Evidence of Clinical Brain Metastases Activity

Rapid intracranial response to osimertinib, without radiotherapy, in nonsmall cell lung cancer patients harboring the EGFR T790M mutation

Contact Info

Product

Resources

About