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  • Romijn, Johannes A  (2)
  • Biology  (2)
  • 1
    In: European Journal of Endocrinology, Oxford University Press (OUP), Vol. 161, No. 6 ( 2009-12), p. 923-931
    Abstract: Treatment options for patients with radioactive iodine (RaI) refractory metastases of differentiated thyroid carcinoma (DTC) are limited. We studied the effects of the multitarget tyrosine kinase inhibitor sorafenib on the reinduction of RaI uptake and tumor progression. Design Open, single center, single arm 26-week prospective phase II study with open-ended extension. Methods We treated 31 patients with progressive metastatic or locally advanced RaI refractory DTC with sorafenib 400 mg b.i.d. The primary endpoint was reinduction of RaI uptake at 26 weeks. Additional endpoints were the radiological response and the influence of bone metastases. Results At 26 weeks of sorafenib therapy, no reinduction of RaI uptake at metastatic sites was observed, but 19 patients (59%) had a clinical beneficial response, eight of whom had a partial response (25%) and 11 had stable disease (34%). Seven patients had progressive disease (22%). Sorafenib was significantly less effective in patients with bone metastases. The estimated median progression free survival was 58 weeks (95% confidence interval, CI, 47–68). In general, thyroglobulin (Tg) response (both unstimulated and TSH stimulated) reflected radiological responses. The median time of the nadir of Tg levels was 3 months. Responses were not influenced by histological subtype, mutational status or other variables. No unusual side effects were observed. Conclusions Sorafenib has a beneficial effect on tumor progression in patients with metastatic DTC, but was less effective in patients with bone metastases. Diagnostic whole body scintigraphy did not reveal an effect of sorafenib on the reinduction of RaI uptake.
    Type of Medium: Online Resource
    ISSN: 0804-4643 , 1479-683X
    RVK:
    Language: Unknown
    Publisher: Oxford University Press (OUP)
    Publication Date: 2009
    detail.hit.zdb_id: 1485160-X
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  • 2
    Online Resource
    Online Resource
    Oxford University Press (OUP) ; 2011
    In:  European Journal of Endocrinology Vol. 164, No. 4 ( 2011-04), p. 621-626
    In: European Journal of Endocrinology, Oxford University Press (OUP), Vol. 164, No. 4 ( 2011-04), p. 621-626
    Abstract: The effects of mitotane on the pharmacokinetics (PK) of co-administered drugs are mostly unknown. The aim of the present study was to describe the effects of mitotane on the PK of the phenotypic probe midazolam and of the tyrosine kinase inhibitor sunitinib. Design A serendipitous observation was made in two of nine patients who volunteered in a sunitinib pharmacokinetic study. Both patients were diagnosed with adrenocortical carcinoma (ACC) and were exposed to mitotane. The sunitinib PK study was designed to determine the relationship between CYP3A4 activity and sunitinib exposure using 7.5 mg midazolam orally as a phenotypic probe. Patient and methods Serial blood samples for PK analysis of midazolam, 1-hydroxy-midazolam, and sunitinib were collected at steady-state sunitinib PK (between days 14 and 20). To confirm this observation in the mitotane-exposed patients, midazolam PK was evaluated in two additional patients with ACC and mitotane treatment. Results The four mitotane-treated patients showed highly induced CYP3A4 activity, even after interrupting mitotane therapy months before study entry, reflected by decreased midazolam exposure compared with the other seven patients (mean AUC 0 – 12 h (95% CI): 7.6 (5.5–9.7) vs 139.0 (95.1–182.9) μg×h/l respectively P =0.001) and increased 1-hydroxy-midazolam exposure (mean AUC 0 – 12 h (95% CI): 409.6 (290.5–528.7) vs 35.0 (26.4–43.6) μg×h/l, P =0.008). Sunitinib exposure was decreased in the two patients who were co-treated with mitotane (267 and 268 μg×h/l versus 1344 (1079–1609) (mean (95% CI)) μg×h/l). Conclusion Mitotane has a strong and long-lasting inducing effect on CYP3A4 activity, which will result in clinically relevant interactions with multiple drugs since many drugs are metabolized by this enzyme.
    Type of Medium: Online Resource
    ISSN: 0804-4643 , 1479-683X
    RVK:
    Language: Unknown
    Publisher: Oxford University Press (OUP)
    Publication Date: 2011
    detail.hit.zdb_id: 1485160-X
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
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