Evaluation of the exposure equivalence of oral versus intravenous temozolomide

Abstract

PurposeOral temozolomide is approved in many countries for malignant glioma and for melanoma in some countries outside the USA. This study evaluated the exposure equivalence and safety of temozolomide by intravenous infusion and oral administration.MethodsSubjects with primary central nervous system malignancies (excluding central nervous system lymphoma) received 200 mg/m2 of oral temozolomide on days 1, 2 and 5. On days 3 and 4, subjects received 150 mg/m2 temozolomide either as a 90-min intravenous infusion on one day or by oral administration on an alternate day.ResultsRatio of log-transformed means (intravenous:oral) of area under the concentration–time curve and maximum concentration of drug after dosing for temozolomide and 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide (MTIC) met exposure equivalence criteria (90% confidence interval = 0.8–1.25). Treatment-emergent adverse events were consistent with those reported previously in subjects with recurrent glioma treated with oral temozolomide, except for mostly mild and transient injection site reactions with intravenous administration.ConclusionsThis study demonstrated an exposure equivalence of a 90-min intravenous infusion of temozolomide and an equivalent oral dose.

Mechanistic Dissection of PARP1 Trapping and the Impact on In Vivo Tolerability and Efficacy of PARP Inhibitors

“…2B). This exceeds the concentration required to observe synergism in vitro and is >20-fold higher than plasma exposures observed in the clinic (32). Time-course experiments indicated that trapping increases for 2 hours and then reaches a plateau (Fig.…”

“…19). The high concentrations of TMZ required (>300 mmol/L) significantly exceed the maximum exposures observed in the clinic (32). This suggests that either clinically tolerated regimens containing PARP inhibitors and TMZ cannot engage the trapping mechanism or currently available assays are not sensitive enough to detect physiologically relevant levels of trapping.…”

Analysis and stability study of temozolomide using capillary electrophoresis

“…Until now, reversed-phase high-performance liquid chromatography (HPLC) with UV [10][11][12] or MS/MS [8,13] detection was used in the analysis of TMZ. Baker et al combined HPLC analysis with radioanalysis ( 14 C-TMZ was applied) [2].…”

“…The half-life for MTIC was calculated to be 2.5 min [2,6] but has been determined to be 1.9 h [7,8] and 25 min [7,9] in human plasma in vivo and in vitro, respectively. AIC is stable in human plasma at room temperature [7].…”

Determination of temozolomide in serum and brain tumor with micellar electrokinetic capillary chromatography

“…Temozolomide demonstrated activity against experimentally induced tumors in mice and rats [5,6]. Positron emission tomography (PET) scanning in patients showed that intravenous 11 C-labeled temozolomide readily crossed the blood-brain barrier and entered brain tissue [7]. A predictive pharmacokinetic model was developed by Gallo et al [2], because the direct measurement of drug concentrations in human tumors was found difficult to achieve.…”