Development and validation of a sensitive liquid chromatography/mass spectrometry method for quantitation of flavopiridol in plasma enables accurate estimation of pharmacokinetic parameters with a clinically active dosing schedule

Phelps, Mitch A.; Rozewski, Darlene M.; Johnston, Jessica; Farley, Katherine L.; Albanese, Katie A.; Byrd, John C.; Lin, Thomas S.; Grever, Michael R.; Dalton, James T.

doi:10.1016/j.jchromb.2008.04.023

Cited by 15 publications

(13 citation statements)

References 27 publications

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“…All patients received allopurinol 300 mg daily for prevention of hyperuricemia and 20 mg dexamethasone IV on days 1, 8, and 15 of flavopiridol treatment for the prevention of cytokine release syndrome [10–12]. An additional dose of 4 mg dexamethasone orally on days 2, 9, and 15 was utilized as needed to diminish symptoms of cytokine release.…”

Section: Methodsmentioning

confidence: 99%

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A phase 1 clinical trial of flavopiridol consolidation in chronic lymphocytic leukemia patients following chemoimmunotherapy

et al. 2016

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Patients with chronic lymphocytic leukemia (CLL) who receive chemoimmunotherapy and do not achieve complete remission experience significantly shortened progression-free interval (PFS). Additionally, the majority of patients treated for relapsed disease demonstrate evidence of measurable disease. Eradication of minimal residual disease (MRD) results in improved PFS and overall survival. Maintenance therapy might result in eradication of MRD and improve response duration but might be associated with an increase in incidence of infectious complications. Flavopiridol is a broad cyclin-dependent kinase (CDK) inhibitor with established safety and efficacy in patients with relapsed CLL, particularly patients with high-risk cytogenetic features. A pharmacologically derived schedule was utilized as consolidation therapy in this phase I study to assess the safety and feasibility of outpatient therapy with flavopiridol in patients with low tumor burden. Flavopiridol was administered as a 30-min loading dose of 30 mg/m2 followed by a 4-h infusion of 30 mg/ m2 once weekly for 3 weeks every 5 weeks (1 cycle) for planned 2 cycles in ten patients. Therapy was extremely well tolerated and no patient developed acute tumor lysis syndrome. The most common toxicities were gastrointestinal. Of the patients, 22 % improved their response from a PR to CR. Eighty-eight percent experienced a reduction in tumor burden as measured by extent of bone marrow involvement including patients with del17p and complex karyotype. The study establishes the safety and efficacy of flavopiridol as consolidation therapy after chemoimmunotherapy for patients with CLL. Further evaluation is required in larger trials for the utility of CDK inhibitors as consolidation or maintenance strategies. Registration number at ClinicalTrials.gov: NCT00377104.

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Section: Methodsmentioning

confidence: 99%

“…Flavopiridol quantification in plasma samples was achieved using a previously validated liquid chromatography-tandem mass spectrometry assay [12]. Plasma flavopiridol concentration–time data were analyzed using standard non-compartmental methods in Phoenix™ WinNonlin ® 6.3 (Pharsight, Mountain View, CA).…”

Section: Methodsmentioning

confidence: 99%

A phase 1 clinical trial of flavopiridol consolidation in chronic lymphocytic leukemia patients following chemoimmunotherapy

et al. 2016

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“…A validated liquid chromatography/mass spectrometry/mass spectrometry (LC-MS/MS) assay with 3 nM lower limit of quantitation (LLOQ) was used to determine parent drug plasma concentrations. 25 …”

Section: Pharmacokinetic Studymentioning

confidence: 99%

Clinical response and pharmacokinetics from a phase 1 study of an active dosing schedule of flavopiridol in relapsed chronic lymphocytic leukemia

Phelps

Lin²,

Johnson³

et al. 2009

Blood

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We previously reported interim results of a phase 1 trial in patients with chronic lymphocytic leukemia (CLL) whereby flavopiridol was administered intravenously as a 30-minute bolus followed by 4-hour infusion. We now report full pharmacokinetic (PK) data, correlations of PK with clinical outcomes, and final response and progression-free survival (PFS). Twenty-one (40%) of 52 patients with relapsed CLL achieved a partial response (PR) with a median PFS of 12 months. Responders included 17 (40%) of 43 fludarabine refractory patients, 7 (39%) of 18 patients with del(17p13), and 14 (74%) of 19 patients with del(11q22). Six responders received repeat therapy at relapse, and 5 responded again with a second median PFS of 10 months. Noncompartmental analysis and nonlinear mixed effects modeling was used to estimate PK parameters and evaluate covariates. Two-compartment population parameter estimates were 31.4 L/h, 65.8 L, 8.49 L/h, and 157 L for CL, V1, Q, and V2, respectively. Flavopiridol area under the plasma concentration-time curve (AUC) correlated with clinical response and cytokine release syndrome, and glucuronide metabolite AUC correlated with tumor lysis syndrome. These composite results confirm high activity of this pharmacokinetically derived schedule in relapsed, genetically high-risk CLL. Furthermore, PK describes some, but not all, variability in response and toxicity.

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“…30,32 Flavo-G concentrations were determined with the use of a flavo-G standard and comparison of flavopiridol concentrations before and after sample treatment with β-glucuronidase as previously described. 30,33 Sodium heparinized blood was obtained during the first dose of administration at the following time points: prior to dosing (t=0), and at 0.5, 1, 3, 4.5, 6, and 8 hours of treatment on day 1; prior to dosing, 0.5, and 4.5 hours on day 2; prior to dosing, and at 0.5, 4.5, 6, 8, and 24 hours of treatment on day 3.…”

Section: Pharmacokinetic Analysismentioning

confidence: 99%

Phase I clinical and pharmacokinetic study of a novel schedule of flavopiridol in relapsed or refractory acute leukemias

Blum¹,

Phelps²,

Klisovic³

et al. 2010

Haematologica

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BackgroundA pharmacokinetically derived schedule of flavopiridol administered as a 30 min intravenous bolus followed by 4-hour continuous intravenous infusion (IVB/CIVI) is active in fludarabinerefractory chronic lymphocytic leukemia, but no studies examining the feasibility and maximum tolerated dose of this schedule have been reported in acute leukemia. Design and MethodsWe conducted a phase I dose escalation trial of single-agent flavopiridol in adults with relapsed/refractory acute leukemias, utilizing a modification of the intravenous bolus/continuous intravenous infusion approach, intensifying treatment for administration on days 1, 2, and 3 of 21-day cycles. ResultsTwenty-four adults with relapsed/refractory acute myeloid leukemia (n=19) or acute lymphoblastic leukemia (n=5) were enrolled. The median age was 62 years (range, 23-78). The maximum tolerated dose of flavopiridol was 40mg/m 2 intravenous bolus plus 60mg/m 2 continuous intravenous infusion (40/60). The dose limiting toxicity was secretory diarrhea. Lifethreatening hyperacute tumor lysis syndrome requiring hemodialysis on day 1 was observed in one patient. Pharmacokinetics were dose-dependent with increased clearance observed at the two highest dose levels. Diarrhea occurrence and severity significantly correlated with flavopiridol concentrations at the end of the 4-hour infusion, volume of distribution, and elimination half-life. Modest anti-leukemic activity was observed, with most patients experiencing dramatic but transient reduction/clearance of circulating blasts lasting for 10-14 days. One refractory acute myeloid leukemia patient had short-lived complete remission with incomplete count recovery. ConclusionsFlavopiridol as a single agent given by intravenous bolus/continuous intravenous infusion causes marked, immediate cytoreduction in relapsed/refractory acute leukemias, but objective clinical responses were uncommon. With this schedule, the dose is limited by secretory diarrhea (ClinicalTrials.gov Identifier: NCT00101231).

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Development and validation of a sensitive liquid chromatography/mass spectrometry method for quantitation of flavopiridol in plasma enables accurate estimation of pharmacokinetic parameters with a clinically active dosing schedule

Cited by 15 publications

References 27 publications

A phase 1 clinical trial of flavopiridol consolidation in chronic lymphocytic leukemia patients following chemoimmunotherapy

A phase 1 clinical trial of flavopiridol consolidation in chronic lymphocytic leukemia patients following chemoimmunotherapy

Clinical response and pharmacokinetics from a phase 1 study of an active dosing schedule of flavopiridol in relapsed chronic lymphocytic leukemia

Phase I clinical and pharmacokinetic study of a novel schedule of flavopiridol in relapsed or refractory acute leukemias

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