Article Figures & Data
Figures
- Fig. 1.
Representative concentration versus time profiles of vorinostat and metabolites after a patient's first oral 400 mg dose.
Tables
- Table 1.
Dose escalation scheme
Schedule Dose level Vorinostat, days 1-14 (mg) Paclitaxel, day 1 (mg/m2) Carboplatin, day 1 (AUC mg/mL × min) No. patients A 1 200 qd 175 6 4 2 300 qd 175 6 3 3 400 qd 175 6 3 4 400 qd 200 6 12 B 5 300 bd (days 1-7) 200 6 6 - Table 2.
Baseline patient characteristics
No. patients 28 Median age (y) 64 (range, 30-77) Sex Male 21 Female 7 Tumor type NSCLC 19 Head and neck 4 Bladder 2 Mesothelioma 1 Others 2 No. patients with no prior chemotherapy 23 - Table 3.
Toxicity
Hematologic toxicity No. patients (all cycles) Grade 2 Grade 3 Grade 4 Anemia 9 3 — Neutropenia 2 8 14 Fever with Neutropenia — — 2 Thrombocytopenia 5 7 4 Nonhematologic toxicity No. patients (all cycles) Grade 1 Grade 2 Grade 3 Altered taste 2 — — Anorexia 15 — — Constipation 5 — — Dehydration 2 — 2 Diarrhea 6 1 — Fatigue 19 6 — Heartburn 3 1 — Myalgia 2 — 1 Neuropathy 11 2 1 Nausea 12 4 — Skin rash 2 1 — Vomiting 4 1 2 NOTE: By worst grade of toxicity per patient, occurring in at least 10% (three) of the patients.
- Table 4.
Pharmacokinetic variables for vorinostat and metabolites on day 1 of treatment
Dose (mg) No. patients Cmax (μmol/L) Tmax (h) AUC (μmol/L × h) t1/2 (h) Clapp (L/min) Vorinostat 200 1 1.45 0.5 2.4 1.8 5.2 300 8 1.36 ± 0.52 1.38 ± 0.52 3.54 ± 1.31 1.37 ± 0.42 5.73 ± 2.04 400 15 1.81 ± 0.70 1.27 ± 0.42 4.67 ± 2.33 1.45 ± 0.56 6.19 ± 1.88 Vorinostat glucuronide 200 1 2.81 1 6.9 2.1 NA 300 8 3.67 ± 2.09 2.19 ± 1.03 11.7 ± 11.3 1.56 ± 0.21 NA 400 15 3.62 ± 1.22 1.50 ± 0.38 12.8 ± 7.2 2.08 ± 1.36 NA 4-Anilino-4-oxobutanoic acid 200 1 3.82 1 15.3 5.9 NA 300 8 4.87 ± 1.99 2.75 ± 1.13 27.2 ± 10.8 6.6 ± 5.0 NA 400 15 5.14 ± 1.42 2.23 ± 1.03 23.5 ± 6.9 4.2 ± 1.8 NA Abbreviations: t1/2, half-life; NA, not applicable.
- Table 5.
Comparison of day 1 versus day 5 pharmacokinetic variables of vorinostat
Variable Median, day 1 Median, day 5 P Cmax (μmol/L) 1.7 1.3 0.52 Tmax (h) 1.5 1.6 0.085 AUC (μmol/L × h) 3.8 5.2 0.011 t1/2 (h) 1.3 2.1 0.012 Clapp (L/min) 6.4 4.4 0.0063 NOTE: Cmax and Tmax are based on 17 patients; other variables are based on 16 patients.
June 2007
Volume 13, Issue 12
Volume 13, Issue 12
Phase I and Pharmacokinetic Study of Vorinostat, A Histone Deacetylase Inhibitor, in Combination with Carboplatin and Paclitaxel for Advanced Solid Malignancies
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