Relationship Between Sunitinib Pharmacokinetics and Administration Time: Preclinical and Clinical Evidence.

BACKGROUND AND OBJECTIVE: Circadian rhythms may influence the pharmacokinetics of drugs. This study aimed to elucidate whether the pharmacokinetics of the orally administered drug sunitinib are subject to circadian variation. METHODS: We performed studies in male FVB-mice aged 8-12 weeks, treated with single-dose sunitinib at six dosing times. Plasma and tissue samples were obtained for pharmacokinetic analysis and to monitor messenger RNA (mRNA) expression of metabolizing enzymes and drug transporters. A prospective randomized crossover study was performed in which patients took sunitinib once daily at 8 a.m., 1 p.m., and 6 p.m at three subsequent courses. Patients were blindly randomized into two groups, which determined the sequence of the sunitinib dosing time. The primary endpoint in both studies was the difference in plasma area under the concentration-time curve (AUC) of sunitinib and its active metabolite SU12662 between dosing times. RESULTS: Sunitinib and SU12662 plasma AUC in mice followed an ~12-h rhythm as a function of administration time (p ≤ 0.04). The combined AUC from time zero to 10 h (AUC10) was 14-27 % higher when sunitinib was administered at 4 a.m. and 4 p.m. than at 8 a.m. and 8 p.m. Twenty-four-hour rhythms were seen in the mRNA levels of drug transporters and metabolizing enzymes. In 12 patients, sunitinib trough concentrations (C trough) were higher when the drug was taken at 1 p.m. or 6 p.m. than when taken at 8 a.m. (C trough-1 p.m. 66.0 ng/mL; C trough-6 p.m. 58.9 ng/mL; C trough-8 a.m. 50.7 ng/mL; p = 0.006). The AUC was not significantly different between dosing times. CONCLUSIONS: Our results indicate that sunitinib pharmacokinetics follow an ~12-h rhythm in mice. In humans, morning dosing resulted in lower C trough values, probably resulting from differences in elimination. This can have implications for therapeutic drug monitoring.

Phase I study of cisplatin, hyperthermia, and lapatinib in patients with recurrent carcinoma of the uterine cervix in a previously irradiated area.

BACKGROUND: Patients with recurrent cervical cancer in a previously irradiated area might benefit from cisplatin combined with hyperthermia. Lapatinib inhibits the intracellular tyrosine kinase domain of the epidermal growth factor receptor (EGFR) and HER2. Overexpression of EGFR and HER2 is frequently seen in patients with cervical cancer and is potentially involved in chemotherapy resistance. In addition, preclinical data suggest a synergistic effect of combining cisplatin and lapatinib. Consequently, this phase I dose-escalation study was performed to determine the maximum tolerated dose (MTD) of lapatinib added to fixed doses of cisplatin and hyperthermia. METHODS: Eight patients with previously irradiated recurrent cervical carcinoma were enrolled and scheduled for 6 weekly administrations of 70 mg/m(2) cisplatin combined with locoregional hyperthermia. Hyperthermia consisted of the achievement of intraluminal temperatures of 40-43°C as homogeneously as possible over 60 minutes. Daily lapatinib was added on days 1-56, starting with a dose level of 1,000 mg. The MTD was defined as the highest dose at which ≤1 of 6 patients experienced dose-limiting toxicity (DLT). DLT was defined as grade 4 neutropenia lasting >7 days, febrile neutropenia grade ≥3, grade 4 thrombocytopenia, grade ≥2 renal toxicity, postponement of cisplatin and hyperthermia for ≥2 weeks, or grade ≥3 nonhematologic adverse events except for nausea or vomiting, diarrhea, or skin toxicity, for which the following DLT definitions were applied: grade ≥3 persistent nausea or vomiting or diarrhea despite optimal medical treatment or grade 4 skin toxicity. Safety, pharmacodynamics, and response were assessed. RESULTS: The first two patients of both the 1,000- and 750-mg dose level experienced DLTs. Of the four patients treated at dose level -2 (500 mg), only one patient was able to complete the treatment as planned, two patients experienced a DLT, and one patient was not evaluable because of early progressive disease. In the evaluable patients, one patient with progressive disease, four patients with stable disease, and two patients with partial response were observed. One patient with a partial response had a resection of the local recurrence. Pathological analysis showed a complete pathological response. Enumeration of circulating endothelial cells measured at baseline and during therapy did not show consistent results. The same applied for the pharmacodynamic effects on Ki-67, p27Kip1, and EGFR in pretreatment and on-therapy skin biopsies. CONCLUSION: It is not feasible to combine lapatinib with fixed doses of cisplatin and hyperthermia in patients with recurrent cervical carcinoma in a previously irradiated area mainly because of increased cisplatin-related toxicity. The observed complete pathological response is intriguing and warrants further investigation of combinations consisting of HER2 blockade and cisplatin plus hyperthermia.

Resistance to platinum-containing chemotherapy in testicular germ cell tumors is associated with downregulation of the protein kinase SRPK1.

Male germ cell tumors (GCTs) are extremely sensitive to platinum-containing chemotherapy, with only 10% of patients showing therapy resistance. However, the biological basis of the high curability of disseminated GCTs by chemotherapy is still unknown. Recently, we demonstrated that the mammalian serine/arginine-rich protein-specific kinase 1 (SRPK1) is a cisplatin-sensitive gene, inactivation of which leads to cisplatin resistance. Because, in mammalians, the expression of SRPK1 is preferentially high in testicular tissues, cisplatin responsiveness of male GCTs might be associated with SRPK1 levels. In the present study, we monitored SRPK1 protein expression in a unique series of nonseminomatous GCTs by immunohistochemistry. Randomly selected GCTs (n = 70) and tumors from patients responding to standard chemotherapy (n = 20) generally showed strong SRPK1 staining. In contrast, expression in refractory GCTs (n = 20) as well as in GCTs from poor-prognosis patients responding to high-dose chemotherapy only (n = 11) was significantly lower (two-sided Wilcoxon rank sum test: P < .001). In conclusion, our data suggest that SRPK1 expression might be an important prognostic indicator for the chemoresponsiveness of nonseminomatous GCTs.