INTERNE GENEESKUNDE Topical psoralenen plus UV-A therapy for Tyrosine kinase inhibitor induced hand foot syndrome. Bos WE, Nijsten TE, de Jonge MJ, Hamberg AP. Arch Dermatol 2012; 148(4):546-547. PMID:22508887. Geen abstract. Effects of CYP induction by rifampicin on tamoxifen exposure. Binkhorst L, van Gelder T, Loos WJ, de Jongh FE, Hamberg AP, Ghobadi Moghaddam-Helmantel IM, de Jonge E, Jager A, Seynaeve C, van Schaik RHN, Verweij J, Mathijssen RHJ. Clin Pharmacol Ther 2012; 92(1): 62-62. PMID: 22617226. Tamoxifen undergoes biotransformation into several metabolites, including endoxifen. Differences in metabolism contribute to the interindividual variability in endoxifen concentrations, potentially affecting treatment efficacy. We evaluated the effects of cytochrome P450 (CYP) induction by rifampicin on the exposure levels of tamoxifen and its metabolites and found that coadministration of rifampicin resulted in markedly reduced (up to 86%, P ≤ 0.040) concentrations of tamoxifen and its metabolites. Given the extensive metabolism undergone by tamoxifen, several factors may have contributed to this effect. Similar drug-drug interactions may exist between tamoxifen and other strong CYP inducers. Phase I and pharmacokinetic study of pazopanib and lapatinib combination therapy in patients with advanced solid tumors. De Jonge MJA, Hamberg AP, Verweij J, Savage S, Suttle AB, Hodge J, Arumugham T, Pandite LN, Hurwitz HI. 38 Investigational New Drugs 2012 Oct 6 [Epub ahead of print]. PMID: 23054212. This phase I, open-label, dose-escalation study assessed the maximum-tolerated dose, safety, pharmacokinetics, and preliminary antitumor activity of pazopanib plus lapatinib combination therapy in patients with solid tumors. Patients were to take pazopanib and lapatinib orally once daily in a fasting condition. During the escalation phase, pazopanib and lapatinib doses were escalated in serial patient cohorts, and a limited blood sampling scheme was applied for pharmacokinetic evaluation. In the expansion phase, potential pharmacokinetic interaction between pazopanib and lapatinib was evaluated more extensively. Seventy-five patients were treated. Multiple dosing levels were studied, combining pazopanib up to 800 mg/day with lapatinib up to 1,500 mg/day. Dose-limiting toxicities observed included grade 3 neutropenia, fatigue, asymptomatic decline in left ventricular ejection fraction, diarrhea, and liver enzyme elevations. The most common drug-related adverse events were diarrhea, nausea, anorexia, fatigue, vomiting, rash, hair depigmentation, and hypertension. The dose recommended for further evaluation was pazopanib 800 mg plus lapatinib 1,500 mg (paz-800/lap-1500). No clinically significant drug-drug interaction was observed at the paz-400/lap-1000 level. However, at paz-800/lap-1500, an increase in both the AUC(0-t) and C(max) of pazopanib was observed. Four partial responses were observed in patients with renal cancer (n=2), giant-cell tumor of the bone (n=1), and thyroid cancer (n=1). Stable disease for ≥18 weeks was seen in 12 patients. Pazopanib and lapatinib can be administered in combination at their respective single-agent doses with an acceptable safety profile. Further evaluation of the combination will be pursued, exploring both paz-800/lap-1500 and paz-400/lap-1000. WETENSCHAPPELIJK jaarverslag 2012 Pagina 37
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