First-in-man study with a novel PEGylated recombinant human insulin-like growth factor-I.

OBJECTIVE: This study is a first time assessment of safety and tolerability, pharmacokinetics, and pharmacodynamics of RO5046013 in human, in comparison with unmodified rhIGF-I. DESIGN: The study was conducted as a single-center, randomized, double-blinded, placebo-controlled, single ascending dose, parallel group study in a clinical research unit in France. A total of 62 healthy volunteers participated in this clinical trial. RO5046013 was given as single subcutaneous injection, or as intravenous infusion over 48h, at ascending dose levels. The active comparator rhIGF-I was administered at 50µg/kg subcutaneously twice daily for 4days. Safety and tolerability, pharmacokinetics, and pharmacodynamics of RO5046013 were evaluated. RESULTS: PEGylation resulted in long exposure to RO5046013 with a half-life of 140-200h. Exposure to RO5046013 increased approximately dose proportionally. RO5046013 was safe and well tolerated at all doses, injection site erythema after SC administration was the most frequent observed AE. No hypoglycemia occurred. Growth hormone (GH) secretion was almost completely suppressed with rhIGF-I administration, whereas RO5046013 caused only a modest decrease in GH at the highest dose given IV. CONCLUSIONS: PEGylation of IGF-I strongly enhances half-life, reduces the negative GH feedback and hypoglycemia potential, and therefore offers a valuable alternative to rhIGF-I in treatment of relevant diseases.

Erlotinib in combination with pemetrexed for patients with advanced non-small-cell lung cancer (NSCLC): a phase I dose-finding study.

BACKGROUND: Erlotinib and pemetrexed are approved single agents for second-line treatment of non-small-cell lung cancer (NSCLC) and, in combination, have shown synergistic antitumor activity in NSCLC cell lines. We investigated the safety, pharmacokinetics and preliminary efficacy of combined erlotinib-pemetrexed in patients with refractory advanced NSCLC. PATIENTS AND METHODS: A nonrandomized, open-label, phase IB study was performed in patients with advanced NSCLC whose disease had progressed on or following first-line chemotherapy with a platinum-containing regimen or for whom the erlotinib-pemetrexed combination was considered appropriate. Patients received i.v. pemetrexed 500-700 mg/m² every 3 weeks and oral erlotinib 100-150 mg/day. RESULTS: Twenty patients were recruited. The most common adverse events (AEs) were rash, diarrhea and fatigue. Serious AEs occurred in eight patients (three treatment related) and there were eight deaths (none treatment related). Dose-limiting toxic effects were not experienced up to erlotinib 150 mg/day plus pemetrexed 600 mg/m². Concurrent administration did not affect pharmacokinetic parameters. Two patients achieved partial responses and nine had stable disease. CONCLUSIONS: Erlotinib-pemetrexed combination is well tolerated at doses equal to the licensed single-agent doses (150 mg/day and 500 mg/m², respectively). The good tolerability profile and promising efficacy indicate that this combination warrants further investigation for patients with advanced NSCLC.

Clinical significance of pharmacokinetic drug interactions between interferon-alpha and antineoplastic drugs.

The major problems in chemotherapy are occasional low response rates in patients despite favourable in vitro action, the development of drug resistance and long or short term adverse effects. Therefore, in the past decade efforts have been made to circumvent these problems by combining antineoplastic drugs with biomodulating or cytoprotective agents. Most of the clinically useful drug regimens consist of a cocktail of drugs with different mechanisms of action, and hence different toxicity profiles. Dose-limiting factors in regard to toxicity and therapeutic efficacy predominate, and it is therefore clinically essential to know whether or not a pharmacokinetic drug interaction occurs. The introduction of interferon-alpha (IFNalpha) in chemotherapy is an alternative investigational approach to amplify the cytotoxicity of an antineoplastic drug in order to increase tumour response. Most of the clinical studies reported with IFNalpha provide useful information and identify major pharmacodynamic interactions, but only a few focus on and report potential pharmacokinetic interactions between antineoplastic drugs and IFNalpha in patients. The broad spectrum of antineoplastic drugs whose activity can be enhanced by IFNalpha argues for multiple levels of drug-drug interactions: protein binding (cisplatin), alteration in cellular uptake, modulation of drug target enzymes (dihydropyrimidine hydrogenase) and changes in biotransformation (tretinoin) or excretion. Pharmacokinetic and/or pharmacodynamic interactions may be beneficial (fluorouracil) or sometimes detrimental and coincidental (doxorubicin). This article focuses on observed pharmacokinetic drug interactions between IFNalpha and antineoplastic drugs and discusses possible mechanisms of action.

[Binding of epirubicin to human plasma protein and erythrocytes: interaction with the cytoprotective amifostine]. / In vitro-Untersuchungen zur Bindung von Epirubicin an humane Plasmaproteine und Erythrozyten: Interaktion mit dem Zytoprotektivum Amifostin.

The in vitro binding rate of epirubicin (EPR) to different plasma proteins, control serum, red blood cells and whole blood was investigated without and with the cytoprotective agent amifostine. The binding rate of EPR to plasma proteins fractions and red blood cells dependend on the concentration of the matrix components. EPR was bound more than 90% to human serum alpha-globulin (alpha-HSG), to human serum albumine (HSA) and human serum beta-globuline (beta-HSG) at 80 to 90%, in the case of human serum gamma-globulin (gamma-HSG) the binding rate amounted 75%. The binding rate of EPR to RBCs in whole blood samples reached 38%. Within the observed concentration range of proteins (1-40 micrograms/ml, depending on the protein concentration) AMI caused a reduction of the protein-bound amount of EPR in the range from 2 to 19% of HSA, 4 to 20 in the case of beta-HSG, 2 to 32% in the case of alpha-HSG and 17 to 21% for gamma-HSG. In the whole blood samples the binding of EPR to proteins dropped from 45 to 32% and RBC-partitioning from 38 to 32%. Two compounds with free thiol groups, cystein and glutathione, were compared with AMI in regard to lowering the binding rate of EPR to HSA: the effect was exactly in the same order of magnitude: -17% for AMI, -21.0% for cystein and -20.8% for glutahion (p < 0.002). For a negative control, cystin and phenylalanin were tested, too: both compounds showed no influence on the protein binding of EPR: 63.8% binding rate in the control group, 65.2% in the presence of cystin and 64.6% in the presence of phenylalanin (statistically not significant). The present results indicate, that binding of EPR to serum proteins is reduced in the presence of AMI by interaction of the thiol-group with the protein and that the thiophosphoric ester bond in the test solution must cleave rapidly.