Clinical benefit from pharmacological elevation of high-density lipoprotein cholesterol: meta-regression analysis.

CONTEXT: Epidemiological evidence that the risk of coronary heart disease is inversely associated with the level of high-density lipoprotein cholesterol (HDL-C) has motivated several phase III programmes with cholesteryl ester transfer protein (CETP) inhibitors. OBJECTIVES: To assess alternative methods to predict clinical response of CETP inhibitors. METHODS: Meta-regression analysis on raising HDL-C drugs (statins, fibrates, niacin) in randomised controlled trials. RESULTS: 51 trials in secondary prevention with a total of 167,311 patients for a follow-up >1 year where HDL-C was measured at baseline and during treatment. The meta-regression analysis showed no significant association between change in HDL-C (treatment vs comparator) and log risk ratio (RR) of clinical endpoint (non-fatal myocardial infarction or cardiac death). CETP inhibitors data are consistent with this finding (RR: 1.03; P5-P95: 0.99-1.21). A prespecified sensitivity analysis by drug class suggested that the strength of relationship might differ between pharmacological groups. A significant association for both statins (p<0.02, log RR=-0.169-0.0499*HDL-C change, R(2)=0.21) and niacin (p=0.02, log RR=1.07-0.185*HDL-C change, R(2)=0.61) but not fibrates (p=0.18, log RR=-0.367+0.077*HDL-C change, R(2)=0.40) was shown. However, the association was no longer detectable after adjustment for low-density lipoprotein cholesterol for statins or exclusion of open trials for niacin. CONCLUSIONS: Meta-regression suggested that CETP inhibitors might not influence coronary risk. The relation between change in HDL-C level and clinical endpoint may be drug dependent, which limits the use of HDL-C as a surrogate marker of coronary events. Other markers of HDL function may be more relevant.

Use of a population pharmacokinetic approach for the clinical development of a fixed-dose subcutaneous formulation of trastuzumab.

A new subcutaneous (s.c.) trastuzumab formulation provides savings in terms of time and is preferred by patients and health care professionals relative to standard intravenous (i.v.) administration due to simpler and more rapid administration (2-5 minutes). Selection of the s.c. dose was based on a pharmacokinetic bridging approach that aimed to achieve noninferior trastuzumab serum trough concentrations (Ctrough) vs. reference i.v. administration. Using population modeling and simulation, we showed that a fixed 600-mg trastuzumab s.c. dose, administered thrice-weekly (Q3W) without a loading dose, would provide Ctrough (predose Cycle 8) and area under the time-concentration curve (AUC0-21 days, Cycle 7) at least as high as Q3W i.v. administration. The model was retrospectively validated using observed pharmacokinetic data from an independent phase III study of (neo)adjuvant trastuzumab (HannaH). These results provide a strong pharmacokinetic rationale for the trastuzumab s.c. 600-mg fixed dose, supported by the noninferior efficacy of this regimen vs. reference i.v. administration.CPT Pharmacometrics Syst. Pharmacol. (2014) 3, e87; doi:10.1038/psp.2013.63; advance online publication 2 January 2014.

Non-clinical pharmacokinetic/pharmacodynamic and early clinical studies supporting development of a novel subcutaneous formulation for the monoclonal antibody rituximab.

This overview article describes the non-clinical pharmacology, pharmacokinetic and clinical dose-finding programs supporting the development of a novel subcutaneous formulation for rituximab, a monoclonal antibody that selectively targets CD20-positive B-lymphocytes. The subcutaneous route of administration is expected to improve convenience for patients and to reduce healthcare professional resource use compared with conventional intravenous infusion. Various non-clinical and clinical studies were conducted to support the bridge from the approved intravenous formulation to the novel subcutaneous treatment. The underlying hypothesis for these studies was that achieving subcutaneous rituximab serum trough concentrations that are at least as high as those reached with the intravenous formulation would result in at least the same degree of receptor saturation. Preclinical mouse xenograft and cynomolgus monkey B-cell depletion studies were performed at intravenous and subcutaneous doses that were previously found to result in comparable serum concentrations in pharmacokinetic studies in the same species. Results from these non-clinical assessments guided dose selection for the subsequent phase 1b dose finding trials in patients with follicular lymphoma as part of maintenance treatment. A fixed dose of 1 400 mg was found to result in noninferior serum trough concentrations to the intravenous formulation. Clinical trials in the induction setting in patients with follicular lymphoma and chronic lymphocytic leukemia are currently ongoing.

Development of a subcutaneous formulation for trastuzumab - nonclinical and clinical bridging approach to the approved intravenous dosing regimen.

A subcutaneous (SC) formulation has been developed for the humanized monoclonal antibody (mAb) trastuzumab as an alternative to established intravenous (IV) infusion. The ready-to-use liquid SC formulation is injected as a fixed dose in approximately 5 min, which is expected to increase patient's convenience, reduce pharmacy preparation time, and administration costs overall.The trastuzumab dose as well as the dose of recombinant human hyaluronidase (rHuPH20), an enzyme that enables SC administration of volumes larger than 2 mL, was selected based on nonclinical xenograft, pharmacology, and pharmacokinetics mouse and minipig studies.The basic assumption for bridging from the IV to the SC regimen was that comparable trastuzumab serum trough concentrations would result in comparable efficacy. This hypothesis is confirmed by the results from the Phase 3 study in the neo-adjuvant/adjuvant setting. The safety profiles of the trastuzumab SC and IV formulations are comparable and consistent with the known safety profile of trastuzumab.