Method validation and measurement of biomarkers in nonclinical and clinical samples in drug development: a conference report.

Biomarkers are increasingly used in drug development to aid scientific and clinical decisions regarding the progress of candidate and marketed therapeutics. Biomarkers can improve the understanding of diseases as well as therapeutic and off-target effects of drugs. Early implementation of biomarker strategies thus promises to reduce costs and time-to-market as drugs proceed through increasingly costly and complex clinical development programs. The 2003 American Association of Pharmaceutical Sciences/Clinical Ligand Assay Society Biomarkers Workshop (Salt Lake City, UT, USA, October 24-25, 2003) addressed key issues in biomarker research, with an emphasis on the validation and implementation of biochemical biomarker assays, covering from preclinical discovery of efficacy and toxicity biomarkers through clinical and postmarketing implementation. This summary report of the workshop focuses on the major issues discussed during presentations and open forums and noted consensus achieved among the participants on topics from nomenclature to best practices. For example, it was agreed that because reliable and accurate data provide the basis for sound decision making, biomarker assays must be validated in a manner that enables the creation of such data. The nature of biomarker measurements often precludes direct application of regulatory guidelines established for clinical diagnostics or drug bioanalysis, and future guidance on biomarker assay validation should therefore be adaptable enough that validation criteria do not stifle creative biomarker solutions.

Effect of concomitant colestipol hydrochloride administration on the bioavailability of diltiazem from immediate- and sustained-release formulations.

Effects of concomitant colestipol administration on plasma concentrations of diltiazem and desacetyldiltiazem from immediate-release (IR) and sustained-release (SR) formulations were assessed in two studies. In the first study, 12 subjects received 120-mg diltiazem hydrochloride (diltiazem) SR capsules or 120-mg diltiazem IR tablets administered alone and in combination with colestipol hydrochloride (colestipol). Following concomitant administration of SR diltiazem with colestipol, AUC(0-infinity ) and C(max), respectively, were 22 and 36% less, and were 27 and 33% lower for IR diltiazem. In the second study, subjects received 120-mg diltiazem SR capsules at staggered times, without colestipol, 1 h prior to or 4 h following multiple doses of colestipol. A 17% decrease in AUC(0-infinity ) was observed when diltiazem was taken 1 h before colestipol was given, and a 22% decrease when diltiazem was taken 4 h after colestipol, relative to diltiazem SR alone. C(max) values were similarly decreased. Results from these two studies show that colestipol can cause a significant decrease in diltiazem absorption from both IR and SR dosage forms. Staggering the administration of colestipol and diltiazem SR did not blunt this effect, indicating that concomitant administration of diltiazem and colestipol should be used with caution, and that the efficacy of diltiazem should be monitored to assure adequate dosing.