Can non-renal clearance and/or bioavailability of drugs be assessed reliably in renal impairment studies with oral drug administration?

Objective: The causes for the variable susceptibility of renal clearance (CLr) and bioavailability (F) of drugs in renal impairment are still unknown. We investigated whether the impact of chronic kidney disease (CKD) on non-renal clearance (CLnr) or F can be appraised when drug administration is by the oral route only in dedicated renal impairment studies (DRIS), as is routinely done when developing drugs intended for oral use.

Materials And Methods: A literature search on DRIS administering drugs orally only or orally and intravenously was conducted.

Quantitative Assessment of the Effect of Chronic Kidney Disease on the Nonrenal Clearance of 10 Drugs After Intravenous Administration.

The investigation identified 10 publications that reported the individual values of total clearance (CL), renal clearance (CLr), nonrenal clearance (CLnr), and the glomerular filtration rate (GFR), in subjects with varying renal functions. We used these data to estimate extent and prevalence of changes in CLnr in chronic kidney disease (CKD) by examining the relationship between clearances and renal function. The investigation was restricted to drugs given intravenously and eliminated by mixed renal and nonrenal pathways.

The Pharmacokinetics of Potassium in Humans Is Unusual.

Potassium is critical for maintaining cellular tonicity, propagation of nerve impulses, contraction of cardiac, skeletal, and smooth muscles, and normal renal function. The focus of this review is on the pharmacokinetics of potassium, K(+) , after administration of liquid and solid formulations of potassium chloride, KCl, to healthy subjects. Potassium can be considered an endogenous and exogenous compound.

Systemic availability of the active metabolite hydroxy-fasudil after administration of fasudil to different sites of the human gastrointestinal tract.

This study evaluated the gastrointestinal absorption of fasudil, a novel Rho kinase inhibitor for the treatment of stable angina, at different sites using remote-controlled capsules and assessed the feasibility of developing an extended-release formulation. Ten healthy male volunteers were enrolled, and 8 subjects completed this single-dose, open-label, randomized, 5-way crossover study. Forty milligrams of fasudil HCl was administered as solution to the distal ileum and ascending colon, as powder to the ascending colon, and orally as an immediate-release tablet and solution.

The pH dependency of the binding of drugs to plasma proteins in man.

An analysis of pH-induced changes of drug binding may contribute to the understanding of the mechanisms involved and the clinical relevance. A literature search was performed, and acceptance criteria set up, to select reported data for quantitative evaluation. The relationship between percentage of unbound drug, fu, and pH was analyzed, and the relevance of physicochemical characteristics of the ligand drugs and the importance of hydrogen ion-induced changes in plasma proteins for the pH sensitivity of the binding were evaluated.

Evaluation of a novel method to estimate absolute bioavailability of drugs from oral data.

The goal of this investigation was to evaluate the performance of a novel method allowing estimation of absolute bioavailability from oral data only. In contrast to the traditional method, which compares areas under the drug concentration time curves after oral and intravenous administration in subjects with normal renal function, the novel method uses total and renal clearance values following oral administration from subjects with varying renal functions to estimate bioavailability. The novel method can also provide estimates for nonrenal clearance.

The pharmacokinetics and pharmacodynamics of fludarabine phosphate in patients with renal impairment: a prospective dose adjustment study.

Unlabelled: A significant number of chronic lymphocytic leukemia, follicular non-Hodgkin's lymphoma and Waldenström's macroglobulinemia patients, treated with fludarabine phosphate (fludarabine), are elderly with diminished renal function. Since the kidney eliminates approximately 60% of fludarabine's primary metabolite (F-ara-A), dose modification is necessary for all patients with impaired renal function including elderly patients. In this study, 22 patients with varying levels of renal function received a single intravenous dose of fludarabine (25 mg/m3), followed one week later by five (one per day) doses that were adjusted according to three predefined creatinine clearance (CLcr) levels.