Pharmacokinetics of intravenous telavancin in healthy subjects with varying degrees of renal impairment.

Purpose: We evaluated the effect of renal impairment (RI) on the pharmacokinetics of telavancin and hydroxypropylbetadex (excipient in the telavancin drug product).

Methods: Adults with normal, mild, moderate or severe RI or end-stage renal disease (ESRD) receiving haemodialysis were included in two open-label, phase I studies of single-dose telavancin at 7.5 mg/kg (study A, n = 29) or 10 mg/kg (study B, n = 43).

Variability in telavancin cross-reactivity among vancomycin immunoassays.

Telavancin is a semisynthetic lipoglycopeptide with a dual mechanism of action against Gram-positive pathogens. Two brief reports have suggested potential cross-reactivity of telavancin with the vancomycin particle-enhanced turbidometric immunoassay (PETIA). The purpose of this study was to evaluate several commercially available vancomycin immunoassays (fluorescence polarization [FPIA], enzyme-multiplied immunoassays [EMIT], PETIA, and chemiluminescent immunoassay [CMIA]) for cross-reactivity with telavancin.

Biotransformation and bioactivation reactions of alicyclic amines in drug molecules.

Aliphatic nitrogen heterocycles such as piperazine, piperidine, pyrrolidine, morpholine, aziridine, azetidine, and azepane are well known building blocks in drug design and important core structures in approved drug therapies. These core units have been targets for metabolic attack by P450s and other drug metabolizing enzymes such as aldehyde oxidase and monoamine oxidase (MAOs). The electron rich nitrogen and/or α-carbons are often major sites of metabolism of alicyclic amines.

Population pharmacokinetics of telavancin in healthy subjects and patients with infections.

A population pharmacokinetic model of telavancin, a lipoglycopeptide antibiotic, was developed and used to identify sources of interindividual variability. Data were obtained from healthy subjects (seven phase 1 studies), patients with complicated skin and skin structure infections (cSSSI; two phase 2 and two phase 3 studies), and patients with hospital-acquired pneumonia (HAP; two phase 3 studies). A two-compartment open model with zero-order input best fit the telavancin data from healthy individuals and patients with cSSSI or HAP.

Scaling in vivo pharmacokinetics from in vitro metabolic stability data in drug discovery.

In this review, the current approach to predicting hepatic clearance from in vitro metabolic systems is discussed along with a survey of current industry practice. The definitive method of determining intrinsic clearance remains the measurement of Michaelis-Menten parameters derived from metabolite formation rate data. However, in drug discovery this method has limitations which result in the method most commonly applied being the half-life method utilizing a single, low substrate concentration.

Unbound drug concentration in brain homogenate and cerebral spinal fluid at steady state as a surrogate for unbound concentration in brain interstitial fluid.

The objective of the present study was to examine the accuracy of using unbound brain concentration determined by a brain homogenate method (C(ub)), cerebral spinal fluid concentration (C(CSF)), and unbound plasma concentration (C(up)) as a surrogate for brain interstitial fluid concentration determined by brain microdialysis (C(m)). Nine compounds-carbamazepine, citalopram, ganciclovir, metoclopramide, N-desmethylclozapine, quinidine, risperidone, 9-hydroxyrisperidone, and thiopental-were selected, and each was administered as an intravenous bolus (up to 5 mg/kg) followed by a constant intravenous infusion (1-9 mg/kg/h) for 6 h in rats. For eight of the nine compounds, the C(ub)s were within 3-fold of their C(m); thiopental had a C(m) 4-fold of its C(ub).