Pharmacokinetics and tolerability of single oral doses of 882C87, a potent, new anti-varicella-zoster virus agent, in healthy volunteers

Abstract

882C87 is a nucleoside analog with potent, specific activity against varicella-zoster virus. It is approximately seven times as potent as acyclovir with an in vitro 50% inhibitory concentration of 1 to 2 M. The tolerability and pharmacokinetics of single doses of 882C87 have been investigated in a series of studies with healthy young and elderly adult volunteers. The young received 50 to 1,600 mg, and the elderly received 50 and 100 mg. Concentrations of 882C87 and its main metabolite, the pyrimidine base 5-(1-propynyl)uracil (5PU), in plasma and urine were assayed by an automated sequential trace enrichment of dialysate-high-performance liquid chromatography procedure, and noncompartmental pharmacokinetic parameters were derived from the data. Concentrations of 882C87 in plasma increased proportionally for doses of up to 400 mg, but after higher doses the increase was less than dose proportional. In young adults, after 200, 400, and 1,600 mg, the maximum concentrations of the drug in plasma were 9.0, 16.3, and 34.7 M, respectively, and the areas under the concentration-time curve (AUC) from 0 h to infinity were 166.6, 333.7, and 822.9 M ⅐ h, respectively. Elimination half-life was 11.3 to 13.0 h after 50 to 400 mg, increasing to 15.3 h after 1,600 mg, associated with a small decrease in renal clearance. In healthy elderly volunteers concentrations of 882C87 in plasma after 50 and 100 mg were similar to those in young adults after twice the dose; apparent clearance and renal clearance were significantly reduced, and half-life was significantly longer at 15 h. Administration of 882C87 with food produced a small, nonsignificant reduction in mean AUC from 0 h to infinity, but in subjects with a low fasting AUC there was an increase after food and in subjects with a high fasting AUC there was a decrease. Concentrations of 5PU in plasma were one-third to one-half those of 882C87 and, in most subjects, were not dose proportional. There was a lag of at least 5 h after dosing with 882C87 before 5PU was detectable in plasma.The most effective treatment for shingles currently available is acyclovir (5, 9). However, after an oral dose of 800 mg, the mean concentration of the drug in plasma (C max ) is 7.5 M, which is below the concentration (IC 50 ) required to inhibit varicella-zoster virus (VZV) replication by 50% in vitro (5). Higher oral doses do not produce higher concentrations in plasma, and in addition, the short half-life (t 1/2 ) of acyclovir necessitates dosing five times a day. 1-(␤-D-Arabinofuranosyl)-5-(1-propynyl)uracil (882C87) (Fig. 1) is a thymidine analog under development as an alternative therapy for VZV infection. In plaque reduction assays in MRC-5 cells it has an IC 50 of 1 to 2 M against a range of VZV strains, making it approximately seven times more potent than acyclovir (7). It has a molecular weight of 282.25, pK a of 8.64, log P (octanolwater) of Ϫ1.02, and mean plasma protein binding (measured by centrifugal ultrafiltration) of 88% at plasma drug concentrations between 1 and 100 M (4). It has...

Combinations of β-Lactam Antibiotics Currently in Clinical Trials Are Efficacious in a DHP-I-Deficient Mouse Model of Tuberculosis Infection

“…The widespread assumption that β-lactams, one of the safest types of antibiotics, are not adequate drugs for the treatment of tuberculosis (TB) infection is grounded on (i) the constitutive production of BlaC, a broad-spectrum class A β-lactamase that protects Mycobacterium tuberculosis from β-lactam action ( 1 ), (ii) the impermeable nature of the mycobacterial cell wall, rendering most β-lactams weakly efficacious in vitro ( 2 ), (iii) their potentially limited penetration into macrophages, (iv) their failure to show significant levels of efficacy in commonly employed TB animal models of infection ( 3 , 4 ), and (v) the unconvincing clinical proof of efficacy reported to date ( 5 , 6 ). These arguments, together with further limitations associated with the lack of active and orally bioavailable β-lactams with long half-lives have profoundly affected the state of opinions in the TB research and development (R&D) community to the point where research in this area has virtually stalled for the best part of the last 3 decades.…”