Pharmacokinetics and absorption of foscarnet after intravenous and oral administration to patients with human immunodeficiency virus

Abstract

Six patients with human immunodeficiency virus were given foscarnet in oral solution, 4000 mg every 6 hours for 3 days, followed by a washout period for 2 days and continuous intravenous infusion of 16,000 mg/24 hr over 72 hours. After oral foscarnet, plasma concentrations were less than 33 mumol/L in four patients; two had occasional concentrations of 35 to 50 mumol/L. The extent of absorption varied between 12% and 22%. During intravenous infusion, plasma concentrations ranged between 75 and 265 mumol/L. The disposition of foscarnet was triphasic, with mean half-lives of 0.45, 3.3, and 18 hours. Excretion data suggested elimination was by tubular secretion and glomerular filtration. Renal clearance was 176 ml/min 1.73 m2. The apparent nonrenal clearance, 40 ml/min 1.73 m2, probably reflects sequestration of foscarnet into bone. Ten percent to 28% of the cumulative dose may have been deposited in bone 2 days after infusion. A slight increase in serum calcium levels and changes in serum phosphate values may reflect the uptake of foscarnet in bone. Five patients had diarrhea (oral) and two had thrombophlebitis (intravenous).

Pharmacokinetics of foscarnet and distribution to cerebrospinal fluid after intravenous infusion in patients with human immunodeficiency virus infection

“…Owing to poor oral absorption (17), the concentrations achieved in plasma after oral dosing have been considered too low for inhibition of HIV or CMV replication in vivo compared with the required in vitro inhibitory concentration of foscarnet (10,13,14). Thus, foscarnet must be administered intravenously.…”

Foscarnet for suppression of human immunodeficiency virus replication

“…Additionally, serial CD4+ cell counts obtained during induction therapy were analyzed by a normalized (adjusted for baseline) area-under-the-curve (NAUC) method; Induction phase concentration-time data were fit to a twocompartment pharmacokinetic model by a Bayesian estimation strategy (13). The a priori population parameters used were taken from the data for foscarnet in the literature (2,14,15). These parameters correspond to a typical half-life at ox phase of 0.31 h, a half-life at X phase of 4.4 h, and a clearance of 0.11 liter/kg/h.…”

Antiviral therapy: current concepts and practices

“…Oral bioavailability is poor (433), although efforts are being made to increase absorption and prolong the half-life by conjugation to fatty alcohols (322). Currently, the drug is available only in intravenous formulations, and it must be given frequently by means of an infusion pump, as the half-life in plasma is very short (9,433). At physiologic pH, foscarnet is highly ionized and has limited cell penetration (328,433).…”

“…Currently, the drug is available only in intravenous formulations, and it must be given frequently by means of an infusion pump, as the half-life in plasma is very short (9,433). At physiologic pH, foscarnet is highly ionized and has limited cell penetration (328,433). Levels in spinal fluid are usually about 40% of those in plasma but may vary by a wide margin (7).…”