Human pharmacokinetics of the antiviral drug DHPG

Abstract

The pharmacokinetics of the antiviral drug 9-[2-hydroxy-1-(hydroxymethyl) ethoxymethyl]guanine (DHPG) were examined in six patients receiving 2.5 or 5.0 mg/kg every 8 or 12 hours for human cytomegalovirus (HCMV) pneumonitis or retinitis. Biexponential decay with a mean distribution t1/2 of 0.23 hours and terminal t1/2 of 2.53 hours was observed. Total clearance correlated well with and exceeded creatinine clearance by a factor of 2.4. Mean volume of the central compartment was 15.26 L/1.73 m2 and the volume of distribution at steady state was 32.8 L/1.73 m2. Peak (model predicted) and trough plasma concentrations were 4.75 to 6.20 micrograms/ml and less than 0.25 to 0.63 microgram/ml, respectively, in patients receiving 2.5 mg/kg. Peak concentrations are well above those needed to inhibit HCMV at the 50% level (ID50) and troughs are near this ID50. Cerebrospinal fluid concentrations of DHPG indicate a penetration of 24% to 67%. No accumulation of DHPG was apparent in these patients. However, dosage reduction is necessary in renal insufficiency. Neutropenia occurred in one patient. The plasma concentration profile of DHPG suggests potential beneficial activity against HCMV.

Ganciclovir treatment in children: evidence of subtherapeutic levels

“…Low trough levels have been previously reported in a small study of paediatric transplant patients, with levels <0.5 mg/L being significantly more common in younger patients [12]. The observation that fewer babies <28 days had trough levels <0.5 mg/L compared with the overall age group <6 months would be in keeping with the almost exclusive renal excretion of GCV and the known immature renal function Peak levels were also in keeping with those reported in other clinical studies and were well above the MIC and IC 50 observed in vitro [6,7]. The relatively high frequency of peak levels <3.0 mg/L in younger age groups would, however, give rise to concerns regarding treatment failure, particularly if the disease-causing virus had an IC 50 at the upper range of those reported in vitro (3.48 mg/L).…”

“…The therapeutic ranges often quoted in clinical studies were first derived from a study in five bone marrow transplant patients and one acquired immune deficiency virus (AIDS) patient with documented CMV retinitis or pneumonitis [7]. In that study, peak plasma concentrations ranged from 4.75 mg/L to 6.2 mg/L and trough concentrations from 0.25 mg/L to 0.63 mg/L.…”

TRAIL enhances thymidine kinase/ganciclovir gene therapy of neuroblastoma cells

“…Unspecific toxicity, as shown by TK À cells, was minimal with the concentrations of GCV applied, which are within the plasma concentrations achievable in patients after intravenous infusion. 11,27 These data show that TK /GCV is effective in SH -EP neuroblastoma cells by affecting proliferation, metabolic cell survival, apoptosis, and clonogenicity.…”

In vitro and in vivo antitumor effects of retrovirus-mediated herpes simplex thymidine kinase gene-transfer in human medulloblastoma

“…Since D341Med-TK cells were killed by GCV treatment DNA synthesis, determined by standard 3 H-thymidine in vitro at concentrations usually reached in a clinical setincorporation assay, and cell growth, studied by MTT ting, 23 we assessed whether D341Med-TK cells were assay, were significantly higher in D341Med-tk cells sensitive to in vivo treatment, as well. Five mice were (Table 1).…”

“…These observations lead to reported for most brain tumor cell lines and which can be obtained in vivo. 23 Moreover, no toxicity was observed the speculation that the transfer of the connexin-43 gene into D341Med cells could increase the bystander effect, at the same GCV concentrations in untransfected D341Med cells. Some decline of cell viability was seen as previously demonstrated in the U87 glioma cell line.…”