IngentaConnect Increased oral ganciclovir bioavailability in HIV-infected patien...

Abstract:

Aims

Despite a lack of data, the antiviral agent ganciclovir is not indicated in AIDS patients with diarrhoea because of its presumed poor oral bioavailability. To assess the effect of diarrhoea on ganciclovir intestinal absorption, we conducted a pharmacokinetic study in 42 HIV-infected patients categorized into three groups: A, HIV stage A and B (n = 15); B, AIDS stage C (n = 13); C, AIDS with chronic diarrhoea and wasting syndrome (n = 14). Methods

Each patient was evaluated for nutritional (body mass index, albumin, transferrin serum levels), inflammatory (haptoglobin, orosomucoid), immunological (CD4 count, plasma viral load) and intestinal (d-xylose test, faecal fat and nitrogen output, intestinal permeability) status. Ganciclovir (1 g) was administered orally to fasted patients. Six blood samples were collected over 24 h. Serum was analysed for ganciclovir by h.p.l.c. Population pharmacokinetic analysis was performed using a nonlinear mixed effects modelling program, MP2. Results

Mean intestinal permeability (lactulose/mannitol urinary ratio) was increased in group C (0.2) compared with group A (0.05) and B (0.1) patients. Drug concentration-time profiles were best described by a two-compartment model. Apparent oral clearance (CL/F) and central volume of distribution (V₁/F) were influenced by clinical status (group). For groups A and B combined, final parameter estimates of CL/F and V₁/F were 256 ± 98 l h⁻¹ and 1320 ± 470 l, respectively. Final parameter estimates for group C were 118 ± 108 l h⁻¹ and 652 ± 573 l for CL/F and V₁/F, respectively. The 95% confidence intervals on differences between A and B combined and C were statistically significant ([ + 70, + 206] for CL/F, and [+ 314, + 1022] for V₁/F). Compared with groups A and B, ganciclovir CL/F was significantly decreased in group C patients. Conclusions

AIDS patients with diarrhoea and severe disease may benefit from ganciclovir therapy, but a dose adjustment may be required according to their digestive and immunological status.

Keywords: CD4; diarrhoea; HIV infection; oral ganciclovir; population pharmacokinetics

Document Type: Research article

DOI: 10.1046/j.0306-5251.2001.01389.x

Affiliations: 1: Department of Internal Medicine, Lariboisiere Hospital, 75475 Paris Cedex 10, 2: Laboratory of Pharmacology, La SalPetriere Hospital, 75013 Paris and 3: Laboratory of Pharmacology, Faculty of Medicine, Henri Mondor Hospital, 94010 Creteil, France

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Increased oral ganciclovir bioavailability in HIV-infected patients with chronic diarrhoea and wasting syndrome—a population pharmacokinetic study