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

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 (V-1/F) were influenced by clinical status (group). For groups A and B combined, final parameter estimates of CL/F and V-1/F were 256 +/- 98 1 h(-1) and 1320 +/- 470 1, respectively. Final parameter estimates for group C were 118 +/- 108 1 h(-1) and 652 +/- 573 1 for CL/F and V-1/F, respectively. The 95% confidence intervals on differences between A and 13 combined and C were statistically significant ([+70, +206] for CL/F, and [+314, +1022] for V-1/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.