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 indicat ed in AIDS patients with diarrhoea because of its presumed poor oral bioava ilability. To assess the effect of diarrhoea on ganciclovir intestinal abso rption, we conducted a pharmacokinetic study in 42 HIV-infected patients ca tegorized 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, albumi n. transferrin serum levels), inflammatory (haptoglobin, orosomucoid), immu nological (CD4 count, plasma viral load) and intestinal (D-xylose test, fae cal fat and nitrogen output, intestinal permeability) status. Ganciclovir ( 1 g) was administered orally to fasted patients. Six blood samples were col lected over 24 h. Serum was analysed for ganciclovir by h.p.l.c. Population pharmacokinetic analysis was performed using a nonlinear mixed effects mod elling 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) patien ts. Drug concentration-time profiles were best described by a two-compartme nt 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 com bined, 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 wer e 118 +/- 108 1 h(-1) and 652 +/- 573 1 for CL/F and V-1/F, respectively. T he 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 d ecreased in group C patients. Conclusions AIDS patients with diarrhoea and severe disease may benefit fro m ganciclovir therapy, but a dose adjustment may be required according to t heir digestive and immunological status.