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

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.

Pharmacokinetics of Drugs in Cachectic Patients: A Systematic Review

“…The results are presented in Table 2 . Four studies included patients with wasting and concomitant diarrhea [ 14 – 17 ] and are represented separately ( Table 3 ). The remaining five studies [ 18 – 22 ] correlated pharmacokinetic parameters in patients with chronic disease with parameters of body composition ( Table 4 ).…”

“…There is no evidence that cachexia influences renal function, although higher incidence of new renal failure after valvular surgery was associated with cardiac cachexia [ 58 ]. The pharmacokinetics of intravenously administered carboplatin, which is eliminated only via kidneys, was not influenced by cachexia [ 11 ] and half-life of another renally excreted drug ganciclovir was also not prolonged in cachectic patients [ 14 ]. However, due to muscle mass loss in cachectic patients, renal function may be overestimated if based on serum creatinine concentration.…”

Population pharmacokinetics of ceftazidime in burn patients

“…In the first step of the analysis, the basic pharmacokinetic model without any covariates was defined [5]. The Akaike information criterion (Akaike value = objective function + 2 × P, where P is the number of estimated parameters and the objective function is similar to the function estimated by NONMEM) decreased from 722 for the one‐compartment model to 712 for the two‐compartment model, which indicated that the latter is better than the former model.…”

Impact of modelling intra‐subject variability on tests based on non‐linear mixed‐effects models in cross‐over pharmacokinetic trials with application to the interaction of tenofovir on atazanavir in HIV patients

“…Some of these interactions are tested in PK trials performed in healthy volunteers. However, an important concern is that the pharmacokinetics of antiretroviral drugs seem to be different in patients, partly because of a modification of absorption characteristics during HIV infection [11][12][13]. The possibility of performing PK interaction and bioequivalence trials in patients, requiring a reduced number of samples per subject, is therefore of a great importance.…”