PHARMACOKINETICS OF FLUCONAZOLE IN PEOPLE WITH HIV-INFECTION - A POPULATION ANALYSIS

1 The population pharmacokinetics of fluconazole have been investigate d in 113 male subjects with HIV infection and AIDS. Plasma concentrati on-time data (between 1 and 17 observations per dose) were collected f rom individuals as part of a pharmacokinetic investigation (13 subject s) or during routine fluconazole therapy (100 subjects) for the treatm ent or prophylaxis of fungal infection. 2 A one-compartment pharmacoki netic mode! was used to describe the disposition of fluconazole after oral and intravenous infusion doses. Population pharmacokinetic parame ters were generated using the NONMEM and P-PHARM computer programs. 3 The population estimates (calculated using NONMEM) of fluconazole clea rance and volume of distribution were 0.78 l h(-1) and 47.61, respecti vely. The intersubject variability for these parameters was 41% and 8% , respectively. The model-dependent estimate of the extent of absorpti on was 0.99 with an intersubject variability of 6%. Mean population es timates generated by NONMEM and P-PHARM were in close agreement. 4 Exa mination of the relationship between patient covariates and pharmacoki netic parameters indicated that intersubject variability in fluconazol e clearance could in part be explained by the severity of disease (as indicated by CD4+ T-lymphocyte count) and renal function (indicated by estimated creatinine clearance). Other pharmacokinetic parameters wer e unaffected by these covariates. 5 Fluconazole clearance (estimated u sing NONMEM) in subjects with a CD4+ T-lymphocyte count less than and greater than 200 cells mm(3) was 0.73 l h(-1) (95% CI;0.64-0.82 l h(-1 )) and 0.99 l h(-1) (95% CI;0.86-1.12 l h(-1)), respectively. The regr ession model for fluconazole clearance that accounted for changes in r enal function and disease severity was CL (l h(-1)) = 0.25 (33%) + 0.0 057 (32%) x CLcr (in mi min(-1)) + 0.00068 (10%) x CD4 cell count (in cells mm(-3)) where intersubject variability (expressed as %CV) is sho wn in brackets. 6 Based on pharmacokinetic considerations a reduction in the dose of fluconazole would appear to be warranted in people with HIV infection who are seriously ill or who have compromised renal fun ction. However, the emergence of resistance to fluconazole must also b e considered when thinking of dosage adjustments.