Durban World AIDS Conference
July 9-14, Durban, South Africa

REPORT 35

A pilot study of nelfinavir therapeutic drug monitoring in HIV infected patients

A Tseng from Toronto General Hospital, K Gallicano from Ottawa Hospital and colleagues reported on this pilot TDM study.  Therapeutic drug monitoring (TDM) is checking blood levels of drugs in a person's regimen to see if the person is receiving the proper amount of drug. Data are lacking on the clinical utility of therapeutic drug monitoring TDM of protease inhibitors (PI).  Potential benefits include improved virologic outcome and reduced toxicity by guiding dose adjustment in patients with malabsorption, suspected drug interactions or nonadherence, hepatic dysfunction, or non-ideal body weight. If a person does not have proper amount of drug in blood dosing can be changed. But there are a number of concerns about TDM including: when do you check blood during dosing period; how often do you need to check during a dosing period; do you need to check blood during several dosing periods; do one or two low drug-blood levels predict virologic failure. The purpose of this pilot study was to determine the potential value of nelfinavir (NFV) TDM in a  clinic population.

Single trough and/or peak NFV and M8 metabolite plasma  concentrations were measured in 10 HIV infected males taking  NFV 1250 mg twice daily for a mean of 7.1 months (range 2-25).  NFV levels were compared to a predetermined reference range (peak: 3.3-4.4 ug/ml; trough: >0.7 ug/ml). Charts were reviewed retrospectively for HIV RNA, CD4, concomitant medications, weight, and medical history.

Eight subjects were PI-experienced. Median CD4 and HIV RNA were 261 (range 35 to 441) cells/mm3 and 4.53 (range >50  to >5.7) log10 copies/mL, respectively, prior to starting NFV.  The median peak NFV (n = 4) was 3.2 ug/mL (range 1.5-5.6), while median trough NFV (n = 8) was 1.0 ug/mL (range 0.1-4.2). Five had NFV concentrations outside the reference range. Two subjects had high concentrations (peak 5.6, trough 4.2 ug/mL) and severe and persistent diarrhea. Three subjects with low NFV (peak 2.8, trough 0.3, 0.1 ug/mL) later (median 5 months) developed viral breakthrough despite initial suppression. Two of five subjects with levels in the desired range had viral RNA >50 copies/mL;  three were heavily PI-experienced and had no decrease in viral  RNA.

The authors concluded that in this pilot study, 50% of patients taking standard NFV had levels outside the reference range, and experienced undesirable clinical effects. The pharmacodynamic relationship between drug levels and virologic efficacy should be further explored through controlled studies using TDM in conjunction with other parameters  such as viral phenotyping.

Comments: I presume similar results, some individuals above, in & outside reference ranges for a particular drug, would be found for any or most drugs tested. An interesting finding is that the 3 heavily PI-experienced individuals had no decrease in viral load. This suggests that evaluating drug-blood levels in a treatment experienced person or a person with drug resistance to protease inhibitors & NNRTIs may be different than in a treatment naÔve person.