Analysis of variation in plasma concentrations of nelfinavir and its active metabolite M8 in HIV-positive patients.
OBJECTIVE
To characterize sources of variation in plasma concentrations of nelfinavir and its active metabolite M8 and to evaluate the use of therapeutic drug monitoring for nelfinavir treatment.


METHODS
Plasma samples and patient's characteristics were obtained from outpatient clinic. Differences between groups of patients were studied by comparing the observed plasma concentrations with the corresponding concentration on a pharmacokinetic population curve based on median plasma levels.


RESULTS
Plasma samples (618) were available from 355 patients taking 1250 mg nelfinavir twice daily. The median ratio between M8 and nelfinavir concentrations was 0.29. This ratio appeared to be independent of the time after ingestion. Statistically significantly lower M8 concentrations were found in Black and Asian patients, or when comedication with CYP3A4 inducers was used. Coadministration of CYP2C19 inhibitors, such as omeprazole, decreased the median M8/nelfinavir ratio. Nevertheless, nelfinavir concentrations and summed concentrations of nelfinavir and M8 were only marginally affected in these patients. Diarrhoea was identified as a cause for lower nelfinavir concentrations, without changing the M8/nelfinavir ratio. In a number of patients with suspected therapy failure or intoxication, abnormal nelfinavir plasma concentrations were found. Dose adjustments based on nelfinavir plasma levels were helpful in a number of patients.


CONCLUSIONS
This study shows that the total concentration of nelfinavir and M8 together is not significantly influenced when variation in M8 levels occurs. Consequently, measuring M8 concentrations in addition to nelfinavir concentrations is not required for the purpose of therapeutic drug monitoring for this drug.
Baede-van Dijk
P A
PA
Section Clinical Assessments, Medicines Evaluation Board Agency, The Hague, the Netherlands.
Hugen
P W
PW
Verweij-van Wissen
C P
CP
Koopmans
P P
PP
Burger
D M
DM
Hekster
Y A
YA
D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D001189:Aryl Hydrocarbon Hydroxylases; D001835:Body Weight; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D016208:Databases, Factual; D003967:Diarrhea / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000097:blood* / Q000378:metabolism / Q000627:therapeutic use; D006679:HIV Seropositivity; D006801:Humans; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D019888:Nelfinavir / Q000097:blood* / Q000378:metabolism / Q000627:therapeutic use; D009853:Omeprazole / Q000627:therapeutic use
D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D017320:HIV Protease Inhibitors; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; C104464:CYP3A protein, human; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D019888:Nelfinavir; D009853:Omeprazole