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Analysis of variation in plasma concentrations of nelfinavir and its active metabolite M8 in HIV-positive patients

Baede-van Dijk, Patricia A.a*; Hugen, Patricia W. H.b; Verweij-van Wissen, Corrien P. W. G. M.b; Koopmans, Peter P.c; Burger, David M.b; Hekster, Yechiel A.b

Clinical Science

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.

Conclusion: 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.

From the aSection Clinical Assessments, Medicines Evaluation Board Agency, The Hague and the Departments of bClinical Pharmacy and cGeneral Internal Medicine, University Medical Centre Nijmegen, Nijmegen, the Netherlands. *Present address: Kinesis Holding BV, Breda, the Netherlands.

Requests for reprints to Dr P. W. H. Hugen, 533 Department of Clinical Pharmacy, University Medical Centre Nijmegen, PO Box 9101, 6500 HB Nijmegen, the Netherlands.

Received: 17 November 2000;

revised: 16 February 2001; accepted: 21 February 2001.

© 2001 Lippincott Williams & Wilkins, Inc.