Lack of pharmacokinetic interaction between nelfinavir and nevirapine

Skowron, Gail; Leoung, Gifford S.; Kerr, Brad; Dusek, Alex; Anderson, Robert F.; Beebe, S. P.; Grosso, Robert

doi:10.1097/00002030-199810000-00017

Cited by 39 publications

(10 citation statements)

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“…Although not statistically significant, these findings suggest inhibition of metabolism in contrast to a previous study indicating no interaction. 23 This warrants additional study and underscores the need for complete pediatric pharmacokinetic evaluations. In this study, smaller children who were Ͻ25 kg generally received the study dose as a powder formulation, whereas larger children who were Ͼ25 kg generally received the study dose in tablet form.…”

Section: Discussionmentioning

confidence: 99%

Nelfinavir Pharmacokinetics in Stable Human Immunodeficiency Virus-Positive Children: Pediatric AIDS Clinical Trials Group Protocol 377

et al. 2003

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ABSTRACT. Objective. Pharmacokinetic data obtained from children who have human immunodeficiency virus (HIV) infection are essential for the safe and effective use of antiretroviral agents in pediatric populations. The objective of this study was to assess the impact of body weight on the pharmacokinetic disposition of nelfinavir (NFV) in the absence and presence of nevirapine (NVP) and compare the pharmacokinetic profiles of twice-daily (BID) and three-times-daily (TID) NFV regimens.Methods. This was an intensive pharmacokinetic substudy nested in a phase II, multicenter, randomized, open-label trial. Forty-five HIV-infected children receiving NFV 30 mg/kg TID and 6 HIV-infected children receiving NFV 55 mg/kg BID were enrolled in this study and assigned to 1 of 4 stavudine-containing regimens, 3 containing NFV and 2 containing NVP. Area under the plasma concentration-time curves from 0 to 8 hours (AUC 0 -8 hours ) and from 0 to 12 hours (AUC 0 -12 hours ) for the TID and BID regimens, respectively, were determined. For comparative purposes, the AUC 0 -24 hours was also calculated for each regimen.Results. NFV exposure in the absence of NVP was decreased in children who were <25 kg compared with those who were >25 kg (a 2.6-fold difference in median AUC 0 -8 hours ). NFV pharmacokinetics in the presence of NVP did not differ between the <25 kg and >25 kg groups. The AUC 0 -24 hours for children who were <30 kg and on NFV BID was comparable to the AUC 0 -24 hours for children who were >25 kg and on NFV TID but was 2.7-fold greater than AUC 0 -24 hours for children who were <25 kg and on NFV TID.Conclusions. NFV in the absence of NVP resulted in less than half the drug exposure in children who were <25 kg compared with children who were >25 kg. NFV dosed at 55 mg/kg BID in children who are <30 kg provides comparable exposure to that measured in children who are >25 kg and receiving NFV 30 mg/kg TID. Pediatrics 2003;112:e220 -e227. URL: http://www. pediatrics.org/cgi/content/full/112/3/e220; pharmacokinetics, nelfinavir, children, HIV, protease inhibitor, nevirapine.

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Section: Discussionmentioning

confidence: 99%

Nelfinavir Pharmacokinetics in Stable Human Immunodeficiency Virus-Positive Children: Pediatric AIDS Clinical Trials Group Protocol 377

et al. 2003

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“…Nelfinavir increases saquinavir levels ∼5-fold and, thus, potentially allows reduced twice-daily dosing of saquinavir soft-gel capsules [17]. Nevirapine, an inducer of cytochrome P-450 CYP3A, reduces saquinavir levels [18] but probably not nelfinavir levels [19]. The effect of nevirapine on the combination of nelfinavir and saquinavir has not been studied and is difficult to predict.…”

Section: Discussionmentioning

confidence: 99%

Novel Four‐Drug Salvage Treatment Regimens after Failure of a Human Immunodeficiency Virus Type 1 Protease Inhibitor–Containing Regimen: Antiviral Activity and Correlation of Baseline Phenotypic Drug Susceptibility with Virologic Outcome

et al. 1999

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Twenty human immunodeficiency virus-infected patients experiencing virologic failure of an indinavir- or ritonavir-containing treatment regimen were evaluated in a prospective, open-label study. Subjects received nelfinavir, saquinavir, abacavir, and either another nucleoside analog (n=10) or nevirapine (n=10). Patients treated with the nevirapine-containing regimen experienced significantly greater virologic suppression at week 24 than those not treated with nevirapine (P=.04). Baseline phenotypic drug susceptibility was strongly correlated with outcome in both treatment arms. Subjects with baseline virus phenotypically sensitive to 2 or 3 drugs in the salvage regimen experienced significantly greater virus load suppression than those with baseline virus sensitive to 0 or 1 drug (median week-24 change=-2.24 log and -0.35 log, respectively; P=.01). In conclusion, non-nucleoside reverse transcriptase inhibitors may represent a potent drug in salvage therapy regimens after failure of an indinavir or ritonavir regimen. Phenotypic resistance testing may provide a useful tool for selecting more effective salvage regimens.

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“…There are indications that clearance decreases and half‐life increases when single doses are increased from 250 to 750 mg [5]. Nelfinavir may induce its own metabolism in healthy volunteers and patients, as suggested by decreases in plasma exposures during the first 6 or 9 days of chronic therapy [6, 7]. The formation of M8 is exclusively mediated by the polymorphic cytochrome P450 (CYP) 2C19 isoenyzme [8], and about 50% of nelfinavir is eliminated by this metabolic pathway in normal metabolizers [4], whereas the elimination of M8 is predominately controlled by CYP3A4 [8].…”

Section: Introductionmentioning

confidence: 99%

Single and multiple dose pharmacokinetics of nelfinavir and CYP2C19 activity in human immunodeficiency virus‐infected patients with chronic liver disease

Khaliq

Gallicano

Seguin

et al. 2000

Brit J Clinical Pharma

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Aims To evaluate the single‐dose and multiple‐dose pharmacokinetics of nelfinavir and its active M8 metabolite in eight HIV‐seropositive patients with liver disease, and to examine the relationship between CYP2C19 activity (genotype and plasma M8/nelfinavir metabolic ratio) and the severity of liver disease in these patients. Methods Nelfinavir was given as a single dose (500 or 750 mg) to patients beginning therapy and twice (500, 750 or 1000 mg) or three times (250 or 750 mg) daily during chronic therapy. Single‐dose pharmacokinetic values were used to predict multiple‐dose regimens. Peak and total plasma exposures between 2–4 µg ml−1 and 45–75 µg ml−1 h, respectively, and predose levels > 0.7 µg ml−1 were targeted for multidose nelfinavir. Genotype was determined by analysis for CYP2C19*1, CYP2C19*2, and CYP2C19*3. Individuals were grouped according to their genotype, molar M8/nelfinavir AUC ratio (low: < 0.1, intermediate: 0.1–0.3, high > 0.3), and Child‐Pugh classification for severity of liver disease. Results Nelfinavir pharmacokinetics were characterized by wide interindividual variability, low clearance (181–496 ml min−1 70 kg−1, n = 7), and prolonged half‐life (5–20 h, n = 7). M8/nelfinavir AUC ratio increased 58% (n = 4) and α1‐acid glycoprotein levels decreased up to 39% (n = 5) from single to multiple dosing. CYP2C19 activity was low (metabolic AUC ratio < 0.1) in four patients with moderate to severe liver disease even though they were genetically extensive CYP2C19 metabolizers (*1/*1 or *1/*2). Three patients required lower daily doses than the standard regimen of 750 mg every 8 h to achieve target concentrations and maintain virologic suppression at < 50 RNA copies ml−1 (up to 20 months). Conclusions Acquired CYP2C19 deficiency from moderate or severe liver disease resulted in decreased M8 formation. Long‐term HIV suppression is possible using low nelfinavir doses in patients with liver disease.

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Lack of pharmacokinetic interaction between nelfinavir and nevirapine

Cited by 39 publications

References 1 publication

Nelfinavir Pharmacokinetics in Stable Human Immunodeficiency Virus-Positive Children: Pediatric AIDS Clinical Trials Group Protocol 377

Nelfinavir Pharmacokinetics in Stable Human Immunodeficiency Virus-Positive Children: Pediatric AIDS Clinical Trials Group Protocol 377

Novel Four‐Drug Salvage Treatment Regimens after Failure of a Human Immunodeficiency Virus Type 1 Protease Inhibitor–Containing Regimen: Antiviral Activity and Correlation of Baseline Phenotypic Drug Susceptibility with Virologic Outcome

Single and multiple dose pharmacokinetics of nelfinavir and CYP2C19 activity in human immunodeficiency virus‐infected patients with chronic liver disease

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