SEARCH · PubMed Health

Results for “Nelfinavir”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 19 recordsLinked to original sources

PubMed2001

Nelfinavir suspension obtained from nelfinavir tablets has equivalent pharmacokinetic profile.

The pharmacokinetics of nelfinavir tablets (A) and an oral simplified nelfinavir suspension (B) were studied. Twelve healthy volunteers randomly received either five 250-mg nelfinavir tablets or a simplified oral suspension obtained from tablets dissolved in water (nelfinavir 1250 mg in 100 mL of water) in a single dose before being crossed over to the second treatment after a one-week washout period. Blood samples were drawn up to 24 h after drug administration. Nelfinavir concentrations in plasma were analyzed by a specific and validated reverse-phase high-performance liquid chromatography assay (HPLC) with UV detection, and pharmacokinetic values were determined. For the AUC(0-infinity) with means+/-SD of 31.71+/-7.85, 30.88+/-10.28 (microg/L) respectively for treatments B and A, the ratio (F(B/A)) was of 1.1 with a C.I. of 0.90-1.24. For Cmax with means+/-SD of 3.1+/-0.6 (treatment B) and 3.2+/-0.8 mg/mL (treatment A), the ratio was 1.0. with C.I. of 0.92-1.08. The two treatments evidenced no significant differences in AUC(0-inifnity) and Cmax values and the two-one sided t-test showed that the two preparations are bioequivalent. There was no significant difference in Tmax between the liquid and tablets. Nelfinavir suspension might be a option for treating HIV-infected patients with swallowing disturbances or compliance problems.

Administration, Oral↗

PubMed1999

A generalized seizure following initiation of nelfinavir in a patient with human immunodeficiency virus type 1 infection, suspected due to interaction between nelfinavir and phenytoin.

Nelfinavir, one of human immunodeficiency virus (HIV) specific protease inhibitors(PIs), is widely used for the treatment of HIV infection. Nelfinavir, which is metabolized with the cytochrome p450 isoforms, elevate the phenytoin level theoretically because nelfinavir acts as an inhibitor of phenytoin metabolism through the enzyme. However, we encountered a case of seizure recurrence caused by a lowered phenytoin level after initiation of nelfinavir. We should be aware of the change in the phenytoin level in concomitant use of nelfinavir.

Adult↗

PubMed2000

Correlation between human immunodeficiency virus genotypic resistance and virologic response in patients receiving nelfinavir monotherapy or nelfinavir with lamivudine and zidovudine.

The relationship between detectable human immunodeficiency virus (HIV) genotypic resistance and virologic response was compared in patients receiving nelfinavir as monotherapy (16 weeks) or in combination with lamuvidine and zidovudine (48 weeks). Two patient groups were defined on the basis of the presence or absence of substitutions associated with nelfinavir, a protease (PR) inhibitor, and/or a reverse transcriptase (RT) inhibitor. HIV RNA levels <50 copies/mL were achieved in 17 (85%) of 20 combination-therapy patients without genotypic resistance (PR-RT(-)) versus only 1 (17%) of 6 patients with genotypic resistance (PR-RT(+)). PR-RT(-) patients exhibited greater and more durable virus suppression compared with PR-RT(+) patients. All 6 PR-RT(+) patients had virus with M184V (lamuvidine resistance); 3 isolates also contained D30N (nelfinavir resistance). M184V preceded D30N in all determinable instances. In this study, suppression of HIV replication to <50 copies/mL was associated with durable response and reduced incidence of resistance. Results also indicate that combination regimens can fail despite the absence of detectable genotypic PR resistance.

Anti-HIV Agents↗

PubMed1998

Nelfinavir. A review of its therapeutic efficacy in HIV infection.

UNLABELLED: Nelfinavir is a selective inhibitor of HIV protease, the enzyme responsible for post-translational processing of HIV propeptides. In the presence of the drug, immature, noninfectious virus particles are produced. Nelfinavir in combination with nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors and/or other protease inhibitors profoundly suppresses viral replication. Plasma HIV RNA levels (viral loan) rapidly fall below the limit of detection (LOD; usually 400 or 500 copies/ml in the majority of patients. When used in combination with NRTIs, nelfinavir 1250mg twice daily produced similar results to 3-times-daily nelfinavir at a range of total daily dosages. In an ongoing study > 70% of adults receiving a nelfinavir based combination regimen had plasma HIV RNA levels below the LOD (< 400 copies/ml) after 84 weeks. In addition, 73% of paediatric patients receiving nelfinavir plus at least 1 new NRTI had viral loads below the LOD (< 400 copies/ml) after 34 weeks. Furthermore, CD4+ cell counts generally increased in conjunction with reductions in viral load. Combination therapy with nelfinavir and saquinavir results in higher saquinavir plasma concentrations, make twice-daily administration of saquinavir feasible and may delay the emergence of resistant viral strains. A unique mutation at codon 30 (D30N) of the protease gene confers resistance to nelfinavir, but HIV with D30N mutation remains fully susceptible to indinavir, ritonavir and saquinavir in vitro. Nonetheless, in clinical use, significant cross-resistance is seen with all currently available protease inhibitors. Diarrhoea is the most frequently reported adverse event in patients receiving nelfinavir-based combination therapy and has been reported in up to 32% of nelfinavir recipients in randomised trials. Diarrhoea is generally of mild to moderate severity and does not result in weight loss. Rash, nausea, headache and asthenia were each reported in < or = 5% of patients. Approximately 5% of patients enrolled in an expanded access programme in the US discontinued nelfinavir because of adverse events. Nelfinavir is metabolised by the cytochrome P450 system. Several clinically significant pharmacokinetic drug interactions between nelfinavir and other drugs (i.e. ketoconazole, rifabutin, rifabutin, rifampicin), including other protease inhibitors (i.e. indinavir, ritonavir, saquinavir) have been documented. As with other available protease inhibitors, hyperglycaemia, hyperlipidaemia and abnormal fat distribution have been reported, albeit infrequently, in association with nelfinavir. CONCLUSION: Nelfinavir-based combination regimens are well tolerated and produce profound and prolonged suppression of HIV replication in adult and paediatric patients. Hence, nelfinavir is suitable for inclusion in antiretroviral regimens for initial therapy for HIV infection and, alternatively, in regimens for patients unable to tolerate other protease inhibitors.

Adult↗

PubMed1998

Characterization of the selectivity and mechanism of human cytochrome P450 inhibition by the human immunodeficiency virus-protease inhibitor nelfinavir mesylate.

In vitro studies with human liver microsomes and P450 probe substrates were performed to characterize selectivity and mechanism of cytochrome P450 inhibition by nelfinavir mesylate. At therapeutic concentrations (steady-state plasma concentrations approximately 4 microM), nelfinavir was found to be a competitive inhibitor of only testosterone 6beta-hydroxylase (CYP3A4) with a Ki concentration of 4. 8 microM. At supratherapeutic concentrations, nelfinavir competitively inhibited dextromethorphan O-demethylase (CYP2D6), S-mephenytoin 4-hydroxylase (CYP2C19), and phenacetin O-deethylase (CYP1A2) with Ki concentrations of 68, 126, and 190 microM, respectively. Nelfinavir did not appreciably inhibit tolbutamide 4-hydroxylase (CYP2C9), paclitaxel 6alpha-hydroxylase (CYP2C8), or chlorzoxaxone 6beta-hydroxylase (CYP2E1) activities. The inhibitory potency of nelfinavir toward CYP3A4 suggested the possibility of in vivo inhibition of this isoform, whereas in vivo inhibition of other P450s was considered unlikely. In a one-sequence crossover study in 12 healthy volunteers, nelfinavir inhibited the elimination of the CYP3A substrate terfenadine and the carboxylate metabolite of terfenadine. The 24-hr urinary recoveries of 6beta-hydroxycortisol were reduced by an average of 27% during nelfinavir treatment, consistent with CYP3A inhibition by nelfinavir. Inhibition of CYP3A4 by nelfinavir in vitro was NADPH-dependent requiring the catalytic formation of a metabolite or a metabolic intermediate. The catechol metabolite of nelfinavir (M3) was considered unlikely to be responsible for inhibition as the addition of catechol O-methyl transferase, S-adenosyl methionine, and ascorbic acid to the preincubation mixture did not protect against the loss of testosterone 6beta-hydroxylase activity. Also, the addition of M3 to human liver microsomes did not inhibit CYP3A4. Although incubations with nelfinavir showed a time- and concentration-dependent loss of CYP3A4 activity, the partial or complete recovery of enzyme activity upon dialysis indicated that inhibition was reversible. Microsomal incubations with nelfinavir and NADPH did not result in a loss of spectral P450 content compared with the NADPH control. Glutathione, N-acetylcysteine, and catalase did not attenuate CYP3A4 inhibition by nelfinavir. Collectively, these results suggest that the probable mechanism for CYP3A4 inhibition by nelfinavir is a transient metabolic intermediate or stable metabolite that coordinates tightly but reversibly to the heme moiety of the P450.

Adolescent↗

PubMed2000

Clinical pharmacokinetics of nelfinavir combined with efavirenz and stavudine during rescue treatment of heavily pretreated HIV-infected patients.

Nelfinavir is a novel protease inhibitor that exhibits good inhibitory activity against human immunodeficiency virus type 1 (HIV-1) and is currently used in combination with reverse transcriptase inhibitors for the management of HIV infection. In this study we analysed the pharmacokinetic profile of nelfinavir after multiple oral doses in 18 HIV-infected patients during a combination regimen of nelfinavir plus efavirenz and stavudine. Patients who received the study drug for >/=4 weeks were considered for pharmacokinetic evaluation. Blood samples were obtained at the following times: 0 (before nelfinavir administration), 1, 2, 3, 4, 6 and 8 h after administration. Nelfinavir plasma concentrations were analysed by a specific and validated HPLC assay with ultraviolet detection. Nelfinavir concentration-time data were analysed by compartmental and non-compartmental techniques and the pharmacokinetic parameters of nelfinavir were determined according to a one-compartment model. We found a high variability between individuals in nelfinavir plasma concentrations. The mean average drug plasma concentration was 2.22 +/- 1.25 mg/L and the mean AUC during the dosing interval was 17.7 +/- 10.0 mg*h/L. The mean nelfinavir trough plasma concentration was 1.58 +/- 1.0 mg/L. A good relationship was found between AUC(0-8h) and the plasma concentrations measured at 6 h, and the trough plasma concentrations made total body exposure for nelfinavir less predictable. Alternatively, a 2 h abbreviated AUC provides a good estimate of the full AUC(0-8h). Comparing the pharmacokinetic parameters obtained in our patients with those reported for patients receiving nelfinavir monotherapy or nelfinavir combined with nucleoside analogues, one observes substantial overlap with nelfinavir concentrations achieved without efavirenz.

Adult↗

PubMed2000

Nelfinavir: an update on its use in HIV infection.

UNLABELLED: Nelfinavir is one of several currently available protease inhibitors used to limit viral replication and improve immune function in HIV-infected individuals. It is administered in combination with other antiretroviral agents. Nelfinavir has been evaluated as first-line therapy with nucleoside reverse transcriptase inhibitors (NRTIs) in treatment-naive patients, or as an additional antiretroviral agent in protease inhibitor-naive patients already receiving NRTIs. These studies have shown good efficacy in terms of HIV viral load reduction and increased CD4+ cell counts. When used in combination with NRTIs, nelfinavir 1250 mg twice daily produced similar results to 750 mg 3 times daily. The more convenient twice-daily dosage schedule, which is now approved in the US, may be beneficial in improving patient adherence to therapy. Nelfinavir has also been used successfully in combination with non-nucleoside reverse transcriptase inhibitors and/or other protease inhibitors, with or without NRTIs. Resistance to nelfinavir has been observed in vitro and in clinical isolates from patients experiencing insufficient or waning viral suppression during treatment. Nelfinavir primarily selects for the D30N mutation, which is not seen with other protease inhibitors, and alone does not cause resistance to other protease inhibitors in vitro. Several studies have shown that patients who experience virological failure while receiving nelfinavir can respond to salvage therapy with other protease inhibitors. Diarrhoea is the most frequent adverse event in patients receiving nelfinavir-based combination therapy, but was generally mild and resulted in minimal discontinuation of therapy in clinical trials. Diarrhoea can usually be controlled with drugs that slow gastrointestinal motility. Metabolic disturbances associated with protease inhibitor use (hypercholesterolaemia, hyperglycaemia and lipodystrophy) have also been reported with nelfinavir. Nelfinavir is associated with a number of clinically significant drug interactions and coadministration of some drugs (e.g. astemizole, cisapride, triazolam) is contraindicated. Coadministration of nelfinavir with other protease inhibitors generally resulted in favourable pharmacokinetic interactions (usually increased area under the concentration-time curve for both drugs). CONCLUSION: Nelfinavir, in combination with reverse transcriptase inhibitors and/or other protease inhibitors, is effective in limiting HIV replication and increasing CD4+ cell counts in HIV-infected adults and children. The convenience of its dosage administration, the low incidence of adverse events, and the potential for salvage therapies indicate that nelfinavir (as part of combined antiretroviral therapy regimens) should be considered as a first-line option in protease inhibitor-naive patients and in those unable to tolerate other protease inhibitors.

Adult↗

PubMed1999

Failure to detect nelfinavir in the cerebrospinal fluid of HIV-1--infected patients with and without AIDS dementia complex.

OBJECTIVE: To assess the penetration of the HIV-1 protease inhibitor, nelfinavir, into cerebrospinal fluid (CSF). DESIGN: Nelfinavir, a commonly used HIV-1 protease inhibitor (PI), is highly effective for reducing plasma viral load. It is deployed clinically in combination with other antiretroviral agents, including nucleoside and nonnucleoside reverse transcriptase inhibitors (NRTIs and NNRTIs). Despite its potency based on plasma HIV-1 RNA results, its effectiveness in reducing HIV-1 RNA levels (i.e., viral load) in the central nervous system (CNS) is less certain. We sampled the CSF as a surrogate for brain because this fluid also is separated from the blood by a barrier to free diffusion, the blood-CSF barrier (BCB), which shares properties with the blood-brain barrier (BBB). These studies of nelfinavir CSF pharmacokinetics exploited the multiple CSF samples derived from individual study subjects who were enrolled in studies the primary objective of which was to compare viral kinetics in CSF and blood in response to antiviral therapy. METHODS: Six study subjects, four with and two without AIDS dementia complex, underwent multiple lumbar punctures (LP). Intervals of CSF sampling after drug dosing were varied (from 0.48 hours to 10.3 hours after nelfinavir administration) to quantitate nelfinavir concentrations throughout the steady-state dosing interval. In four study subjects, CSF sampling was accompanied by assessment of nelfinavir levels in plasma before and after LP, whereas in the other two subjects, a single plasma sample was obtained before or after the LP. In total, 25 CSF samples were analyzed. Nelfinavir concentrations in CSF and plasma were determined using an high-performance liquid chromatography (HPLC) method with a limit of quantitation of 25 and 50 ng/ml, respectively. RESULTS: Plasma concentrations before and after LP averaged 2420+/-1365 ng/ml and 2528+/-1132 ng/ml, respectively. Nelfinavir was not detected in any of the CSF samples and levels >25 ng/ml were not present in the CSF. Thus, standard therapy with nelfinavir does not result in CSF drug concentrations at or exceeding the IC95 level for most HIV-1 isolates. However, study subjects with high CSF viral loads experienced a marked reduction in the context of the combination-drug regimen including nelfinavir with two subjects showing a comparable CSF response with that in plasma. CONCLUSIONS: Nelfinavir does not appreciably penetrate into the CSF. The clinical importance of this observation is not certain, in that in four study subjects who initiated nelfinavir in combination with other antiretroviral therapy, a comparable degree of viral suppression was obtained in both the CSF and the blood when sampled 4 weeks or later after initiating therapy.

AIDS Dementia Complex↗

PubMed1999

Nelfinavir mesylate: a protease inhibitor.

OBJECTIVE: To review the clinical pharmacology, pharmacokinetics, efficacy, adverse effects, drug interactions, and dosage guidelines of nelfinavir mesylate. DATA SOURCE: A MEDLINE search restricted to English-language literature from January 1966 to February 1998 and an extensive review of journals was conducted to prepare this article. MeSH headings included protease inhibitors, nelfinavir mesylate, and AG1343. Abstracts presented at meetings and data submitted to the Food and Drug Administration (FDA) were also reviewed. DATA EXTRACTION: The data on efficacy, pharmacokinetics, adverse effects, and drug interactions were obtained from in vitro studies, as well as open-label and controlled trials. DATA SYNTHESIS: Nelfinavir inhibits HIV protease enzyme resulting in formation of immature and noninfectious virions. In combination with nucleoside reverse transcriptase inhibitors, nelfinavir is effective in reducing the viral load below the quantifiable limit (< 500 copies/mL) and increasing the mean CD4+ cell count. This antiviral effect is sustained at least over 21 months. The bioavailability of nelfinavir ranges from 20% to 80%, and it increases when nelfinavir is administered with food. Following multiple dosing of nelfinavir 750 mg three times daily, maximum concentration at steady-state was 3-4 micrograms/mL and minimum concentration was 1-3 micrograms/mL. The elimination half-life for nelfinavir ranges from three to five hours. Nelfinavir is primarily metabolized in the liver by the cytochrome P450 isoenzymes and excreted in the feces. Current dosing recommendations are 750 mg three times daily for adults and adolescents and 20-30 mg/kg/dose three times daily for children aged 2-13 years. Studies of twice-daily regimens in adults are being conducted and are promising. Use of nelfinavir as salvage therapy is also being studied. Some of the commonly reported adverse events of nelfinavir are diarrhea, nausea, vomiting, and abdominal pain. CONCLUSIONS: Despite the limited published data, the FDA has approved nelfinavir in combination therapy for the treatment of HIV infection. The choice of antiretroviral (ARV) regimens should be made based on the risk of disease progression as indicated by HIV RNA concentrations and CD4+ cell counts, patients' previous ARV experiences and responses, concomitant drug therapy, compliance history, underlying disease states, and adverse reaction history.

Adolescent↗

PubMed2001

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. 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.

Adolescent↗

PubMed2001

Randomized, double-blind comparison of two nelfinavir doses plus nucleosides in HIV-infected patients (Agouron study 511).

OBJECTIVE: To evaluate the safety and antiretroviral activity of nelfinavir mesylate at two doses as part of a combination regimen in HIV-infected, antiretroviral-naive patients. DESIGN: Phase III, multicenter, double-blind, placebo-controlled trial. PATIENTS AND METHODS: Two-hundred and ninety-seven patients were randomized to one of three treatment groups: nelfinavir 750 mg three times daily (tid), nelfinavir 500 mg tid, or matching placebo, each in combination with open-label zidovudine (ZDV) 200 mg tid and lamivudine (3TC) 150 mg twice daily (bid). Data were analyzed on an intent-to-treat basis. RESULTS: Sixty-seven percent of patients receiving nelfinavir 750 mg tid, and 50% receiving nelfinavir 500 mg tid in combination with ZDV/3TC achieved HIV RNA < 400 copies/ml compared to 7% receiving ZDV/3TC plus placebo (P < 0.001); 55% and 30% of patients in the nelfinavir-containing arms achieved HIV RNA < 50 copies/ml at week 24. This compared with 4% in the placebo-containing arm. For patients continuing nelfinavir treatment (750 mg or 500 mg tid as treated) for a further 6 months, the proportions achieving < 400 copies/ml at week 48 were 75% and 54% (P = 0.001) and < 50 copies/ml 61% and 37%, respectively (P = 0.004). The mean increases from baseline in CD4 cell counts were also durable in patients receiving the triple combination nelfinavir therapy. The range and incidence of adverse events was similar for the two nelfinavir-containing arms, with diarrhea being the most common adverse event. CONCLUSIONS: Nelfinavir plus ZDV/3TC was superior to ZDV/3TC/placebo. In addition, the 750 mg tid nelfinavir dose was better than the 500 mg tid dose. Virologic responses were sustained over 12 months.

Adult↗

PubMed1999

The safety profile and antiviral activity of the combination of stavudine, didanosine, and nelfinavir in patients with HIV infection.

We assessed the safety profile, tolerability, and antiviral effect of 12 weeks of triple combination therapy with stavudine (d4T), didanosine (ddI), and nelfinavir in patients who had not previously received therapy with d4T, ddI, or a protease inhibitor. We also assessed the effect of the buffered tablet formulation of ddI on the pharmacokinetics of nelfinavir. The study had a single-arm, open-label design and enrolled patients aged > or =18 years who had HIV infection and > or =10,000 plasma HIV RNA copies/mL. Patients received the full recommended doses of oral d4T, ddI, and nelfinavir. Efficacy was assessed in terms of change from baseline in plasma HIV RNA and CD4+ cell counts, as well as in terms of the proportion of patients achieving HIV RNA levels <400 copies/mL. The first 10 patients enrolled in the study were included in a substudy to determine the effects of the buffered tablet formulation of ddI on the pharmacokinetic profile of nelfinavir. A dose of ddI was given 1 hour before nelfinavir, after which the maximum plasma concentration (Cmax), time to Cmax (Tmax), and area under the concentration-time curve (AUC) of nelfinavir were determined. A total of 22 patients entered the trial, of whom 1 (5%) had AIDS, 12 (55%) had symptomatic HIV infection, and 9 (41%) were asymptomatic. The median baseline CD4+ cell count was 315 cells/microL (range, 70-709 cells/microL), and the median plasma viral load was 4.8 log10 copies/mL (range, 4.0-5.6 log10 copies/mL). ddI had no clinically significant effects on the plasma pharmacokinetics of nelfinavir. At the end of 12 weeks of treatment, the mean (+/- SE) decrease in plasma viral load was 1.36+/-0.24 log10 copies/mL, and 8 of 16 patients (50%) achieved plasma HIV RNA levels <400 copies/mL; the mean (+/- SE) increase in CD4+ cell count was 111.4+/-31.7 cells/microL. Patients who were judged to be compliant with antiretroviral therapy (ie, who missed <7 days of all 3 study drugs during 12 weeks of treatment) experienced mean decreases in viral load exceeding 2.0 log10 copies/mL, and 6 of 7 patients achieved HIV RNA levels <400 copies/mL after 12 weeks of therapy. Although 95% of patients reported an adverse event of grade 1 or higher, only 1 patient experienced a grade 3 or 4 adverse event (maculopapular rash) related to nelfinavir. As reflected in the Cmax, Tmax, and AUC, administration of ddI 1 hour before nelfinavir did not influence the pharmacokinetic profile of the protease inhibitor. Triple drug therapy with d4T, ddI, and nelfinavir was well tolerated and associated with few clinically significant toxicities. This treatment resulted in substantial reductions in viral load and improvements in CD4+ cell count over 12 weeks.

Administration, Oral↗

PubMed2001

Circulating metabolites of the human immunodeficiency virus protease inhibitor nelfinavir in humans: structural identification, levels in plasma, and antiviral activities.

Nelfinavir mesylate (Viracept, formally AG1343) is a potent and orally bioavailable human immunodeficiency virus (HIV) type 1 (HIV-1) protease inhibitor (K(i) = 2 nM) and is being widely prescribed in combination with HIV reverse transcriptase inhibitors for the treatment of HIV infection. The current studies evaluated the presence of metabolites circulating in plasma following the oral administration of nelfinavir to healthy volunteers and HIV-infected patients, as well as the levels in plasma and antiviral activities of these metabolites. The results showed that the parent drug was the major circulating chemical species, followed in decreasing abundance by its hydroxy-t-butylamide metabolite (M8) and 3'-methoxy-4'-hydroxynelfinavir (M1). Antiviral assays with HIV-1 strain RF-infected CEM-SS cells showed that the 50% effective concentrations (EC50) of nelfinavir, M8, and M1 were 30, 34, and 151 nM, respectively, and that the corresponding EC50 against another HIV-1 strain, IIIB, in MT-2 cells were 60, 86, and 653 nM. Therefore, apparently similar in vitro antiviral activities were demonstrated for nelfinavir and M8, whereas an approximately 5- to 11-fold-lower level of antiviral activity was observed for M1. The active metabolite, M8, showed a degree of binding to human plasma proteins similar to that of nelfinavir (ca. 98%). Concentrations in plasma of nelfinavir and its metabolites in 10 HIV-positive patients receiving nelfinavir therapy (750 mg three times per day) were determined by a liquid chromatography tandem mass spectrometry assay. At steady state (day 28), the mean plasma nelfinavir concentrations ranged from 1.73 to 4.96 microM and the M8 concentrations ranged from 0.55 to 1.96 microM, whereas the M1 concentrations were low and ranged from 0.09 to 0.19 microM. In conclusion, the findings from the current studies suggest that, in humans, nelfinavir forms an active metabolite circulating at appreciable levels in plasma. The active metabolite M8 may account for some of the antiviral activity associated with nelfinavir in the treatment of HIV disease.

Blood Proteins↗

PubMed2001

Nelfinavir, efavirenz, or both after the failure of nucleoside treatment of HIV infection.

BACKGROUND: The optimal antiretroviral treatment for patients who have human immunodeficiency virus (HIV) viremia despite treatment with nucleoside reverse-transcriptase inhibitors (nucleoside analogues) remains uncertain. We studied treatment with regimens that combined two nucleoside analogues, at least one of which was new, with the protease inhibitor nelfinavir, the nonnucleoside reverse-transcriptase inhibitor efavirenz, or both. METHODS: The study included 195 patients who had been treated with nucleoside analogues only, and had a plasma HIV type 1 (HIV-1) RNA level of at least 500 copies per milliliter. Patients were randomly assigned to receive, in addition to two nucleoside analogues, nelfinavir, efavirenz, or nelfinavir plus efavirenz. The primary end point was a plasma HIV-1 RNA level of less than 500 copies per milliliter at week 16. A secondary end point was the composite of the HIV-1 RNA levels measured at weeks 40 and 48. RESULTS: At week 16 and at weeks 40 and 48, the proportions of patients in whom a plasma HIV-1 RNA level of less than 500 copies per milliliter was achieved were, respectively, 81 percent and 74 percent in the nelfinavir-plus-efavirenz group, 69 percent and 60 percent in the efavirenz group, and 64 percent and 35 percent in the nelfinavir group. Quadruple therapy resulted in a higher rate of viral suppression in both the short term (P=0.03) and the long term (P=0.001) than did triple therapy with nelfinavir. Triple therapy with efavirenz conferred a higher rate of long-term suppression than triple therapy with nelfinavir (P=0.004). Quadruple therapy also achieved a higher rate of virologic suppression than triple therapy with efavirenz (P=0.008). CONCLUSIONS: In HIV-infected patients previously treated with nucleoside analogues, treatment with nelfinavir plus efavirenz and at least one new nucleoside analogue achieves a higher rate of viral suppression than do regimens with nucleoside analogues and nelfinavir or efavirenz alone.

Adult↗

PubMed2001

Pharmacokinetics of nelfinavir in human immunodeficiency virus-infected infants.

BACKGROUND: Nelfinavir dosed at approximately 20 to 30 mg/kg three times a day (TID) in older children provides exposure similar to 750 mg TID in adults. However, the pharmacokinetics (PK) of nelfinavir in infants who are < 2 years of age is not well-described. The objective of this study was to determine the pharmacokinetics of nelfinavir in infants < 2 years of age. METHODS: Nelfinavir concentrations were evaluated in 22 HIV-infected infants between 15 days and 2 years of age receiving nelfinavir as part of Pediatric ACTG Study 356. Nelfinavir therapy was initiated at approximately 25 mg/kg TID (n = 18) or approximately 55 mg/kg twice a day (n = 4) and given in combination with nevirapine, stavudine and lamivudine. PK samples were obtained predose and 1.5 and 4 h postdose at approximately 6-month intervals. Eight infants (all < or = 3 months of age) also had intensive PK samples collected at Week 1. RESULTS: The median apparent clearance in the infants with intensive pharmacokinetic sampling was 2.7 liters/h/kg (range, 1.8 to > or = 10) and was similar between twice a day and TID dosing cohorts. Overall nelfinavir concentrations at all collection times were lower in these infants than previously reported in older pediatric patients. CONCLUSIONS: Nelfinavir concentrations in infants are highly variable and lower than those seen in adult or older pediatric populations receiving labeled dosing. Therefore it is necessary to further evaluate nelfinavir safety, effectiveness and pharmacokinetics at higher doses than used among other pediatric populations.

Anti-HIV Agents↗

PubMed2000

A study of the pharmacokinetics of azithromycin and nelfinavir when coadministered in healthy volunteers.

A two-way, open-label, crossover study in 12 subjects was undertaken to study the potential for azithromycin to alter the pharmacokinetics of nelfinavir and/or its active metabolite, M8. A secondary objective was to characterize any potential interaction that nelfinavir may have with azithromycin. During one dosing arm, subjects received a single 1200 mg oral dose of azithromycin. During the other, subjects received 11 days of nelfinavir 750 mg q8h with a single 1200 mg oral dose of azithromycin given concurrently with the Day 9 morning nelfinavir dose. Serum samples were collected after each azithromycin dose for 168 hours and after the Day 8 and 9 morning nelfinavir doses for 8 hours to characterize azithromycin, nelfinavir, and M8 pharmacokinetic parameters during both control and test periods. Both dosing regimens were well tolerated, with only mild to moderate GI side effects being the most frequently reported. Azithromycin was found to cause a statistically, though not clinically, significant decrease in nelfinavir and M8 exposures. In contrast, nelfinavir caused azithromycin Cmax and exposure (AUC) values to increase by > 100%. Inhibition of p-glycoprotein by nelfinavir may be responsible for this significant interaction. This increase in azithromycin exposure has the potential to increase clinical antibacterial efficacy without significantly increasing gastrointestinal side effects, though the impact on other systemic sites needs to be studied.

Adult↗

PubMed2002

Determination of nelfinavir free drug concentrations in plasma by equilibrium dialysis and liquid chromatography/tandem mass spectrometry: important factors for method optimization.

A method was developed and validated for measuring the free fraction of nelfinavir in plasma employing equilibrium dialysis for the separation of free (unbound) drug and liquid chromatography/tandem mass spectrometry for quantitation. Nelfinavir, widely used to treat HIV infection, is a highly bound HIV protease inhibitor with the fraction bound in plasma being greater than 98%. Thus variations in the free fraction may be clinically important when interpreting total drug concentrations. Optimization of the method was carried out considering the influence of sample matrix and physicochemical and absorptive properties of nelfinavir. Nelfinavir free fraction averaged 0.41 +/- 0.094, 0.43 +/- 0.087 and 0.41 +/- 0.063% at nelfinavir plasma concentrations of 1000, 2000 and 3000 ng/ml, respectively. Free nelfinavir concentrations were underestimated with this assay by approximately 25% because of unavoidable losses to adsorption. However, the adsorptive loss was reproducible and consistent across the concentration range of the assay. Within-day and between-day precisions ranged from 6.0 to 9.4% and 15.2 to 27.3%, respectively. The lower limit of quantitation of the unbound concentration of nelfinavir was 1.0 ng/ml, permitting analysis of samples with total concentrations of nelfinavir in plasma that are > or = 400 ng/ml. This developed method proves reproducible and sensitive and its application to patient plasma samples is also reported.

Adsorption↗

PubMed2000

A randomized, comparative study of lamivudine plus stavudine, with indinavir or nelfinavir, in treatment-experienced HIV-infected patients.

OBJECTIVE: To compare adherence and clinical outcome with two modalities of highly active antiretroviral therapy (HAART), in HIV-infected patients. DESIGN: Randomized, open-label, prospective study. SETTING: Tertiary care centre in Spain. PATIENTS: A total of 112 non-naive HIV-infected patients, recruited from March 1998 through August 1998, were studied. INTERVENTIONS: Triple drug therapy with stavudine and lamivudine, plus indinavir or nelfinavir. MAIN OUTCOME MEASURES: Adherence, side-effects, and immunological, virological, and clinical efficacy of treatment were assessed at 3-month intervals. RESULTS: After a median follow-up of 9 months, 32% of patients in the indinavir group versus 50% of those in the nelfinavir group showed adequate adherence in all clinical appointments (P= 0.0559). Adherence was superior in the nelfinavir group in every visit. After 6 months of treatment 48% of subjects in the indinavir group and 70% of those in the nelfinavir group exhibited adequate adherence (P= 0.0311). After 9 months 35% of patients in the indinavir group and 59% of those in the nelfinavir group showed adequate adherence (P= 0.0291). Side-effects provoked discontinuation of treatment in 34% of patients in the indinavir group and 12% of patients in the nelfinavir group (P= 0.0073). Immunological and virological efficacy were similar in both groups. CONCLUSIONS: Adherence to a HAART regimen with stavudine plus lamivudine plus nelfinavir was superior to a regimen with stavudine plus lamivudine plus indinavir. Side-effects provoked more discontinuation of treatment in the indinavir group than in the nelfinavir group.

Adult↗