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PubMed2004

Intracellular and plasma pharmacokinetics of nelfinavir and M8 in HIV-infected patients: relationship with P-glycoprotein expression.

One of the targets of antiretroviral therapy is within cells infected with HIV. In order to improve therapeutic efficacy, it is therefore important that the intracellular pharmacokinetics of drugs, such as nelfinavir mesylate and its active metabolite M8, are studied in addition to plasma pharmacokinetics. Previously, the intracellular accumulation of protease inhibitors has been reported in vivo, displaying the following hierarchy: nelfinavir > saquinavir > ritonavir > indinavir. Multidrug resistance transporters, such as P-glycoprotein (P-gp), may result in a lower intracellular concentration of drug via an efflux mechanism, thus contributing to sanctuary site formation. The objective of this study was to determine concentrations of nelfinavir and M8 in plasma and peripheral blood mononuclear cells from HIV-infected patients, and to ascertain the relationship between intracellular accumulation and lymphocyte P-gp expression. Venous blood samples from 12 HIV-infected patients (viral load <50 copies/ml) receiving nelfinavir (1250 mg twice daily) and dual nucleoside reverse transcriptase inhibitor therapy were collected over a full dosage interval (0, 2, 4, 8 and 12 h). Plasma and intracellular (cell-associated) drug concentrations were measured by HPLC-MS/MS. Drug exposure in plasma and cells was expressed as the area under the concentration-time curve (AUC(0-12h)), derived from non-compartmental modelling. The ratio of intracellular AUC(0-12h)/total plasma AUC(0-12h) was calculated to determine cellular drug accumulation. P-gp expression on lymphocytes was determined by flow cytometry. The median (range) AUC(0-12h) of nelfinavir in plasma and cellular compartments was 21.8 mg x h x l(-1) (5.64-50.8) and 104.6 mg x h x l(-1) (23.1-265.7), respectively. Corresponding values for M8 in plasma and cells were 6.60 mg x h x l(-1) (2.16-17.3) and 19.6 mg x h x l(-1) (5.14-60.8). A ratio of plasma M8/plasma nelfinavir (AUC(0-12h)) and intracellular M8/intracellular nelfinavir (AUC(0-12h)) gave median values of 0.32 and 0.17, respectively. The cellular accumulations [median; (range)] of nelfinavir and M8 were 5.30 (2.28-16.2) and 2.32 (1.01-10.7), respectively. A significant correlation between plasma and intracellular nelfinavir minimum concentration (Cmin) (r2=0.34; P=0.049), but not between plasma and intracellular M8 Cmin was observed. C(0h) concentrations were higher than C(12h) for both nelfinavir and M8. No relationship was observed between nelfinavir or M8 accumulation and lymphocyte cell surface expression of P-gp. This study illustrates that intracellular concentrations were higher than plasma concentrations for both nelfinavir and M8, suggesting lymphocyte accumulation. The mechanism of differential intracellular accumulation of nelfinavir and M8 remains to be elucidated. It may be that affinities for influx transporters or fundamental drug characteristics play a major role in the greater accumulation of nelfinavir than M8.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
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↗
PubMed2004

Intracellular accumulation of nelfinavir and its relationship to P-glycoprotein expression and function in HIV-infected patients.

OBJECTIVE: To compare plasma and intracellular nelfinavir pharmacokinetics, and determine their relationship to P-glycoprotein (P-gp) expression and function in lymphocytes of HIV-infected patients. METHODS: A pharmacokinetic study of 12 patients receiving nelfinavir plus dual nucleoside analogue therapy. Blood samples were taken at intervals to 12 h. Peripheral blood mononuclear cells (PBMCs) were isolated by density gradient centrifugation, and nelfinavir extracted from cells in the presence of 60% methanol and evaporated to dryness. Both plasma and intracellular nelfinavir samples were assayed by high performance liquid chromatography linked to mass spectrometry. P-gp expression and function were measured by flow cytometric analysis. Data were analysed by non-compartmental analysis using WinNonLin pharmacokinetic software. RESULTS: The mean intracellular nelfinavir AUC(0-12) (mean +/-SE) was about ninefold higher than that of plasma (264,200 +/- 63,420 vs 29,250 +/- 6629 ng/ml/h; P<0.001, and intracellular Cmin and C0 values for nelfinavir were five- to sixfold higher than that of plasma (Cmin: 5712 +/- 2156 vs 1062 +/- 357 ng/ml; C0: 15,860 +/- 3662 vs 2553 +/- 539 ng/ml; P<0.0005). The intracellular nelfinavir Cmax was 15-fold higher than plasma (59,420 +/- 13,940 vs 3986 +/- 822 ng/ml; P<0.0005). There were no differences between plasma and intracellular values for Tmax, elimination half-life or mean residence time. In patients chronically treated with nelfinavir mean P-gp expression was 8.85 +/- 1.3 MFI, there was no correlation between P-gp expression and either intracellular AUC(0-12) (r=-0.35; P=0.29) or intracellular C0 values. There was a correlation between intracellular nelfinavir concentrations and P-gp function at baseline (r=0.59; P<0.05). Basal P-gp-mediated rhodamine efflux was 61.0 +/- 4.2%. In the presence of ritonavir, cellular rhodamine efflux decreased to 25.6 +/- 5.5% (P=0.001), representing an additional reversible efflux potential of 56.1 +/- 9.78%. There was a strong correlation between plasma and intracellular AUC(0-12) for nelfinavir (r=0.75; P=0.011). CONCLUSIONS: Nelfinavir undergoes significant intracellular accumulation within the PBMCs of HIV-infected patients, which may be in part related to its moderate ability to inhibit P-gp-mediated drug efflux. The addition of ritonavir further reduced P-gp function. Intracellular accumulation of nelfinavir correlated with P-gp function but not P-gp expression, suggesting pump activity is substrate concentration-dependant. There was a significant correlation between plasma and intracellular nelfinavir concentrations, suggesting one is a good surrogate marker of the other.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2003

Pharmacokinetics, food intake requirements and tolerability of once-daily combinations of nelfinavir and low-dose ritonavir in healthy volunteers.

AIMS: This study was performed to evaluate the steady-state pharmacokinetics, food intake requirements and short-term tolerability of once-daily combinations of nelfinavir and low-dose ritonavir. METHODS: Twenty-seven healthy volunteers were randomized over three groups to receive a once-daily regimen of nelfinavir/ritonavir 2,000/200 mg (group 1), 2,000/400 mg (group 2) or 2,500/200 mg (group 3) with food for 14 days. Pharmacokinetic parameters for nelfinavir and its active metabolite M8 were assessed on study days 15 and 16, after administration of the regimens with a full (610 kcal) or light (271 kcal) breakfast, respectively. RESULTS: Pharmacokinetic data were evaluable for eight volunteers in group 1, eight in group 2 and four in group 3. Administration of nelfinavir/ritonavir with a full breakfast resulted in geometric mean (GM) nelfinavir AUC(24h) values of 76.8, 51.3, and 61.9 h*mg/l in group 1, 2 and 3, respectively. GM 24-h Cmin concentrations of nelfinavir were 0.76 mg l(-1), 0.43 mg l(-1) and 0.47 mg l(-1), respectively. Co-administration of ritonavir increased M8 concentrations more than nelfinavir concentrations, resulting in GM AUC(24h) and Cmin values for nelfinavir plus M8 that were higher than or comparable to reference values for the approved regimen of nelfinavir (1,250 mg BID without ritonavir). In the 2,000/200 mg group, seven out of eight subjects had a Cmin value of nelfinavir plus M8 above a threshold of 1.0 mg l-1. Administration of the combinations with a light breakfast resulted in significant decreases in the AUC(24h) and Cmin of nelfinavir and nelfinavir plus M8, compared with intake with a full breakfast. For the Cmin of nelfinavir plus M8, the GM ratio (light/full breakfast) was 0.76 (90% confidence interval 0.67-0.86, participants from all groups combined). Short-term tolerability was satisfactory, apart from a higher than expected incidence of mild rash (12%). CONCLUSIONS: Administration of nelfinavir in a once-daily regimen appears feasible. A nelfinavir/ritonavir 2,000/200 mg combination appears appropriate for further evaluation. Once-daily nelfinavir/ritonavir should be taken with a meal containing at least 600 kcal.

Adolescent↗
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↗
PubMed2006

Pregnancy-related effects on nelfinavir-M8 pharmacokinetics: a population study with 133 women.

A relationship between nelfinavir antiretroviral efficacy and plasma concentrations has been previously established. As physiological changes associated with pregnancy have a large impact on the pharmacokinetics of many drugs, a nelfinavir population study with women was developed, and the large intersubject variability was analyzed in order to optimize individual treatment schedules for this drug during pregnancy. A population pharmacokinetic model was developed in order to describe the concentration time course of nelfinavir and its metabolite M8 in pregnant and nonpregnant women. Individual characteristics, such as age, body weight, and weeks of gestation or delivery, which may influence nelfinavir-M8 pharmacokinetics were investigated. Data from therapeutic drug monitoring in 133 women treated with nelfinavir were retrospectively analyzed with NONMEM. Nelfinavir pharmacokinetics was described by a one-compartment model with linear absorption and elimination and M8 produced from the nelfinavir central compartment. Mean pharmacokinetic estimates and the corresponding intersubject percent variabilities for a nonpregnant woman were the following: absorption rate, 0.83 h(-1); absorption lag time, 0.85 h; apparent nelfinavir elimination clearance (CL(10)/F), 35.5 liters/h (50%); apparent volume of distribution (V/F), 596 liters (118%); apparent formation clearance to M8 (CL(1M)/F), 0.65 liters/h (69%); and M8 elimination rate constant (k(M0)), 3.3 h(-1) (59%). During pregnancy, we observed significant increases in nelfinavir (44.4 liters/h) and M8 (5 h(-1)) elimination but unchanged nelfinavir transformation clearance to M8, suggesting an induction of CYP3A4 but no effect on CYP2C19. Apparent nelfinavir clearance and volume showed a twofold increase on the day of delivery, suggesting a decrease in bioavailability on this day. The M8 elimination rate was increased by concomitant administration of nonnucleoside reverse transcriptase inhibitors. A trough nelfinavir plasma concentration above 1 mg/liter was previously shown to improve the antiretroviral response. The Bayesian individual pharmacokinetic estimates suggested that the dosage should not be changed in pregnant women but may be doubled on the day of delivery.

Adult↗
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↗
PubMed2004

Differences in rates of diarrhea in patients with human immunodeficiency virus receiving lopinavir-ritonavir or nelfinavir.

STUDY OBJECTIVE: To determine and compare rates of diarrhea in patients receiving an antiretroviral regimen containing lopinavir-ritonavir versus nelfinavir and in patients who received these drugs sequentially. DESIGN: Retrospective cohort analysis. SETTING: Hospital-based human immunodeficiency virus (HIV) clinic. PATIENTS: Four hundred one participants in the HIV Atlanta VA Cohort Study who were prescribed lopinavir-ritonavir or nelfinavir from 1996-2002. MEASUREMENTS AND MAIN RESULTS: Chart review identified episodes of diarrhea that potentially were associated with an antiretroviral agent. Data collected included antidiarrheal agents dispensed, baseline viral load and CD4+ cell counts, demographic variables, and previous therapy Diarrhea associated with an antiretroviral regimen occurred in 175 (49%) of 354 patients receiving nelfinavir and 17 (17%) of 99 patients receiving lopinavir-ritonavir (p < 0.001). Treatment for the diarrhea occurred in 118 (33%) of 354 patients receiving nelfinavir and 9 (9%) of 99 receiving lopinavir-ritonavir (p < 0.001). Patients in the lopinavir-ritonavir group were more likely to have received highly active antiretroviral therapy and azithromycin than patients receiving nelfinavir, and they had lower baseline CD4+ cell counts (p < or = 0.01 for each comparison). The average number of months/person-year of diarrhea treatment was 2.0 for the nelfinavir group and 0.13 for the lopinavir-ritonavir group. Of the 10 antiretroviral-naive patients who received lopinavir-ritonavir, none needed treatment for diarrhea, whereas 78 (36%) of 217 antiretroviral-naive patients who received nelfinavir required treatment for diarrhea. Of the 52 patients who had been taking nelfinavir and were switched to lopinavir-ritonavir, they were more likely to start antidiarrheal treatment while taking nelfinavir (14 [27%]) than while receiving lopinavir-ritonavir (3 [6%]) (p = 0.004). CONCLUSIONS: Patients receiving lopinavir-ritonavir were significantly less likely to have diarrhea or to require treatment for diarrhea than patients receiving nelfinavir. The same results occurred when the drugs were given to the same patients sequentially (nelfinavir followed by lopinavir-ritonavir). The diarrhea associated with lopinavir-ritonavir was less frequent, less severe, and shorter in duration than diarrhea associated with nelfinavir.

Adult↗
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↗
PubMed2006

Nelfinavir down-regulates hypoxia-inducible factor 1alpha and VEGF expression and increases tumor oxygenation: implications for radiotherapy.

The phosphatidylinositol 3-kinase (PI3K)/Akt pathway can increase vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1alpha (HIF-1alpha) expression. We examined the effect of nelfinavir, an HIV protease inhibitor that inhibits Akt signaling, on VEGF and HIF-1alpha expression and on angiogenesis, tumor oxygenation, and radiosensitization. Nelfinavir decreases VEGF expression under normoxia via the transcription factor Sp1, which regulates the proximal core VEGF promoter. Nelfinavir decreased Sp1 phosphorylation and decreased Sp1 binding to a probe corresponding to the proximal VEGF promoter in a gel shift assay. Nelfinavir also decreased the hypoxic induction of HIF-1alpha, which also regulates the VEGF promoter, most likely by decreasing its translation. The effect of nelfinavir on VEGF expression had the functional consequence of decreasing angiogenesis in an in vivo Matrigel plug assay. To determine the effect this might have on tumor radiosensitization, we did tumor regrowth assays with xenografts in nude mice. The combination of nelfinavir and radiation increased time to regrowth compared with radiation alone whereas nelfinavir alone had little effect on tumor regrowth. This radiosensitizing effect was greater than suggested by in vitro clonogenic survival assays. One possible explanation for the discordance is that nelfinavir has an effect on tumor oxygenation. Therefore, we examined this with the hypoxia marker EF5 and found that nelfinavir leads to increased oxygenation within tumor xenografts. Our results suggest that nelfinavir decreases HIF-1alpha/VEGF expression and tumor hypoxia, which could play a role in its in vivo radiosensitizing effect. These data support the use of nelfinavir in combination with radiation in future clinical trials.

Animals↗
PubMed2005

Assessment of the bioequivalence of two nelfinavir tablet formulations under fed and fasted conditions in healthy subjects.

OBJECTIVES: This study was designed to assess the bioequivalence between the commercial 250 mg nelfinavir tablet and the new 625 mg nelfinavir tablet (Roche) which was developed to reduce the daily pill burden for patients from 10 to 4 tablets in a nelfinavir 1250 mg twice daily regimen. METHODS: A total of 52 healthy male subjects were enrolled in this randomized four-period crossover study to receive single oral doses of 1250 mg nelfinavir administered as five commercial 250 mg tablets (reference formulation) and as two new 625 mg tablets (test formulation). Each of the two formulations were taken after an overnight fast and immediately after intake of a standard breakfast (820 kcal) on separate occasions. Blood samples were collected pre-dose and at appropriate intervals after drug administration. Plasma concentrations of nelfinavir and its main metabolite M8 were assayed by a validated LC-MS/ MS assay and the pharmacokinetics of nelfinavir and M8 were derived using standard non-compartmental analysis. RESULTS: The primary parameters for bioequivalence testing were the logarithmically transformed AUC(0-inf) and C(max) of nelfinavir taken from 50 subjects who completed all four treatments. Bioequivalence was accepted if the 90% confidence interval (CI) was contained entirely in the equivalence region (80%, 125%). In the fed state, this criterion was met for AUC (effect ratio = 95%; CI = 87%, 103%) and Cmax (effect ratio = 101%; CI = 94%, 109%) and bioequivalence of the two treatments could be concluded. In the fasted state, AUC clearly failed to meet the bioequivalence criteria (effect ratio = 73%; CI = 59%, 90%) and Cmax was borderline outside the lower acceptance region (effect ratio = 97%; CI = 79.6%, 118%). Therefore, bioequivalence could not be concluded under fasted condition. Food increased the systemic exposure to nelfinavir (as reflected by comparison of the logarithmically transformed AUC(0-inf) values under fed and fasted conditions) by six- and eight-fold after dosing with the 250 mg and the 625 mg tablet, respectively. CONCLUSIONS: Bioequivalence of the new 625 mg nelfinavir tablet relative to the commercial 250 mg tablet, at a dose of 1250 mg, was confirmed in the fed state but not under fasted conditions. As nelfinavir is recommended to be taken with food, the new tablet is well-suited to decrease the daily pill burden for patients on a nelfinavir twice daily regimen and to enhance patient's compliance and adherence.

Administration, Oral↗
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↗
PubMed2006

Pharmacokinetic interaction of nelfinavir and methadone in intravenous drug users.

UNLABELLED: The effect of nelfinavir 1250 mg twice daily (b.i.d.) on the pharmacokinetics of methadone was determined in 14 HIV-negative methadone users. DESIGN: The methadone dose (20-140 mg/day) was stabilized and fixed for at least 1 month before nelfinavir (1250 mg b.i.d. for 8 days) was added to the regimen. The concentrations of methadone enantiomers were measured before and during nelfinavir treatment, and the concentrations of nelfinavir and its active metabolite, AG1402, were measured during nelfinavir treatment. Adverse events and withdrawal/intoxication symptoms were monitored throughout the study. RESULTS: Nelfinavir reduced the area under the concentration-time curve of R-methadone, and S-methadone by 43% and 51%, respectively. Nelfinavir and AG1402 concentrations were within the normal range of historical data, and no subject experienced withdrawal symptoms during the study or required dose adjustment during or after the study. CONCLUSIONS: Although nelfinavir reduced the plasma concentrations of both R- and S-methadone, it seems to have no impact on the maintenance dose of methadone. A routine reduction of methadone dose is not recommended when coadministered with nelfinavir.

Administration, Oral↗
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↗