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Clinical Science

Pharmacokinetics and safety of amprenavir and ritonavir following multiple-dose, co-administration to healthy volunteers

Sadler, Brian M.a; Piliero, Peter J.b,c; Preston, Sandra L.c; Lloyd, Peggy P.a; Lou, Yua; Stein, Daniel S.a,d

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Author Information

From the aDivision of Clinical Pharmacology, GlaxoSmithKline, Research Triangle Park, North Carolina, USA, the bDivision of HIV Medicine and the cDivision of Clinical Pharmacology, Albany Medical College, Albany, New York, USA and the dUniversity of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.

Correspondence to Dr Daniel Stein, Division of Clinical Pharmacology, GlaxoSmithKline, 5 Moore Dr, 17, 2235, Research Triangle Park, North Carolina, 27709 USA. Tel: +1 919 483 1449; fax: +1 919 483 6380; e-mail:

Received: 1 November 2000;

revised: 26 February 2001; accepted: 8 March 2001.

Sponsorship: Supported by a grant from GlaxoSmithKline.

Note: This work was presented in part at the Seventh Conference on Retroviruses and Opportunistic Infections, San Francisco, California, USA, January 30–February 2, 2000 (Abstract 77) and at the First International Workshop on Clinical Pharmacology of HIV Therapy, Noordwijk, The Netherlands, March 2000 (Abstract 2.10).

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Objective: To evaluate the safety and pharmacokinetic interaction between amprenavir (APV) and ritonavir (RTV).

Methods: Three open-label, randomized, two-sequence, multiple-dose studies having the same design (7 days of APV or RTV alone followed by 7 days of both drugs together) used 450 or 900 mg APV with 100 or 300 mg RTV every 12 h with pharmacokinetic assessments on days 7 and 14. Safety was monitored as clinical adverse events (AEs) and laboratory abnormalities.

Results: Relative to APV alone, RTV co-administration resulted in a 3.3- to 4-fold and 10.84 to 14.25-fold increase in the geometric least-square (GLS) mean area under the plasma concentration–time curve (AUCτ,ss) and minimum concentration (Cmin,ss), respectively. APV 900 mg with RTV 100 mg resulted in a 2.09-fold and 6.85-fold increase in the GLS mean AUCτ,ss and Cmin,ss, respectively. On day 14, the geometric mean (95% confidence interval) for 450 mg APV AUCτ,ss (μg • h/mL) was 23.49 (19.32–28.57) with 300 mg RTV and 35.42 (30.46–44.42) with 100 μg RTV, and for the 900 mg APV with 100 mg RTV 47.11 (39.47–61.24). The 450 mg APV Cmin,ss (μg/ml) were 1.32 (1.05–1.67) and 2.01 (1.70–2.61), and 2.47 (2.08–3.32) for 900 mg APV. The most common AEs were mild and included diarrhea, nausea/vomiting, oral parasthesias, and rash. The triglyceride and cholesterol increased significantly from RTV exposure.

Conclusion: Adding RTV to APV resulted in clinically and statistically significant increases in APV AUC and Cmin with variable effects on maximum concentration. The two RTV doses had similar effects on APV but AEs were more frequent with 300 mg RTV.

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Combination regimens containing a protease inhibitor (PI) and two nucleoside reverse transcriptase inhibitors can suppress HIV type 1 (HIV-1) replication to levels below the detection limits of assays, increase CD4+ cell counts, and reduce progression to AIDS [1–5]. Despite these favorable attributes, combination therapies often demand complex treatment regimens involving frequent dosing, food or fluid restrictions, and are associated with numerous adverse events [6,7]. The inconvenience of some of these regimens has made it difficult for patients to adhere to treatment, leading to reductions in virological response [8] and the potential for development of drug-resistant variants of HIV. Thus, there is a need for simpler, safer, and more convenient PI-containing regimens that can facilitate adherence.

Amprenavir (APV; Agenerase 141W94; GlaxoSmithKline, Research Triangle Park, North Carolina, USA) is a recently introduced HIV PI. In in vitro studies, the mean 50% inhibitory concentration (IC50) of APV against 334 HIV clinical isolates from patients naive to protease inhibitors was shown to be 0.0146 μg/ml [9]. In a similar manner to other HIV PIs, APV binds to plasma proteins (≈ 90%), predominantly to α1-acid glycoprotein (AAG), and to a lesser extent, to albumin. Because AAG is an acute-phase protein whose levels change during certain disease states [10,11] these changes in AAG affect the pharmacokinetic profile of APV [12].

Amprenavir, as with the other approved HIV PIs, is metabolized primarily by the hepatic cytochrome P450 enzyme system, specifically CYP3A4 [13,14]. All HIV PIs are inhibitors of CYP3A4, but the HIV PI RTV is the most potent inhibitor of CYP3A4 [14]. Previous studies have indicated significant increases in drug exposure from co-administration of ritonavir (RTV) with indinavir, saquinavir, and nelfinavir [15–21]. In a recent study, co-administration of RTV with APV resulted in significant increases in APV exposures, thus confirming that a significant drug–drug interaction between RTV and APV exists [22]. To address the magnitude of the interaction between APV and RTV and to assess short term safety and tolerance, a series of three randomized, two-sequence, two-period, multiple-dose studies were conducted.

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Healthy male and female individuals were eligible to participate in each study if they met the following criteria: 18–55 years of age; weighed 55–95 kg; had a body mass index of 20–28 kg/m2; and were seronegative for HIV (confirmed using standard methodologies). All patients provided written informed consent to participate in the trials. Participants were ineligible if they had conditions that would interfere with drug absorption, a history of adverse reactions to protease inhibitors, alcohol or illicit drug use, and abnormal laboratory values outside of prespecified ranges. No concomitant medications were allowed during the study.

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Study design

Three multiple-dose, open-label, randomized, two-sequence, two-period drug–drug interaction studies (GlaxoSmithKline protocols PRO10017, PRO10022, and PRO10023) were conducted at single study centers in the United States. All study protocols were reviewed and approved by the Institutional Review Board at the respective study sites. Each period consisted of a screening assessment performed within 14 days prior to dosing, a dosing period during which participants received the study drug, and a follow-up evaluation.

In each study, 18 participants were planned to be randomly assigned to one of two treatment sequences; APV followed by APV+RTV in sequence 1 or RTV followed by APV+RTV in sequence 2 (nine individuals per sequence). In the first study (PRO10017), 450 mg APV every 12 h (q12h) alone (sequence 1) or 300 mg RTV q12h alone (sequence 2) was administered for 7 days. In the following 7 days, all participants received both APV and RTV (APV + RTV) at these same doses. In the subsequent two studies (PRO10022 and PRO10023), the study design remained the same but 450 mg APV q12h and 100 mg RTV q12h (PRO10022), or 900 mg APV q12h and 100 mg RTV q12h (PRO10023) were investigated. Due to the lack of availability of ritonavir capsules at the time, the ritonavir oral solution was used in the first study. Ritonavir capsules were used in the other two studies.

As the affinity of APV for CYP3A4 is similar to that of indinavir [14] and RTV increased the area under the concentration–time curve of indinavir by approximately three-fold [17], a 450 mg dose of APV (approximately one-third the recommended dose) was initially selected to avoid potential exposures in healthy individuals which could greatly exceed those of 1200 mg APV alone (the usual clinical dose). The 300 mg q12h dose of RTV in study PRO10017 was selected to assess the maximal drug interaction with APV, with subsequent dose reduction in PRO10022 and PRO10023 to assess the dependence of the interaction on the degree of RTV exposure.

Participants reported to the study center no later than 1800 h on the evening before dosing days 1, 7, and 14, and received a standardized meal, and with the exception of day 1, were administered their evening dose of study medication(s). After fasting for 8 h overnight, participants were administered their randomized treatment with water (360 ml) on the morning of days 1, 7, and 14. They remained at the center until completion of all post-dosing procedures (24 h on day 1 and 12 h on days 7 and 14). Standard balanced meals were provided during the time that the participants were at the study center.

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For determination of drug concentrations, 3 to 4 ml blood samples (serum for APV, plasma for RTV) were collected on dosing day 1 at 5 min before the first dose and at 0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, 5.0, 6.0, 8.0, 10.0, 12.0, 16.0, and 24.0 h post-dosing. On dosing days 7 and 14, blood samples were collected up to 12 h post-dosing only. The AAG concentrations were determined from blood samples taken prior to dosing on days 1, 7, and 14. Blood samples were centrifuged within 30 min of collection to separate the serum or plasma, and the samples stored at −20°C until further analysis.

Safety assessments, including medical history, physical examination, hematology, clinical chemistry, urinalysis, and clinical adverse experiences, were carried out on dosing days 1, 7, and 14 before the dose was given. In addition, vital signs and electrocardiograms were performed at the screening evaluation only. Adverse events occurring during the trial were evaluated by the investigator and graded according to protocol toxicity scales and for relationship to study drug.

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Bioanalysis of amprenavir, ritonavir and AAG

Serum concentrations of APV were determined by a validated method using protein precipitation followed by high-performance liquid chromatography and detection by tandem mass spectrometry using a positive ion multiple reaction monitoring technique. RTV concentrations in plasma were quantified by PPD-Pharmaco (Richmond, Virginia, USA). Quality control concentrations ranged from 10 to 5000 ng/ml and 25 to 10 000 ng/ml for APV and RTV, respectively. The assay calibration curve was linear from 10 to 5000 ng/ml for APV, and 10 to 15 000 ng/ml for RTV. Accuracy (expressed as % bias) ranged from -3.9 to 5.3% and 0.245 to 5.15% for validation controls for APV and RTV, respectively. Inter-assay precision, expressed as percentage coefficient of variance (%CV), ranged from 4.5 to 8.8% for APV, and 3.97 to 9.19% for RTV. Intra-assay precision ranged from 3.3 to 10.1% for APV. Intra-assay precision and accuracy for RTV ranged from 2.89 to 26.1% and 2.09 to 9.22%, respectively. The AAG assays were performed using a commercially available assay (Quest Diagnostics, Inc., San Juan Capistrano, California, USA).

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Pharmacokinetic analysis

Pharmacokinetic parameters were calculated from concentration–time data using non-compartmental pharmacokinetic methods (WinNonlin Pro version 1.5; Scientific Consulting Inc., Cary, North Carolina, USA). Single- and multiple-dose pharmacokinetic parameters were calculated from concentration data derived from samples collected on dosing day 1 and days 7 and 14, respectively. The maximum serum concentration (Cmax, Cmax,ss) and the time to reach Cmax (Tmax, Tmax,ss) were obtained by direct inspection of individual plasma concentration–time data.

Single-dose parameters were estimated for day 1. The elimination half-life (t½) was calculated using the equation t½ = ln(2)/λz, where λz, the apparent terminal elimination rate constant, was estimated by log-linear regression of the terminal portion of the concentration–time curve. The area under the concentration–time curve (AUC0←t) from time zero to the time of the last quantifiable sample (tlast) was calculated using the linear trapezoidal rule. AUC0←t was extrapolated from tlast to infinity (AUC0←∞) by adding Clastz, where Clast is the concentration of the last quantifiable sample. Apparent total clearance (CL/ F) was calculated as Dose/ AUC0←∞. The apparent volume of distribution during the terminal elimination phase (Vz/ F) was calculated as (CL/ F)/ λz.

Steady-state parameters were estimated for days 7 and 14. Cmin,ss, the minimum drug concentration at steady state was calculated as (C0 +Ct)/2, where C0 is the plasma concentration before dosing and Ct is the concentration of the last sample of the steady-state dosing interval. If necessary, AUC0←t was extrapolated to the end of the dosing interval (AUCτ,ss) at time t =t, the steady-state dosing interval, using the formula:EQUATION

Equation U1
Equation U1
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The apparent total clearance at steady state, CL/ F, was calculated as Dose/ AUCτ,ss.

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Statistical analysis

Eight evaluable patients per treatment sequence were estimated to be necessary to detect a 40% difference in AUC for APV and a 50% difference in AUC for RTV on a log scale with 80% of power at the 0.05 level. To account for potential dropouts, nine patients per treatment sequence were enrolled.

All pharmacokinetic parameters (except Tmax) were log-transformed prior to analysis. Comparisons in log-transformed pharmacokinetic parameters (AUCτ,ss, Cmax,ss, Cmin,ss, and CL/ F) between treatment regimens were analyzed by analysis of variance using the PROC MIXED procedure (SAS, version 6.12; SAS Institute Inc., Cary, North Carolina, USA). The analysis included treatment, period, and sequence as fixed effects and subject-within-sequence as a random effect. AAG concentration was used as a covariate in the analysis (except for PRO10017 where AAG data were not available for analysis when RTV was administered alone due to study error). Geometric least-squares (GLS) mean ratios and their associated 90% confidence intervals (CI) were used for within-subject treatment comparisons of pharmacokinetic parameters. Treatments were considered to have no pharmacokinetic interaction if the 90% CI of the estimated GLS mean differences between the treatments on a log-scale shows less than a 40% difference for APV and a 50% difference for RTV. This indicates that the 90% CIs of the GLS mean ratios fall within 0.67–1.49 for APV and 0.61–1.65 for RTV. Non-parametric methods were used to analyze the 95% CI of median Tmax values for each treatment. Treatment comparisons of Tmax values and their associated 90% CI was performed using the Wilcoxon rank sum test.

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The demographic and baseline characteristics of the normal volunteers enrolled in each study were comparable between the studies (Table 1). Eighteen, 18, and 19 individuals were enrolled and 17, 15, and 16 individuals completed studies PRO10017, PRO10022, and PRO10023, respectively.

Table 1
Table 1
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Pharmacokinetic analysis

The median APV concentration–time curves after administration of APV alone or in combination with RTV are shown in Figure 1. The geometric mean (95% CI) values of selected APV pharmacokinetic parameters (Cmax, AUC, and Cmin) for each study day in each study and the GLS mean and ratios are shown in Table 2. Single-dose APV pharmacokinetics predicted steady-state pharmacokinetics in all three studies. RTV significantly increased APV AUCτ,ss and Cmin,ss compared with those achieved when APV was administered alone. The Cmax was not uniformly affected by RTV and in only one study (PRO10022) was there a significant effect.

Fig. 1
Fig. 1
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Table 2
Table 2
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RTV had a complicated inhibition-autoinduction pattern in all three studies (Table 3) consistent with previous reports [16,23,24]. Single-dose RTV pharmacokinetics did not predict steady-state pharmacokinetics. In the first 7 days, RTV significantly increased its AUC and Cmax. In the next 7 days there were significant decreases in Cmax, AUC, and Cmin. There was no significant sequence effect on APV concentrations indicating that the interaction effect of ritonavir was maximal despite its own time-dependent pharmacokinetics. There were no significant effects on Tmax for either APV or RTV.

Table 3
Table 3
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Safety assessment

The 100 mg RTV q12h dose alone or in combination with APV resulted in fewer adverse events than the 300 mg q12h dose alone or in combination with APV. The occurrence of adverse events regardless of relation to study drug was greater with APV and RTV in combination than with either drug alone (Table 4). The most common drug-related adverse events reported by participants were diarrhea, nausea, and oral paresthesia in PRO10017; nausea/vomiting, headache and dizziness in PRO10022; and diarrhea, nausea/vomiting, headache, and oral paresthesia in PRO10023. In PRO10017 one individual withdrew from the study with rash that progressed after the addition of RTV; in PRO10022 two participants withdrew from the study, one due to rash following the first dose of APV alone, and the other withdrew due to rash and pruritis after APV in combination with RTV; and in PRO10023 three participants withdrew from the study, one due to nausea after the first dose of APV, one due to oral/perioral numbness, rash, edema of the face, ocular swelling and pruritis during APV/RTV, and one due to lightheadedness after RTV alone followed by vomiting and oral lesions.

Table 4
Table 4
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There were also significant effects found on clinical chemistry changes from pre-therapy (Table 5). The 300 mg dose of RTV in combination with APV resulted in a trend towards increases in serum glucose concentration but was not statistically significant. In the study with 300 mg RTV, the glucose change from baseline for the APV to APV/RTV sequence at day 7 was -1.39 ± 14.12 and at day 14 14.5 ± 22.26 mg/dl (P = 0.07), and the RTV to RTV/APV sequence at day 7 was 9.17 ± 24.69 and at day 14 it was 12.72 ± 18.54 mg/dl (P = 0.07). In contrast, the 100 mg dose of RTV had no effect on serum glucose concentration in either study (data not shown). There were significant increases in cholesterol and triglyceride values from pre-treatment (P < 0.05) with both doses of RTV but the time frame differed (Table 5) suggesting a cumulative exposure effect. There were no other clinically significant laboratory changes observed.

Table 5
Table 5
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The series of interaction studies presented here demonstrated statistically and clinically significant effects of RTV on APV AUCτ,ss and Cmin,ss. Given the inconsistent effect on Cmax these results suggest an effect of RTV on inhibition of APV's metabolism than by an effect on its bioavailability. This is similar to the effects of RTV on indinavir rather than on saquinavir and to a lesser extent nelfinavir, where very large increases in Cmax result from increases in bioavailability [15–21].

Single-dose APV pharmacokinetics predicted steady-state pharmacokinetics in each of these studies. As the participants were normal volunteers with little change in their AAG concentrations this was expected. The findings are consistent with our study showing changes in values of the area under the concentration–time curve were correlated to changes in AAG concentration both between- and within-subjects [12].

The combination of 450 mg APV q12h with the lower dose of RTV (100 mg q12h) tended to be better tolerated than the combination with the higher RTV (300 mg q12h) dose or the higher APV dose (900 mg q12h) in combination with RTV. As the oral solution and capsule formulations of ritonavir are bioequivalent we would expect most of these differences to persist if capsules were available for use in all the trials.

Gastrointestinal symptoms were the adverse events most commonly reported in participants and were mild to moderate in intensity. Differences in the incidence of adverse events between studies may be attributed to differences in the reporting of adverse events between the three study sites. Serum cholesterol and triglyceride concentrations were elevated to a greater magnitude by both RTV doses in combination with APV than by APV administered alone. These findings are consistent with the results of previous studies that have shown RTV to be associated with increases in plasma triglyceride and cholesterol concentrations [23,24]. It cannot be ruled out that the higher dose of APV (900 mg q12h) may have contributed to the higher cholesterol concentrations observed in PRO10023.

Co-administration of RTV with APV 450 or 900 mg q12h resulted in APV Cmax, AUC, and Cmin values that were similar to or slightly greater than those achieved with the approved 1200 mg twice daily APV dose alone as noted in Table 2. These increases in APV Cmin are consistent with the magnitude of increases in indinavir Cmin produced by the co-administration of 100 or 200 mg RTV with 800 or 1200 mg indinavir in healthy volunteers and HIV-1 infected patients [18–20]. Several clinical studies have demonstrated a strong correlation between antiviral activity and plasma trough concentrations of PIs [24–31]. Subtherapeutic concentrations of HIV PIs in plasma can be associated with viral rebound and the development of drug resistance [24–31], indicating the importance of maintaining consistent drug concentrations in plasma. Increased trough concentrations of APV may lead to improved efficacy over time, and minimize development of drug-resistant viral strains.

The pharmacokinetic data from these studies were combined in a nonlinear mixed-effect modelling analysis (NONMEM; NONMEM Project Group, University of California – San Francisco, California, USA) to evaluate potential twice daily and once daily regimens [32]. The details of this population analysis will be described in another manuscript. For the twice daily regimen, consideration was given to the potential use of therapy in populations with viral isolates of reduced susceptibilities [9]. When considering a population with reduced viral susceptibility, a simulated regimen of 600 mg APV twice daily with 100 mg RTV twice daily gives similar Cmin to protein binding-adjusted IC50 ratios as the 1200 mg APV dose for wild-type isolates [9]. As might be anticipated from the degree of interaction demonstrated in the current studies, once-daily regimens were clearly feasible for patients with susceptible virus.

In summary, co-administration of 100 or 300 mg RTV q12h with 450 or 900 mg APV q12h resulted in statistically and clinically significant increases in APV plasma concentrations. Clinical studies are in progress to evaluate the efficacy, pharmacokinetics and safety profile of various doses and schedules of APV in combination with RTV, with emphasis on 600 mg APV twice daily in combination with 100 mg RTV twice daily [33,34].

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The authors wish to thank Luwanda Chandler (GlaxoSmithKline) for performing the drug assays and Terry R. Paul for his writing and editorial assistance with this manuscript.

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British Journal of Clinical Pharmacology
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Antiviral Therapy
Salvage therapy with amprenavir, lopinavir and ritonavir 200 mg/d or 400 mg/d in HIV-infected patients in virological failure
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Amprenavir or fosamprenavir plus ritonavir in HIV infection - Pharmacology, efficacy and tolerability profile
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Antimicrobial Agents and Chemotherapy
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Journal of Pharmacy and Pharmacology
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HIV Clinical Trials, 6(2): 73-80.

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Antimicrobial Agents and Chemotherapy
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Journal of Antimicrobial Chemotherapy, 53(1): 4-9.
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Pharmacokinetics of amprenavir and lopinavir in combination with nevirapine in highly pretreated HIV-infected patients
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Antimicrobial Agents and Chemotherapy
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Antimicrobial Agents and Chemotherapy
Pharmacokinetic and safety evaluation of high-dose combinations of fosamprenavir and ritonavir
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SOLO: 48-week efficacy and safety comparison of once-daily fosamprenavir/ritonavir versus twice-daily nelfinavir in naive HIV-1-infected patients
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Boosted saquinavir hard gel formulation exposure in HIV-infected subjects: ritonavir 100 mg once daily versus twice daily
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Current Pharmaceutical Analysis
Therapeutic drug monitoring: A tool to individualize highly active antiretroviral therapy in HIV infected patients
Langmann, P; Zilly, M; Winzer, R; Klinker, H
Current Pharmaceutical Analysis, 2(3): 205-217.

Current Drug Metabolism
Relationship between extent of inhibition and inhibitor dose: Literature evaluation based on the metabolism and transport drug interaction database
Levy, RH; Hachad, H; Yao, C; Ragueneau-Majlessi, I
Current Drug Metabolism, 4(5): 371-380.

Clinical Pharmacology & Therapeutics
Pharmacokinetic interaction between amprenavir and delavirdine: Evidence of induced clearance by amprenavir
Tran, JQ; Petersen, C; Garrett, M; Hee, B; Kerr, BM
Clinical Pharmacology & Therapeutics, 72(6): 615-626.
Current Pharmaceutical Design
Update on the pharmacokinetic aspects of antiretroviral agents: Implications in therapeutic drug monitoring
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Current Pharmaceutical Design, 12(9): 1129-1145.

Effects of ritonavir and amprenavir on insulin sensitivity in healthy volunteers
Lee, GA; Rao, M; Mulligan, K; Lo, JC; Aweeka, F; Schwarz, JM; Schambelan, M; Grunfeld, C
AIDS, 21(): 2183-2190.

Danish Medical Bulletin
Protease inhibitor plasma concentrations in HIV antiretroviral therapy
Justesen, US
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Antimicrobial Agents and Chemotherapy
Genotypic inhibitory quotient as predictor of virological response to ritonavir-amprenavir in human immunodeficiency virus type 1 protease inhibitor-experienced patients
Marcelin, AGV; Lamotte, C; Delaugerre, C; Ktorza, N; Mohand, HA; Cacace, R; Bonmarchand, M; Wirden, M; Simon, A; Bossi, P; Bricaire, F; Costagliola, D; Katlama, C; Peytavin, G; Calvez, V
Antimicrobial Agents and Chemotherapy, 47(2): 594-600.
Annals of Pharmacotherapy
Low-dose ritonavir for protease inhibitor pharmacokinetic enhancement
Rathbun, RC; Rossi, DR
Annals of Pharmacotherapy, 36(4): 702-706.

Therapeutic drug monitoring in HIV infection: current status and future directions
Back, D; Gatti, G; Fletcher, C; Garaffo, R; Haubrich, R; Hoetelmans, R; Kurowski, M; Luber, A; Merry, C; Perno, CF
AIDS, 16(): S5-S37.

Current Topics in Medicinal Chemistry
Peptidomimetic inhibitors of HIV protease
Randolph, JT; DeGoey, DA
Current Topics in Medicinal Chemistry, 4(): 1079-1095.

Bmc Infectious Diseases
Twice-daily amprenavir 1200 mg versus amprenavir 600 mg/ritonavir 100 mg, in combination with at least 2 other antiretroviral drugs, in HIV-1-infected patients
Nadler, JP; Gathe, JC; Pollard, RB; Richmond, GJ; Liao, QM; Griffith, S; Lancaster, CT; Hernandez, JE; Pappa, KA
Bmc Infectious Diseases, 3(): -.
Clinical Infectious Diseases
Effects of formulation and dosing strategy on amprenavir concentrations in the seminal plasma of human immunodeficiency virus type 1-infected men
Chaudry, NI; Eron, JJ; Naderer, OJ; Pereira, AS; Wire, MB; Fiscus, SA; Kashuba, ADM
Clinical Infectious Diseases, 35(6): 760-762.

Antimicrobial Agents and Chemotherapy
Amprenavir inhibitory quotient and virological response in human immunodeficiency virus-infected patients on an amprenavir-containing salvage regimen without or with ritonavir
Duval, X; Lamotte, C; Race, E; Descamps, D; Damond, F; Clavel, F; Leport, C; Peytavin, G; Vilde, JL
Antimicrobial Agents and Chemotherapy, 46(2): 570-574.

Clinical Pharmacology & Therapeutics
Effect of coadministration of nelfinavir, indinavir, and saquinavir on the pharmacolkinetics of amprenavir
Pfister, M; Labbe, L; Lu, JF; Hammer, SM; Mellors, J; Bennett, KK; Rosenkranz, S; Sheiner, LB
Clinical Pharmacology & Therapeutics, 72(2): 133-141.
Journal of Antimicrobial Chemotherapy
Inhibition of P-glycoprotein and multidrug resistance-associated proteins modulates the intracellular concentration of lopinavir in cultured CD4 T cells and primary human lymphocytes
Janneh, O; Jones, E; Chandler, B; Owen, A; Khoo, SH
Journal of Antimicrobial Chemotherapy, 60(5): 987-993.
Antimicrobial Agents and Chemotherapy
In vitro-in vivo model for evaluating the antiviral activity of amprenavir in combination with ritonavir administered at 600 and 100 milligrams, respectively, every 12 hours
Preston, SL; Piliero, PJ; Bilello, JA; Stein, DS; Symonds, WT; Drusano, GL
Antimicrobial Agents and Chemotherapy, 47(): 3393-3399.
Antimicrobial Agents and Chemotherapy
Pharmacokinetic study of human immunodeficiency virus protease inhibitors used in combination with amprenavir
Sadler, BM; Gillotin, C; Lou, Y; Eron, JJ; Lang, W; Haubrich, R; Stein, DS
Antimicrobial Agents and Chemotherapy, 45(): 3663-3668.

AIDS Patient Care and Stds
Impact of drug levels and baseline genotype and phenotype on the virologic response to amprenavir/ritonavir-based salvage regimens
Valer, L; De Requena, DG; De Mendoza, C; Martin-Carbonero, L; Gonzalez-Lahoz, J; Soriano, V
AIDS Patient Care and Stds, 18(1): 1-6.

HIV Medicine
Efficacy, safety and predictive factors of virological success of a boosted amprenavir-based salvage regimen in heavily antiretroviral-experienced HIV-1-infected patients
Clevenbergh, P; Boulme, R; Kirstetter, M; Dellamonica, P
HIV Medicine, 5(4): 284-288.

Back to Top | Article Outline

Protease inhibitors; amprenavir; ritonavir; safety; pharmacokinetics; drug interaction

© 2001 Lippincott Williams & Wilkins, Inc.


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