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  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 . 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 .
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 . 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 . 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.
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.
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  and RTV increased the area under the concentration–time curve of indinavir by approximately three-fold , 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.
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.
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).
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 (C max, C max,ss) and the time to reach C max (T max, T max,ss) were obtained by direct inspection of individual plasma concentration–time data.
Single-dose parameters were estimated for day 1. The elimination half-life (t ½) was calculated using the equation t ½ = 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 (AUC 0← t) from time zero to the time of the last quantifiable sample (t last) was calculated using the linear trapezoidal rule. AUC 0← t was extrapolated from t last to infinity (AUC 0←∞) by adding C last/λz, where C last is the concentration of the last quantifiable sample. Apparent total clearance (CL/ F) was calculated as Dose/ AUC 0←∞. The apparent volume of distribution during the terminal elimination phase (V z/ F) was calculated as (CL/ F)/ λz.
Steady-state parameters were estimated for days 7 and 14. C min,ss, the minimum drug concentration at steady state was calculated as (C 0 +Ct)/2, where C 0 is the plasma concentration before dosing and Ct is the concentration of the last sample of the steady-state dosing interval. If necessary, AUC 0← t was extrapolated to the end of the dosing interval (AUC τ,ss) at time t =t, the steady-state dosing interval, using the formula:EQUATION
The apparent total clearance at steady state, CL/ F, was calculated as Dose/ AUC τ,ss.
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 T max) were log-transformed prior to analysis. Comparisons in log-transformed pharmacokinetic parameters (AUC τ,ss, C max,ss, C min,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 T max values for each treatment. Treatment comparisons of T max values and their associated 90% CI was performed using the Wilcoxon rank sum test.
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.
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 (C max, AUC, and C min) 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 AUC τ,ss and C min,ss compared with those achieved when APV was administered alone. The C max was not uniformly affected by RTV and in only one study (PRO10022) was there a significant effect.
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 C max. In the next 7 days there were significant decreases in C max, AUC, and C min. 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.
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.
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.
The series of interaction studies presented here demonstrated statistically and clinically significant effects of RTV on APV AUC τ,ss and C min,ss. Given the inconsistent effect on C max 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 C max 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 .
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 C max, AUC, and C min 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 C min are consistent with the magnitude of increases in indinavir C min 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 . 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 . 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 C min to protein binding-adjusted IC50 ratios as the 1200 mg APV dose for wild-type isolates . 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].
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.
1. Gulick R, Mellors J, Havlir D. et al
. Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy. N Engl J Med 1997, 337: 734 –739.
2. Hammer S, Squires K, Hughes M. et al
. A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. N Engl J Med 1997, 337: 725 –733.
3. Palella F, Delaney K, Moorman A. et al
. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N Engl J Med 1998, 338: 853 –860.
4. Ledergerber B, Egger M, Opravil M. et al
. Clinical progression and virological failure on highly active antiretroviral therapy in HIV-1 patients: a prospective cohort study. Lancet 1999, 353: 863 –868.
5. Carpenter C, Cooper D, Fischl M. et al
. Antiretroviral therapy in adults. Updated recommendations of the International AIDS Society-USA panel.
JAMA 2000, 283: 381 –390.
6. Mehta S, Moore R, Graham N. Potential factors affecting adherence with HIV therapy. AIDS 1997, 11: 1665 –1670.
7. Hirschhorn L, Stone V, Boswell S. Discontinuation (D/C) of protease inhibitor (PI) therapy: reasons and risk factors. XII International Conference on AIDS.
Geneva, June 1998 [abstract 12443].
8. Haubrich RH, Little SJ, Currier JS. et al
. The value of patient-reported adherence to antiretroviral therapy in predicting virologic and immunologic response. California Collaborative Treatment Group.
AIDS 1999, 13: 1099 –107.
9. Stein DS, Sadler B, Sale M. Pharmacodynamic effects of amprenavir (APV) + ritonavir (RTV) on different viral populations. First International Workshop on Clinical Pharmacology of HIV Therapy
. Noordwijk, The Netherlands, March 2000 [abstract 5.2].
10. Stellrecht K, Drusano G, Stein D, Bilello J. Plasma alpha-1 acid glycoprotein is reduced in HIV-infected patients co-infected with hepatitis C virus (HCV). Third Conference on Retroviruses and Opportunistic Infections.
Washington, DC, January–February 1996 [abstract 84].
11. Kremer J, Wilting J, Janssen λ. Drug binding to human alpha-1 glycoprotein in health and disease. Pharmacol Rev 1998, 40: 1 –47.
12. Sadler B, Gillotin C, Lou Y, Stein D. Effect of demographic, laboratory, and clinical covariates on the pharmacokinetics (PK) of amprenavir (APV). Sixth Conference on Retroviruses and Opportunistic infections.
Chicago, IIIinois, January–February 1999 [abstract 375].
13. Decker C, Laitinen λ, Bridson G, Raybuck S, Tung R, Chaturvedi P. Metabolism of amprenavir
in liver microsomes: role of CYP3A4 inhibition for drug interactions. J Pharm Sci 1998, 87: 803 –807.
14. Woolley J, Studenberg S, Boehlert C, Bowers G, Sinhababu A, Adams P. Cytochrome P-450 isoenzyme induction, inhibition, and metabolism studies with the HIV protease inhibitor, 141W94. 37th Interscience Conference on Antimicrobial Agents and Chemotherapy
. Toronto, Canada, September–October 1997 [abstract A60].
15. Merry C, Barry MG, Mulcahy F. et al
. Saquinavir pharmacokinetics
alone and in combination with ritonavir
in HIV-infected patients. AIDS 1997, 11: F29 –F33.
16. Hsu A, Granneman G, Cao G. et al
. Pharmacokinetic interactions between two human immunodeficency virus protease inhibitors
and saquinavir. Clin Pharmacol Ther 1998, 63: 453 –464.
17. Hsu A, Granneman G, Cao G. et al
. Pharmacokinetic interaction between ritonavir
and indinavir in healthy volunteers. Antimicrob Agents Chemother 1998, 42: 2784 –2791.
18. Burger D, Hugen P, Hofstede H, et al
. Dose-finding study of a once-daily indinavir/ritonavir regimen in healthy volunteers. 39th Interscience Conference on Antimicrobial Agents and Chemotherapy.
San Francisco, September 1999 [abstract 321].
19. Saah A, Winchell G, Senuik M, Deutsch P. Multiple-dose pharmacokinetics (PK) and tolerability of indinavir (IDV) and ritonavir (RTV) combinations in a once-daily regimen in healthy volunteers (Merck 089). 39th Interscience Conference on Antimicrobial Agents and Chemotherapy.
San Francisco, September 1999 [abstract 329].
20. van Heeswijk RP, Veldkamp AI, Hoetelmans RM. et al
. The steady-state plasma pharmacokinetics
of indinavir alone and in combination with a low dose of ritonavir
in twice daily dosing regimens in HIV-1-infected individuals. AIDS 1999, 13: F95 –F99.
21. Agouron Pharmaceuticals, Agouron Pharmaceuticals, Inc. Viracept← Product Information
. Physician's Desk Reference.
Montvale, NJ: Medical Economics Company Inc.; 2001.
22. Piscitelli S, Bechtel C, Sadler B, Falloon J. The addition of a second protease inhibitor eliminates amprenavir-efavirenz drug interactions and increases plasma amprenavir concentrations. Seventh Conference on Retroviruses and Opportunistic Infections
. San Francisco, California, January–February 2000 [abstract 78].
23. Hsu A, Granneman G, Witt G. et al
. Multiple-dose pharmacokinetics
in human immunodeficiency virus-infected subjects. Antimicrob Agents Chemother 1997, 41: 898 –905.
24. Danner S, Carr A, Leonard J. et al
. A short-term study of the safety
, and efficacy of ritonavir
, an inhibitor of HIV-1 protease. N Engl J Med 1995, 333: 1528 –1533.
25. Schapiro J, Winters M, Stewart F. et al
. The effect of high-dose saquinavir on viral load and CD4+ T-cell counts in HIV infected patients. Ann Intern Med 1996, 124: 1039 –1050.
26. Stein DS, Fish D, Bilello J, Preston S, Martineau G, Drusano G. A 24-week open-label phase I/II evaluation of the HIV protease inhibitor MK-639 (indinavir). AIDS 1996, 10: 485 –492.
27. Acosta E, Henry K, Baken λ, Page λ, Fletcher C. Indinavir concentrations and antiviral effect. Pharmacotherapy 1999, 19: 708 –712.
28. Fletcher C. Pharmacologic considerations for therapeutic success with antiviral agents. Ann Pharmacother 1999, 33: 989 –995.
29. Fletcher C, Brundage R, Remmel R. et al
. Pharmacologic characteristics of indinavir, didanosine, and stavudine in human immunodeficiency virus-infected children receiving combination therapy. Antimicrob Agents Chemother 2000, 44: 1029 –1034.
30. Lorenzi P, Yerly S, Abderrakim K. et al
. Toxicity, efficacy, plasma drug concentrations and protease mutations in patients with advanced HIV infection treated with ritonavir
and saquinavir. AIDS 1997, 11: F95 –F99.
31. Drusano G, Sadler B, Millard J, et al
. Pharmacodynamics of 141W94 as determined by short term change in HIV RNA: influence of viral isolate baseline EC50. 37th Interscience Conference on Antimicrobial Agents and Chemotherapy
. Toronto, Canada, September–October 1997 [abstract A-16].
32. Sale M, Stein DS, Sadler B. Concomitant ritonavir decreases the clearance of amprenavir-a pharmacokinetic model of protease inhibitor interaction. First International Workshop on Clinical Pharmacology of HIV Therapy
. Noordwijk, The Netherlands, March 2000 [abstract 2.10].
33. Katlama C, Schneider L, Agher R, et al
. Ritonavir (RTV)/amprenavir (APV) combination therapy in HIV infected patients who failed several protease inhibitor containing regimen. Fifth International Congress on Drug Therapy in HIV Infection.
Glasgow, UK, October 2000 [abstract 41].
34. Wood R, Trepo, C, Livrozet JM, et al
. Amprenavir (APV) 600 mg/ritonavir (RTV) 100 mg BID or APV 1200 mg/RTV 200 mg QD given in combination with abacavir (ABC) and lamivudine (3TC) maintains efficacy in ART-naïve HIV-1 infected adults over 12 weeks (APV20001). Eighth Conference on Retroviruses and Opportunistic Infections
. Chicago, Illinois, February 2001 [abstract 332].
Keywords:© 2001 Lippincott Williams & Wilkins, Inc.
Protease inhibitors; amprenavir; ritonavir; safety; pharmacokinetics; drug interaction