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Use of Pharmacokinetic Enhancement in Antiretroviral Treatment-Experienced HIV Patients

Optimizing Therapy for Patients With Multidrug-Resistant HIV -- Part I

July 31, 2006


Protease inhibitors (PIs) are potent agents for controlling HIV infection. The physicochemical properties that make these drugs inherently effective for suppressing intracellular infection also predispose them to the effects of drug-metabolizing enzymes and transporters. This results in significant challenges to achieving adequate systemic exposure. A number of compounds have been investigated to inhibit metabolism and transport, thereby elevating drug concentrations. Low-dose ritonavir appears to be the most potent compound for inhibiting cytochrome P450 enzyme activity and P-glycoprotein activity. Its use as a pharmacoenhancer for most PIs has significantly improved the management of HIV. Most recently, dual PI therapy in combination with ritonavir has been explored as an option for treatment-experienced patients. This article will focus on the mechanisms of first-pass metabolism for PIs, how these activities can be overcome by ritonavir, and the theoretical benefits to dual-boosted PI therapy. Studies evaluating combinations of PIs will be reviewed to illustrate the complications of predicting these interactions and the need for formal pharmacokinetic studies. Additionally, the use of pharmacokinetic enhancement with new classes of antiretroviral agents will be discussed.


Pharmacokinetic enhancement is the strategy of exploiting pharmacokinetics to optimize exposure to drug therapy. As currently applied to the management of HIV infection, it is used to increase exposure to protease inhibitors (PIs), all of which are associated with limited oral bioavailability. Typically, it involves enhancing or "boosting" exposure to a primary PI administered at a therapeutic dosage with a low, non-therapeutic dose of ritonavir (r), itself a PI. It is now well established that when boosted, some PIs exhibit greater virologic potency by increasing plasma trough concentrations, which provides an improved barrier against the development of antiretroviral drug resistance.1,2 In addition, boosted PI regimens extend the duration of adequate drug exposure, allowing less frequent dosing (in some cases to once a day, e.g., atazanavir/r, fosamprenavir/r and lopinavir/r).3 There is evidence that if necessary, this approach can also be useful for increasing exposure to fusion inhibitors that block viral entry via CCR5 chemokine co-receptors; currently, the lead CCR5 inhibitors in clinical trials are maraviroc (UK-427,857, Pfizer; phase III clinical trials) and vicriviroc (SCH 417690, Schering-Plough; phase II treatment-experienced HIV patients).

PI Pharmacology Overview

Oral bioavailability of PIs is generally low due to extensive first-pass metabolism by multidrug resistance transporters (particularly P-glycoprotein), and the cytochrome P450 system (CYP450)4 found in the intestine and the liver. Inter- (and occasionally intra-) individual expression of both P-glycoprotein and CYP3A4, the CYP450 isozyme primarily responsible for PI metabolism, is highly variable.4 Furthermore, most PIs are highly protein bound in serum. As only free drug is pharmacologically active, inter-individual variations in the extent of protein binding may have significant effects on PI exposure as well as antiviral activity.4 These factors explain much of the observed inter-patient variability in the absorption, distribution, metabolism, and excretion of PIs and contribute to why patients may experience treatment failure.

First-Pass Metabolism

P-glycoprotein is an adenosine triphosphate-dependent drug efflux pump that protects cells from accumulating a wide range of toxic compounds. It is located on cell membranes and is expressed at high levels in a variety of tissues, including the gastrointestinal tract and liver.5 All currently available PIs are substrates for P-glycoprotein to a varying degree.6-9 Transport of PIs by P-glycoprotein may regulate their bioavailability by several mechanisms, including limiting their uptake in the small intestine and increasing their metabolism by intestinal CYP3A4 through repeated cycles of uptake and efflux.10 It is also worth noting that P-glycoprotein activity in other tissues such as the brain and testes may lead to protected sanctuaries of HIV replication as a result of limited drug accumulation at these sites.10 As well as being substrates for P-glycoprotein, PIs, particularly ritonavir, inhibit this transporter's activity in various cells,11 including CD4 and CD8 cells and CD34+ progenitor cells.12 To complicate matters further, some PIs may also increase the activity of P-glycoprotein. For example, tipranavir has been reported to be a potent inducer of this transporter.8 Other drug transporters have also been implicated in the transport of PIs, although these interactions are not well defined.10

All PIs are metabolized by the CYP450 system in the intestine and liver, primarily by the CYP3A4 isozyme and to a lesser extent by CYP2D6, CYP2C9, and CYP2C19.13 The extensive first-pass metabolism by CYP450 reduces oral bioavailability of PIs to varying degrees. For example the bioavailability of saquinavir is 60%.14,15 As with P-glycoprotein, the situation is complicated by the fact that PIs are inhibitors and may also be inducers (lopinavir, ritonavir, amprenavir, tipranavir) of CYP3A4.4 Ritonavir is the most potent inhibitor, followed by amprenavir > indinavir > nelfinavir > saquinavir.16 The potent inhibition of CYP3A4 by low (non-therapeutic) doses of ritonavir has led to its utility in boosting exposure to the primary PI used at a therapeutic dose (PI/r).4

Protein Binding

PIs generally bind to albumin and alpha-1-acid glycoprotein in blood plasma.4 Mean protein binding ranges from 60% for indinavir to 98% for lopinavir, nelfinavir, saquinavir and tipranavir.8,14,17-19 As an acute phase reactant, there can be significant intra- and inter-individual differences in the concentrations of alpha-1-acid glycoprotein.4 The clinical significance of these alterations on antiretroviral efficacy is unknown.

Exposure and Response

A narrow therapeutic window exists for many antiretroviral agents. Maintaining high plasma drug concentrations, and preventing these from dipping below the recommended minimal concentrations required for inhibition of viral replication during a dosing interval, increases the antiviral potency of PIs. On the other hand, all PIs are associated with adverse side effects and toxicities, and as such, increased exposure to these drugs may increase the incidence and/or severity of these. Thus, an "ideal" PI-based antiretroviral regimen would maintain high PI trough concentrations that provide adequate antiviral activity to protect against the development of drug resistance, and low peak concentrations that protect against toxicity. Although there are no strategies to markedly reduce peak concentrations, PI boosting has been widely adopted to maintain high PI trough concentrations that enhance antiviral efficacy. There are promising reports indicating that boosted PIs provide beneficial virological outcomes (described below). However, studies employing therapeutic drug monitoring have revealed that maintaining adequate plasma drug concentrations is not straightforward. The wide variability of plasma PI concentrations with specified doses of PIs and ritonavir may in some cases cause excessive toxicity that leads to reduced adherence or, alternatively, insufficient plasma concentrations that lead to the development of resistance. For example, a study of patients receiving either indinavir or boosted indinavir found wide intra- and inter-patient variability in plasma indinavir concentrations (indinavir, mean = 3,260 ng/mL ± 3,385 ng/mL vs boosted indinavir, mean = 4,191 ng/mL ± 4,251 ng/mL, not significant).20

Pharmacologic Enhancement of PIs

Pharmacokinetic Effects of Ritonavir on Other PIs

Ritonavir is by far the most common compound used in clinical practice to boost the antiviral activity of PIs for the treatment of HIV infection. Its inhibitory effects on CYP450 and P-glycoprotein can increase the extent of absorption and slow the clearance of the primary PI, which raises plasma trough concentrations and may also raise peak concentrations (Figure 1).15 The boosting effects of ritonavir are specific to individual PIs, all of which may be boosted for clinical purposes except for nelfinavir, on which it has little effect. Furthermore, as both ritonavir and nelfinavir have been associated with diarrhea, with rates of 30-40% reported with the latter,3 combining these agents may further exaggerate this side effect. The pharmacokinetic effects of ritonavir boosting of individual PIs are summarized in Table 1.

Figure 1. Pharmacological enhancement: 'boosting' of protease inhibitors (PIs).
Figure 1. Pharmacological enhancement: "boosting" of protease inhibitors (PIs).21

Clinical Experience With Boosted PIs

There is accumulating clinical data indicating that boosted PI regimens are equivalent or more efficacious than single PI regimens in treatment-naive and -experienced patients.

Comparisons of un-boosted versus boosted PIs
Indinavir/r. Boosting indinavir with ritonavir simplifies therapy by allowing twice-daily dosing and removing the need for dietary restrictions. A comparison of indinavir/r 800 mg/100 mg bid versus indinavir 800 mg tid in combination with zidovudine/lamivudine in nucleoside-experienced HIV- infected patients demonstrated similar antiviral activity after 112 weeks of follow-up (percentage of patients with viral load <50 copies/mL, 64% vs 59%, P = 0.86).25

Comparisons of a boosted PI with nelfinavir
Fosamprenavir/r. Fosamprenavir is a prodrug of amprenavir that, when combined with ritonavir, offers a once-daily dosing option for the treatment of antiretroviral-naive HIV-infected patients.

A comparison of fosamprenavir/r 1400 mg/200 mg once daily versus nelfinavir 1250 mg bid in combination with abacavir/lamivudine in antiretroviral-naive HIV-infected patients demonstrated similar antiviral activity after 48 weeks of therapy (percentage of patients with viral load <50 copies/mL, 55% vs 53%).26

Lopinavir/r. Lopinavir is co-formulated with ritonavir. This helps simplify dosing by reducing the pill burden of the individual agents. A comparison of lopinavir/r 400 mg/100 mg bid versus nelfinavir 750 mg tid in combination with stavudine/lamivudine in antiretroviral-naive HIV patients demonstrated superior antiviral activity of the lopinavir regimen after 48 weeks of follow-up (percentage of patients with viral load <50 copies/mL, 67% vs 52%, P < 0.001).1

Comparisons of boosted PI regimens
Atazanavir/r versus lopinavir/r. Atazanavir is an azapeptide PI that has the advantage of once-daily dosing. Boosted atazanavir has only been tested in clinical trials of treatment-experienced patients to date. A comparison of atazanavir/r 300 mg/100 mg once daily versus lopinavir/r 400 mg/100 mg bid in combination with tenofovir and one nucleoside reverse transcriptase inhibitor (NRTI) in HIV patients who had failed HAART regimens containing PIs demonstrated similar antiviral activity after 48 weeks of follow-up (decrease in HIV RNA from baseline, 1.58 vs 1.70 log10 copies/mL). (The study was not powered to detect similarity between efficacy of regimens to achieve viral load below the limit of detection.22)

Saquinavir/r versus indinavir/r or lopinavir/r. Boosting saquinavir with ritonavir provides a significant increase in bioavailability (Table 1). The new 500-mg tablet formulation of saquinavir now offers a reduced pill burden.27

Table 1. Effects of ritonavir boosting on the pharmacokinetics of protease inhibitors (PIs).
Primary PIDose
(Primary PI/r)
Fold-change in primary PI (mean)
Atazanavir22300 mg/100 mg qd1.9-fold ≠5.3-fold ≠3.1-fold ≠
Fosamprenavir231400 mg/200 mg qd
700 mg/100 mg bid
1.5-fold ≠
1.3-fold ≠
4.1-fold ≠
6.1-fold ≠
2.1-fold ≠
2.4-fold ≠
Indinavir17800 mg/100 mg bid
800 mg/200 mg bid
1.6-fold ≠
1.2-fold ≠
1.6-fold ≠
4.7-fold ≠
1.7-fold ≠
2-fold ≠
Lopinavir24400 mg/50 mg single dose55-fold ≠--77-fold ≠
Saquinavir (hard-gel)141000 mg/100 mg bid13.3-fold ≠--11.2-fold ≠
Tipranavir8500 mg/200 mg bid4-fold ≠48-fold ≠--
Cmax = maximum drug concentration; Cmin = minimum drug concentration; AUC = area under the plasma concentration curve ; qd = once daily.

A comparison of saquinavir/r 1000 mg/100 mg bid versus indinavir/r 800 mg/100 mg bid in combination with at least two NRTIs/NNRTIs in a heterogeneous population including PI-naive, PI-intolerant, and PI-experienced HIV-infected patients demonstrated similar antiviral activity after 48 weeks of follow-up (percentage of patients with virological failure, 25% vs 27%, P = 0.76).28

A comparison of saquinavir/r 1000 mg/100 mg bid versus lopinavir/r 400 mg/100 mg bid in combination with two or more NRTIs/non-NRTIs in antiretroviral-naive, PI-naive, or PI-experienced HIV patients demonstrated superior antiviral activity of the lopinavir/r regimen after 48 weeks of follow-up (percentage of patients with treatment failure, 33% vs 18%, P = 0.002).29

Tipranavir/r. Boosted tipranavir is indicated for combination therapy for the treatment of HIV-1-infected adults who have evidence of viral replication, are highly treatment-experienced, or have multiple-PI-resistant HIV-1 strains.

A comparison of tipranavir/r 500 mg/200 mg bid versus comparator PI (lopinavir, amprenavir, saquinavir, or indinavir)/r in combination with an optimized background regimen in extensively pretreated HIV patients demonstrated superior antiviral activity of the tipranavir/r regimen after 24 weeks of follow-up in this patient population (percentage of patients with at least 1 log10 HIV-1 RNA decrease, 40% vs 18%).8

Common dosing of boosted PIs in clinical practice
Common dosing of ritonavir-enhanced PI combinations is shown in Table 2. Of note, hard-gel saquinavir (now available in tablet form) has improved gastrointestinal tolerance compared to the soft-gel formulation. Since ritonavir boosting of saquinavir produces similar plasma exposure to saquinavir for both formulations, the former may be preferred.30 Furthermore, the improved tolerability of the hard tablet formulation is facilitating investigations of higher doses of saquinavir (up to 2000 mg with 100 mg or 200 mg of ritonavir once daily).

Table 2. Common dosing for boosted PIs.
PI/ritonavir (r)Dosage
Atazanavir/r300 mg/100 mg qd
Fosamprenavir/r700 mg/100 mg bid or 1400 mg/200 mg qd
Indinavir/r800 mg/100 mg bid (PI-naive patients)
800 mg/200 mg bid (PI-experienced patients)
Lopinavir/r400 mg/100 mg bid
Saquinavir/r1000 mg/100 mg bid or 1600 mg/100 mg qd
(2000 mg/100 mg or 200 mg qd under evaluation)
Tipranavir/r500 mg/200 mg bid

Double-Boosted PIs

Double-boosted PI therapy is the combination of a boosted PI combination with another PI administered at therapeutic doses. This strategy has become a new area of investigation for the treatment of HIV-infected patients who have extensive resistance. In these patients, one boosted PI may retain activity despite the evolution of HIV variants that are resistant to the other.

Theoretically, favorable ritonavir-boosted combinations may include the use of agents that show synergy, complementary resistance patterns, or those with mutually exclusive resistance profiles. For example:

  • Saquinavir and lopinavir -- synergistic inhibition of HIV replication has been demonstrated between these agents in vitro.31

  • Saquinavir and atazanavir -- atazanavir has a unique I50L signature resistance mutation that produces increased susceptibility to indinavir, lopinavir, ritonavir, and saquinavir.32 Furthermore, atazanavir remains susceptible after selection of L90M, a primary mutation associated with resistance to saquinavir.14,22

  • Saquinavir and amprenavir -- these PIs have distinct mutations associated with reduced susceptibility (amprenavir, V32I, M46I/L, I47V, I50V, I54L/M, and I84V23; saquinavir G48V and L90M.14

  • Atazanavir and amprenavir -- substitution of I50L or I50V produces mutually exclusive resistance to atazanavir and amprenavir, respectively, without cross-resistance.22

However, no prospective comparative-outcome data regarding the efficacy of double-boosted PIs compared to single-boosted PIs are yet available. As multiple interactions with P-glycoprotein, CYP450 isoenzymes, and plasma-binding proteins influence PI pharmacokinetics, the net effect of combination regimens containing more than two PIs is very difficult to predict.

Studies of pharmacokinetic interactions of double-boosted PIs
The pharmacokinetic effects of adding an additional PI to a boosted regimen have been evaluated in a number of studies in healthy volunteers and HIV-infected patients. These studies show that although some combinations result in pharmacokinetic enhancement, others lead to significant reductions in drug exposure.

Saquinavir/r plus atazanavir. The combination of atazanavir 300 mg once daily with saquinavir/r 1600 mg/100 mg once daily was evaluated in HIV patients who had been receiving a stable antiretroviral regimen containing saquinavir/r and two NRTIs. Over 24 hours, the double-boosted regimen significantly increased saquinavir and ritonavir exposure (Table 3). Atazanavir concentration was not significantly affected.

Table 3. Effect of double-boosted regimen of saquinavir/r plus atazanavir on pharmacokinetics.33
Saquinavir≠ 112%≠ 42%≠ 60%
Ritonavir↓ 27%*≠ 34%≠ 41%
*Not significant.

Lopinavir/r plus fosamprenavir. The combination of fosamprenavir 700 mg bid and lopinavir/r 400 mg/100 mg bid compared with fosamprenavir/r 700 mg/100 mg bid was evaluated in healthy volunteers. The double-boosted regimen decreased amprenavir and lopinavir exposure (Table 4). Furthermore, similar decreases were observed in PI-experienced HIV patients (Table 5).

Table 4. Effect of double-boosted regimen of lopinavir/r plus fosamprenavir on pharmacokinetics in healthy volunteers.34
Amprenavir↓ 78%↓ 72%↓ 76%
Lopinavir↓ 49%↓ 22%↓ 25%

Table 5. Effect of double-boosted regimen of lopinavir/r plus fosamprenavir on pharmacokinetics in PI-experienced patients.35
Amprenavir↓ 69%*↓ 64%*
Lopinavir↓ 61%†↓ 48%‡
*P < 0.0001; †P = 0.0001; ‡P = 0.0008.

A study separating the time of dosing of fosamprenavir and lopinavir/r by 4 hours or 12 hours was conducted to examine the possibility that a chemical interaction within the gut was causing these negative pharmacokinetic interactions. Although dose separation had a favorable effect on lopinavir exposure (most likely due to the increased amount of ritonavir administered), it did not improve amprenavir exposure.34

The combination of ritonavir-boosted fosamprenavir 700 mg/100 mg bid with lopinavir/r 400 mg/100 mg bid decreased amprenavir exposure in healthy volunteers, to a similar degree (Table 6).

Table 6. Effect of double-boosted regimen of fosamprenavir/r plus lopinavir/r on pharmacokinetics.36
Amprenavir↓ 65%↓ 58%↓ 63%

Tipranavir/r plus saquinavir, amprenavir, or lopinavir. The combination of tipranavir/r 500 mg/200 mg bid with saquinavir 1000 mg bid, amprenavir 600 mg bid, or lopinavir 400 mg bid decreased exposure to all three PIs (Table 7).

Table 7. Effect of tipranavir/r on saquinavir, amprenavir, and lopinavir pharmacokinetics in double-boosted regimens.37
Saquinavir↓ 81%↓ 66%↓ 70%
Amprenavir↓ 56%↓ 40%↓ 45%
Lopinavir↓ 55%↓ 43%↓ 49%

The evidence collected to date indicates that double-boosted PI regimens can have potentially favorable or unfavorable pharmacokinetics (Table 8). Due to the paucity of pharmacokinetic data supporting the safety and efficacy of specific regimens in naive or treatment-experienced HIV-infected patient populations, it is highly advisable that therapeutic drug monitoring be utilized when prescribing double-boosted combinations, to ensure that reasonable exposure to antiretroviral drugs is achieved and maintained.

Table 8. Pharmacokinetic interactions of double-boosted PIs.
Potentially favorable pharmacokinetics
400 mg/100 mg bid
300 mg qd
1. Atazanavir Cmax and AUC similar, ≠ Cmin38
2. Lopinavir exposure similar to historical controls38
400 mg/100 mg
1000 mg bid
1. Lopinavir and saquinavir exhibit synergistic antiviral activity in vitro31
2. The reformulation of hard-gel saquinavir as a 500 mg tablet has reduced the pill burden from five capsules per day to two tablets per day27
3. Saquinavir exposure is largely unchanged by lopinavir/r.14
400 mg/100 mg
1000 mg bid
1. Nelfinavir Cmax and AUC similar, ≠ Cmin
2. Lopinavir ↓
3. Lopinavir/r should not be administered once daily in combination with nelfinavir18
1600 mg/100 mg
300 mg qd
1. Saquinavir exposure is substantially increased (Cmin, Cmax, and AUC)33
2. Hyperbilirubinemia was quite common (33%), but reversible on stopping atazanavir33
3. Trough concentrations of saquinavir may be insufficient for resistant virus; consider therapeutic drug monitoring in combination with phenotypic resistance testing
1000 mg/100 mg or 200 mg
700 mg
1. Saquinavir exposure was not significantly altered by the addition of fosamprenavir or vice versa39
2. Trough concentrations of saquinavir may be insufficient for resistant virus; consider therapeutic drug monitoring in combination with phenotypic resistance testing
Potentially unfavorable pharmacokinetics
533 mg/133 mg
1400 mg bid
1. Amprenavir Cmin concentrations ↓ 42% compared with fosamprenavir/r 700 mg/100 mg bid23
2. Lopinavir concentrations similar23
3. The double-boosted regimen was poorly tolerated, with a high incidence of gastrointestinal intolerance36
4. Optimal dosing unknown
400 mg/100 mg
600 mg or 800 mg bid
1. Similar AUC, ↓ Cmax, and ≠ Cmin, of indinavir with 600-mg vs 800-mg dose18
2. Lopinavir exposure ↓40
3. Combination not well tolerated
Contraindicated1. Increased risk of hyperbilirubinemia17
Not recommended1. Significant ↓ in saquinavir, lopinavir, and amprenavir exposure37
2. Optimal dosing unknown

PI-Chemokine Receptor Antagonist Interactions

CCR5 chemokine receptor antagonists under evaluation as antiretroviral agents for the treatment of HIV infection include maraviroc and vicriviroc. Like the PIs, these drugs are substrates of CYP3A4. In the case of maraviroc, there does not appear to be any clinically relevant inhibition or induction of CYP3A4 itself.41 Changes in drug exposure have been observed when these compounds are combined with other drugs that are inhibitors or inducers of CYP3A4. For example, pharmacokinetic interactions with saquinavir, ketoconazole, efavirenz, and lopinavir/r have been documented. Efavirenz-containing HAART regimens in HIV-infected patients reduced maraviroc exposure by approximately 50%, while lopinavir/r approximately doubled exposure.42 In a study of healthy volunteers, saquinavir and ketoconazole were found to have even greater effects on plasma concentrations of maraviroc (>3-fold increase in Cmax and >4-fold increase in AUC).43 Similarly, a dose-independent boosting of vicriviroc exposure was observed with ritonavir (Cmax ≠ approximately 500%; AUC ≠ approximately 350%).44 These data suggest that, if necessary, pharmacokinetic enhancement of CCR5 antagonists with CYP3A4 inhibitors will be possible.


Pharmacokinetic enhancement with ritonavir can improve the pharmacokinetic characteristics of PIs used in the treatment of HIV infection by increasing plasma trough concentrations and providing more sustained antiviral activity. Importantly, this helps to extend the dosing interval and reduce pill burden. In some cases, double-boosted PIs may also provide favorable pharmacokinetic interactions, although these are difficult to predict. Furthermore, intra- and inter-patient variation is likely a major confounder. Until more data are available, it is advisable to approach double-boosting with caution and to evaluate individual patients regularly with therapeutic drug monitoring. Although ritonavir is the most potent boosting agent identified to date, it is associated with toxicity and adverse effects and is expensive. Although the boosting effects of other drugs used to treat HIV disease (such as ketoconazole) have been evaluated, they have been found to be less potent and have their own toxicity issues. Further studies to identify potent but less toxic boosting compounds are needed.

Read Part I, Part II and Part III of this article.


  1. Walmsley S, Bernstein B, King M, et al; for the M98-863 study team. Lopinavir-ritonavir versus nelfinavir for the initial treatment of HIV infection. N Engl J Med. 2002;346:2039-2046.

  2. Rodriguez-French A, Boghossian J, Gray GE, et al. The NEAT Study: A 48-week open-label study to compare the antiviral efficacy and safety of GW433908 versus nelfinavir in antiretroviral therapy-naive HIV-1-infected patients. J Acquir Immune Defic Syndr. 2004;35:22-32.

  3. Guidelines for the use of antiretroviral agents in HIV-1 infected adults and adolescents, May 4, 2006. Rockville, Md: US Department of Health and Social Services (DHHS), Panel on Clinical Practices for Treatment of HIV Infection. Available at: AdolescentGL.pdf. Accessed May 10, 2006.

  4. Becker SL. The role of pharmacological enhancement in protease inhibitor-based highly active antiretroviral therapy. Expert Opin Investig Drugs. 2003;12:401-412.

  5. Thiebaut F, Tsuruo T, Hamada H, Gottesman MM, Pastan I, Willingham MC. Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues. Proc Natl Acad Sci USA. 1987;84:7735-7738.

  6. Srinivas RV, Middlemas D, Flynn P, Fridland A. Human immunodeficiency virus protease inhibitors serve as substrates for multidrug transporter proteins MDR1 and MRP1 but retain antiviral efficacy in cell lines expressing these transporters. Antimicrob Agents Chemother. 1998;42:3157-3162.

  7. Lucia MB, Golotta C, Rutella S, Rastrelli E, Savarino A, Cauda R. Atazanavir inhibits P-glycoprotein and multidrug resistance-associated protein efflux activity. J Acquir Immune Defic Syndr. 2005;39:635-637.

  8. Aptivus (tipranavir) [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; 2005.

  9. van der Sandt ICJ, Vos CMP, et al. Assessment of active transport of HIV protease inhibitors in various cell lines and the in vitro blood-brain barrier. AIDS. 2001;15:483-491.

  10. Sankatsing SUC, Beijnen JH, Schinkel AH, Lange JMA, Prins JM. P glycoprotein in human immunodeficiency virus type 1 infection and therapy. Antimicrob Agents Chemother. 2004;48:1073-1081.

  11. Gutmann H, Fricker G, Drewe J, Toeroek M, Miller DS. Interactions of HIV protease inhibitors with ATP-dependent drug export proteins. Mol Pharmacol. 1999;56:383-389.

  12. Lucia MB, Rutella S, Leone G, Vella S, Cauda R. HIV-protease inhibitors contribute to P-glycoprotein efflux function defect in peripheral blood lymphocytes from HIV-positive patients receiving HAART. J Acquir Immune Defic Syndr. 2001;27:321-330.

  13. Ford J, Khoo SH, Back DJ. The intracellular pharmacology of antiretroviral protease inhibitors. J Antimicrob Chemother. 2004;54:982-990.

  14. Invirase (saquinavir mesylate) [package insert]. Nutley, NJ: Roche Pharmaceuticals; 2005.

  15. Zeldin RK, Petruschke RA. Pharmacological and therapeutic properties of ritonavir-boosted protease inhibitor therapy in HIV-infected patients. J Antimicrob Chemother. 2004;53:4-9.

  16. Granfors MT, Wang J-S, Kajosaari LI, Laitila J, Neuvonen J, Backman JT. Differential inhibition of cytochrome P450 3A4, 3A5 and 3A7 by five human immunodeficiency virus (HIV) protease inhibitors in vitro. Basic Clin Pharmacol Toxicol. 2006;98:79-85.

  17. Crixivan (indinavir sulfate) [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; 2005.

  18. Kaletra (lopinavir/ritonavir) [package insert]. North Chicago, Ill: Abbott Laboratories; 2005.

  19. Viracept (nelfinavir mesylate) [package insert]. New York, NY: Agouron Pharmaceuticals, Inc; 2004.

  20. Langmann P, Zilly M, Weissbrich B, Desch S, Väth T, Klinker H. Therapeutic drug monitoring of indinavir in HIV-infected patients undergoing HAART. Infection. 2002;30:13-16.

  21. Kashuba ADM. Use of pharmacokinetic enhancement in treatment-experienced patients. Presented at: Management of Treatment-Experienced Patients [CME Symposium at 45th Interscience Conference on Antimicrobial Agents and Chemotherapy]; December 17, 2005; Washington, DC.

  22. Reyataz (atazanavir sulfate) [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2005.

  23. Lexiva (fosamprenavir calcium) [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2005.

  24. Sham HL, Kempf DJ, Molla A, et al. ABT-378, a highly potent inhibitor of the human immunodeficiency virus protease. Antimicrob Agents Chemother. 1998;42:3218-3224.

  25. Boyd M, Duncombe C, Ruxrungtham K, et al. HIV- NAT 005: A randomised, open label trial of indinavir /ritonavir vs indinavir in combination with AZT/3TC for the treatment of HIV infection in nucleoside experienced patients. Results of 112 weeks follow up. Presented at: 9th Conference on Retroviruses and Opportunistic Infections; February 24-28, 2002; Seattle, Wash. Poster G30e.

  26. Gathe JC Jr, Ive P, Wood R, et al. SOLO: 48-week efficacy and safety comparison of once-daily fosamprenavir/ritonavir versus twice-daily nelfinavir in naive HIV-1-infected patients. AIDS. 2004;18:1529-1537.

  27. Antiviral Briefs. Pill burden reduced for saquinavir. AIDS Patient Care STDS. 2005;19:127-130.

  28. Dragsted UB, Gerstoft J, Pedersen C, et al; for the MaxCmin1 trial group. Randomized trial to evaluate indinavir/ritonavir versus saquinavir/ritonavir in human immunodeficiency virus type 1-infected patients: the MaxCmin1 trial. J Infect Dis. 2003;188:635-642.

  29. Dragsted UB, Gerstoft J, Youle M, et al; for the MaxCmin2 trial group. A randomized trial to evaluate lopinavir/ritonavir versus saquinavir/ritonavir in HIV-1-infected patients: the MaxCmin2 trial. Antivir Ther. 2005;10:735-743.

  30. Kurowski M, Sternfeld T, Sawyer A, Hill A, Möcklinghoff C. Pharmacokinetic and tolerability profile of twice-daily saquinavir hard gelatin capsules and saquinavir soft gelatin capsules boosted with ritonavir in healthy volunteers. HIV Med. 2003;4:94-100.

  31. Molla A, Mo H, Vasavanonda S, et al. In vitro antiviral interaction of lopinavir with other protease inhibitors. Antimicrob Agents Chemother. 2002;46:2249-2253.

  32. Weinheimer S, Discotto L, Friborg J, Colonno R. Recombinant HIV Gag-Pol proteins display unique I50L phenotype of selective atazanavir resistance and increased susceptibility to other PI. Presented at: 11th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2004; San Francisco, Calif. Poster 625.

  33. Boffito M, Kurowski M, Kruse G, et al. Atazanavir enhances saquinavir hard-gel concentrations in a ritonavir-boosted once-daily regimen. AIDS. 2004;18:1291-1297.

  34. Corbett AH, Davidson L, Park JJ, et al. Dose separation strategies to overcome the pharmacokinetic interaction of a triple protease inhibitor regimen containing fosamprenavir, lopinavir, and ritonavir. Presented at: 11th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2004; San Francisco, Calif. Poster 611.

  35. Kashuba ADM, Tierney C, Downey GF, et al. Combining fosamprenavir with lopinavir/ritonavir substantially reduces amprenavir and lopinavir exposure: ACTG protocol A5143 results. AIDS. 2005;19:145-152.

  36. Wire MB, Naderer OJ, Masterman AL, Lou Y, Stein DS. The pharmacokinetic (PK) interaction between GW433908 (908) with lopinavir (LPV)/ritonavir (RTV) (APV10011 and APV10012). Presented at: 11th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2004; San Francisco, Calif. Poster 612.

  37. Walmsley S, Leith J, Katlama C, et al. Pharmacokinetics and safety of tipranavir (TPV/r) alone or in combination with saquinavir (SQV), amprenavir (APV), or lopinavir (LPV): interim analysis of BI1182.51. Presented at: XV International AIDS Conference; July 11-16, 2004; Bangkok, Thailand. Abstract WeOrB1236.

  38. Pham P, Parsons T, Flexner C, et al. Pharmacokinetic interaction between atazanavir and lopinavir/ritonavir. Presented at: 13th Conference on Retroviruses and Opportunistic Infections; February 5-8, 2006; Denver, Colo. Abstract 585.

  39. Boffito M, Dickinson L, Hill A, Back D, et al. Steady-state pharmacokinetics of saquinavir hard-gel/ritonavir/fosamprenavir in HIV-1-infected patients. J Acquir Immune Defic Syndr. 2004;37:1376-1384.

  40. Antoniou T, Tseng AL, van Heeswijk RPG, Walker SE, Giguere P, Phillips EJ. Steady-state pharmacokinetics and tolerability of indinavir-lopinavir/r combination therapy in antiretroviral-experienced patients. Ther Drug Monit. 2005;27:779-781.

  41. Abel S, Russell D, Ridgway C, et al. Effect of CCR5 antagonist UK-427,857 on the pharmacokinetics of CYP3A4 substrates in healthy volunteers. Presented at: 5th International Workshop on Clinical Pharmacology of HIV Therapy; April 1-3, 2004; Rome, Italy. Poster 5.7.

  42. Muirhead G, Pozniak A, Gazzard B, et al. A novel probe drug interaction study to investigate the effect of selected ARV combinations on the pharmacokinetics of a single oral dose of maraviroc (UK-427,857) in HIV +ve subjects. Presented at: 12th Conference on Retroviruses and Opportunistic Infections; February 22-25, 2005; Boston, Mass. Poster 663.

  43. Abel S, Russell D, Ridgway C, Medhurst C, Weissgerber G, Muirhead G. Effect of CYP3A4 inhibitors on the pharmacokinetics of CCR5 antagonist UK-427,857 in healthy volunteers. Presented at: 5th International Workshop on Clinical Pharmacology of HIV Therapy; April 1-3, 2004; Rome, Italy. Poster 5.8.

  44. Seiberling M, Kraan M, Keung A, Martinho M, Sansone A. Similar increase in SCH 417690 plasma exposure with coadministration of varying doses of ritonavir in healthy volunteers. Presented at: 3rd International AIDS Society Conference; July 24-27, 2005; Rio de Janeiro, Brazil. Poster TuPe3.1B06.

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