Original Article Pharmacokinetics of Atazanavir/Ritonavir Once Daily and Lopinavir/Ritonavir Twice and Once Daily Over 72 H Following Drug Cessation

Antiviral Therapy 13:901–907

Original article Pharmacokinetics of atazanavir/ritonavir once daily and lopinavir/ritonavir twice and once daily over 72 h following drug cessation

Marta Boffito1*, Laura Else 2, David Back2, Jessica Taylor1, Saye Khoo2, Marta Sousa1, Anton Pozniak1, Brian Gazzard1 and Graeme Moyle1

1St Stephen’s Centre, Chelsea and Westminster Hospital, London, UK 2Department of Pharmacology, University of Liverpool, Liverpool, UK

*Corresponding author: E-mail: [email protected]

Background: We investigated the pharmacokinetics of half-life over the respective dosing intervals (7.15 and atazanavir/ritonavir once daily and lopinavir/ritonavir twice 4.88 h for 0–12 and 0–24 h, respectively). No partici- and once daily over 72 h following drug intake cessation. pant on atazanavir had concentrations below the min- Methods: This was an open-label, three-session, imum effective concentration (MEC) of 150 ng/ml at pharmacokinetic trial. Healthy volunteers received ata- 24 h. In total, 44% of the participants on lopinavir once zanavir/ritonavir 300/100 mg once daily and lopinavir/ daily had concentrations below the MEC of 1,000 ng/ml ritonavir 400/100 mg twice daily and 800/200 mg once at 24 h. At 16 h and 20 h, 13% and 63% of participants daily separately for 10 days. Pharmacokinetic profiles were below target for twice daily lopinavir, respectively. were assessed for each phase on day 10 over 72 h. At 36 h, all participants on lopinavir and 31% on ata- Pharmacokinetic parameters were determined over 12 zanavir were below target. Ritonavir area under the or 24 h and to the last measurable concentration by plasma concentration–time curve was 30% lower and non-compartmental methods. 26% higher when dosed at 100 mg or 200 mg with Results: Sixteen participants completed the study. lopinavir versus atazanavir. Geometric mean terminal elimination half-life to 72 h Conclusions: This study investigated the pharmacokinetic of atazanavir was 8.35 h and not different from the forgiveness of two boosted protease inhibitors. Whereas 0–24 h half-life (9.91 h). Terminal elimination half- the decline in lopinavir concentrations occured rapidly as life of lopinavir was 2.33 h (twice daily) and 2.44 h the boosting effect of ritonavir diminished, the rate of (once daily). These values were lower compared with the decline of atazanavir remained constant to 72 h.

Introduction

Combination antiretroviral therapy has transformed the patients [1]. Importantly, most protease inhibitors management of HIV infection and dramatically reduced must be coadministered with low dose ritonavir (100 HIV-related morbidity and mortality [1]. Despite these or 200 mg daily) in order to enhance patient exposure benefits, taking antiretroviral therapy can be challeng- to the full-dose protease inhibitor, thus preventing or ing. Many of the combination regimens are complex, overcoming resistance and allowing less frequent dos- have important adverse effects, can be difficult for ing. The advantages offered by ritonavir boosting are patients to adhere to and could lead to antiretroviral primarily attributable to its pharmacokinetic proper- drug resistance [1]. These concerns continue to limit ties. Ritonavir reduces the metabolism of concomitantly the success of antiretroviral therapy and complicate the administered protease inhibitors and changes their management of HIV-infected patients. pharmacokinetic parameters by inhibiting cytochrome The combination of a protease inhibitor and two P450 (mainly the isoform 3A4 [CYP3A4]) [2]. nucleoside or nucleotide reverse transcriptase inhibitors Boosted protease inhibitors differ in terms of dosing (N[t]RTIs) has been shown to achieve durable viral sup- schedule. Some are approved for once daily use; oth- pression in most antiretroviral-naive and -experienced ers are not, but in clinical practice are administered

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once daily to antiretroviral-naive patients in order to especially when their plasma concentrations decline simplify the daily dosing schedule and reduce the likeli- rapidly because of short half-lives. Delaying drug dos- hood of missed doses [1]. ing and allowing drug concentrations to fall to subther- Atazanavir is a potent HIV protease inhibitor that apeutic levels might lead to poorer virological control shows efficacy in both antiretroviral-naive and experi- and the emergence of resistance. However, information enced patients [3,4]. Atazanavir is a substrate of CYP3A4 on how frequently doses must be delayed in order to and coadministration with ritonavir has been shown to facilitate the emergence of resistance is lacking. significantly increase plasma atazanavir concentrations Recently, a study by Cohen et al. [9] examined the [4]. It has good oral bioavailability and pharmaco- feasibility of intermittent antiretroviral combination ther- kinetic properties that allow once daily dosing, either apy taken 5 days a week, with two consecutive days off. with or without ritonavir [4]. In the United States, ata- The study found that doses might be missed in the case of zanavir has been approved for first-line use either with regimens containing long half-life drugs, such as the non- or without ritonavir boosting, whereas in Europe it is NRTI efavirenz. However, the strategy appeared much only licensed for use in treatment-experienced patients, riskier for patients on protease inhibitors. In fact, five of boosted by ritonavir [1]. the six individuals on lopinavir/ritonavir or saquinavir/ Coformulated lopinavir/ritonavir-based antiretroviral ritonavir had subtherapeutic drug concentrations at the therapy (Kaletra®, Abbott Laboratories, North Chicago, end of the second day off therapy, suggesting that despite IL, USA) has shown durable virological treatment efficacy the presence of the ritonavir-boosting effect, lopinavir in clinical trials in both treatment-naive and -experienced and saquinavir plasma concentrations decline rapidly. patients [5] and is generally well tolerated. In this study we assessed the pharmacokinetics of The rapid and extensive first-pass oxidative metabo- atazanavir/ritonavir once daily and lopinavir/ritonavir lism of lopinavir in the liver is mediated primarily by twice and once daily over 72 h following drug intake CYP3A4/5 isoenzymes; ritonavir inhibits the activity cessation. of CYP3A4 in a concentration-dependent manner in human liver microsomes resulting in increased plasma Methods lopinavir concentrations [5]. Lopinavir/ritonavir has been approved for twice daily Participants and ethics use (400/100 mg) in Europe and for twice (400/100 mg) The study protocol was approved by the Riverside and once (800/200 mg) daily use in the United States. Research Ethics Committee (London, UK) and by the Different clinical trials have shown similar virologi- Medicines and Healthcare products Regulatory Agency cal responses when comparing twice with once daily (London, UK) and was conducted according to the administration (in combination with two N[t]RTIs) in Declaration of Helsinki. patients with baseline viral loads <100,000 copies/ml. Written informed consent was obtained from healthy However, when comparing outcomes between these male and female volunteers aged between 18 and 65 treatments for patients with plasma HIV RNA levels years. Before entering the study, the volunteers were >100,000 copies/ml, a significant difference favouring established as HIV-negative and in good health by twice daily dosing was observed [6,7]. medical history, physical examination, electrocardio- Interestingly, protease inhibitors that are boosted by gram and standard haematological and blood chem- ritonavir could themselves affect ritonavir pharmaco- istry tests. None of the volunteers were receiving any kinetics. An analysis of several crossover pharmaco- concomitant medication, including oral contraceptives kinetic trials and clinical datasets showed that ritonavir or natural products. concentrations were different in the presence of different full-dose protease inhibitors [8]. Whereas slightly Study design higher than expected concentrations have been observed This was an open-label, three-session, pharmacokinetic following the administration of 100 mg of ritonavir trial carried out at the Pharmacokinetic Unit of the with atazanavir, significantly lower concentrations have St Stephen’s Centre, Chelsea and Westminster Hospital, been observed in the presence of lopinavir, fosampre- London, UK. navir and tipranavir [8]. This might be explained by During session one, volunteers were administered the different effects that the protease inhibitors have on atazanavir/ritonavir 300/100 mg once daily in the CYP3A4 activity, as this isoenzyme is also responsible morning for 10 days. On study days 10–13, atazanavir for ritonavir metabolism itself. and ritonavir plasma concentrations were assessed pre- Adherence to antiretroviral therapy is key for suc- dose and 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, cessful treatment of HIV-infected persons [1]. Theoreti- 48, 60 and 72 h after dose administration. cally, antiretroviral agents should also be taken follow- After a washout period of 7 days, all participants were ing any restrictions on food and at the right time of day, administered lopinavir/ritonavir 400/100 mg twice daily

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for 10 days, with the omission of the evening lopinavir/ Intraindividual changes in atazanavir and lopinavir ritonavir dose on day 27. On study day 27, a witnessed terminal elimination half-life over 72 h relative to the dose of lopinavir/ritonavir 400/100 mg was adminis- half-life observed within the dosing interval were assessed tered in the morning and blood was drawn over 72 h at using geometric mean ratios (GMRs) with 90% CIs. The the same time points reported above. Following a second CIs were determined using logarithms of the individual washout period of 7 days, lopinavir/ritonavir was admin- geometric mean values and the calculated values were istered at 800/200 mg once daily for 10 days and drug then expressed as linear values. Differences between the concentrations were measured on study days 44–47, over half-lives were considered significant when the CI did 72 h following the last dose. On the pharmacokinetic not cross the value of one. days, the study medication was taken with a standard- Intraindividual changes in ritonavir pharmaco- ized breakfast (626 Kcal) and 240 ml of water. kinetic parameters were also evaluated by calculating GMRs and 90% CIs. The ritonavir concentrations Safety assessment measured in the presence of atazanavir were used as The safety and tolerability of study medications were reference points. evaluated throughout the study on the basis of clinical Interindividual variability in drug pharmacokinetic adverse events (using the AIDS Clinical Trials Group parameters was expressed as a coefficient of variation toxicity grading scale to characterize abnormal find- ([s d /mean] ×100). ings), clinical laboratory tests (at screening, on days Linear regression analysis was used to assess any 1, 5, 22 and 39, and at follow-up), vital signs and correlation between body mass index (BMI) and ata- physical examinations. zanavir or lopinavir AUC. Comparison of pharmacokinetic parameters between males and females was Analytical and pharmacokinetic methods performed by analysis of covariance. Concentrations of atazanavir, lopinavir and ritonavir in All data were analysed with the statistical programme plasma were measured using validated HPLC–tandem SAS (version 9.1; SAS Institute Inc., Cary, NC, USA). mass spectrometry methods [10]. The lower limit of quantification was 26, 5 and 2 ng/ml for atazanavir, Results lopinavir and ritonavir, respectively. For concentrations below the assay limit of quantification, a value of one Study population half of the quantification limit (13.0, 2.5 and 1.0 ng/ml, A total of 18 volunteers were screened. Two withdrew respectively) was used. for personal reasons before any pharmacokinetic assess- The calculated pharmacokinetic parameters for ment and 16 were enrolled and completed all phases atazanavir, lopinavir and ritonavir were the trough of the study. Of the 16 evaluable participants, median

plasma concentration (Ctrough) defined as the 12 h (for age was 42 years (range 25–55) and median BMI was twice daily administration) or 24 h (for once daily 26 kg/m2 (range 20–32). Six (37.5%) were females, 11 administration) concentration after the observed dose, were Caucasian, three were Hispanic and two were

the maximum observed plasma concentration (Cmax) Black. No major protocol deviations were recorded and the area under the plasma concentration–time during the study. curve (AUC) from 0–12 h (for twice daily administration), from 0–24 h (for once daily administration) and Pharmacokinetics from 0–72 h (for all dosages). The half-life was deter- Geometric mean values and 90% CIs for the steady-state mined from the elimination phase within the normal pharmacokinetic parameters measured over the sched- dosing interval of 0–12 h (for twice daily administra- uled dosing interval and over 72 h for atazanavir, lopi- tion) or 0–24 h (for once daily administration) and navir and ritonavir are summarized in Table 1. Plasma as a terminal elimination half-life, to the last measur- concentration–time curves for atazanavir, lopinavir and able concentration within 72 h. All pharmacokinetic ritonavir are shown in Figure 1. The atazanavir geo- parameters were calculated using actual blood sam- metric mean terminal half-life over 72 h was 8.35 h and pling times and non-compartmental modelling tech- was slightly, but significantly, reduced ∼( 16%) relative niques (WinNonlin Professional™ software version to the 0–24 h dosing interval half-life (9.91 h, GMR 5.0; Pharsight Corp., Mountain View, CA, USA). 0.84 [90% CI 0.76–0.94]). Geometric mean terminal half-life to 72 h of lopinavir Statistical analyses was 2.3 h following twice daily dosing and 2.44 h fol- Descriptive statistics, including geometric mean values lowing once daily dosing. These values were significantly and 90% confidence intervals (CIs), were calculated reduced (∼67% for twice daily dosing and ∼50% for for atazanavir, lopinavir and ritonavir pharmaco- once daily dosing) compared with the half-life measured kinetic parameters. over the respective dosing intervals: 7.15 and 4.88 h

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Table 1. Geometric mean values and 90% confidence intervals for the steady-state pharmacokinetic parameters measured over the scheduled dosing intervals*

Atazanavir/ritonavir 300/100 mg Lopinavir/ritonavir 400/100 mg Lopinavir/ritonavir 800/200 mg Atazanavir Ritonavir Lopinavir Ritonavir Lopinavir Ritonavir 0–24 h 0–72 h 0–24 h 0–72 h 0–12 h 0–72 h 0–12 h 0–72 h 0–24 h 0–72 h 0–24 h 0–72 h Parameter Day 10 Days 10–13 Day 10 Days 10–13 Day 27 Days 27–30 Day 27 Days 27–30 Day 44 Days 44–47 Day 44 Days 44–47

AUC, 34,556 43,248 7,268 7,692 88,697 117,661 4,456 5,401 155,593 163,007 9,146 9,483 ng•h/ml (31,063– (36,526– (6,318– (6,687– (79,480– (100,951– (3,545– (4,304– (141,611– (148,052– (8,428– (8,736– 43,547) 51,207) 8,361) 8,848) 98,983) 137,138) 5,602) 6,779) 182,908) 193,040) 10,804) 11,208)

Cmax, 3,257 3,257 966 966 10,265 10,265 779 779 12,025 12,025 1,380 1,380 ng/ml (2,996– (2,996– (878– (878– (9,515– (9,515– (619– (619– (11,147– (11,147– (1,249– (1,249– 3,829) 3,829) 1,166) 1,166) 11,075) 11,075) 979) 979) 13,459) 13,459) 1,728) 1,728)

Ctrough, 636 ND 40 ND 4,597 ND 135 ND 1,283 ND 35 ND ng/ml (491– (30– (3,790– (104– (877– (26– 824) 53) 5,575) 176) 1,877) 47) Half-life, h 9.91 8.35 5.34 6.85 7.15 2.33 3.42 4.90 4.88 2.44 4.06 4.60 (8.96– (7.54– (4.61– (5.63– (5.67– (2.06– (3.10– (4.03– (3.81– (2.07– (3.81– (4.02– 11.94) 9.25) 6.18) 8.33) 9.03) 2.64) 3.77) 5.95) 6.24) 2.89) 4.45) 5.28)

All values shown are geometric mean values (95% confidence interval). *Scheduled dosing intervals were 24 h for atazanavir/ritonavir 300/100 mg and lopinavir/ ritonavir 800/200 mg, 12 h for lopinavir/ritonavir 400/100 mg and 72 h for atazanavir, lopinavir and ritonavir. AUC, area under the plasma concentration–time curve;

Cmax, maximum observed plasma concentration; Ctrough, trough plasma concentration; ND, not detectable.

Figure 1. Steady-state plasma concentrations and geometric mean concentration–time curves* A 10,000

1,000 Atazanavir MEC=150 ng/ml 100

10 LOQ=26 ng/ml Atazanavir, ng/ml Atazanavir,

1 04812162024283236 40 44 48 52 56 60 64 68 72 Time post-dose, h B C 100,000 100,000 10,000 10,000 Lopinavir MEC=1,000 ng/ml Lopinavir MEC=1,000 ng/ml 1,000 1,000

100 100

Lopinavir, ng/ml Lopinavir, LOQ=5 ng/ml

Lopinavir, ng/ml Lopinavir, 10 LOQ=5 ng/ml 10

1 1 04812162024 28 32 36 40 44 48 52 56 60 64 68 72 04812162024 28 28 36 40 44 48 52 56 60 64 68 72 Time post-dose, h Time post-dose, h

*Geometric mean concentration–time curves denoted by thick black lines. (A) Atazanavir/ritonavir 300/100 mg once daily. (B) Lopinavir/ritonavir 400/100 mg twice daily. (C) Lopinavir/ritonavir 800/200 mg once daily. LOQ, limit of quantification; MEC, minimum effective concentration.

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for the 0–12 and 0–24 h dosing intervals, respectively The interindividual variability in Ctrough of atazanavir, (GMR [90% CI] 0.33 [0.25–0.43] for twice daily dosing lopinavir, and ritonavir administered twice and once and 0.50 [0.38–0.66] for once daily dosing). daily was 63%, 48% and 86%, respectively. When coadministered with atazanavir, the low-dose Interestingly, when comparing ritonavir pharmaco- ritonavir geometric mean terminal elimination half-life kinetic parameters, significantly lower concentrations was significantly longer ∼( 28%) relative to the half-life were observed when 100 mg ritonavir was adminis- observed over the 0–24 h dosing interval (GMR [90% tered with 400 mg lopinavir than with atazanavir

CI] 1.28 [1.02–1.61]). Equally, in the presence of lopi- (GMR [90% CI] AUC0–72 0.70 [0.58–0.83], Cmax 0.81 navir, following twice daily and once daily dosing, the [0.67–0.97] and half-life over 72 h 0.72 [0.60–0.86]. ritonavir terminal elimination half-life was significantly Moreover, when comparing these parameters during prolonged (43% and 13%) in comparison to the dosing 200 mg ritonavir administration with 800 mg lopi-

interval half-life over the 0–12 and 0–24 h dosing inter- navir and 100 mg with atazanavir, ritonavir Cmax and

vals (GMR [90% CI] 1.43 [1.15–1.78] for twice daily AUC0–24 were only 43% and 26% higher despite the dosing and 1.13 [1.02–1.26] for once daily dosing). double dose and its half-life was significantly lower Table 2 reports the number of participants with (GMR [90% CI] 0.76 [0.66–0.88] over 24 h and 0.67 concentrations below the proposed minimum effec- [0.56–0.80] over 72 h). tive concentration (MEC) for atazanavir and lopina- A significant relationship between lopinavir AUC vir at the time points studied over 72 h following drug (only when dosed twice daily) and BMI was observed intake cessation. (P=0.038), whereas no differences in lopinavir or ata- At the time of the next due dose (24 h for once daily zanavir pharmacokinetic parameters were seen between dosing and 12 h for twice daily dosing), no partici- males and females. pants had atazanavir concentrations below the MEC

of 150 ng/ml [11] (geometric mean Ctrough 636 ng/ml). Safety and tolerability Although no participants receiving lopinavir twice Treatment was generally well tolerated and no serious daily had lopinavir concentrations below the MEC adverse events occurred during the study. The most

of 1,000 ng/ml [11] at 12 h (geometric mean Ctrough common adverse events observed throughout the study 4,597 ng/ ml), 44% of participants on lopinavir once were diarrhoea, scleral icterus (during the atazanavir/ daily had concentrations <1,000 ng/ml at 24 h (geomet- ritonavir session) and headache reported in 8, 5 and 3 of

ric mean Ctrough 1,283 ng/ml), respectively. the volunteers, respectively. All adverse events were of At 48 h (once daily dosing) and 24 h (twice daily grade 1 or 2 of severity. No clinically relevant changes in dosing), the times at which dosing would be delayed by laboratory or cardiovascular variables were reported. an additional 24 h (once daily dosing) or 12 h (twice daily dosing) in the case of a participant omitting a Discussion single dose, 69% of participants on atazanavir, 100% on lopinavir once daily and 81% on lopinavir twice We report here the steady-state plasma pharmaco- daily were below the proposed MEC. kinetics of atazanavir/ritonavir (300/100 mg once daily)

Table 2. Number of participants with concentrations below the MEC for atazanavir and lopinavir at the time points studied over 72 h following drug intake cessation

Participants, n (%) Atazanavir 300/100 Lopinavir 400/100 Lopinavir 800/200 Time point, h <150 ng/ml <1,000 ng/ml <1,000 ng/ml

12* None None None 16 None 2 (13) None 20 None 10 (63) None 24† None 13 (81) 7 (44) 30 2 (13) 15 (94) 15 (94) 36 5 (31) 16 (100) 16 (100) 48‡ 11 (69) 16 (100) 16 (100) 60 16 (100) 16 (100) 16 (100) 72 16 (100) 16 (100) 16 (100)

*Indicates 12 h from intake cessation: end of twice daily dosing interval/time of next due twice daily dose. †Indicates 24 h from intake cessation: end of once daily dosing interval/time of next due once daily dose and 12 h beyond the time of next due twice daily dose. ‡Indicates 48 h from intake cessation: 24 h beyond the time of next due once daily dose. MEC, minimum effective concentration.

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and lopinavir/ritonavir (400/100 mg twice daily and to those observed in HIV-infected patients [18,19]. We 800/200 mg once daily) over 72 h following drug intake measured mean atazanavir concentrations of 763, 455 cessation, in 16 healthy male and female volunteers. and 262 ng/ml at 24, 30 and 36 h after dose adminis- Whereas atazanavir elimination half-life over 72 h tration, respectively. These values are higher than the was only 16% lower compared with the 24 h half- suggested MEC for atazanavir. life, the half-life measured for lopinavir over 72 h was Interestingly, we measured higher ritonavir concen- ≥50% lower than during the scheduled dosing intervals trations during coadministration with atazanavir than of 12 and 24 h. This shows a remarkable difference with lopinavir. Ritonavir is not only an inhibitor but between the two protease inhibitors; whereas lopinavir/ also a substrate of CYP3A4. Therefore, its plasma con- ritonavir disappears rapidly from plasma if a dose was centrations are increased in the presence of a moderate omitted at the end of the dosing interval, atazanavir CYP3A4 inhibitor such as atazanavir [8]. The slightly concentrations decline at a slower rate. Moreover, most longer plasma persistence of ritonavir might be one of participants had atazanavir concentrations higher than the reasons behind the slightly longer persistence of the suggested MEC 36 h following drug intake while on atazanavir than lopinavir. atazanavir/ritonavir. The clinical significance of the slower decay in ataza- Atazanavir/ritonavir and lopinavir/ritonavir were navir concentrations compared with lopinavir concen- well tolerated, with adverse events limited to a small trations remains unclear. These data confirm the findings number of study participants who reported grade 1 or of the FOTO study, in which short half-life drugs also 2 diarrhoea, scleral icterus and headache during the disappeared rapidly when doses were omitted over 48 h study period. [9]. However, data on how many antiretroviral doses Antiretroviral therapy is lifelong and adherence to drug can be delayed in order to prevent virological failure intake has been shown to be fundamental for treatment associated with the development of resistance are lack- success [12,13]. Importantly, preliminary data from recent ing. Nevertheless, the fast decay observed for lopinavir/ studies demonstrated that higher than anticipated levels ritonavir when dosed once daily suggests there is the of adherence are required in HIV therapeutics [12]. likelihood of the achievement of subtherapeutic concen- Antiretroviral combination regimens involve the trations that can explain the higher occurrence of viro- administration of three to four different agents charac- logical failure and development of protease inhibitor- terized by different half-lives. Therefore, the different related mutations observed in some clinical trials in the components of the regimen might persist in body fluids past [6,7]. HIV-infected patients on once daily lopina- and cells for different times. The precise effect of taking vir/ritonavir should therefore observe drug intake time the drug at the right time on therapeutic outcome has strictly, whereas this might not be as important for those not been fully measured. Although good adherence is taking a more forgiving drug such as atazanavir/ritona- crucial for virological success, a number of variables, vir. By contrast, it has been speculated that detectable such as time of intake, could modify the possibility of concentrations persisting below the MEC and within achieving such success. the hypothetical resistance selection window (or zone of Certain antiretroviral agents, when characterized by selective pressure) might also lead to the development of longer half-lives, might be more forgiving than others by mutations conferring drug resistance [20,21]. allowing for delayed doses without the achievement of In conclusion, our study has explored the pharma- subtherapeutic concentrations before the following dose. cokinetic forgiveness of two boosted protease inhibi- One of the limitations of this study was that the tors. Whereas the decline in lopinavir concentrations enrolled participants were healthy volunteers rather occurs rapidly as the boosting effect of ritonavir than HIV-infected patients. However, for safety reasons diminishes, the rate of decline of atazanavir remains HIV-infected patients could not be studied because in constant to 72 h, resulting in a delayed onset of sub- these individuals drug intake should not be stopped therapeutic concentrations. unless clinically required [14,15]. The potential for differences in drug disposition between HIV-infected Acknowledgements patients and HIV-negative patients is high and it is important to recognize that the pharmacokinetics of a We would like to thank St Stephen’s AIDS Trust Charity drug might be altered in persons with HIV infection for allowing us to undertake the study, Dr Richard Bertz compared with healthy individuals [16]. There are data for scientific advice, Mr Richard O’Connell for assis- indicating that atazanavir concentrations are lower tance with data management and Bristol Myers–Squibb in patients with HIV infection than in HIV-negative (Uxbridge, UK) for funding the study. healthy volunteers [17]. However, although the ata- The results of this study have been presented at zanavir concentrations measured in our study were the 11th European AIDS Conference, Madrid, Spain obtained from healthy volunteers, they were similar (24–27 October 2007).

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10. Dickinson L, Robinson L, Tjia J, Khoo S, Back D. Disclosure statement Simultaneous determination of HIV protease inhibitors amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir and saquinavir in human plasma by high- The authors declare no competing interests. performance liquid chromatography-tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life References Sci 2005; 829:82–90. 11. La Porte CJL, Back DJ, Blaschke T, et al. Updated guideline 1. Gazzard B, Bernard AJ, Boffito M, et al. British HIV to perform therapeutic drug monitoring for antiretroviral Association (BHIVA) guidelines for the treatment of HIV- agents. Rev Antivir Ther 2006; 3:4–14. infected adults with antiretroviral therapy (2006). HIV Med 2006; 7:487–503. 12. Bangsberg DR, Kroetz DL, Deeks SG. Adherence-resistance relationships to combination HIV antiretroviral therapy. 2. Moyle GJ, Back D. Principles and practice of HIV-protease Curr HIV/AIDS Rep 2007; 4:65–72. inhibitor pharmacoenhancement. HIV Med 2001; 2:105–113. 13. Claxton AJ, Cramer J, Pierce C. A systematic review of 3. Molina J‑M, Andrade-Villanueva J, Echevarria J, et al. the associations between dose regimens and medication Efficacy and safety of once-daily atazanavir/ritonavir compliance. Clin Ther 2001; 23:1296–1310. compared to twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine in ARV- 14. The Strategies for Management of Antiretroviral Therapy naive HIV-1-infected subjects: the CASTLE study, (SMART) Study Group, El‑Sadr WM, Lundgren JD, et al. 48‑week results. 15th Conference on Retroviruses and CD4+ count-guided interruption of antiretroviral treatment. Opportunistic Infections. 3–6 February 2008, Boston, N Engl J Med 2006; 355:2283–2296. MA, USA. Abstract 37. 15. Taylor S, Boffito M, Khoo S, Smit E, Back D. Stopping 4. Swainston Harrison T, Scott LJ. Atazanavir: a review of antiretroviral therapy. AIDS 2007; 21:1673–1682. its use in the management of HIV infection. Drugs 2005; 65:2309–2336. 16. Dickinson L, Khoo S, Back D. Differences in the 5. Oldfield V, Plosker GL. Lopinavir/ritonavir: a review of pharmacokinetics of protease inhibitors between healthy its use in the management of HIV infection. Drugs 2006; volunteers and HIV-infected patients. Curr Opin HIV AIDS 66:1275–1299. 2008; 3:296–305. 6. DeJesus E, Ortiz R, Khanlou H, et al. Efficacy and safety 17. Reyataz® (atazanavir). Package insert 2007. Bristol–Myers of darunavir/ritonavir versus lopinavir/ritonavir in ARV Squibb, Princeton, NJ, USA. treatment-naïve HIV-1-infected patients at week 48: ® ARTEMIS. 47th Interscience Conference on Antimicrobial 18. Reyataz (atazanavir). Summary of product characteristics Agents and Chemotherapy. 17–20 September 2007, 2007. Bristol–Myers Squibb, Uxbridge, UK. Chicago, IL, USA. Abstract H-718b. 19. Boffito M, Kurowski M, Kruse G, et al. Atazanavir 7. Mildvan D, Tierney C, Gross R, et al. Randomized enhances saquinavir hard-gel concentrations in a ritonavir- comparison in treatment-naive patients of once-daily vs boosted once-daily regimen. AIDS 2004; 18:1291–1297. twice-daily lopinavir/ritonavir-based ART and comparison of 20. González de Requena D, Bonora S, Garazzino S, et al. once-daily self-administered vs directly observed therapy. 14th Conference on Retroviruses and Opportunistic Infections. Nevirapine plasma exposure affects both durability of 25–28 February 2007, Los Angeles, CA, USA. Abstract 138. viral suppression and selection of nevirapine primary resistance mutations in a clinical setting. Antimicrob Agents 8. Boffito M, Hill A. Effect of protease inhbitors on ritonavir Chemother 2005; 49:3966–3969. pharmacokinetics. 8th International Workshop on Clinical Pharmacology of HIV Therapy. 16–18 April 2007, 21. Kempf D, King M, Bauer E, et al. Comparative incidence Budapest, Hungary. Abstract 50. and temporal accumulation of PI and NRTI resistance in HIV-infected subjects receiving lopinavir/ritonavir 9. Cohen CJ, Morris A, Bazner S, et al. The FOTO study: a pilot study of short-cycle treatment interruption, taking or nelfinavir as initial therapy. 10th Conference on antiretroviral medications for five days on, two days off Retroviruses and Opportunistic Infections. 10–14 February (FOTO), for those with viral load suppression on either PI 2003, Boston, MA, USA. Abstract 600. or EFV-based regimens. XV International AIDS Conference. 11–16 July 2004, Bangkok, Thailand. Abstract TuPeB4575.

Accepted for publication 17 July 2008

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