Original Article Pharmacokinetics of Atazanavir/Ritonavir Once Daily and Lopinavir/Ritonavir Twice and Once Daily Over 72 H Following Drug Cessation
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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 © 2008 International Medical Press 1359-6535 901 Boffito.indd 901 20/10/08 13:49:01 M Boffito et al. 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 differ- ent 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 902 © 2008 International Medical Press Boffito.indd 902 20/10/08 13:49:01 Protease inhibitor concentration persistence for 10 days, with the omission of the evening lopinavir/