Management of drug-to-drug interactions between cyclosporine A and the protease-inhibitor lopinavir/ritonavir in liver-transplanted HIV-infected patients

Vogel, Martin; Voigt, Esther; Michaelis, Hans-Christoph; Sudhop, Thomas; Wolff, Martin; Türler, Andreas; Sauerbruch, Tilman; Rockstroh, Jürgen K.; Spengler, Ulrich

doi:10.1002/lt.20165

Cited by 91 publications

(66 citation statements)

References 20 publications

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“…Because of the flat absorption/elimination profiles of cyclosporine during combination with ritonavirboosted HAART therapy, cyclosporine exposure could be reliably monitored long-term by measuring cyclosporine trough concentrations. 27 Treatment of posttransplant patients coinfected with HIV/HCV with antiretrovirals and telaprevir could be even more challenging, depending on the drugs involved. Telaprevir levels are not significantly affected by ritonavir 28 ; however, whether the net effect of antiretroviral drugs on cyclosporine and tacrolimus PK would be similar or different is hard to predict, as these drugs may have their own effects.…”

Section: Discussionmentioning

confidence: 99%

Effect of telaprevir on the pharmacokinetics of cyclosporine and tacrolimus

Heeswijk²,

et al. 2011

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The hepatitis C virus protease inhibitor telaprevir is an inhibitor of the enzyme cytochrome P450 3A, responsible for the metabolism of both cyclosporine and tacrolimus. This Phase I, open-label, nonrandomized, single-sequence study assessed the effect of telaprevir coadministration on the pharmacokinetics of a single dose of either cyclosporine or tacrolimus in two separate panels of 10 healthy volunteers each. In Part A, cyclosporine was administered alone as a single 100-mg oral dose, followed by a minimum 8-day washout period, and subsequent coadministration of a single 10-mg oral dose of cyclosporine with either a single dose of telaprevir (750 mg) or with steady-state telaprevir (750 mg every 8 hours [q8h]). In Part B, tacrolimus was administered alone as a single 2-mg oral dose, followed by a minimum 14-day washout period, and subsequent coadministration of a single 0.5-mg dose of tacrolimus with steady-state telaprevir (750 mg q8h). Coadministration with steady-state telaprevir increased cyclosporine dose-normalized (DN) exposure (DN_AUC 0-' ) by approximately 4.6-fold and increased tacrolimus DN_AUC 0-' by approximately 70-fold. Coadministration with telaprevir increased the terminal elimination half-life (t ½ ) of cyclosporine from a mean (standard deviation [SD]) of 12 (1.67) hours to 42.1 (11.3) hours and t ½ of tacrolimus from a mean (SD) of 40.7 (5.85) hours to 196 (159) hours. Conclusion: In this study, telaprevir increased the blood concentrations of both cyclosporine and tacrolimus significantly, which could lead to serious or lifethreatening adverse events. Telaprevir has not been studied in organ transplant patients; its use in these patients is not recommended because the required studies have not been completed to understand appropriate dose adjustments needed for safe coadministration of telaprevir with cyclosporine or tacrolimus, and regulatory approval has not been obtained.

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Section: Discussionmentioning

confidence: 99%

Effect of telaprevir on the pharmacokinetics of cyclosporine and tacrolimus

Heeswijk²,

et al. 2011

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“…Drug regimen alterations that required repeating the protocol PK studies occurred in 22 patients; the 1 Total of 38 organs; includes two subjects who had combined liver-kidney transplants, one subject had a liver graft that failed and was retransplanted with a combined liver-kidney graft. 2 One subject with a failed renal allograft had a second renal transplant. 3 Includes five studies on combination CsA and SrL.…”

Section: Subject Characteristicsmentioning

confidence: 99%

Immunosuppressant Pharmacokinetics and Dosing Modifications in HIV-1 Infected Liver and Kidney Transplant Recipients

Frassetto¹,

Browne²,

Cheng³

et al. 2007

American Journal of Transplantation

158

140

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Solid organ transplantation in human immunodeficiency virus (HIV)-infected individuals requiring con) is complicated by significant drug interactions. To assist in appropriate clinical management, we describe the pharmacokinetics and dosing modifications in 35 patients (20 kidney, 13 liver and two kidney-liver HIV-infected subjects with end-stage kidney or liver disease), on both IS and NNRTIs, PIs, and combined NNRTIs + PIs, in studies done at weeks 2-4 and/or 12 weeks after transplantation or after a change in IS or ARV drug regimen (n = 97 studies). CsA, SrL and FK concentrations were measured in whole blood by LC/MS. HIV-infected transplant recipients using PIs with IS had marked increases in CsA, FK or SrL trough levels compared to those on NNRTIs alone or to patients not on ARVs, necessitating either a reduction in dose or an increase in dosing interval. Subjects on efavirenz (EFV) and CsA required much higher doses of CsA than those using any other ARV. Changes in antiretroviral therapy should be carefully managed to avoid insufficient immunosuppression or toxicity due to drug interactions.

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“…Hence, based on pharmacokinetic interaction, RTV-boosted HAART has great potential for drug-drug interactions with CYP3A and Pgp. 13,14) Moreover, it was also reported that RTV is not only a potent inhibitor but also a potent inducer of CYP3A and Pgp with chronic use. 15,16) This contradictory characteristic of RTV would further complicate drug-drug interactions and facilitate the clinical difficulties of HIV patients whose HIV infection must be controlled by RTV-boosted HAART.…”

mentioning

confidence: 99%

Long-Term Pharmacokinetic Efficacy and Safety of Low-Dose Ritonavir as a Booster and Atazanavir Pharmaceutical Formulation Based on Solid Dispersion System in Rats

Fukushima

Haraya

Terasaka

et al. 2008

Biological & Pharmaceutical Bulletin

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The use of highly active antiretroviral therapy (HAART) has resulted in significant reductions in human immunodeficiency virus (HIV)-related mortality and morbidity, and transformed HIV disease to a chronic syndrome.1,2) Despite improved clinical outcomes with protease inhibitor (PI)-based HAART regimens, there are still many problems, such as high pill burden, resistance to antiretrovirals and metabolic abnormalities (e.g., hyperlipidemia, hyperglycemia). [3][4][5] Moreover, the transformation of HIV disease to a chronic syndrome also practically means that once patients start HAART, they should receive the drugs included in the HAART regimen for the rest of their life; therefore, not only long-term efficacy but also the safety of these drugs are of clinical significance.Atazanavir (ATV) is an azapeptide compound and the seventh addition to the family of HIV PIs. ATV may have an advantage over other PIs because of once-daily dosing, a distinct resistance profile, and a lack of insulin resistance and lipid increase.6,7) With these advantages, ATV has been successfully used in treatment-native and -experienced HIV patients.8) Similar to other PIs, however, ATV is poorly watersoluble and is known as a substrate of both a hepatic metabolizing enzyme, cytochrome P450 (CYP) 3A, and an intestinal drug efflux pump, P-glycoprotein (Pgp), thus resulting in low oral bioavailability (BA). 9) Clinically, to resolve this disadvantage, ATV is generally used with low-dose ritonavir (RTV) in the HAART regimen. RTV is also classified as a PI and is well known as a potent inhibitor of both CYP3A and Pgp. With this potent inhibition property, low-dose RTV has been demonstrated clinically to boost the BA of another concomitant PI. [10][11][12] HIV patients are typically treated with multiple drugs in addition to their HAART regimen. Hence, based on pharmacokinetic interaction, RTV-boosted HAART has great potential for drug-drug interactions with CYP3A and Pgp. 13,14) Moreover, it was also reported that RTV is not only a potent inhibitor but also a potent inducer of CYP3A and Pgp with chronic use. 15,16) This contradictory characteristic of RTV would further complicate drug-drug interactions and facilitate the clinical difficulties of HIV patients whose HIV infection must be controlled by RTV-boosted HAART. In addition, there are few studies on the effect of chronic use of lowdose RTV on its boosting effect and on pharmacokinetic interactions with concomitant drugs in addition to the HARRT regimen.We previously reported that the ATV pharmaceutical formulation, the physical mixture of Gelucire 50/13 and ATV solid dispersion in sodium lauryl sulfate (ATV-SLS SDϩG), could improve the BA of ATV without pharmacokinetic interaction with RTV.17) The aim of this study was to investigate the long-term efficacy and safety of RTV-boosted ATV and ATV-SLS SDϩG and to directly compare both formulations; therefore, we administered RTV-boosted ATV or ATV-SLS SDϩG for 14 d to rats and compared the pharmacoki- Atazanavir (ATV) is clinically coadminis...

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Management of drug-to-drug interactions between cyclosporine A and the protease-inhibitor lopinavir/ritonavir in liver-transplanted HIV-infected patients

Cited by 91 publications

References 20 publications

Effect of telaprevir on the pharmacokinetics of cyclosporine and tacrolimus

Effect of telaprevir on the pharmacokinetics of cyclosporine and tacrolimus

Immunosuppressant Pharmacokinetics and Dosing Modifications in HIV-1 Infected Liver and Kidney Transplant Recipients

Long-Term Pharmacokinetic Efficacy and Safety of Low-Dose Ritonavir as a Booster and Atazanavir Pharmaceutical Formulation Based on Solid Dispersion System in Rats

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