Case Report Drop in Trough Blood Concentrations of Tacrolimus After Switching from Nelfinavir to Fosamprenavir in Four HIV-Infected Liver Transplant Patients

Antiviral Therapy 13:739–742

Case report Drop in trough blood concentrations of tacrolimus after switching from nelfinavir to fosamprenavir in four HIV-infected liver transplant patients

Federico Pea1*, Marcello Tavio 2, Federica Pavan1, Angela Londero 2, Vittorio Bresadola 3, Gian Luigi Adani 3, Mario Furlanut 1 and Pierluigi Viale 2

1Institute of Clinical Pharmacology & Toxicology, Department of Experimental and Clinical Pathology and Medicine, Medical School, University of Udine, Udine, Italy 2Clinic of Infectious Diseases, Department of Medical and Morphological Research, Medical School, University of Udine, Udine, Italy 3Department of Surgery and Transplantation, Medical School, University of Udine, Udine, Italy

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

Solid organ transplantation in HIV-infected individuals ±0.48 mg/ day, 1–3 days before and 3 weeks after the requires concomitant use of immunosuppressants and switch, respectively; P=0.046) to attain the desired tar- antiretrovirals that may cause significant drug inter- get (8.7 ±2.3 ng/ml). Consistently, marked changes of actions. Here we report on a peculiar pharmacokinetic the concentration/dose ratio of tacrolimus were observed interaction between tacrolimus and protease inhibitors in all cases (27.2 ±9.7 ng/ml per mg/kg/day versus 9.7 (PIs) which occurred in four HIV-infected liver trans- ±4.0 ng/ml per mg/kg/day before and after the switch, plant patients who had to shift PI therapy from nelfi- respectively; P<0.001). Our findings suggest that fosam- navir to fosamprenavir as a consequence of regulatory prenavir may be less potent than nelfinavir in inhibiting restrictions. After the switch, tacrolimus trough blood tacrolimus clearance and support the need for higher tac- concentrations significantly dropped in all patients rolimus dosage to avoid insufficient immunosuppression (mean ±s d 6.9 ±2.6 versus 3.2 ±2.0 ng/ml before and in HIV-infected liver transplant patients when switching after the switch, respectively; P=0.01), so that a marked from nelfinavir to fosamprenavir or even when directly dosage increase was needed (0.29 ±0.14 versus 0.88 starting antiretroviral therapy with fosamprenavir.

Introduction

The current use of highly active antiretroviral therapy appropriately handling immunosuppressant therapy (HAART) has enhanced the overall life expectancy for under these circumstances [4,9]. patients with HIV [1]. Accordingly, orthotopic liver Here we report on a peculiar pharmacokinetic inter- transplantation (OLTx) has become a therapeutic action between PIs and tacrolimus, which occurred in option for selected HIV-infected patients concomitantly four HIV-infected OLTx patients who had to change affected by end-stage liver disease [2,3]. their HAART as a consequence of regulatory restric- Solid organ transplantation in HIV-infected individu- tions concerning nelfinavir. als requires concomitant use of immunosuppressants, On 5 June 2007, the European Medicines Agency like cyclosporin, sirolimus or tacrolimus, and antiretro- was warned by Roche Registration Limited of a harm- virals, including protease inhibitors (PIs) and/or non-nu- ful contamination affecting the production of nelfinavir cleoside reverse transcriptase inhibitors, and may there- due to unacceptably high levels of an impurity known fore be complicated by significant drug interactions [4]. as ethyl methanesulfonate. As a result, the drug was In HIV transplant patients, different PIs were shown recalled from the European Union market with imme- to cause marked increases of blood concentrations of diate effect [10]. At that time, four HIV-infected OLTx either cyclosporin [5] or tacrolimus [6–8], so that major patients (3 male, 1 female; age range 41–59 years; weight dosage reductions coupled with intensive therapeu- range 53–64 kg; range of time from OLTx 4–26 months) tic drug monitoring (TDM) have been advocated for followed at Udine University Hospital (Udine, Italy)

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Table 1. Changes of dosage and blood concentrations of tacrolimus after switching from nelfinavir to fosamprenavir in four HIV-infected liver transplant patients

Patient 1 Patient 2 Patient 3 Patient 4 Mean ±s d

FK dosage during NFV* 0.5 mg q24h 0.5 mg q48h 0.5 mg q72h 0.5 mg q48h 0.29 ±0.14

Last FK Cmin during NFV, ng/ml 10.8 6.2 5.5 5.2 6.9 ±2.6 † First FK Cmin after PI switch, ng/ml 5.7 3.3 0.9 2.8 3.2 ±2.0 FK dosage during fAMP, 1 mg q12h 0.5 mg q24h 0.5 mg q24h 1 mg q24h 1.00 ±0.71‡ 2 weeks after switching* § FK Cmin during fAMP, 11.1 8.8 5.9 8.7 8.6 ±2.1 2 weeks after switching, ng/ml FK dosage during fAMP, 1.5 mg q24h 0.5 mg q24h 0.5 mg q24h 1 mg q24h 0.88 ±0.48¶ 3 weeks after switching* # FK Cmin during fAMP, 10.9 10.3 6.0 7.5 8.7 ±2.3 3 weeks after switching, ng/ml

Values are expressed as means (±s d ) because the Kolmogorov–Smirnov test showed normal distribution. Statistical significance was tested by paired t-test. The desired

ranges of tacrolimus (FK) Cmin were 8–15 ng/ml for patients with less than 6 months from orthotopic liver transplantation (OLTx; patients 1 and 2) and 5–10 ng/ml in those † ‡ beyond 6 months from OLTx (patients 3 and 4). *Average dosage, mg/day. Significant (P=0.01) versus last tacrolimus Cmin during nelfinavir (NFV). Not significant (P=0.089) § ¶ # versus last FK dosage during NFV. Not significant (P=0.124) versus last FK Cmin during NFV. Significant (P=0.046) versus last FK dosage during NFV. Not significant

(P=0.153) versus last FK Cmin during NFV. Cmin, trough blood concentration; fAMP, fosamprenavir; q12h, every 12 h; q24h, every 24 h; q48h, every 48 h; q72h, every 72 h; TDM, therapeutic drug monitoring.

were receiving nelfinavir (1,250 mg every 12 h) in their for each mg/kg/day dose [ng/ml per mg/kg/day]) were HAART regimen. For all patients, nelfinavir represented observed in all of the cases after the switch (C/D pre- the major moiety potentially interfering with tacrolimus switch 27.2 ±7.6 ng/ml per mg/kg/day; C/D post-switch elimination, because the other co-administered antiret- 9.7 ±4.0 ng/ml per mg/kg/day; P<0.001) (Figure 1). rovirals were almost equal in all cases (tenofovir [n=4], No episodes of acute or chronic rejection had pre- lamivudine [n=3] and emtricitabine [n=1]) and were not viously been noted in any of the patients during both expected to cause significant drug interactions. the study period and the follow-up. At last TDM while on nelfinavir cotreatment, all of To the best of our knowledge, this is the first report the patients were receiving low tacrolimus doses (mean showing the pharmacokinetic drug–drug interaction ±s d 0.29 ±0.14 mg/day) for the maintenance of tac- occurring between fosamprenavir and tacrolimus

rolimus trough blood concentrations (Cmin) (determined and addressing the different relevance that nelfinavir by means of microparticulate enzyme immunoassay and fosamprenavir may have in impairing tacrolimus using an IMx Analyzer [Abbott Laboratories, Abbott clearance in HIV-infected liver transplant patients. Rome, Italy]) within the desired therapeutic range (6.9 Our findings seem to suggest that fosamprenavir may ±2.6 ng/ml) (Table 1). be less potent than nelfinavir in inhibiting tacrolimus As a consequence of the regulatory restriction, a clearance. We recognize that a 12 h pharmacokinetic switch from nelfinavir to fosamprenavir (1,400 mg study before and after the PI switch would have been every 12 h without a ritonavir booster in order to avoid more informative. However, this was simply an obser- an exaggerated toxicity risk) [5] was promptly decided. vational study that reports occurrences of daily clinical Fosamprenavir was preferred for two reasons: it has a practice, taking into consideration the wide acceptance

favourable tolerability profile and can be safely adminis- of drug Cmin as a valuable tool for optimal management tered without a ritonavir booster, providing comparable of immunosuppressant therapy in OLTx patients. efficacy in terms of virological response [11]. Fosamprenavir is a phosphate ester prodrug of

Interestingly, when shifting PI therapy, tacrolimus Cmin amprenavir with improved solubility over the parent significantly dropped in all of the patients (3.2± 2.0 ng/ml, drug, which is rapidly and almost completely hydro- P=0.01) (Table 1), so that a two- to fourfold increase lyzed to amprenavir and inorganic phosphate in the of tacrolimus dosage was needed (1.00 ±0.71 mg/day at gut epithelium during absorption; thus, amprenavir 2 weeks after switching, P=0.089; 0.88 ±0.48 mg/day represents the active moiety reaching the systemic at 3 weeks after switching, P=0.046) for maintenance circulation [12]. of the desired target (8.6 ±2.1 ng/ml at 2 weeks after Tacrolimus is primarily metabolized in the liver and switching [non significant, P=0.124]; 8.7 ±2.3 ng/ml in the gut by the cytochrome P450 enzyme CYP3A4 at 3 weeks after switching [non-significant, P=0.153]). [13], and it is well known that PIs, being potent inhibi- Consistently, marked changes of the concentration/dose tors of CYP3A4 activity, can reduce tacrolimus clear-

ratio (C/D) of tacrolimus (that is, blood Cmin normalized ance [13,14] even if differential inhibition among the

16_Pea.indd 740 22/7/08 13:26:19 Tacrolimus–protease inhibitor interactions in HIV-infected transplant patients

Figure 1. Concentration/dose ratio of tacrolimus over time shows the effect of switching nelfinavir to fosamprenavir on trough blood concentration of tacrolimus

Patient 1 Patient 2 Nelfinavir Fosamprenavir Nelfinavir Fosamprenavir 1,250 mg q12h 1,400 mg q12h 1,250 mg q12h 1,400 mg q12h 30 35

25 30

20 25

15 20

10 15

5 10

0 5 -30 -20 -10 010203040 -30 -20 -10 0102030 Time versus nelfinavir recall, days Time versus nelfinavir recall, days Tacrolimus concentration/dose ratio, ng/ml per mg/kg/day Tacrolimus Tacrolimus concentration/dose ratio, ng/ml per mg/kg/day Tacrolimus

Patient 3 Patient 4

Nelfinavir Fosamprenavir Nelfinavir Fosamprenavir 1,250 mg q12h 1,400 mg q12h 1,250 mg q12h 1,400 mg q12h 50 25

40 20

30 15

20 10

10 5

0 0 -40 -30 -20 -10 010203040 -30 -20 -10 010203040 Time versus nelfinavir recall, days Time versus nelfinavir recall, days Tacrolimus concentration/dose ratio, ng/ml per mg/kg/day Tacrolimus Tacrolimus concentration/dose ratio, ng/ml per mg/kg/day Tacrolimus

q12h, every 12 h.

various compounds was observed according to their Tacrolimus is also a substrate of P-glycoprotein physicochemical properties [15]. Indeed, nelfinavir (P-gp) [17], the efflux pump highly represented in the and amprenavir were shown to be almost equipotent gut and in the emunctory organs, which is devoted to inhibitors of CYP3A4 activity in various in vitro studies the extrusion of xenobiotics from the body [18]. It assessing the inhibitory potency of different PIs [15,16]. should not be overlooked that the PIs may be potent It seems unlikely, therefore, that the differential impair- P-gp inhibitors [17]. Interestingly, in a recent com- ment of tacrolimus elimination induced by these two prehensive in vitro study comparatively assessing the PIs could be attributable to this mechanism. P-gp inhibitory potency of the vast majority of the

Antiviral Therapy 13.5 741

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5. Guaraldi G, Cocchi S, Codeluppi M, et al. Pharmacokinetic antiretrovirals currently used to treat HIV infection, interaction between Amprenavir/Ritonavir and nelfinavir was shown to be the most potent whereas FosAmprenavir on cyclosporine in two patients with human immunodeficiency virus infection undergoing orthotopic amprenavir was found to be among the least potent liver transplantation. Transplant Proc 2006; 38:1138–1140. [19]. Consistently, it is our contention that the dif- 6. Jain AB, Venkataramanan R, Eghtesad B, et al. Effect ferent modulation of P-gp-mediated excretion of tac- of coadministered lopinavir and ritonavir (Kaletra) on tacrolimus blood concentration in liver transplantation rolimus induced by nelfinavir and fosamprenavir could patients. Liver Transpl 2003; 9:954–960. explain our findings. 7. Jain AK, Venkataramanan R, Shapiro R, et al. The Whatever the mechanism responsible for this effect, interaction between antiretroviral agents and tacrolimus in liver and kidney transplant patients. Liver Transpl 2002; our findings support the need for higher tacrolimus 8:841–845. dosage to avoid insufficient immunosuppression in 8. Schvarcz R, Rudbeck G, Soderdahl G, Stahle L. Interaction HIV-infected liver transplant patients when switching between nelfinavir and tacrolimus after orthoptic liver transplantation in a patient coinfected with HIV and PI therapy from nelfinavir to fosamprenavir. More- hepatitis C virus (HCV). Transplantation 2000; over, these results suggest that increases might also be 69: 2194–2195. necessary even when starting antiretroviral therapy 9. Teicher E, Vincent I, Bonhomme-Faivre L, et al. Effect of highly active antiretroviral therapy on tacrolimus directly with fosamprenavir. Our observations rein- pharmacokinetics in hepatitis C virus and HIV co‑infected force the helpful role that intensive TDM may play in liver transplant recipients in the ANRS HC‑08 study. Clin Pharmacokinet 2007; 46:941–952. appropriately handling immunosuppressant therapy 10. Viracept contaminated in Europe. AIDS patient care and with tacrolimus under these circumstances. STDs 2007; 21:521. 11. Ross L, Vavro C, Wine B, Liao Q. Fosamprenavir clinical study meta-analysis in ART-naive subjects: rare occurrence Disclosure statement of virologic failure and selection of protease-associated mutations. HIV Clin Trials 2006; 7:334–338. No sources of funding were used to assist in the prep- 12. Wire MB, Shelton MJ, Studenberg S. Fosamprenavir: clinical aration of this article. FP has been on the speakers’ pharmacokinetics and drug interactions of the amprenavir prodrug. Clin Pharmacokinet 2006; 45:137–168. bureau for GlaxoSmithKline. PV has received grant 13. Iwasaki K. Metabolism of tacrolimus (FK506) and support from and been on the speakers’ bureau for recent topics in clinical pharmacokinetics. Drug Metab GlaxoSmithKline. MF has received grant support Pharmacokinet 2007; 22:328–335. from GlaxoSmithKline. The other authors declare no 14. Walubo A. The role of cytochrome P450 in antiretroviral drug interactions. Expert Opin Drug Metab Toxicol 2007; conflicts of interest. 3:583–598. 15. Granfors MT, Wang JS, Kajosaari LI, Laitila J, Neuvonen PJ, Backman JT. Differential inhibition of References cytochrome P450 3A4, 3A5 and 3A7 by five human 1. Honda M, Oka S. Current therapy for human immunodeficiency virus (HIV) protease inhibitors in vitro. Basic Clin Pharmacol Toxicol 2006; 98:79–85. immunodeficiency virus infection and acquired immunodeficiency syndrome. Int J Hematol 2006; 16. Ernest CS, 2nd, Hall SD, Jones DR. Mechanism-based 84:18–22. inactivation of CYP3A by HIV protease inhibitors. J Pharmacol Exp Ther 2005; 312:583–591. 2. Ragni MV, Belle SH, Im K, et al. Survival of human immunodeficiency virus-infected liver transplant recipients. 17. Balayssac D, Authier N, Cayre A, Coudore F. Does J Infect Dis 2003; 188:1412–1420. inhibition of P‑glycoprotein lead to drug-drug interactions? Toxicol Lett 2005; 156:319–329. 3. Neff GW, Bonham A, Tzakis AG, et al. Orthotopic liver transplantation in patients with human immunodeficiency 18. Marchetti S, Mazzanti R, Beijnen JH, Schellens JH. Concise virus and end-stage liver disease. Liver Transpl 2003; review: clinical relevance of drug drug and herb drug 9:239–247. interactions mediated by the ABC transporter ABCB1 (MDR1, P‑glycoprotein). Oncologist 2007; 12:927–941. 4. Frassetto LA, Browne M, Cheng A, et al. Immunosuppressant pharmacokinetics and dosing 19. Storch CH, Theile D, Lindenmaier H, Haefeli WE, Weiss J. modifications in HIV-1 infected liver and kidney transplant Comparison of the inhibitory activity of anti-HIV drugs on recipients. Am J Transplant 2007; 7:2816–2820. P‑glycoprotein. Biochem Pharmacol 2007; 73:1573–1581. Accepted for publication 30 April 2008

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