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AIDS:
doi: 10.1097/QAD.0b013e328328f79d
Correspondence

Pharmacokinetics of darunavir, etravirine and raltegravir in an HIV-infected patient on haemodialysis

Giguère, Pierrea,b; la Porte, Charlesb,c,d; Zhang, Guijunb; Cameron, Billb,c,d

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aPharmacy Department, The Ottawa Hospital, Canada

bThe Ottawa Health Research Institute, Canada

cDivision of Infectious Disease, The Ottawa Hospital, Canada

dFaculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.

Received 11 December, 2008

Accepted 18 December, 2008

Correspondence to Pierre Giguère, BPharm, MSc, Pharmacy Department, The Ottawa Hospital, 501 Smyth Road, Ottawa, ON K1H 8L6, Canada. Tel: +1 613 737 8922; e-mail: Pgiguere@toh.on.ca

The use of haemodialysis in HIV-infected patients with end-stage renal disease is common and may affect the pharmacokinetics of the antiretroviral drugs. Factors such as a low molecular weight, low protein binding and water solubility increase the extraction fraction of haemodialysis. Thus, important changes to antiretroviral exposure can be expected with certain antiretrovirals [1]. For nucleoside reverse transcriptase inhibitors, the general recommendation is to dose after dialysis [2]. No dose adjustments are recommended for protease inhibitors and nonnucleoside reverse transcriptase inhibitors (NNRTIs) [3], except for unboosted atazanavir, for which the exposure decreased by 25–40% after haemodialysis [4] and for which boosting with ritonavir may be warranted. Nevertheless, for clinical management of patients with changed renal function, the current treatment guidelines advise the use of therapeutic drug monitoring [5].

The relatively new antiretrovirals, darunavir and etravirine, undergo extensive hepatic metabolism by CYP3A4, 2C9 and 2C19, whereas the integrase inhibitor, raltegravir, is metabolized through UGT1A1. Renal excretion of darunavir, etravirine and raltegravir is 7.7, 1.2 and 9% and their protein binding is 95, 99.9 and 83%, respectively [6–8]. On the basis of these characteristics, the effect of haemodialysis is expected to be small; however, no information is available.

We present a 49-year-old HIV-infected man who is currently treated with darunavir/ritonavir (600/100 mg) twice daily, etravirine (200 mg) twice daily and raltegravir (400 mg) twice daily. Previous antiretroviral therapies include multiple protease inhibitor intolerance and failure of NNRTI-based therapy associated with the initiation of haemodialysis. Underlying diseases include diabetes, hypertension and nephrectomy for renal cell carcinoma after remote acute renal failure due to remote electrocution and rhabdomyolysis. The patient undergoes haemodialysis thrice weekly (Fresenius 2008K, ultrafiltration) pending renal transplantation. Current antiretroviral therapy maintains complete virological suppression.

To study the effect of haemodialysis on the pharmacokinetics of darunavir, etravirine, raltegravir and ritonavir, predialysis and postdialysis samples were collected from an indwelling dialysis catheter during haemodialysis sessions. Plasma drug concentrations were determined using a sensitive and validated high-performance liquid chromatography (HPLC) tandem mass spectrometry method. All solvents and chemicals were obtained from Sigma (Oakville, Ontario, Canada) and were HPLC grade. Standards for darunavir and etravirine were donated by Tibotec (Toronto, Canada); raltegravir and ritonavir were donated by Merck & Co. and Abbott Laboratories (Montreal, Canada), respectively.

Table 1 [9–11] provides a summary of the plasma concentrations from the three haemodialysis sessions. The first session was done with the regular medication intake schedule, in which the patient was instructed to take the morning dose of the twice-daily regimen after the completion of the 4-h morning haemodialysis session. After dialysis, darunavir, etravirine, raltegravir and ritonavir concentrations decreased from predialysis level by 57, 29, 82 and 60%, respectively. These data suggest that all drugs were removed by haemodialysis to a certain extent.

Table 1
Table 1
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In the second session, we instructed the patient to take a supplementary dose of darunavir (600 mg) and raltegravir (400 mg) before the haemodialysis session in addition to the regular dose after the haemodialysis session to compensate for removal during haemodialysis. We did not supplement the dose for etravirine and ritonavir as the former was removed by less than 30% and the latter was given as a booster. The prehaemodialysis supplemental dose counteracted the apparent dialysis clearance of darunavir, with the postdialysis level approximately equal to an expected population trough level [geometric mean (range), 3016 (1620–6190) ng/ml] [9]. Raltegravir plasma levels were inconsistent. The prehaemodialysis level showed a wide variability (range, 0.04–0.19 mg/l). The effect of supplemental predialysis dose did not increase the posthaemodialysis level of raltegravir, although it approximated the C12h level of 0.06 mg/l described elsewhere in the literature [10,12]. The known wide intrapatient and interpatient variability of raltegravir may explain our findings [7]. Etravirine and ritonavir plasma levels were unaffected by the change in darunavir and raltegravir dosing.

In the third session, after 4 weeks of supplemental predialysis dosing, plasma concentrations did not suggest drug accumulation for any of the studied drugs. During the entire observation period, the patient did not report any side effects. Virological suppression has been maintained and CD4 cell count has increased by 400 cell/μl after 1 year of therapy.

In conclusion, plasma levels for all four drugs were decreased during haemodialysis. For darunavir, this was corrected by administering a supplemental dose of 600 mg before haemodialysis. The variability in raltegravir plasma levels is not instructive for supplemental dosing. Data from this case report, combined with the evidence that dosing errors in this patient population is associated with poorer survival [13], may support the use of therapeutic drug monitoring to avoid antiretroviral suboptimal exposure and virological failure.

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Acknowledgements

P.G., C.laP., B.C. and G.Z. provided substantial contributions to the design and interpretation of the analysis and participated in the writing of the manuscript. C.laP. and G.Z. did the pharmacokinetic and bioanalysis.

No funding was received as a support for this research. Standards for darunavir and etravirine were donated by Tibotec; raltegravir and ritonavir were donated by Merck & Co. and Abbott Laboratories, respectively.

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References

1. Izzedine H, Launay-Vacher V, Baumelou A, Deray G. An appraisal of antiretroviral drugs in hemodialysis. Kidney Int 2001; 60:821–830.

2. Berns JS, Kasbekar N. Highly active antiretroviral therapy and the kidney: an update on antiretroviral medications for nephrologists. Clin J Am Soc Nephrol 2006; 1:117–129.

3. Izzedine H, Deray G. The nephrologist in the HAART era. AIDS 2007; 21:409–421.

4. Agarwala S, Eley T, Child M, Wang Y, Persson A, Filoramo D, et al. Pharmacokinetics of atazanavir in severely renally impaired subjects including those on hemodialysis [abstract 2]. 8th International Workshop on Clinical Pharmacology of HIV Therapy; 16–18 April 2007; Budapest; 2007.

5. Panel on antiretroviral guidelines for adult and adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Bethesda, MD: Department of Health and Human Services; 2008. pp. 1–139.

6. Darunavir product monograph. Janssen-Ortho Inc.; 2008. pp. 1–52.

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8. Etravirine product monograph. Janssen-Ortho Inc.; 2008. pp. 1–44.

9. Boffito MA, Winston AA, Jackson AA, Fletcher CA, Pozniak AA, Nelson MA, et al. Pharmacokinetics and antiretroviral response to darunavir/ritonavir and etravirine combination in patients with high-level viral resistance. AIDS 2007; 21:1449–1455.

10. Anderson MS, Kakuda TN, Hanley W, Miller J, Kost JT, Stoltz R, et al. Minimal pharmacokinetic interaction between the human immunodeficiency virus nonnucleoside reverse transcriptase inhibitor etravirine and the integrase inhibitor raltegravir in healthy subjects. Antimicrob Agents Chemother 2008; 52:4228–4232.

11. Scholler-Gyure M, Kakuda TN, Sekar V, Woodfall B, De Smedt G, Lefebvre E, et al. Pharmacokinetics of darunavir/ritonavir and TMC125 alone and coadministered in HIV-negative volunteers. Antivir Ther 2007; 12:789–796.

12. Wenning LA, Friedman EJ, Kost JT, Breidinger SA, Stek JE, Lasseter KC, et al. Lack of a significant drug interaction between raltegravir and tenofovir. Antimicrob Agents Chemother 2008; 52:3253–3258.

13. Tourret J, Tostivint I, Tezenas du Montcel S, Karie S, Launay-Vacher V, Vigneau C, et al. Antiretroviral dose errors among HIV-infected hemodialyzed patients [abstract WEPEA096]. International AIDS Conference; 22–25 July 2007; Sydney, Australia; 2007.

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