# Doravirine Exposure Decreased by Dialysis in a HIV Patient: A Grand Round

Yeleen Fromage, Cyrielle Codde, Caroline Monchaud, Marc Labriffe, Minh Lê, Jean-François Faucher, Jean-Baptiste Woillard

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Yeleen Fromage, Cyrielle Codde, Caroline Monchaud, Marc Labriffe, Minh Lê, et al. Doravirine Exposure Decreased by Dialysis in a HIV Patient: A Grand Round. Therapeutic Drug Monitoring, 2023, 45 (2), pp.133-135. 10.1097/FTD.0000000000001062. hal-04093983

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1 Doravirine exposure decreased by dialysis in a HIV patient: a grand round.

2 Yeleen Fromage1, Cyrielle Codde2, Caroline Monchaud1,3, Marc Labriffe1,3, Minh P.

3 Lê4,5, JF Faucher2, JB Woillard1,3

4 1 Department of Pharmacology, Toxicology and Pharmacovigilance, CHU de Limoges,

5 Limoges, France

6 2 Department of Infectious disease CHU de Limoges, Limoges, France

7 3 Pharmacology and Transplantation, INSERM U1248, Université de Limoges, 2 rue du Pr

8 Descottes, 87000 Limoges, France

9 4 AP-HP, Bichat Claude Bernard Hospital, Pharmacology-Toxicology Department, Paris,

10 France

11 5 Université Paris Cité, Inserm, UMRS1144, Optimisation Thérapeutique en

12 Neuropsychopharmacologie, F-75006 Paris, France

13 Corresponding author:
14 Jean-Baptiste Woillard

15 Title: PharmD, PhD

16 Address:

17 ORCID: 0000-0003-1695-0695

18 Univ. Limoges,

19 INSERM U1248 IPPRITT,

20 2 rue du Pr Descottes,

21 F-87000 Limoges, France.

22 Phone: +33 5 55 05 61 40

23 Fax: +33 5 55 05 61 62

24 Email: jean-baptiste.woillard@unilim.fr

25

26
27 Abstract

28 Aim: We report the case of a 66-year-old male patient, hemodialysed 3 times per week for
29 chronic renal failure, and treated with 100 mg doravirine once daily in combination with
30 dolutegravir for HIV1. No dose adjustment is required for doravirine in the case of severe
31 renal injury but the effect of dialysis on its exposure is poorly known.

32 Results: Two series of 2 samples were drawn before and after 4-hour-hemodialysis and
33 showed an average decrease of 48.1±6.7%. The effects of hemodialysis were important,
34 contrary to what was expected and previously reported. Additionally, the intra-individual
35 variability was low. Nevertheless, as the concentrations reported were largely above the
36 inhibitory concentration 50 (IC50), no dose adjustment was required.

37 Conclusion: The decrease of doravirin concentration by hemodialysis observed in this case
38 report was quite significant. Therefore, therapeutic drug monitoring might be recommended in
39 some cases for hemodialysed patients treated with doravirin.

40 **Keywords:** doravirine; HIV; haemodialysis; therapeutic drug monitoring; case report
## Introduction

Doravirine is a nonnucleoside reverse transcriptase inhibitor (NNRTI) indicated in the treatment of human immunodeficiency virus 1 (HIV-1) infections. According to the latest European AIDS clinical society (EACS) recommendations (https://www.eacsociety.org/guidelines/eacs-guidelines/), anti-retroviral treatment (ART) strategies including NNRTI are adapted to naïve adult patients with HIV. Classical combinations use 2 NRTI + 1 INTI, 2 NRTI + 1 INST or 1 NRTI + 1 INST, and finally 2 NRTI + 1 NNRTI. These strategies are facilitated by combination regimens, which provide a combination of the essential characteristics to ensure optimal treatment, such as long-term efficacy, resistance barrier, safety, tolerability and a limited number of drug interactions.

## Case report

### Clinician

We have a question about a 66-year-old man treated for 12 months with doravirine 100 mg once daily (OD) in combination with dolutegravir 50 mg OD for a HIV1 infection contracted after a blood transfusion and diagnosed in 1984. His ART drug history consists of 12 different drug associations; the changes are mainly due to tolerance issues or just for simplification. The patient has been successively treated with 13 different molecules (nelfinavir, tenofovir, efavirenz, abacavir, saquinavir, emtricitabine, atazanavir, raltegravir, etravirine, rilpivirine, lamuvidine and finally dolutegravir and doravirine). The patient's most recent viral genotyping was performed in 2017 and revealed mutations to the M36I, R41K, and I62V class of protease inhibitors. His viral load has been undetectable (<30 copies/mL, log<1.47) since 2016.

The patient's medical history includes post-transfusion hepatitis C complicated by cirrhosis and hepatocellular carcinoma leading to a liver transplant in 2005 which is still functioning. The patient also suffers from haemophilia A, hypertension, atrial fibrillation, severe ischemic heart disease, and insulin-dependent diabetes. Finally, he is on haemodialysis three times a week due to severe chronic renal insufficiency related to an immunoglobulin-A linked nephropathy and a chronic treatment by ciclosporin (glomerular filtration rate estimated with the CKD-EPI formula (eGFR), 7 mL/min). The dialysis characteristics are as follows: 4-hour haemodialysis (bicarbonates) using a Theradial® FDX 210 GW dialyser (PEPA® membrane) with a blood flow of 400 mL/min. The co-treatments are tacrolimus (1.5 mg OD), hydrocortisone (10 mg OD), sucro-ferric oxide (500 mg OD), lansoprazole (30 mg OD), spironolactone (25 mg OD), warfarin (4 mg OD), insulin aspartate and human insulin.
74 What are the consequences of haemodialysis on doravirine concentrations?

75 TDM specialist

76 The effect of renal impairment on doravirine exposure has recently been studied. No
77 significant clinical difference has been observed on doravirin concentrations measured 24h
78 after drug intake (C<sub>24h</sub>), in patients with an eGFR <30 ml/min/1.73 m<sup>2</sup> in comparison with
79 controls with eGFR &ge;80 ml/min/1.73 m<sup>2</sup> (geometric mean ratio [90% confidence interval] of
80 C<sub>24h</sub>=1.38 [0.99, 1.92]). <sup>1-3</sup> The Summary of Product Characteristics (SPC) of doravirin<sup>3</sup>
81 reports that the effect of dialysis has not been studied. Recently, Molto et al<sup>4</sup> reported cases of
82 hemodialysis in 8 patients treated with doravirine. They did not recommend dose adjustments
83 because the observed ratio between doravirin concentrations before and after hemodialysis
84 was 0.80. The effect of hemodialysis on dolutegravir concentrations is already known and is
85 not expected to be significant (median extraction ratio of 7%)<sup>5</sup>.

86 We recommend drawing one sample before and one after dialysis to collect information on
doravirin extraction. There is nothing in the literature about a possible redistribution of
88 doravirine, as observed for vancomycin just after dialysis⁶. Anyway, we cannot keep an
outpatient waiting at the hospital to draw a sample 2h after the end of the dialysis.
89

90 Clinician

91 Two series of 2 samples (before and after dialysis) were collected: in February and March
92 2021, just before and 10 minutes after dialysis in the first case and just before but only 5
93 minutes after for the second (Figure 1).

94 TDM specialist

95 The 2 series provide some new information about the intra-individual variability of the effect
96 of hemodialysis on doravirine concentrations, which is currently not known. Doravirine
97 plasma concentrations were measured using a validated LC-MS/MS method which has not
98 been published but has been adapted from Jung et al<sup>7</sup> by implementation of the LC-MS/MS
99 transitions for the new antiretrovirals). The concentrations measured were respectively 3453
100 µg/L and 1628 µg/L in the first series, leading to a dialysis extraction ratio of 0.47, and 2698
101 µg/L and 1527 µg/L in the second series, leading to a dialysis extraction ratio of 0.57 (Figure
102 1). The reported trough (C<sub>0</sub>) and maximum doravirine concentrations (C<sub>max</sub>) for a dose
103 regimen of 100 mg QD are approximately 396±250 µg/L and 962±183 µg/L<sup>3</sup>. The
concentrations observed in our patient are much higher than the usual values but they are not
104
105
106

C₀ or Cₘₐₓ, rendering them rather complicated to interpret. However, with this information,
we can estimate the effect of dialysis on doravirin plasma concentrations in our patient.

107

Clinician

108
109
110
111
112

We question the high concentrations observed in this patient given that doravirine is not eliminated through the kidney (<10% of elimination occurring via the renal pathway¹). It is of note that the results of the fibroscan (performed 2 months before the sample) and liver MRI (performed 10 days before the sample) showed an advanced fibrosis without rejection (grade A1F4) and a dysmorphic cirrhosis liver. Could this explain the high concentrations?

113

TDM specialist

114
115
116
117
118
119
120
121

The main cause of the high concentrations observed in this patient is probably his cirrhosis.
Indeed, the literature⁸,⁹ and SPC³ recommend caution in patients with severe hepatic
impairment, as there are no data on this clinical situation. Another hypothesis could be drug-
drug interactions, but no medications known for interacting with doravirine have been
identified in our patient's treatment. Notable interactions with doravirine, have only been
reported with strong enzymatic inhibitors (ritonavir and ketoconazole), in line with its
metabolism by cytochromes CYP450 3A4 and 3A5.¹⁰,¹¹ However, in the literature, no
association has been reported between high concentrations and adverse effects¹¹,¹².

122
123
124

Clinician

We request some advice on the necessity of dose adjustment of doravirine in our patient in the light of the significant decrease of concentrations with dialysis.

125
126
127
128
129
130
131
132
133
134

TDM specialist

The average decrease caused by dialysis is 48.1 ± 6.7% (the standard deviation being small, synonym of a small intra-individual variability). Despite the strong decrease of doravirine concentrations in this patient, there is very little risk that the concentrations become subtherapeutic, given the IC50 of 5.1 µg/L¹³, IC90 of 8.08 g/L in patients with a wild type HIV1 virus or 95% effective concentration with 10% human serum (4.6–12.7 ng/dL according to the NNRTI resistance-associated mutations)¹⁴. The dialysis extraction ratio is slightly different from those reported in the literature⁴ (0.8 vs 0.5 for us). One reason could be, given the large range of concentrations observed by Molto et al, their samples were drawn at different times within the interdose.
135

Conclusion

136

Dose adjustment was not recommended in this patient treated by doravirine while on
haemodialysis, which is consistent with reports of other patients in similar situations⁴,¹¹,¹⁵.

137

138

However, the fraction cleared by dialysis in this case report was non negligible. Therefore,
therapeutic drug monitoring might be recommended in some cases for hemodialysed patients
139
140
treated with doravirine especially in those displaying concentrations close to the protein-
adjusted IC90.
141

140

141

142

**Declaration of interest:** All authors: none to declare.

143
145 References

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149 2. Côté B, Burch JD, Asante-Appiah E, et al. Discovery of MK-1439, an orally bioavailable non-nucleoside reverse transcriptase inhibitor potent against a wide range of resistant mutant HIV viruses. *Bioorg Med Chem Lett*. 2014;24(3):917-922.
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153 3. EMA. Pifeltro. European Medicines Agency. https://www.ema.europa.eu/en/medicines/human/EPAR/pifeltro. Published September 24, 2018. Accessed August 24, 2022.

156 4. Moltó J, Graterol F, Curran A, et al. Removal of doravirine by haemodialysis in people living with HIV with end-stage renal disease. *J Antimicrob Chemother*. 2022;77(7):1989-1991. doi:10.1093/jac/dkac126

159 5. Moltó J, Graterol F, Miranda C, et al. Removal of Dolutegravir by Hemodialysis in HIV-Infected Patients with End-Stage Renal Disease. *Antimicrob Agents Chemother*. 2016;60(4):2564-2566. doi:10.1128/AAC.03131-15

162 6. Pollard TA, Lampasona V, Akkerman S, et al. Vancomycin redistribution: dosing recommendations following high-flux hemodialysis. *Kidney Int*. 1994;45(1):232-237.
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165 7. Jung BH, Rezk NL, Bridges AS, Corbett AH, Kashuba ADM. Simultaneous determination of 17 antiretroviral drugs in human plasma for quantitative analysis with liquid chromatography-tandem mass spectrometry. *Biomed Chromatogr*. 2007;21(10):1095-1104. doi:10.1002/bmc.865

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172 9. Yee KL, Ouerdani A, Claussen A, de Greef R, Wenning L. Population Pharmacokinetics of Doravirine and Exposure-Response Analysis in Individuals with HIV-1. *Antimicrob Agents Chemother*. 2019;63(4):e02502-18. doi:10.1128/AAC.02502-18

175 10. Bleasby K, Fillgrove KL, Houle R, et al. In Vitro Evaluation of the Drug Interaction Potential of Doravirine. *Antimicrob Agents Chemother*. 2019;63(4):e02492-18.
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178 11. Boyle A, Moss CE, Marzolini C, Khoo S. Clinical Pharmacodynamics, Pharmacokinetics, and Drug Interaction Profile of Doravirine. *Clin Pharmacokinet*. 2019;58(12):1553-1565. doi:10.1007/s40262-019-00806-9

181 12. Anderson MS, Gilmartin J, Cilissen C, et al. Safety, tolerability and pharmacokinetics of doravirine, a novel HIV non-nucleoside reverse transcriptase inhibitor, after single and
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184 doi:10.3851/IMP2920

185 13. Feng M, Wang D, Grobler JA, Hazuda DJ, Miller MD, Lai MT. In vitro resistance

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187 inhibitor with distinct mutation development pathways. *Antimicrob Agents Chemother*.

188 2015;59(1):590-598. doi:10.1128/AAC.04201-14

189 14. Tiraboschi J, Scévola S, Penchala SD, et al. Total and Unbound Doravirine

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192 15. Kobayashi M, Chinen M, Hirano A, Hayashida T, Watanabe K, Masuda J. Successful

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194 under chronic haemodialysis. *J Antimicrob Chemother*. 2021;76(5):1370-1372.

195 doi:10.1093/jac/dkab001

196

197
198 **Figure legends**

199 Figure 1: Case timeline presenting drug administration, hemodialysis and measurements of

200 drug concentrations.