Removal of Doravirine by Hemodialysis in HIV-Infected Patients With End-stage Renal Disease (ESRD)

Removal of Doravirine by Hemodialysis in HIV-Infected Patients With End-Stage Renal Disease (ESRD)

Doravirine is a novel non-nucleoside reverse transcriptase inhibitor that has demonstrated good efficacy, tolerability, and safety for the treatment of patients with HIV infection in phase III clinical trials. Doravirine achieved non- inferiority when compared with efavirenz- and darunavir/ritonavir-based regimens. Doravirine is mainly metabolized and eliminated by the liver, with only 6% of the drug being excreted unchanged through the urine.In a study comparing 8 subjects with severe renal disease to 8 subjects without renal impairment, the single dose exposure of doravirine was 43% higher in subjects with severe renal function impairment.However, according to prescribing information, no dosage adjustment of doravirine is required in patients with mild, moderate, or severe renal impairment. On the other hand, data on doravirine pharmacokinetics in patients with ESRD on dialysis are lacking. This may be of special interest because doravirine has a relatively low molecular weight and it is only 76% bound to proteins in plasma. These characteristics could make possible for hemodialysis to remove doravirine from plasma, potentially leading to subtherapeutic concentrations of doravirine after the dialysis sessions. On the contrary, doravirine volume of distribution is about 60 liters,15 what could limit extraction of doravirine by hemodialysis. Since data on doravirine pharmacokinetics in PLWH with ESRD on dialysis are lacking, our aim is to evaluate the effect of intermittent hemodialysis on doravirine concentrations in HIV-infected patients with ESRD

Study Overview

• Status: Completed
• Conditions: HIV-infected Participants With ESRD Undergoing Routine Hemodialysis
• Intervention / Treatment: Drug: Doravirine

Detailed Description

Doravirine is a novel non-nucleoside reverse transcriptase inhibitor that has demonstrated good efficacy, tolerability, and safety for the treatment of patients with HIV infection in phase III clinical trials. Doravirine achieved non- inferiority when compared with efavirenz- and darunavir/ritonavir-based regimens. Doravirine is mainly metabolized and eliminated by the liver, with only 6% of the drug being excreted unchanged through the urine.In a study comparing 8 subjects with severe renal disease to 8 subjects without renal impairment, the single dose exposure of doravirine was 43% higher in subjects with severe renal function impairment.However, according to prescribing information, no dosage adjustment of doravirine is required in patients with mild, moderate, or severe renal impairment. On the other hand, data on doravirine pharmacokinetics in patients with ESRD on dialysis are lacking. This may be of special interest because doravirine has a relatively low molecular weight and it is only 76% bound to proteins in plasma. These characteristics could make possible for hemodialysis to remove doravirine from plasma, potentially leading to subtherapeutic concentrations of doravirine after the dialysis sessions. On the contrary, doravirine volume of distribution is about 60 liters,15 what could limit extraction of doravirine by hemodialysis. Since data on doravirine pharmacokinetics in PLWH with ESRD on dialysis are lacking, our aim is to evaluate the effect of intermittent hemodialysis on doravirine concentrations in HIV-infected patients with ESRD.

• Study Type: Interventional
• Enrollment (Actual): 8
• Phase: Phase 4

Contacts and Locations

Study Locations

• Spain
  • Barcelona, Spain, 08035
    • Valle Hebrón Hospital
  • Barcelona
    • Badalona, Barcelona, Spain, 08916
      • Germans Trias I Pujol Hospital
    • Hospitalet de Llobregat, Barcelona, Spain, 08907
      • Universitario Bellvitge Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Males and females* aging ≥ 18 years.
2. Documented HIV infection).
3. Stable antiretroviral treatment for at least 2 weeks prior to enrolment.
4. Optimal adherence to antiretroviral treatment, defined as less than 2 missed doses within the previousweek.
5. End-stage renal disease in renal replacement therapy with periodic hemodialysis.
6. Agree with the study procedures and signature of the informed consent. *Women of childbearing potential must have a negative pregnancy test prior to randomization into the study and commitment to useat least one of these birth control methods: male or female condom with or without spermicide, cap, diaphragm or sponge with orwithout spermicide, intrauterine device, bilateral tubal occlusion, vasectomized partner, sexual abstinence during the study. Condomuse is considered as an additional method of contraception only and cannot be the only method of contraception used as not beenconsidered an effective method by the Clinical Trial Facilitation Group (CTFG) guidelines.

Based on ICH, M3 (R2) 2009 a woman is considered of childbearing potential: fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilization methods include tubal ligation, hysterectomy, bilateral oophorectomy.

Exclusion Criteria:

1. Evidence or clinical suspicion that the patient will not be able to comply with the study protocol.
2. Hypersensitivity to doravirine

3. Concomitant therapy within the previous 4 weeks with any of the following drugs:

   • Anticonvulsants: carbamazepine, oxcarbazepine, phenobarbital, phenytoin
   • Androgen receptor inhibitor: enzalutamide
   • Antimycobacterials: rifampin, rifapentine
   • Cytotoxic agent: mitotane
   • St. John's wort (Hypericum perforatum)
4. Females who are pregnant or breastfeeding.
5. ALT and/ or AST ≥ 4 times the upper limit of normal (ULN) at screening.
6. Hemoglobin < 7,5 g/dL at screening.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Experimental group; Doravirine (Pifeltro, MSD) will be added to participant's cART (100 mg once daily) for 5 days	Drug: Doravirine; Participants will be told to take one tablet of doravirine (Pifeltro, MDS) once daily, with or without food, approximately at the day time that they usually finish the hemodialysis sessions. The rest of their antiretroviral regimen and concomitant medications will remain unchanged; Other Names: Pifeltro

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Doravirine hemodialysis extraction ratio	% doravirina in blood samples entering ('Cin') and leaving ('Cout') the dialyzer collected during the dialysis session	At day 6
Doravirine Concentration in plasma at the beginning of dialysis session	mg/dl	At day 6
Percentage of participants developing related adverse events grade 3-4 related to doravirine		Baseline to day 20

Collaborators and Investigators

• Sponsor: Fundación FLS de Lucha Contra el Sida, las Enfermedades Infecciosas y la Promoción de la Salud y la Ciencia
• Collaborators: Merck Sharp & Dohme LLC

Publications and helpful links

General Publications

• Molto J, Graterol F, Curran A, Ramos N, Imaz A, Sandoval D, Perez F, Bailon L, Khoo S, Else L, Paredes R. Removal of doravirine by haemodialysis in people living with HIV with end-stage renal disease. J Antimicrob Chemother. 2022 Jun 29;77(7):1989-1991. doi: 10.1093/jac/dkac126.

Study record dates

Study Major Dates

• Study Start (Actual): March 20, 2021
• Primary Completion (Actual): June 14, 2021
• Study Completion (Actual): June 14, 2021

Study Registration Dates

• First Submitted: December 29, 2020
• First Submitted That Met QC Criteria: December 29, 2020
• First Posted (Actual): December 30, 2020

Study Record Updates

• Last Update Posted (Actual): July 7, 2021
• Last Update Submitted That Met QC Criteria: July 6, 2021
• Last Verified: July 1, 2021

More Information

Terms related to this study

• Keywords: HIV; ESRD; Doravirine
• Additional Relevant MeSH Terms: Kidney Diseases; Urologic Diseases; Renal Insufficiency; Renal Insufficiency, Chronic; Kidney Failure, Chronic
• Other Study ID Numbers: Dora-HD

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No