HIV-infected Participants With ESRD Undergoing Routine Hemodialysis
Conditions
Keywords
HIV, ESRD, Doravirine
Brief summary
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
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.
Interventions
DRUGDoravirine
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
Sponsors
Merck Sharp & Dohme LLC
Fundación FLS de Lucha Contra el Sida, las Enfermedades Infecciosas y la Promoción de la Salud y la Ciencia
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
NONE
Intervention model description
This is a multi-centre, single-arm, open-label, pilot study in HIV-infected participants with ESRD undergoing routine hemodialysis. All participants will receive doravirine 100 mg once daily during the study (5 days).
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentatge of Doravirine Dialysis Extraction Ratio (ER) | At day 6 | The haemodialysis extraction ratio (ER) for doravirine was calculated as: ER(%) = ((Cin - Cout)/ Cin) × 100 where Cin is the pre-dialyser doravirine concentration (i.e. blood entering the dialyser) and Cout is the post-dialyser doravirine concentration (i.e. blood leaving the dialyser). Post-dialyser doravirine concentrations (Cout) were corrected for haemoconcentration by a factor F based on total protein (TP) concentration pre- and post-dialyser: F = TPin / TPout. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Developing Related Adverse Events Grade 3-4 Related to Doravirine | Baseline to day 20 | Percentage of participants developing related adverse events grade 3 or grade 4 related to doravirine. Defining Grade 3 (severe) as symptoms causing inability to perform usual social and functional activities and Grade 4 (potentially life-threatening)as Symptoms causing inability to perform basic self-care functions or Medical or operative intervention indicated to prevent permanent impairment, persistent disability, or death. |
| Doravirine Concentration (mg/dl) | At day 6 | Doravirine Concentration (mg/dl) in plasma at the end of the haemodialysis session. |
Countries
Spain
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Experimental Group Doravirine (Pifeltro, MSD) will be added to participant's cART (100 mg once daily) for 5 days
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 | 8 |
| Total | 8 |
Baseline characteristics
| Characteristic | Experimental Group | — |
|---|---|---|
| Age, Categorical <=18 years | 0 Participants | — |
| Age, Categorical >=65 years | 1 Participants | — |
| Age, Categorical Between 18 and 65 years | 7 Participants | — |
| Race and Ethnicity Not Collected | — | — Participants |
| Region of Enrollment Spain | 8 participants | — |
| Sex: Female, Male Female | 2 Participants | — |
| Sex: Female, Male Male | 6 Participants | — |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 8 |
| other Total, other adverse events | 3 / 8 |
| serious Total, serious adverse events | 2 / 8 |
Outcome results
Primary
Percentatge of Doravirine Dialysis Extraction Ratio (ER)
The haemodialysis extraction ratio (ER) for doravirine was calculated as: ER(%) = ((Cin - Cout)/ Cin) × 100 where Cin is the pre-dialyser doravirine concentration (i.e. blood entering the dialyser) and Cout is the post-dialyser doravirine concentration (i.e. blood leaving the dialyser). Post-dialyser doravirine concentrations (Cout) were corrected for haemoconcentration by a factor F based on total protein (TP) concentration pre- and post-dialyser: F = TPin / TPout.
Time frame: At day 6
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Experimental Group | Percentatge of Doravirine Dialysis Extraction Ratio (ER) | 34.3 percentage of doravirine dialysis ER |
Secondary
Doravirine Concentration (mg/dl)
Doravirine Concentration (mg/dl) in plasma at the end of the haemodialysis session.
Time frame: At day 6
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Experimental Group | Doravirine Concentration (mg/dl) | 785 mg/dl |
Secondary
Percentage of Participants Developing Related Adverse Events Grade 3-4 Related to Doravirine
Percentage of participants developing related adverse events grade 3 or grade 4 related to doravirine. Defining Grade 3 (severe) as symptoms causing inability to perform usual social and functional activities and Grade 4 (potentially life-threatening)as Symptoms causing inability to perform basic self-care functions or Medical or operative intervention indicated to prevent permanent impairment, persistent disability, or death.
Time frame: Baseline to day 20
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Experimental Group | Percentage of Participants Developing Related Adverse Events Grade 3-4 Related to Doravirine | 2 Participants |