Clinical Evaluation of Adjusted Doses of Darunavir/Ritonavir With Rifampicin in HIV-infected Volunteers

NCT03892161 | Terminated Phase 1 DMC

• 1 other identifier: Darifi
• Study Type: interventional
• Target: 17
• Locations: 1 country
• Sites: 1

Brief Summary

The DaRifi study aims:

1. 1.Develop adjusted doses of darunavir/ritonavir for use in HIV-infected patients requiring co-treatment of TB with a rifampicin-based regimen.
2. 2.Compare the steady state pharmacokinetics of doubled doses of DRV/r with rifampicin (in once daily and 12-hourly approaches) to standard daily doses without rifampicin.
3. 3.Twenty-eight volunteers will be enrolled for a target of 24 participants completing the study.

Conditions

HIV Infections

Outcome Measures

Primary Outcomes (1)

• Darunavir plasma concentrations nanogram per milliliter (ng/ml)

  Darunavir plasma concentrations will be compared with rifampicin and without rifampicin.

  1 year

Secondary Outcomes (1)

• Alanine Transaminase (ALT) blood level (iu/L)

  1 Year

Study Arms (5)

Standard dose DRV/r

EXPERIMENTAL

Standard dose DRV/r 800/100mg without Rifampicin

Drug: Darunavir/ritonavir 800/100 mg tablet

Standard DRV/r with Rifampicin

EXPERIMENTAL

Rifampicin 600mg QD will be added and darunavir/ritonavir steady state pharmacokinetic analysis will be performed.

Drug: Darunavir/ritonavir 800/100 mg tablet; Drug: Rifampicin 600mg QD tablet and DTG 50mg BD

Boosed ritonavir 200mg

EXPERIMENTAL

Rifampicin 600mg QD continued with ritonavir 200mg dose doubled QD and darunavir remains 800mg QD. The darunavir/ritonavir steady state pharmacokinetic analysis will be performed and compared.

Drug: Darunavir/ritonavir 800/100 mg tablet; Drug: Rifampicin 600mg QD tablet and DTG 50mg BD

Double dose DRV/r 1600/200mg QD

EXPERIMENTAL

Rifampicin 600mg QD and DTG QD continued. Double dose DRV/r QD. The darunavir/ritonavir steady state pharmacokinetic analysis will be performed and compared.

Drug: Darunavir/ritonavir 800/100 mg tablet; Drug: Rifampicin 600mg QD tablet and DTG 50mg BD

Double dose DRV/r 800/100mg BD

EXPERIMENTAL

Rifampicin 600mg QD and DTG BD continued. Double dose DRV/r QD. The darunavir/ritonavir steady state pharmacokinetic analysis will be performed and compared.

Drug: Darunavir/ritonavir 800/100 mg tablet; Drug: Rifampicin 600mg QD tablet and DTG 50mg BD

Interventions

Darunavir/ritonavir 800/100 mg tablet DRUG

Standard dose DRV/r administered

Boosed ritonavir 200mg; Double dose DRV/r 1600/200mg QD; Double dose DRV/r 800/100mg BD; Standard DRV/r with Rifampicin; Standard dose DRV/r

Rifampicin 600mg QD tablet and DTG 50mg BD DRUG

Rifampicin and DTG added

Boosed ritonavir 200mg; Double dose DRV/r 1600/200mg QD; Double dose DRV/r 800/100mg BD; Standard DRV/r with Rifampicin

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Male or female
• Aged 18 to 60 years, inclusive
• Weighing \> 38 kg
• BMI \> 18.5 kg/m2
• HIV-1 infected
• HIV-1 RNA \<50 copies/mL
• CD4+ lymphocyte count \> 200 cells/L
• C-reactive protein \<10 mg/L
• Established on current ART regimen of boosted protease inhibitor plus 2 NRTIs for at least 3 months.
• Women must be postmenopausal, surgically sterile or practicing an effective birth control method (established before and maintained throughout the trial). Women who are not sexually active must agree to use an effective birth control method if they become heterosexually active during the trial.
• Understand the purpose of and procedures required for the study and having confirmed they are willing to participate in the study by signing the informed consent document.

You may not qualify if:

• TB (confirmed or suspected)
• Any symptoms of TB - as assessed by the WHO symptom-screening algorithm: self-reported or documented weight loss, cough, night sweats or fever.
• Clinical or laboratory evidence of significantly impaired hepatic function, or documented hepatic cirrhosis
• Clinical or laboratory evidence of acute viral hepatitis
• Co-infected with HBV or HCV.
• ALT grade 2 or higher (as defined by DAIDS grading table (ALT \>2.5 x ULN)
• DAIDS grade 3 or 4 laboratory abnormality
• Active (not clinically stabilized \>4 weeks) AIDS defining illness (Category C conditions according to the Center for Disease Control Classification System for HIV infection) with the following exceptions:
• Stable cutaneous Kaposi's Sarcoma (no internal organ involvement other than oral lesions) that is unlikely to require any form of systemic therapy during the study.
• Estimated creatinine clearance \<50 mL/min.
• Active clinically significant renal or gastro-intestinal disease.
• Any active clinically significant or life-threatening disease, medical or psychiatric condition, or findings during screening, that in the investigator's opinion would compromise the safety of the participant or the study outcome, or their ability to comply with the study procedures.
• Chronic medical requirement for any drugs that are known to affect the PK of the study drugs.
• Active drug/alcohol abuser.
• Pregnant or breastfeeding.

Sponsors & Collaborators

• University of Cape Town: lead
• Wits Reproductive Health and HIV Institute: collaborator
• Desmond Tutu HIV Centre: collaborator

Study Sites (1)

Clinical Research Centre

Cape Town, Western Cape, 7725, South Africa

Location

Related Publications (25)

• Baietto L, Calcagno A, Motta I, Baruffi K, Poretti V, Di Perri G, Bonora S, D'Avolio A. A UPLC-MS-MS method for the simultaneous quantification of first-line antituberculars in plasma and in PBMCs. J Antimicrob Chemother. 2015 Sep;70(9):2572-5. doi: 10.1093/jac/dkv148. Epub 2015 Jun 11.

  PMID: 26066583 BACKGROUND

• Chirehwa MT, Rustomjee R, Mthiyane T, Onyebujoh P, Smith P, McIlleron H, Denti P. Model-Based Evaluation of Higher Doses of Rifampin Using a Semimechanistic Model Incorporating Autoinduction and Saturation of Hepatic Extraction. Antimicrob Agents Chemother. 2015 Nov 9;60(1):487-94. doi: 10.1128/AAC.01830-15. Print 2016 Jan.

  PMID: 26552972 BACKGROUND

• D'Avolio A, Simiele M, Siccardi M, Baietto L, Sciandra M, Oddone V, Stefani FR, Agati S, Cusato J, Bonora S, Di Perri G. A HPLC-MS method for the simultaneous quantification of fourteen antiretroviral agents in peripheral blood mononuclear cell of HIV infected patients optimized using medium corpuscular volume evaluation. J Pharm Biomed Anal. 2011 Mar 25;54(4):779-88. doi: 10.1016/j.jpba.2010.10.011. Epub 2010 Nov 10.

  PMID: 21071165 BACKGROUND

• Decloedt EH, McIlleron H, Smith P, Merry C, Orrell C, Maartens G. Pharmacokinetics of lopinavir in HIV-infected adults receiving rifampin with adjusted doses of lopinavir-ritonavir tablets. Antimicrob Agents Chemother. 2011 Jul;55(7):3195-200. doi: 10.1128/AAC.01598-10. Epub 2011 May 2.

  PMID: 21537021 BACKGROUND

• Decloedt EH, Maartens G, Smith P, Merry C, Bango F, McIlleron H. The safety, effectiveness and concentrations of adjusted lopinavir/ritonavir in HIV-infected adults on rifampicin-based antitubercular therapy. PLoS One. 2012;7(3):e32173. doi: 10.1371/journal.pone.0032173. Epub 2012 Mar 7.

  PMID: 22412856 BACKGROUND

• De Nicolo A, Bonifacio G, Boglione L, Cusato J, Pensi D, Tomasello C, Di Perri G, D'Avolio A. UHPLC-MS/MS method with automated on-line solid phase extraction for the quantification of entecavir in peripheral blood mononuclear cells of HBV+ patients. J Pharm Biomed Anal. 2016 Jan 25;118:64-69. doi: 10.1016/j.jpba.2015.10.017. Epub 2015 Oct 22.

  PMID: 26517850 BACKGROUND

• Dooley KE, Sayre P, Borland J, Purdy E, Chen S, Song I, Peppercorn A, Everts S, Piscitelli S, Flexner C. Safety, tolerability, and pharmacokinetics of the HIV integrase inhibitor dolutegravir given twice daily with rifampin or once daily with rifabutin: results of a phase 1 study among healthy subjects. J Acquir Immune Defic Syndr. 2013 Jan 1;62(1):21-7. doi: 10.1097/QAI.0b013e318276cda9.

  PMID: 23075918 BACKGROUND

• Haas DW, Koletar SL, Laughlin L, Kendall MA, Suckow C, Gerber JG, Zolopa AR, Bertz R, Child MJ, Hosey L, Alston-Smith B, Acosta EP; A5213 StudyTeam. Hepatotoxicity and gastrointestinal intolerance when healthy volunteers taking rifampin add twice-daily atazanavir and ritonavir. J Acquir Immune Defic Syndr. 2009 Mar 1;50(3):290-3. doi: 10.1097/QAI.0b013e318189a7df.

  PMID: 19194314 BACKGROUND

• la Porte CJ, Colbers EP, Bertz R, Voncken DS, Wikstrom K, Boeree MJ, Koopmans PP, Hekster YA, Burger DM. Pharmacokinetics of adjusted-dose lopinavir-ritonavir combined with rifampin in healthy volunteers. Antimicrob Agents Chemother. 2004 May;48(5):1553-60. doi: 10.1128/AAC.48.5.1553-1560.2004.

  PMID: 15105105 BACKGROUND

• L'homme RF, Nijland HM, Gras L, Aarnoutse RE, van Crevel R, Boeree M, Brinkman K, Prins JM, Juttmann JR, Burger DM. Clinical experience with the combined use of lopinavir/ritonavir and rifampicin. AIDS. 2009 Apr 27;23(7):863-5. doi: 10.1097/QAD.0b013e328329148e.

  PMID: 19352137 BACKGROUND

• Nijland HM, L'homme RF, Rongen GA, van Uden P, van Crevel R, Boeree MJ, Aarnoutse RE, Koopmans PP, Burger DM. High incidence of adverse events in healthy volunteers receiving rifampicin and adjusted doses of lopinavir/ritonavir tablets. AIDS. 2008 May 11;22(8):931-5. doi: 10.1097/QAD.0b013e3282faa71e.

  PMID: 18453852 BACKGROUND

• Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf

  BACKGROUND

• Rabie et al., Pharmacokinetics of lopinavir/ritonavir superboosting in infants and young children co-infected with HIV and TB. 7th Int WS on HIV Pediatrics 2015, Vancouver

  BACKGROUND

• Ren Y, Nuttall JJ, Egbers C, Eley BS, Meyers TM, Smith PJ, Maartens G, McIlleron HM. Effect of rifampicin on lopinavir pharmacokinetics in HIV-infected children with tuberculosis. J Acquir Immune Defic Syndr. 2008 Apr 15;47(5):566-9. doi: 10.1097/QAI.0b013e3181642257.

  PMID: 18197120 BACKGROUND

• Roberts O, Khoo S, Owen A, Siccardi M. Interaction of Rifampin and Darunavir-Ritonavir or Darunavir-Cobicistat In Vitro. Antimicrob Agents Chemother. 2017 Apr 24;61(5):e01776-16. doi: 10.1128/AAC.01776-16. Print 2017 May.

  PMID: 28193650 BACKGROUND

• Sekar VJ, Lefebvre E, De Pauw M, Vangeneugden T, Hoetelmans RM. Pharmacokinetics of darunavir/ritonavir and ketoconazole following co-administration in HIV-healthy volunteers. Br J Clin Pharmacol. 2008 Aug;66(2):215-21. doi: 10.1111/j.1365-2125.2008.03191.x. Epub 2008 Apr 8.

  PMID: 18460033 BACKGROUND

• Sekar V, Lefebvre E, De Marez T, De Pauw M, De Paepe E, Vangeneugden T, Hoetelmans RM. Pharmacokinetic interaction between indinavir and darunavir with low-dose ritonavir in healthy volunteers. Intervirology. 2010;53(3):176-82. doi: 10.1159/000289341. Epub 2010 Mar 3.

  PMID: 20197684 BACKGROUND

• Sekar V, Lavreys L, Van de Casteele T, Berckmans C, Spinosa-Guzman S, Vangeneugden T, De Pauw M, Hoetelmans R. Pharmacokinetics of darunavir/ritonavir and rifabutin coadministered in HIV-negative healthy volunteers. Antimicrob Agents Chemother. 2010 Oct;54(10):4440-5. doi: 10.1128/AAC.01749-09. Epub 2010 Jul 26.

  PMID: 20660678 BACKGROUND

• Siccardi, et al. In Silico Simulation of Interaction Between Rifampicin and Boosted Darunavir. Conference on Retroviruses and opportunistic infections, abstr: 532. Seattle 2015.

  BACKGROUND

• Soon GH, Shen P, Yong EL, Pham P, Flexner C, Lee L. Pharmacokinetics of darunavir at 900 milligrams and ritonavir at 100 milligrams once daily when coadministered with efavirenz at 600 milligrams once daily in healthy volunteers. Antimicrob Agents Chemother. 2010 Jul;54(7):2775-80. doi: 10.1128/AAC.01564-09. Epub 2010 Apr 12.

  PMID: 20385850 BACKGROUND

• Sunpath H, Winternheimer P, Cohen S, Tennant I, Chelin N, Gandhi RT, Murphy RA. Double-dose lopinavir-ritonavir in combination with rifampicin-based anti-tuberculosis treatment in South Africa. Int J Tuberc Lung Dis. 2014 Jun;18(6):689-93. doi: 10.5588/ijtld.13.0492.

  PMID: 24903940 BACKGROUND

• Zhang C, McIlleron H, Ren Y, van der Walt JS, Karlsson MO, Simonsson US, Denti P. Population pharmacokinetics of lopinavir and ritonavir in combination with rifampicin-based antitubercular treatment in HIV-infected children. Antivir Ther. 2012;17(1):25-33. doi: 10.3851/IMP1915.

  PMID: 22267466 BACKGROUND

• Zhang C, Denti P, Decloedt EH, Ren Y, Karlsson MO, McIlleron H. Model-based evaluation of the pharmacokinetic differences between adults and children for lopinavir and ritonavir in combination with rifampicin. Br J Clin Pharmacol. 2013 Nov;76(5):741-51. doi: 10.1111/bcp.12101.

  PMID: 23432610 BACKGROUND

• Zhang C, Denti P, Decloedt E, Maartens G, Karlsson MO, Simonsson US, McIlleron H. Model-based approach to dose optimization of lopinavir/ritonavir when co-administered with rifampicin. Br J Clin Pharmacol. 2012 May;73(5):758-67. doi: 10.1111/j.1365-2125.2011.04154.x.

  PMID: 22126409 BACKGROUND

• De Nicolo A, Calcagno A, Motta I, De Vivo E, D'Avolio A, Di Perri G, Wiesner L, Ebrahim IE, Maartens G, Orrell C, McIlleron H. The Effect of Rifampicin on Darunavir, Ritonavir, and Dolutegravir Exposure within Peripheral Blood Mononuclear Cells: a Dose Escalation Study. Antimicrob Agents Chemother. 2022 Jun 21;66(6):e0013622. doi: 10.1128/aac.00136-22. Epub 2022 May 18.

  PMID: 35583344 DERIVED

MeSH Terms

Conditions

HIV Infections

Interventions

Darunavir; Ritonavir; Tablets; Rifampin; dolutegravir

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Intervention Hierarchy (Ancestors)

Sulfonamides; Amides; Organic Chemicals; Carbamates; Acids, Acyclic; Carboxylic Acids; Sulfones; Sulfur Compounds; Furans; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Thiazoles; Azoles; Dosage Forms; Pharmaceutical Preparations; Rifamycins; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds

Study Officials

• Helen McIlleron, PhD

  University of Cape Town

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Masking Details: Eligible volunteers will be switched from their standard of care PI to DRV/r 800/100 mg daily, and intensive sampling for measurement of drug concentrations will be performed at steady state. Rifampicin (600-750 mg daily depending on body weight) will then be started and subsequently the protease inhibitor doses escalated to DRV/r 1600/200 mg daily (participants randomized to arm A), OR 800/100 mg 12-hourly (arm B) for 7 days, after which patients will be switched from the daily to the 12-hourly dosing schedule (arm A) or vice versa (arm B) for a further 7 days. Rifampicin will then be stopped but the increased doses of DRV/r will be continued for a further week, before participants are switched back to their standard-of-care ART regimen. Dolutegravir (DTG) 50 mg twice daily (the dose which overcomes any interaction with rifampicin (Dooley 2013) will be added to minimize the risk of viral rebound due to possible suboptimal protease inhibitor exposures during the study.
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Model Details: A phase I, open-label, cross-over, single center, PK drug-drug interaction study will be conducted in 24 medically stable HIV-1 infected adults with viral suppression (viral load \<50 copies/mL).

Study Record Dates

• First Submitted: April 23, 2018
• First Posted: March 27, 2019
• Study Start: April 12, 2018
• Primary Completion: November 22, 2018
• Study Completion: November 22, 2018
• Last Updated: April 3, 2019

Record last verified: 2019-04

Data Sharing

• IPD Sharing: Will not share

Locations

ZA (1)