Cytokine-Mediated Systemic Adverse Drug Reactions in a Drug-Drug Interaction Study of Dolutegravir with Once-Weekly Isoniazid and Rifapentine.

Cytokine-Mediated Systemic Adverse Drug Reactions in a Drug-Drug Interaction Study of Dolutegravir with Once-Weekly Isoniazid and Rifapentine.

Clin Infect Dis. 2018 Feb 03;:

Authors: Brooks KM, George JM, Pau AK, Rupert A, Mehaffy C, De P, Dobos KM, Kellogg A, McLaughlin M, McManus M, Alfaro RM, Hadigan C, Kovacs JA, Kumar P

Abstract
Background: Once-weekly isoniazid and rifapentine for 3 months is a treatment option in persons with human immunodeficiency virus and latent tuberculosis infection. This study aimed to examine pharmacokinetic drug-drug interactions between this regimen and dolutegravir, a first-line antiretroviral medication.
Methods: This was a single-center, open-label, fixed-sequence, drug-drug interaction study in healthy volunteers. Subjects received oral dolutegravir 50 mg once-daily alone (Days 1-4) and concomitantly with once-weekly isoniazid 900 mg, rifapentine 900 mg, and pyridoxine 50 mg (Days 5-19). Dolutegravir concentrations were measured on days 4, 14, and 19, and rifapentine, 25-desacetyl-rifapentine, and isoniazid concentrations were measured on Day 19. Cytokines and anti-drug antibodies to isoniazid and rifapentine were examined at select time points during and after study drug completion.
Results: The study was terminated following the development of serious toxicities in two of four subjects after the third isoniazid-rifapentine dose. Flu-like syndrome and elevated transaminase levels occurred. Markedly elevated levels of interferon-γ, CXCL10, CRP and other cytokines were temporally associated with symptoms. Anti-drug antibodies were infrequently detected. Dolutegravir area under the curve (AUC) was decreased by 46% (90% CI [0.27, 1.10], p=0.13) on Day 14, ~48-72 hours following the second isoniazid-rifapentine dose. Rifapentine and 25-desacetyl rifapentine levels were comparable to reference data, whereas isoniazid AUCs were ~67-92% higher in the subjects who developed toxicities.
Conclusion: The combined use of dolutegravir with once-weekly isoniazid-rifapentine resulted in unexpected and serious toxicities that were mediated by endogenous cytokine release. Additional investigations are necessary to examine the safety and efficacy of co-administering these medications.
Clinical Trials Registration: NCT02771249.

PMID: 29415190 [PubMed - as supplied by publisher]

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